Mark P. Trolice, MD

Marklund A, Lekberg T, Hedayati E, et al. Relapse rates and disease-specific mortality following procedures for fertility preservation at time of breast cancer diagnosis. JAMA Oncol. 2022;8:1438-1446. doi:10.1001/jamaoncol.2022.3677.

EXPERT COMMENTARY

Breast cancer is the most diagnosed cancer among US women after skin cancer.¹ As of the end of 2020, 7.8 million women were alive who were diagnosed with breast cancer in the past 5 years, making it the world’s most prevalent cancer. Given the wide reach of breast cancer and the increase in its distant stage by more than 4% per year in women of reproductive age (20–39 years), clinicians are urged to address fertility preservation due to reproductive compromise of gonadotoxic therapies and gonadectomy.² To predict the risk of infertility following chemotherapy, a Cyclophosphamide Equivalent Dose (CED) calculator can be used. A CED of 4,000 mg/m² has been associated with a significant risk of infertility.³

In 2012, the American Society for Reproductive Medicine removed the experimental label of oocyte cryopreservation then recently endorsed ovarian cryopreservation, thereby providing acceptable procedures for fertility preservation.⁴ Gonadotropin-releasing hormone agonist use during chemotherapy, which is used to protect the ovary in premenopausal women against the effects of chemotherapy, has been shown to have inconsistent findings and should not replace the established modalities of oocyte/embryo/ovarian tissue cryopreservation.^2,5

Details of the study

While studies have been reassuring that ovarian stimulation for fertility preservation in women with breast cancer does not worsen the prognosis, findings are limited by short-term follow-up.⁶

The recent study by Marklund and colleagues presented an analysis of breast cancer relapse and mortality following fertility preservation with and without hormonal stimulation. In their prospective cohort study of 425 Swedish women who underwent fertility preservation, the authors categorized patients into 2 groups: oocyte and embryo cryopreservation by ovarian hormonal stimulation and ovarian tissue cryopreservation without hormonal stimulation. The control group included 850 women with breast cancer who did not undergo fertility preservation. The cohort and the control groups were matched on age, calendar period of diagnosis, and region. Three Swedish registers for breast cancer were used to obtain the study cohort, and for each participant, 2 breast cancer patients who were unexposed to fertility preservation were used for comparison. The primary outcome was mortality while the secondary outcome was any event of death due to breast cancer or relapse.

Results. A total of 1,275 women were studied at the time of breast cancer diagnosis. After stratification, which included age, parity at diagnosis, tumor size, number of lymph node metastases, and estrogen receptor status, disease-specific mortality was similar in all categories of women, that is, hormonal fertility preservation, nonhormonal fertility preservation, and controls. In the subcohort of 723 women, the adjusted rate of relapse and disease-specific mortality remained the same among all groups.

Study strengths and limitations

This study prompts several areas of criticism. The follow-up of breast cancer patients was only 5 years, adding to the limitations of short-term monitoring seen in prior studies. The authors also considered a delay in pregnancy attempts following breast cancer treatment of hormonally sensitive cancers of 5 to 10 years. However, the long-term safety of pregnancy following breast cancer has shown a statistically significantly superior disease-free survival (DFS) in patients who became pregnant less than 2 years from diagnosis and no difference in those who became pregnant 2 or more years from diagnosis.⁷

Only 58 women in the nonhormonal fertility preservation group (ovarian tissue cryopreservation) were studied, which may limit an adequate evaluation although it is not expected to negatively impact breast cancer prognosis. Another area of potential bias was the use of only a subcohort to assess relapse-free survival as opposed to the entire cohort that was used to assess mortality.

Strengths of this study include obligatory reporting to the registry and equal access to anticancer treatment and fertility preservation in Sweden. Ovarian stimulating drugs were examined, as letrozole is often used in breast cancer patients to maintain lower estradiol levels due to aromatase inhibition. Nevertheless, this study did not demonstrate a difference in mortality with or without letrozole use. ●

Marklund A, Lekberg T, Hedayati E, et al. Relapse rates and disease-specific mortality following procedures for fertility preservation at time of breast cancer diagnosis. JAMA Oncol. 2022;8:1438-1446. doi:10.1001/jamaoncol.2022.3677.

EXPERT COMMENTARY

Breast cancer is the most diagnosed cancer among US women after skin cancer.¹ As of the end of 2020, 7.8 million women were alive who were diagnosed with breast cancer in the past 5 years, making it the world’s most prevalent cancer. Given the wide reach of breast cancer and the increase in its distant stage by more than 4% per year in women of reproductive age (20–39 years), clinicians are urged to address fertility preservation due to reproductive compromise of gonadotoxic therapies and gonadectomy.² To predict the risk of infertility following chemotherapy, a Cyclophosphamide Equivalent Dose (CED) calculator can be used. A CED of 4,000 mg/m² has been associated with a significant risk of infertility.³

In 2012, the American Society for Reproductive Medicine removed the experimental label of oocyte cryopreservation then recently endorsed ovarian cryopreservation, thereby providing acceptable procedures for fertility preservation.⁴ Gonadotropin-releasing hormone agonist use during chemotherapy, which is used to protect the ovary in premenopausal women against the effects of chemotherapy, has been shown to have inconsistent findings and should not replace the established modalities of oocyte/embryo/ovarian tissue cryopreservation.^2,5

Details of the study

While studies have been reassuring that ovarian stimulation for fertility preservation in women with breast cancer does not worsen the prognosis, findings are limited by short-term follow-up.⁶

The recent study by Marklund and colleagues presented an analysis of breast cancer relapse and mortality following fertility preservation with and without hormonal stimulation. In their prospective cohort study of 425 Swedish women who underwent fertility preservation, the authors categorized patients into 2 groups: oocyte and embryo cryopreservation by ovarian hormonal stimulation and ovarian tissue cryopreservation without hormonal stimulation. The control group included 850 women with breast cancer who did not undergo fertility preservation. The cohort and the control groups were matched on age, calendar period of diagnosis, and region. Three Swedish registers for breast cancer were used to obtain the study cohort, and for each participant, 2 breast cancer patients who were unexposed to fertility preservation were used for comparison. The primary outcome was mortality while the secondary outcome was any event of death due to breast cancer or relapse.

Results. A total of 1,275 women were studied at the time of breast cancer diagnosis. After stratification, which included age, parity at diagnosis, tumor size, number of lymph node metastases, and estrogen receptor status, disease-specific mortality was similar in all categories of women, that is, hormonal fertility preservation, nonhormonal fertility preservation, and controls. In the subcohort of 723 women, the adjusted rate of relapse and disease-specific mortality remained the same among all groups.

Study strengths and limitations

This study prompts several areas of criticism. The follow-up of breast cancer patients was only 5 years, adding to the limitations of short-term monitoring seen in prior studies. The authors also considered a delay in pregnancy attempts following breast cancer treatment of hormonally sensitive cancers of 5 to 10 years. However, the long-term safety of pregnancy following breast cancer has shown a statistically significantly superior disease-free survival (DFS) in patients who became pregnant less than 2 years from diagnosis and no difference in those who became pregnant 2 or more years from diagnosis.⁷

Only 58 women in the nonhormonal fertility preservation group (ovarian tissue cryopreservation) were studied, which may limit an adequate evaluation although it is not expected to negatively impact breast cancer prognosis. Another area of potential bias was the use of only a subcohort to assess relapse-free survival as opposed to the entire cohort that was used to assess mortality.

Strengths of this study include obligatory reporting to the registry and equal access to anticancer treatment and fertility preservation in Sweden. Ovarian stimulating drugs were examined, as letrozole is often used in breast cancer patients to maintain lower estradiol levels due to aromatase inhibition. Nevertheless, this study did not demonstrate a difference in mortality with or without letrozole use. ●

Marklund A, Lekberg T, Hedayati E, et al. Relapse rates and disease-specific mortality following procedures for fertility preservation at time of breast cancer diagnosis. JAMA Oncol. 2022;8:1438-1446. doi:10.1001/jamaoncol.2022.3677.

EXPERT COMMENTARY

Breast cancer is the most diagnosed cancer among US women after skin cancer.¹ As of the end of 2020, 7.8 million women were alive who were diagnosed with breast cancer in the past 5 years, making it the world’s most prevalent cancer. Given the wide reach of breast cancer and the increase in its distant stage by more than 4% per year in women of reproductive age (20–39 years), clinicians are urged to address fertility preservation due to reproductive compromise of gonadotoxic therapies and gonadectomy.² To predict the risk of infertility following chemotherapy, a Cyclophosphamide Equivalent Dose (CED) calculator can be used. A CED of 4,000 mg/m² has been associated with a significant risk of infertility.³

In 2012, the American Society for Reproductive Medicine removed the experimental label of oocyte cryopreservation then recently endorsed ovarian cryopreservation, thereby providing acceptable procedures for fertility preservation.⁴ Gonadotropin-releasing hormone agonist use during chemotherapy, which is used to protect the ovary in premenopausal women against the effects of chemotherapy, has been shown to have inconsistent findings and should not replace the established modalities of oocyte/embryo/ovarian tissue cryopreservation.^2,5

Details of the study

While studies have been reassuring that ovarian stimulation for fertility preservation in women with breast cancer does not worsen the prognosis, findings are limited by short-term follow-up.⁶

The recent study by Marklund and colleagues presented an analysis of breast cancer relapse and mortality following fertility preservation with and without hormonal stimulation. In their prospective cohort study of 425 Swedish women who underwent fertility preservation, the authors categorized patients into 2 groups: oocyte and embryo cryopreservation by ovarian hormonal stimulation and ovarian tissue cryopreservation without hormonal stimulation. The control group included 850 women with breast cancer who did not undergo fertility preservation. The cohort and the control groups were matched on age, calendar period of diagnosis, and region. Three Swedish registers for breast cancer were used to obtain the study cohort, and for each participant, 2 breast cancer patients who were unexposed to fertility preservation were used for comparison. The primary outcome was mortality while the secondary outcome was any event of death due to breast cancer or relapse.

Results. A total of 1,275 women were studied at the time of breast cancer diagnosis. After stratification, which included age, parity at diagnosis, tumor size, number of lymph node metastases, and estrogen receptor status, disease-specific mortality was similar in all categories of women, that is, hormonal fertility preservation, nonhormonal fertility preservation, and controls. In the subcohort of 723 women, the adjusted rate of relapse and disease-specific mortality remained the same among all groups.

Study strengths and limitations

This study prompts several areas of criticism. The follow-up of breast cancer patients was only 5 years, adding to the limitations of short-term monitoring seen in prior studies. The authors also considered a delay in pregnancy attempts following breast cancer treatment of hormonally sensitive cancers of 5 to 10 years. However, the long-term safety of pregnancy following breast cancer has shown a statistically significantly superior disease-free survival (DFS) in patients who became pregnant less than 2 years from diagnosis and no difference in those who became pregnant 2 or more years from diagnosis.⁷

Only 58 women in the nonhormonal fertility preservation group (ovarian tissue cryopreservation) were studied, which may limit an adequate evaluation although it is not expected to negatively impact breast cancer prognosis. Another area of potential bias was the use of only a subcohort to assess relapse-free survival as opposed to the entire cohort that was used to assess mortality.

Strengths of this study include obligatory reporting to the registry and equal access to anticancer treatment and fertility preservation in Sweden. Ovarian stimulating drugs were examined, as letrozole is often used in breast cancer patients to maintain lower estradiol levels due to aromatase inhibition. Nevertheless, this study did not demonstrate a difference in mortality with or without letrozole use. ●

In 2019, a New York Times opinion piece titled, “The Big IVF Add-On Racket – This is no way to treat patients desperate for a baby”¹ alleged exploitation of infertility patients based on a Fertility and Sterility article, “Do à la carte menus serve infertility patients? The ethics and regulation of in vitro fertility add-ons.”² The desperation of infertility patients combined with their financial burden, caused by inconsistent insurance coverage, has resulted in a perfect storm of frustration and overzealous recommendations for a successful outcome. Since the inception of in vitro fertilization (IVF) itself, infertility patients have been subjected to many unproven tests and procedures that enter the mainstream of care before unequivocal efficacy and safety have been shown.

From ovarian stimulation with intrauterine insemination (IUI) or IVF along with intracytoplasmic sperm injection (ICSI), assisted hatching, and preimplantation genetic testing for aneuploidy (PGT-A), a multitude of options with varying success can overwhelm fertility patients as they walk the tightrope of wanting “the kitchen sink” of treatment while experiencing sticker shock. This month’s article examines the top 10 infertility add-ons that have yet to be shown to improve pregnancy outcomes.

1. Blood testing: Prolactin and FSH

In a woman with ovulatory monthly menstrual cycles, a serum prolactin level provides no elucidation of the cause of infertility. If obtained following ovulation, prolactin can often be physiologically elevated, thereby compelling a repeat blood level, which is ideally performed during the early proliferative phase. False elevations of prolactin can be caused by an early morning blood sample, eating, and stress – which may result from worry caused by having to repeat the unnecessary initial blood test!

Follicle-stimulating hormone (FSH) was a first-line hormone test to assess for ovarian age. For nearly 15 years now, FSH has been replaced by anti-Müllerian hormone as a more reliable and earlier test for diminished ovarian reserve. However, FSH is still the hormone test of choice to diagnose primary ovarian insufficiency. Note that the use of ovarian age testing in a woman without infertility can result in both unnecessary patient anxiety and additional testing.
 

2. Endometrial scratch

The concept was understandable, that is, induce endometrial trauma by a biopsy or “scratch,” that results in an inflammatory and immunologic response to increase implantation. Endometrial sampling was recommended to be performed during the month prior to the embryo transfer cycle. While the procedure is brief, the pain response of women varies from minimal to severe. Unfortunately, a randomized controlled trial of over 1,300 patients did not show any improvement in the IVF live birth rate from the scratch procedure.³

3. Diagnostic laparoscopy

In years past, a diagnosis of unexplained infertility was not accepted until a laparoscopy was performed that revealed a normal pelvis. This approach subjected many women to an unindicated and a potentially risky surgery that has not shown benefit. The American Society for Reproductive Medicine’s ReproductiveFacts.org website states: “Routine diagnostic laparoscopy should not be performed unless there is a suspicion of pelvic pathology based on clinical history, an abnormal pelvic exam, or abnormalities identified with less invasive testing. In patients with a normal hysterosalpingogram or the presence of a unilaterally patent tube, diagnostic laparoscopy typically will not change the initial recommendation for treatment.”

4. Prescribing clomiphene citrate without IUI

Ovulation dysfunction is found in 40% of female factors for fertility. Provided testing reveals a reasonably normal sperm analysis and hysterosalpingogram, ovulation induction medication with ultrasound monitoring along with an hCG trigger is appropriate. In women who ovulate with unexplained infertility and/or mild male factor, the use of clomiphene citrate or letrozole with timed intercourse is often prescribed, particularly in clinics when IUI preparation is not available. Unfortunately, without including IUI, the use of oral ovarian stimulation has been shown by good evidence to be no more effective than natural cycle attempts at conception.⁴

5. Thrombophilia testing

Recurrent miscarriage, defined by the spontaneous loss of two or more pregnancies (often during the first trimester but may include up to 20 weeks estimated gestational age), has remained an ill-defined problem that lacks a consensus on the most optimal evaluation and treatment. In 2006, an international consensus statement provided guidance on laboratory testing for antiphospholipid syndrome limited to lupus anticoagulant, anticardiolipin IgG and IgM, and IgG and IgM anti–beta₂-glycoprotein I assays.⁵ ASRM does not recommend additional thrombophilia tests as they are unproven causative factors of recurrent miscarriage.

6. Screening hysteroscopy

A standard infertility evaluation includes ovulation testing, assessment of fallopian tube patency, and a sperm analysis. In a subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work‐up, a Cochrane data review concluded there is no definitive evidence for improved outcome with a screening hysteroscopy prior to IUI or IVF.^6,7 Two large trials included in the Cochrane review, confirmed similar live birth rates whether or not hysteroscopy was performed before IVF. There may value in screening patients with recurrent implantation failure.

7. PGT-A for all

As the efficacy of the first generation of embryo preimplantation genetic testing, i.e., FISH (fluorescence in situ hybridization) was disproven, so has the same result been determined for PGT-A, specifically in women younger than 35.⁸ In an elegant randomized prospective trial, Munne and colleagues showed no improvement in the ongoing pregnancy rate (OPR) of study patients of all ages who were enrolled with the intention to treat. However, a subanalysis of patients aged 35-40 who completed the protocol did show an improved OPR and lower miscarriage rate per embryo transfer. While there is no evidence to support improved outcomes with the universal application of PGT-A, there may be some benefit in women older than 35 as well as in certain individual patient circumstances.

8. ICSI for nonmale factor infertility; assisted hatching

In an effort to reduce the risk of fertilization failure, programs have broadened the use of ICSI to nonmale factor infertility. While it has been used in PGT to reduce the risk of DNA contamination, particularly in PGT-M (monogenic disorder) and PGT-SR (structural rearrangement) cases, ICSI has not been shown to improve outcomes when there is a normal sperm analysis.⁹ During IVF embryo development, assisted hatching involves the thinning and/or opening of the zona pellucida either by chemical, mechanical, or laser means around the embryo before transfer with the intention of facilitating implantation. The routine use of assisted hatching is not recommended based on the lack of increase in live birth rates and because it may increase multiple pregnancy and monozygotic twinning rates.¹⁰

9. Acupuncture

Four meta-analyses showed no evidence of the overall benefit of acupuncture for improving live birth rates regardless of whether acupuncture was performed around the time of oocyte retrieval or around the day of embryo transfer. Consequently, acupuncture cannot be recommended routinely to improve IVF outcomes.¹¹

10. Immunologic tests/treatments

Given the “foreign” genetic nature of a fetus, attempts to suppress the maternal immunologic response to sustain the pregnancy have been made for decades, especially for recurrent miscarriage and recurrent implantation failure with IVF. Testing has included natural killer (NK) cells, human leukocyte antigen (HLA) genotypes, and cytokines. While NK cells can be examined by endometrial biopsy, levels fluctuate based on the cycle phase, and no correlation between peripheral blood testing and uterine NK cell levels has been shown. Further, no consensus has been reached on reliable normal reference ranges in uterine NK cells.¹²

Several treatments have been proposed to somehow modulate the immune system during the implantation process thereby improving implantation and live birth, including lipid emulsion (intralipid) infusion, intravenous immunoglobulin, leukocyte immunization therapy, tacrolimus, anti–tumor necrosis factor agents, and granulocyte colony-stimulating factor. A recent systematic review and meta-analysis cited low-quality studies and did not recommend the use of any of these immune treatments.¹³ Further, immunomodulation has many known side effects, some of which are serious (including hepatosplenomegaly, thrombocytopenia, leukopenia, renal failure, thromboembolism, and anaphylactic reactions). Excluding women with autoimmune disease, taking glucocorticoids or other immune treatments to improve fertility has not been proven.¹³

Conclusion

To quote the New York Times opinion piece, “IVF remains an under-regulated arena, and entrepreneurial doctors and pharmaceutical and life science companies are eager to find new ways to cash in on a growing global market that is projected to be as large as $40 billion by 2024.” While this bold statement compels a huge “Ouch!”, it reminds us of our obligation to provide evidence-based medicine and to include emotional and financial harm to our oath of Primum non nocere.

References

1. The News York Times. 2019 Dec 12. Opinion.

2. Wilkinson J et al. Fertil Steril. 2019;112(6):973-7.

3. Lensen S et al. N Engl J Med. 2019 Jan 24;380(4):325-34.

4. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2020;113(2):305-22.

5. Miyakis S et al. J Thromb Haemost. 2006;4(2):295-306.

6. Kamath MS et al. Cochrane Database Syst Rev. 2019 Apr 16;4(4):CD012856.

7. Bosteels J et al. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD009461.

8. Munne S et al. Fertil Steril. 2019;112(6):1071-9.

9. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Fertil Steril. 2020;114(2):239-45.

10. Lacey L et al. Cochrane Database Syst Rev. March 7 2021;3:2199.

11. Coyle ME et al. Acupunct Med. 2021;39(1):20-9.

12. Von Woon E et al. Hum Reprod Update. 2022;30;28(4):548-82.

13. Achilli C et al. Fertil Steril. 2018;110(6):1089-100.

In 2019, a New York Times opinion piece titled, “The Big IVF Add-On Racket – This is no way to treat patients desperate for a baby”¹ alleged exploitation of infertility patients based on a Fertility and Sterility article, “Do à la carte menus serve infertility patients? The ethics and regulation of in vitro fertility add-ons.”² The desperation of infertility patients combined with their financial burden, caused by inconsistent insurance coverage, has resulted in a perfect storm of frustration and overzealous recommendations for a successful outcome. Since the inception of in vitro fertilization (IVF) itself, infertility patients have been subjected to many unproven tests and procedures that enter the mainstream of care before unequivocal efficacy and safety have been shown.

From ovarian stimulation with intrauterine insemination (IUI) or IVF along with intracytoplasmic sperm injection (ICSI), assisted hatching, and preimplantation genetic testing for aneuploidy (PGT-A), a multitude of options with varying success can overwhelm fertility patients as they walk the tightrope of wanting “the kitchen sink” of treatment while experiencing sticker shock. This month’s article examines the top 10 infertility add-ons that have yet to be shown to improve pregnancy outcomes.

1. Blood testing: Prolactin and FSH

In a woman with ovulatory monthly menstrual cycles, a serum prolactin level provides no elucidation of the cause of infertility. If obtained following ovulation, prolactin can often be physiologically elevated, thereby compelling a repeat blood level, which is ideally performed during the early proliferative phase. False elevations of prolactin can be caused by an early morning blood sample, eating, and stress – which may result from worry caused by having to repeat the unnecessary initial blood test!

Follicle-stimulating hormone (FSH) was a first-line hormone test to assess for ovarian age. For nearly 15 years now, FSH has been replaced by anti-Müllerian hormone as a more reliable and earlier test for diminished ovarian reserve. However, FSH is still the hormone test of choice to diagnose primary ovarian insufficiency. Note that the use of ovarian age testing in a woman without infertility can result in both unnecessary patient anxiety and additional testing.
 

2. Endometrial scratch

The concept was understandable, that is, induce endometrial trauma by a biopsy or “scratch,” that results in an inflammatory and immunologic response to increase implantation. Endometrial sampling was recommended to be performed during the month prior to the embryo transfer cycle. While the procedure is brief, the pain response of women varies from minimal to severe. Unfortunately, a randomized controlled trial of over 1,300 patients did not show any improvement in the IVF live birth rate from the scratch procedure.³

3. Diagnostic laparoscopy

In years past, a diagnosis of unexplained infertility was not accepted until a laparoscopy was performed that revealed a normal pelvis. This approach subjected many women to an unindicated and a potentially risky surgery that has not shown benefit. The American Society for Reproductive Medicine’s ReproductiveFacts.org website states: “Routine diagnostic laparoscopy should not be performed unless there is a suspicion of pelvic pathology based on clinical history, an abnormal pelvic exam, or abnormalities identified with less invasive testing. In patients with a normal hysterosalpingogram or the presence of a unilaterally patent tube, diagnostic laparoscopy typically will not change the initial recommendation for treatment.”

4. Prescribing clomiphene citrate without IUI

Ovulation dysfunction is found in 40% of female factors for fertility. Provided testing reveals a reasonably normal sperm analysis and hysterosalpingogram, ovulation induction medication with ultrasound monitoring along with an hCG trigger is appropriate. In women who ovulate with unexplained infertility and/or mild male factor, the use of clomiphene citrate or letrozole with timed intercourse is often prescribed, particularly in clinics when IUI preparation is not available. Unfortunately, without including IUI, the use of oral ovarian stimulation has been shown by good evidence to be no more effective than natural cycle attempts at conception.⁴

5. Thrombophilia testing

Recurrent miscarriage, defined by the spontaneous loss of two or more pregnancies (often during the first trimester but may include up to 20 weeks estimated gestational age), has remained an ill-defined problem that lacks a consensus on the most optimal evaluation and treatment. In 2006, an international consensus statement provided guidance on laboratory testing for antiphospholipid syndrome limited to lupus anticoagulant, anticardiolipin IgG and IgM, and IgG and IgM anti–beta₂-glycoprotein I assays.⁵ ASRM does not recommend additional thrombophilia tests as they are unproven causative factors of recurrent miscarriage.

6. Screening hysteroscopy

A standard infertility evaluation includes ovulation testing, assessment of fallopian tube patency, and a sperm analysis. In a subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work‐up, a Cochrane data review concluded there is no definitive evidence for improved outcome with a screening hysteroscopy prior to IUI or IVF.^6,7 Two large trials included in the Cochrane review, confirmed similar live birth rates whether or not hysteroscopy was performed before IVF. There may value in screening patients with recurrent implantation failure.

7. PGT-A for all

As the efficacy of the first generation of embryo preimplantation genetic testing, i.e., FISH (fluorescence in situ hybridization) was disproven, so has the same result been determined for PGT-A, specifically in women younger than 35.⁸ In an elegant randomized prospective trial, Munne and colleagues showed no improvement in the ongoing pregnancy rate (OPR) of study patients of all ages who were enrolled with the intention to treat. However, a subanalysis of patients aged 35-40 who completed the protocol did show an improved OPR and lower miscarriage rate per embryo transfer. While there is no evidence to support improved outcomes with the universal application of PGT-A, there may be some benefit in women older than 35 as well as in certain individual patient circumstances.

8. ICSI for nonmale factor infertility; assisted hatching

In an effort to reduce the risk of fertilization failure, programs have broadened the use of ICSI to nonmale factor infertility. While it has been used in PGT to reduce the risk of DNA contamination, particularly in PGT-M (monogenic disorder) and PGT-SR (structural rearrangement) cases, ICSI has not been shown to improve outcomes when there is a normal sperm analysis.⁹ During IVF embryo development, assisted hatching involves the thinning and/or opening of the zona pellucida either by chemical, mechanical, or laser means around the embryo before transfer with the intention of facilitating implantation. The routine use of assisted hatching is not recommended based on the lack of increase in live birth rates and because it may increase multiple pregnancy and monozygotic twinning rates.¹⁰

9. Acupuncture

Four meta-analyses showed no evidence of the overall benefit of acupuncture for improving live birth rates regardless of whether acupuncture was performed around the time of oocyte retrieval or around the day of embryo transfer. Consequently, acupuncture cannot be recommended routinely to improve IVF outcomes.¹¹

10. Immunologic tests/treatments

Given the “foreign” genetic nature of a fetus, attempts to suppress the maternal immunologic response to sustain the pregnancy have been made for decades, especially for recurrent miscarriage and recurrent implantation failure with IVF. Testing has included natural killer (NK) cells, human leukocyte antigen (HLA) genotypes, and cytokines. While NK cells can be examined by endometrial biopsy, levels fluctuate based on the cycle phase, and no correlation between peripheral blood testing and uterine NK cell levels has been shown. Further, no consensus has been reached on reliable normal reference ranges in uterine NK cells.¹²

Several treatments have been proposed to somehow modulate the immune system during the implantation process thereby improving implantation and live birth, including lipid emulsion (intralipid) infusion, intravenous immunoglobulin, leukocyte immunization therapy, tacrolimus, anti–tumor necrosis factor agents, and granulocyte colony-stimulating factor. A recent systematic review and meta-analysis cited low-quality studies and did not recommend the use of any of these immune treatments.¹³ Further, immunomodulation has many known side effects, some of which are serious (including hepatosplenomegaly, thrombocytopenia, leukopenia, renal failure, thromboembolism, and anaphylactic reactions). Excluding women with autoimmune disease, taking glucocorticoids or other immune treatments to improve fertility has not been proven.¹³

Conclusion

To quote the New York Times opinion piece, “IVF remains an under-regulated arena, and entrepreneurial doctors and pharmaceutical and life science companies are eager to find new ways to cash in on a growing global market that is projected to be as large as $40 billion by 2024.” While this bold statement compels a huge “Ouch!”, it reminds us of our obligation to provide evidence-based medicine and to include emotional and financial harm to our oath of Primum non nocere.

References

1. The News York Times. 2019 Dec 12. Opinion.

2. Wilkinson J et al. Fertil Steril. 2019;112(6):973-7.

3. Lensen S et al. N Engl J Med. 2019 Jan 24;380(4):325-34.

4. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2020;113(2):305-22.

5. Miyakis S et al. J Thromb Haemost. 2006;4(2):295-306.

6. Kamath MS et al. Cochrane Database Syst Rev. 2019 Apr 16;4(4):CD012856.

7. Bosteels J et al. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD009461.

8. Munne S et al. Fertil Steril. 2019;112(6):1071-9.

9. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Fertil Steril. 2020;114(2):239-45.

10. Lacey L et al. Cochrane Database Syst Rev. March 7 2021;3:2199.

11. Coyle ME et al. Acupunct Med. 2021;39(1):20-9.

12. Von Woon E et al. Hum Reprod Update. 2022;30;28(4):548-82.

13. Achilli C et al. Fertil Steril. 2018;110(6):1089-100.

In 2019, a New York Times opinion piece titled, “The Big IVF Add-On Racket – This is no way to treat patients desperate for a baby”¹ alleged exploitation of infertility patients based on a Fertility and Sterility article, “Do à la carte menus serve infertility patients? The ethics and regulation of in vitro fertility add-ons.”² The desperation of infertility patients combined with their financial burden, caused by inconsistent insurance coverage, has resulted in a perfect storm of frustration and overzealous recommendations for a successful outcome. Since the inception of in vitro fertilization (IVF) itself, infertility patients have been subjected to many unproven tests and procedures that enter the mainstream of care before unequivocal efficacy and safety have been shown.

From ovarian stimulation with intrauterine insemination (IUI) or IVF along with intracytoplasmic sperm injection (ICSI), assisted hatching, and preimplantation genetic testing for aneuploidy (PGT-A), a multitude of options with varying success can overwhelm fertility patients as they walk the tightrope of wanting “the kitchen sink” of treatment while experiencing sticker shock. This month’s article examines the top 10 infertility add-ons that have yet to be shown to improve pregnancy outcomes.

1. Blood testing: Prolactin and FSH

In a woman with ovulatory monthly menstrual cycles, a serum prolactin level provides no elucidation of the cause of infertility. If obtained following ovulation, prolactin can often be physiologically elevated, thereby compelling a repeat blood level, which is ideally performed during the early proliferative phase. False elevations of prolactin can be caused by an early morning blood sample, eating, and stress – which may result from worry caused by having to repeat the unnecessary initial blood test!

Follicle-stimulating hormone (FSH) was a first-line hormone test to assess for ovarian age. For nearly 15 years now, FSH has been replaced by anti-Müllerian hormone as a more reliable and earlier test for diminished ovarian reserve. However, FSH is still the hormone test of choice to diagnose primary ovarian insufficiency. Note that the use of ovarian age testing in a woman without infertility can result in both unnecessary patient anxiety and additional testing.
 

2. Endometrial scratch

The concept was understandable, that is, induce endometrial trauma by a biopsy or “scratch,” that results in an inflammatory and immunologic response to increase implantation. Endometrial sampling was recommended to be performed during the month prior to the embryo transfer cycle. While the procedure is brief, the pain response of women varies from minimal to severe. Unfortunately, a randomized controlled trial of over 1,300 patients did not show any improvement in the IVF live birth rate from the scratch procedure.³

3. Diagnostic laparoscopy

In years past, a diagnosis of unexplained infertility was not accepted until a laparoscopy was performed that revealed a normal pelvis. This approach subjected many women to an unindicated and a potentially risky surgery that has not shown benefit. The American Society for Reproductive Medicine’s ReproductiveFacts.org website states: “Routine diagnostic laparoscopy should not be performed unless there is a suspicion of pelvic pathology based on clinical history, an abnormal pelvic exam, or abnormalities identified with less invasive testing. In patients with a normal hysterosalpingogram or the presence of a unilaterally patent tube, diagnostic laparoscopy typically will not change the initial recommendation for treatment.”

4. Prescribing clomiphene citrate without IUI

Ovulation dysfunction is found in 40% of female factors for fertility. Provided testing reveals a reasonably normal sperm analysis and hysterosalpingogram, ovulation induction medication with ultrasound monitoring along with an hCG trigger is appropriate. In women who ovulate with unexplained infertility and/or mild male factor, the use of clomiphene citrate or letrozole with timed intercourse is often prescribed, particularly in clinics when IUI preparation is not available. Unfortunately, without including IUI, the use of oral ovarian stimulation has been shown by good evidence to be no more effective than natural cycle attempts at conception.⁴

5. Thrombophilia testing

Recurrent miscarriage, defined by the spontaneous loss of two or more pregnancies (often during the first trimester but may include up to 20 weeks estimated gestational age), has remained an ill-defined problem that lacks a consensus on the most optimal evaluation and treatment. In 2006, an international consensus statement provided guidance on laboratory testing for antiphospholipid syndrome limited to lupus anticoagulant, anticardiolipin IgG and IgM, and IgG and IgM anti–beta₂-glycoprotein I assays.⁵ ASRM does not recommend additional thrombophilia tests as they are unproven causative factors of recurrent miscarriage.

6. Screening hysteroscopy

A standard infertility evaluation includes ovulation testing, assessment of fallopian tube patency, and a sperm analysis. In a subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work‐up, a Cochrane data review concluded there is no definitive evidence for improved outcome with a screening hysteroscopy prior to IUI or IVF.^6,7 Two large trials included in the Cochrane review, confirmed similar live birth rates whether or not hysteroscopy was performed before IVF. There may value in screening patients with recurrent implantation failure.

7. PGT-A for all

As the efficacy of the first generation of embryo preimplantation genetic testing, i.e., FISH (fluorescence in situ hybridization) was disproven, so has the same result been determined for PGT-A, specifically in women younger than 35.⁸ In an elegant randomized prospective trial, Munne and colleagues showed no improvement in the ongoing pregnancy rate (OPR) of study patients of all ages who were enrolled with the intention to treat. However, a subanalysis of patients aged 35-40 who completed the protocol did show an improved OPR and lower miscarriage rate per embryo transfer. While there is no evidence to support improved outcomes with the universal application of PGT-A, there may be some benefit in women older than 35 as well as in certain individual patient circumstances.

8. ICSI for nonmale factor infertility; assisted hatching

In an effort to reduce the risk of fertilization failure, programs have broadened the use of ICSI to nonmale factor infertility. While it has been used in PGT to reduce the risk of DNA contamination, particularly in PGT-M (monogenic disorder) and PGT-SR (structural rearrangement) cases, ICSI has not been shown to improve outcomes when there is a normal sperm analysis.⁹ During IVF embryo development, assisted hatching involves the thinning and/or opening of the zona pellucida either by chemical, mechanical, or laser means around the embryo before transfer with the intention of facilitating implantation. The routine use of assisted hatching is not recommended based on the lack of increase in live birth rates and because it may increase multiple pregnancy and monozygotic twinning rates.¹⁰

9. Acupuncture

Four meta-analyses showed no evidence of the overall benefit of acupuncture for improving live birth rates regardless of whether acupuncture was performed around the time of oocyte retrieval or around the day of embryo transfer. Consequently, acupuncture cannot be recommended routinely to improve IVF outcomes.¹¹

10. Immunologic tests/treatments

Given the “foreign” genetic nature of a fetus, attempts to suppress the maternal immunologic response to sustain the pregnancy have been made for decades, especially for recurrent miscarriage and recurrent implantation failure with IVF. Testing has included natural killer (NK) cells, human leukocyte antigen (HLA) genotypes, and cytokines. While NK cells can be examined by endometrial biopsy, levels fluctuate based on the cycle phase, and no correlation between peripheral blood testing and uterine NK cell levels has been shown. Further, no consensus has been reached on reliable normal reference ranges in uterine NK cells.¹²

Several treatments have been proposed to somehow modulate the immune system during the implantation process thereby improving implantation and live birth, including lipid emulsion (intralipid) infusion, intravenous immunoglobulin, leukocyte immunization therapy, tacrolimus, anti–tumor necrosis factor agents, and granulocyte colony-stimulating factor. A recent systematic review and meta-analysis cited low-quality studies and did not recommend the use of any of these immune treatments.¹³ Further, immunomodulation has many known side effects, some of which are serious (including hepatosplenomegaly, thrombocytopenia, leukopenia, renal failure, thromboembolism, and anaphylactic reactions). Excluding women with autoimmune disease, taking glucocorticoids or other immune treatments to improve fertility has not been proven.¹³

Conclusion

To quote the New York Times opinion piece, “IVF remains an under-regulated arena, and entrepreneurial doctors and pharmaceutical and life science companies are eager to find new ways to cash in on a growing global market that is projected to be as large as $40 billion by 2024.” While this bold statement compels a huge “Ouch!”, it reminds us of our obligation to provide evidence-based medicine and to include emotional and financial harm to our oath of Primum non nocere.

References

1. The News York Times. 2019 Dec 12. Opinion.

2. Wilkinson J et al. Fertil Steril. 2019;112(6):973-7.

3. Lensen S et al. N Engl J Med. 2019 Jan 24;380(4):325-34.

4. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2020;113(2):305-22.

5. Miyakis S et al. J Thromb Haemost. 2006;4(2):295-306.

6. Kamath MS et al. Cochrane Database Syst Rev. 2019 Apr 16;4(4):CD012856.

7. Bosteels J et al. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD009461.

8. Munne S et al. Fertil Steril. 2019;112(6):1071-9.

9. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Fertil Steril. 2020;114(2):239-45.

10. Lacey L et al. Cochrane Database Syst Rev. March 7 2021;3:2199.

11. Coyle ME et al. Acupunct Med. 2021;39(1):20-9.

12. Von Woon E et al. Hum Reprod Update. 2022;30;28(4):548-82.

13. Achilli C et al. Fertil Steril. 2018;110(6):1089-100.

Arguably, no topic during an infertility consultation generates more of an emotional reaction than discussing body mass index (BMI), particularly when it is high. Patients have become increasingly sensitive to weight discussions with their physicians because of concerns about body shaming. Among patients with an elevated BMI, criticism on social media of health care professionals’ counseling and a preemptive presentation of “Don’t Weigh Me” cards have become popular responses. Despite the medical evidence on impaired reproduction with an abnormal BMI, patients are choosing to forgo the topic. Research has demonstrated “extensive evidence [of] strong weight bias” in a wide range of health staff.¹ A “viral” TikTok study revealed that medical “gaslighting” founded in weight stigma and bias is harmful, as reported on KevinMD.com.² This month, we review the effect of abnormal BMI, both high and low, on reproduction and pregnancy.

A method to assess relative weight was first described in 1832 as its ratio in kilograms divided by the square of the height in meters, or the Quetelet Index. The search for a functional assessment of relative body weight began after World War II when reports by actuaries noted the increased mortality of overweight policyholders. The relationship between weight and cardiovascular disease was further revealed in epidemiologic studies. The Quetelet Index became the BMI in 1972.³

Weight measurement is a mainstay in the assessment of a patient’s vital signs along with blood pressure, pulse rate, respiration rate, and temperature. Weight is vital to the calculation of medication dosage – for instance, administration of conscious sedative drugs, methotrexate, and gonadotropins. Some state boards of medicine, such as Florida, have a limitation on patient BMI at office-based surgery centers (40 kg/m²).
 

Obesity is a disease

As reported by the World Health Organization in 2022, the disease of obesity is an epidemic afflicting more than 1 billion people worldwide, or 1 in 8 individuals globally.⁴ The health implications of an elevated BMI include increased mortality, diabetes, heart disease, and stroke, physical limitations to activities of daily living, and complications affecting reproduction.

Female obesity is related to poorer outcomes in natural and assisted conception, including an increased risk of miscarriage. Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction,⁵ infertility,⁶ a lower chance for conception,⁷ higher rate of miscarriage, and low birth weight.^8,9During pregnancy, women with obesity have three to four times higher rates of gestational diabetes and preeclampsia,¹⁰ as well as likelihood of delivering preterm,¹¹ having a fetus with macrosomia and birth defects, and a 1.3- to 2.1-times higher risk of stillbirth.¹²

Obesity is present in 40%-80% of women with polycystic ovary syndrome,¹³ the most common cause of ovulatory dysfunction from dysregulation of the hypothalamic-pituitary-ovarian axis. While PCOS is associated with reproductive and metabolic consequences, even in regularly ovulating women, increasing obesity appears to be associated with decreasing spontaneous pregnancy rates and increased time to pregnancy.¹⁴

Obesity and IVF

Women with obesity have reduced success with assisted reproductive technology, an increased number of canceled cycles, and poorer quality oocytes retrieved. A prospective cohort study of nearly 2,000 women reported that every 5 kg of body weight increase (from the patient’s baseline weight at age 18) was associated with a 5% increase in the mean duration of time required for conception (95% confidence interval, 3%-7%).¹⁵ Given that approximately 90% of these women had regular menstrual cycles, ovulatory dysfunction was not the suspected pathophysiology.

A meta-analysis of 21 cohort studies reported a lower likelihood of live birth following in vitro fertilization for women with obesity, compared with normal-weight women (risk ratio, 0.85; 95% CI, 0.82-0.87).¹⁶ A further subgroup analysis that evaluated only women with PCOS showed a reduction in the live birth rate following IVF for individuals with obesity, compared with normal-weight individuals (RR, 0.78; 95% CI, 0.74-0.82).

In a retrospective study of almost 500,000 fresh autologous IVF cycles, women with obesity had a 6% reduction in pregnancy rates and a 13% reduction in live birth rates, compared with normal-weight women. Both high and low BMI were associated with an increased risk of low birth weight and preterm delivery.¹⁷ The live birth rates per transfer for normal-weight and higher-weight women were 38% and 33%, respectively.

Contrarily, a randomized controlled trial showed that an intensive weight-reduction program resulted in a large weight loss but did not substantially affect live birth rates in women with obesity scheduled for IVF.¹⁸

Low BMI

A noteworthy cause of low BMI is functional hypothalamic amenorrhea (FHA), a disorder with low energy availability either from decreased caloric intake and/or excessive energy expenditure associated with eating disorders, excessive exercise, and stress. Consequently, a reduced GnRH drive results in a decreased pulse frequency and amplitude leading to low levels of follicle-stimulating hormone and luteinizing hormone, resulting in anovulation. Correction of lifestyle behaviors related to FHA can restore menstrual cycles. After normal weight is achieved, it appears unlikely that fertility is affected.¹⁹ In 47% of adolescent patients with anorexia, menses spontaneously returned within the first 12 months after admission, with an improved prognosis in secondary over primary amenorrhea.^20,21 Interestingly, mildly and significantly underweight infertile women have pregnancy and live birth rates similar to normal-weight patients after IVF treatment.²²

Pregnancy is complicated in underweight women, resulting in an increased risk of anemia, fetal growth retardation, and low birth weight, as well as preterm birth.²¹

Take-home message

The extremes of BMI both impair natural reproduction. Elevated BMI reduces success with IVF but rapid weight loss prior to IVF does not improve outcomes. A normal BMI is the goal for optimal reproductive and pregnancy health.

Dr. Trolice is director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Talumaa B et al. Obesity Rev. 2022;23:e13494.

2. https://bit.ly/3rHCivE.

3. Eknoyan G. Nephrol Dial Transplant. 2008;23:47-51.

4. Wells JCK. Dis Models Mech. 2012;5:595-607.

5. Brewer CJ and Balen AH. Reproduction. 2010;140:347-64.

6. Silvestris E et al. Reprod Biol Endocrinol. 2018;16:22.

7. Wise LA et al. Hum Reprod. 2010;25:253-64.

8. Bellver J. Curr Opin Obstet Gynecol. 2022;34:114-21.

9. Dickey RP et al. Am J Obstet Gynecol. 2013;209:349.e1.

10. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.

11. Cnattingius S et al. JAMA. 2013;309:2362-70.

12. Aune D et al. JAMA. 2014;311:1536-46.

13. Sam S. Obes Manag. 2007;3:69-73.

14. van der Steeg JW et al. Hum Reprod. 2008;23:324-8.

15. Gaskins AJ et al. Obstet Gynecol. 2015;126:850-8.

16. Sermondade N et al. Hum Reprod Update. 2019;25:439-519.

17. Kawwass JF et al. Fertil Steril. 2016;106[7]:1742-50.

18. Einarsson S et al. Hum Reprod. 2017;32:1621-30.

19. Chaer R et al. Diseases. 2020;8:46.

20. Dempfle A et al. Psychiatry. 2013;13:308.

21. Verma A and Shrimali L. J Clin Diagn Res. 2012;6:1531-3.

22. Romanski PA et al. Reprod Biomed Online. 2020;42:366-74.

Arguably, no topic during an infertility consultation generates more of an emotional reaction than discussing body mass index (BMI), particularly when it is high. Patients have become increasingly sensitive to weight discussions with their physicians because of concerns about body shaming. Among patients with an elevated BMI, criticism on social media of health care professionals’ counseling and a preemptive presentation of “Don’t Weigh Me” cards have become popular responses. Despite the medical evidence on impaired reproduction with an abnormal BMI, patients are choosing to forgo the topic. Research has demonstrated “extensive evidence [of] strong weight bias” in a wide range of health staff.¹ A “viral” TikTok study revealed that medical “gaslighting” founded in weight stigma and bias is harmful, as reported on KevinMD.com.² This month, we review the effect of abnormal BMI, both high and low, on reproduction and pregnancy.

A method to assess relative weight was first described in 1832 as its ratio in kilograms divided by the square of the height in meters, or the Quetelet Index. The search for a functional assessment of relative body weight began after World War II when reports by actuaries noted the increased mortality of overweight policyholders. The relationship between weight and cardiovascular disease was further revealed in epidemiologic studies. The Quetelet Index became the BMI in 1972.³

Weight measurement is a mainstay in the assessment of a patient’s vital signs along with blood pressure, pulse rate, respiration rate, and temperature. Weight is vital to the calculation of medication dosage – for instance, administration of conscious sedative drugs, methotrexate, and gonadotropins. Some state boards of medicine, such as Florida, have a limitation on patient BMI at office-based surgery centers (40 kg/m²).
 

Obesity is a disease

As reported by the World Health Organization in 2022, the disease of obesity is an epidemic afflicting more than 1 billion people worldwide, or 1 in 8 individuals globally.⁴ The health implications of an elevated BMI include increased mortality, diabetes, heart disease, and stroke, physical limitations to activities of daily living, and complications affecting reproduction.

Female obesity is related to poorer outcomes in natural and assisted conception, including an increased risk of miscarriage. Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction,⁵ infertility,⁶ a lower chance for conception,⁷ higher rate of miscarriage, and low birth weight.^8,9During pregnancy, women with obesity have three to four times higher rates of gestational diabetes and preeclampsia,¹⁰ as well as likelihood of delivering preterm,¹¹ having a fetus with macrosomia and birth defects, and a 1.3- to 2.1-times higher risk of stillbirth.¹²

Obesity is present in 40%-80% of women with polycystic ovary syndrome,¹³ the most common cause of ovulatory dysfunction from dysregulation of the hypothalamic-pituitary-ovarian axis. While PCOS is associated with reproductive and metabolic consequences, even in regularly ovulating women, increasing obesity appears to be associated with decreasing spontaneous pregnancy rates and increased time to pregnancy.¹⁴

Obesity and IVF

Women with obesity have reduced success with assisted reproductive technology, an increased number of canceled cycles, and poorer quality oocytes retrieved. A prospective cohort study of nearly 2,000 women reported that every 5 kg of body weight increase (from the patient’s baseline weight at age 18) was associated with a 5% increase in the mean duration of time required for conception (95% confidence interval, 3%-7%).¹⁵ Given that approximately 90% of these women had regular menstrual cycles, ovulatory dysfunction was not the suspected pathophysiology.

A meta-analysis of 21 cohort studies reported a lower likelihood of live birth following in vitro fertilization for women with obesity, compared with normal-weight women (risk ratio, 0.85; 95% CI, 0.82-0.87).¹⁶ A further subgroup analysis that evaluated only women with PCOS showed a reduction in the live birth rate following IVF for individuals with obesity, compared with normal-weight individuals (RR, 0.78; 95% CI, 0.74-0.82).

In a retrospective study of almost 500,000 fresh autologous IVF cycles, women with obesity had a 6% reduction in pregnancy rates and a 13% reduction in live birth rates, compared with normal-weight women. Both high and low BMI were associated with an increased risk of low birth weight and preterm delivery.¹⁷ The live birth rates per transfer for normal-weight and higher-weight women were 38% and 33%, respectively.

Contrarily, a randomized controlled trial showed that an intensive weight-reduction program resulted in a large weight loss but did not substantially affect live birth rates in women with obesity scheduled for IVF.¹⁸

Low BMI

A noteworthy cause of low BMI is functional hypothalamic amenorrhea (FHA), a disorder with low energy availability either from decreased caloric intake and/or excessive energy expenditure associated with eating disorders, excessive exercise, and stress. Consequently, a reduced GnRH drive results in a decreased pulse frequency and amplitude leading to low levels of follicle-stimulating hormone and luteinizing hormone, resulting in anovulation. Correction of lifestyle behaviors related to FHA can restore menstrual cycles. After normal weight is achieved, it appears unlikely that fertility is affected.¹⁹ In 47% of adolescent patients with anorexia, menses spontaneously returned within the first 12 months after admission, with an improved prognosis in secondary over primary amenorrhea.^20,21 Interestingly, mildly and significantly underweight infertile women have pregnancy and live birth rates similar to normal-weight patients after IVF treatment.²²

Pregnancy is complicated in underweight women, resulting in an increased risk of anemia, fetal growth retardation, and low birth weight, as well as preterm birth.²¹

Take-home message

The extremes of BMI both impair natural reproduction. Elevated BMI reduces success with IVF but rapid weight loss prior to IVF does not improve outcomes. A normal BMI is the goal for optimal reproductive and pregnancy health.

Dr. Trolice is director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Talumaa B et al. Obesity Rev. 2022;23:e13494.

2. https://bit.ly/3rHCivE.

3. Eknoyan G. Nephrol Dial Transplant. 2008;23:47-51.

4. Wells JCK. Dis Models Mech. 2012;5:595-607.

5. Brewer CJ and Balen AH. Reproduction. 2010;140:347-64.

6. Silvestris E et al. Reprod Biol Endocrinol. 2018;16:22.

7. Wise LA et al. Hum Reprod. 2010;25:253-64.

8. Bellver J. Curr Opin Obstet Gynecol. 2022;34:114-21.

9. Dickey RP et al. Am J Obstet Gynecol. 2013;209:349.e1.

10. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.

11. Cnattingius S et al. JAMA. 2013;309:2362-70.

12. Aune D et al. JAMA. 2014;311:1536-46.

13. Sam S. Obes Manag. 2007;3:69-73.

14. van der Steeg JW et al. Hum Reprod. 2008;23:324-8.

15. Gaskins AJ et al. Obstet Gynecol. 2015;126:850-8.

16. Sermondade N et al. Hum Reprod Update. 2019;25:439-519.

17. Kawwass JF et al. Fertil Steril. 2016;106[7]:1742-50.

18. Einarsson S et al. Hum Reprod. 2017;32:1621-30.

19. Chaer R et al. Diseases. 2020;8:46.

20. Dempfle A et al. Psychiatry. 2013;13:308.

21. Verma A and Shrimali L. J Clin Diagn Res. 2012;6:1531-3.

22. Romanski PA et al. Reprod Biomed Online. 2020;42:366-74.

Arguably, no topic during an infertility consultation generates more of an emotional reaction than discussing body mass index (BMI), particularly when it is high. Patients have become increasingly sensitive to weight discussions with their physicians because of concerns about body shaming. Among patients with an elevated BMI, criticism on social media of health care professionals’ counseling and a preemptive presentation of “Don’t Weigh Me” cards have become popular responses. Despite the medical evidence on impaired reproduction with an abnormal BMI, patients are choosing to forgo the topic. Research has demonstrated “extensive evidence [of] strong weight bias” in a wide range of health staff.¹ A “viral” TikTok study revealed that medical “gaslighting” founded in weight stigma and bias is harmful, as reported on KevinMD.com.² This month, we review the effect of abnormal BMI, both high and low, on reproduction and pregnancy.

A method to assess relative weight was first described in 1832 as its ratio in kilograms divided by the square of the height in meters, or the Quetelet Index. The search for a functional assessment of relative body weight began after World War II when reports by actuaries noted the increased mortality of overweight policyholders. The relationship between weight and cardiovascular disease was further revealed in epidemiologic studies. The Quetelet Index became the BMI in 1972.³

Weight measurement is a mainstay in the assessment of a patient’s vital signs along with blood pressure, pulse rate, respiration rate, and temperature. Weight is vital to the calculation of medication dosage – for instance, administration of conscious sedative drugs, methotrexate, and gonadotropins. Some state boards of medicine, such as Florida, have a limitation on patient BMI at office-based surgery centers (40 kg/m²).
 

Obesity is a disease

As reported by the World Health Organization in 2022, the disease of obesity is an epidemic afflicting more than 1 billion people worldwide, or 1 in 8 individuals globally.⁴ The health implications of an elevated BMI include increased mortality, diabetes, heart disease, and stroke, physical limitations to activities of daily living, and complications affecting reproduction.

Female obesity is related to poorer outcomes in natural and assisted conception, including an increased risk of miscarriage. Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction,⁵ infertility,⁶ a lower chance for conception,⁷ higher rate of miscarriage, and low birth weight.^8,9During pregnancy, women with obesity have three to four times higher rates of gestational diabetes and preeclampsia,¹⁰ as well as likelihood of delivering preterm,¹¹ having a fetus with macrosomia and birth defects, and a 1.3- to 2.1-times higher risk of stillbirth.¹²

Obesity is present in 40%-80% of women with polycystic ovary syndrome,¹³ the most common cause of ovulatory dysfunction from dysregulation of the hypothalamic-pituitary-ovarian axis. While PCOS is associated with reproductive and metabolic consequences, even in regularly ovulating women, increasing obesity appears to be associated with decreasing spontaneous pregnancy rates and increased time to pregnancy.¹⁴

Obesity and IVF

Women with obesity have reduced success with assisted reproductive technology, an increased number of canceled cycles, and poorer quality oocytes retrieved. A prospective cohort study of nearly 2,000 women reported that every 5 kg of body weight increase (from the patient’s baseline weight at age 18) was associated with a 5% increase in the mean duration of time required for conception (95% confidence interval, 3%-7%).¹⁵ Given that approximately 90% of these women had regular menstrual cycles, ovulatory dysfunction was not the suspected pathophysiology.

A meta-analysis of 21 cohort studies reported a lower likelihood of live birth following in vitro fertilization for women with obesity, compared with normal-weight women (risk ratio, 0.85; 95% CI, 0.82-0.87).¹⁶ A further subgroup analysis that evaluated only women with PCOS showed a reduction in the live birth rate following IVF for individuals with obesity, compared with normal-weight individuals (RR, 0.78; 95% CI, 0.74-0.82).

In a retrospective study of almost 500,000 fresh autologous IVF cycles, women with obesity had a 6% reduction in pregnancy rates and a 13% reduction in live birth rates, compared with normal-weight women. Both high and low BMI were associated with an increased risk of low birth weight and preterm delivery.¹⁷ The live birth rates per transfer for normal-weight and higher-weight women were 38% and 33%, respectively.

Contrarily, a randomized controlled trial showed that an intensive weight-reduction program resulted in a large weight loss but did not substantially affect live birth rates in women with obesity scheduled for IVF.¹⁸

Low BMI

A noteworthy cause of low BMI is functional hypothalamic amenorrhea (FHA), a disorder with low energy availability either from decreased caloric intake and/or excessive energy expenditure associated with eating disorders, excessive exercise, and stress. Consequently, a reduced GnRH drive results in a decreased pulse frequency and amplitude leading to low levels of follicle-stimulating hormone and luteinizing hormone, resulting in anovulation. Correction of lifestyle behaviors related to FHA can restore menstrual cycles. After normal weight is achieved, it appears unlikely that fertility is affected.¹⁹ In 47% of adolescent patients with anorexia, menses spontaneously returned within the first 12 months after admission, with an improved prognosis in secondary over primary amenorrhea.^20,21 Interestingly, mildly and significantly underweight infertile women have pregnancy and live birth rates similar to normal-weight patients after IVF treatment.²²

Pregnancy is complicated in underweight women, resulting in an increased risk of anemia, fetal growth retardation, and low birth weight, as well as preterm birth.²¹

Take-home message

The extremes of BMI both impair natural reproduction. Elevated BMI reduces success with IVF but rapid weight loss prior to IVF does not improve outcomes. A normal BMI is the goal for optimal reproductive and pregnancy health.

Dr. Trolice is director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Talumaa B et al. Obesity Rev. 2022;23:e13494.

2. https://bit.ly/3rHCivE.

3. Eknoyan G. Nephrol Dial Transplant. 2008;23:47-51.

4. Wells JCK. Dis Models Mech. 2012;5:595-607.

5. Brewer CJ and Balen AH. Reproduction. 2010;140:347-64.

6. Silvestris E et al. Reprod Biol Endocrinol. 2018;16:22.

7. Wise LA et al. Hum Reprod. 2010;25:253-64.

8. Bellver J. Curr Opin Obstet Gynecol. 2022;34:114-21.

9. Dickey RP et al. Am J Obstet Gynecol. 2013;209:349.e1.

10. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.

11. Cnattingius S et al. JAMA. 2013;309:2362-70.

12. Aune D et al. JAMA. 2014;311:1536-46.

13. Sam S. Obes Manag. 2007;3:69-73.

14. van der Steeg JW et al. Hum Reprod. 2008;23:324-8.

15. Gaskins AJ et al. Obstet Gynecol. 2015;126:850-8.

16. Sermondade N et al. Hum Reprod Update. 2019;25:439-519.

17. Kawwass JF et al. Fertil Steril. 2016;106[7]:1742-50.

18. Einarsson S et al. Hum Reprod. 2017;32:1621-30.

19. Chaer R et al. Diseases. 2020;8:46.

20. Dempfle A et al. Psychiatry. 2013;13:308.

21. Verma A and Shrimali L. J Clin Diagn Res. 2012;6:1531-3.

22. Romanski PA et al. Reprod Biomed Online. 2020;42:366-74.

Pain is classified as chronic when it lasts or recurs for more than 3-6 months (“Classification of chronic pain” 2nd ed. Seattle: IASP Press, 1994). This universally accepted definition does not distinguish between physical and emotional pain. Categorically, pain is pain. Two prevalent chronic gynecologic diseases are closely related medically and emotionally. Forty percent to 50% of women with endometriosis have infertility; 30%-50% of women with infertility are found to have coexisting endometriosis. The approach to both is, typically, symptomatic treatment. In this month’s column, I examine the relationship between these ailments and how we can advise women on management.

Endometriosis is simply defined as the displacement of normal endometrial glands and stroma from their natural anatomical location to elsewhere in the body. With the recent identification of the disease in the spleen, endometriosis has been found in every organ system. Endometriosis is identified in 6%-10% of the general female population. The prevalence ranges from 2% to 11% among asymptomatic women and from 5% to 21% in women hospitalized for pelvic pain (Best Pract Res Clin Obstet Gynaecol. 2018;51:1-15). Compared with fertile women, infertile women are six to eight times more likely to have endometriosis (Fertil Steril. 2012;98:591-8).

Retrograde menstruation is the presumed theory for the origins of endometriosis, that is, the reflux of menstrual debris containing active endometrial cells through the fallopian tubes into the peritoneal cavity (Am J Obstet Gynecol. 1927;14:422-69). Because of the varied etiologies of the most common symptoms of endometriosis, dysmenorrhea, dyspareunia, dyschezia, and infertility, women visit, on average, seven physicians before being diagnosed (Fertil Steril. 2011;96:366). The delay in promptly identifying endometriosis is further impaired by the lack of specific biomarkers, awareness, and inadequate evaluation (N Engl J Med. 2020;382:1244-56).

The 2008 U.S. health care costs for endometriosis were approximately $4,000 per affected woman, analogous to the costs for other chronic conditions such as type 2 diabetes, Crohn’s disease, and rheumatoid arthritis (Hum Reprod. 2012;27:1292-9). The management of symptoms further increases the financial burden because of the effect of the disease on physical, mental, sexual, and social well-being, as well as productivity (Health Qual Life Outcomes. 2019;17:123).

We have known the paradoxical relationship between the stage of endometriosis and symptoms: Women with low-stage disease may present with severe pain and/or infertility but those with advanced-stage disease may be asymptomatic. Endometriotic cells and tissue elicit a localized immune and inflammatory response with the production of cytokines, chemokines, and prostaglandins. Given the usual intra-abdominal location and the small size of implants, endometriosis requires a surgical diagnosis, ideally with histopathology for confirmation. However, imaging – transvaginal ultrasound or MRI – has more than 90% sensitivity and specificity for identifying endometriomas (Cochrane Database Syst Rev. 2016;2[2]:CD009591).

The effect of endometriosis on fertility, particularly in women with minimal to mild stages, is not clear, and many studies have been retrospective. Tubal factor infertility can be a result of endometriosis. Per the 2020 Cochrane Database Systemic Reviews (2020 Oct;2020[10]:CD011031), “Compared to diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis; no data were reported on live birth. There is moderate-quality evidence that laparoscopic surgery increases viable intrauterine pregnancy rates confirmed by ultrasound compared to diagnostic laparoscopy only.” In women undergoing IVF, more advanced stages of endometriosis have reduced pregnancy outcomes as shown in recent meta-analyses (Obstet Gynecol. 2015;125:79-88).

The revised ASRM (rASRM) surgical staging classification of endometriosis has been widely used to describe the degree, although it poorly correlates with fertility potential (Fertil Steril. 2012;98:591-8). Women diagnosed with endometriosis may benefit from the Endometriosis Fertility Index (EFI), published in 2010 as a useful scoring system to predict postoperative non-IVF pregnancy rates (both by natural means and intrauterine insemination) based on patient characteristics, rASRM staging and “least function” score of the adnexa (Fertil Steril. 2010;94:1609-15).

Compared with diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis. “Further research is needed considering the management of different subtypes of endometriosis and comparing laparoscopic interventions with lifestyle and medical interventions (Cochrane Database Syst Rev. 2020 Oct;2020[10]:CD011031).”

The treatment of endometriosis is directly related to the desire for and timing of fertility since therapy is often contraceptive, as opposed to surgery. Because endometriosis is exacerbated by estradiol, the mainstay of medical therapy is initially combined hormonal or progestin-only contraception as a means of reducing pelvic pain by reducing estradiol production and action, respectively. GnRH-agonist suppression of follicle stimulation hormone and luteinizing hormone remains the standard for inactivating endogenous estradiol. In 2018, the U.S. Food and Drug Administration approved elagolix for the treatment of pain associated with endometriosis – the first pill specifically approved for endometriosis pain relief. An off-label approach for women is letrozole, the aromatase inhibitor, to reduce circulating estradiol levels. Unfortunately, estradiol suppression cannot be used solely long term without add-back therapy, because of the risk of bone loss and vasomotor symptoms.

Excision of endometriomas adversely affects ovarian follicular reserve (as indicated by lower levels of anti-müllerian hormone and reduced ovarian antral follicle counts on ultrasound). For women who want to preserve their fertility, the potential benefits of surgery should be weighed against these negative effects. Surgical treatment of endometriosis in women without other identifiable infertility factors may improve rates of spontaneous pregnancy. In women with moderate to severe endometriosis, intrauterine insemination with ovarian stimulation may be of value, particularly with preceding GnRH-agonist therapy (J Endometr Pelvic Pain Disord. 2018;10[3]:158-73).

Despite the reduction in IVF outcomes in women with moderate to severe endometriosis, it remains unclear whether surgery improves the likelihood of pregnancy with IVF as does the concurrent use of prolonged GnRH agonist during IVF stimulation. (Fertil Steril. 2012;98:591-8).

Summary

• Medical therapy alone does not appear to improve fertility in endometriosis.
• Surgical treatment of endometriosis improves natural fertility, particularly in lower-stage endometriosis.
• EFI is a useful tool to predict postoperative natural fertility and assess the need for IVF.
• Despite advanced endometriosis reducing IVF outcomes, surgery or medical pretreatment to increase IVF success remains unproven.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Pain is classified as chronic when it lasts or recurs for more than 3-6 months (“Classification of chronic pain” 2nd ed. Seattle: IASP Press, 1994). This universally accepted definition does not distinguish between physical and emotional pain. Categorically, pain is pain. Two prevalent chronic gynecologic diseases are closely related medically and emotionally. Forty percent to 50% of women with endometriosis have infertility; 30%-50% of women with infertility are found to have coexisting endometriosis. The approach to both is, typically, symptomatic treatment. In this month’s column, I examine the relationship between these ailments and how we can advise women on management.

Endometriosis is simply defined as the displacement of normal endometrial glands and stroma from their natural anatomical location to elsewhere in the body. With the recent identification of the disease in the spleen, endometriosis has been found in every organ system. Endometriosis is identified in 6%-10% of the general female population. The prevalence ranges from 2% to 11% among asymptomatic women and from 5% to 21% in women hospitalized for pelvic pain (Best Pract Res Clin Obstet Gynaecol. 2018;51:1-15). Compared with fertile women, infertile women are six to eight times more likely to have endometriosis (Fertil Steril. 2012;98:591-8).

Retrograde menstruation is the presumed theory for the origins of endometriosis, that is, the reflux of menstrual debris containing active endometrial cells through the fallopian tubes into the peritoneal cavity (Am J Obstet Gynecol. 1927;14:422-69). Because of the varied etiologies of the most common symptoms of endometriosis, dysmenorrhea, dyspareunia, dyschezia, and infertility, women visit, on average, seven physicians before being diagnosed (Fertil Steril. 2011;96:366). The delay in promptly identifying endometriosis is further impaired by the lack of specific biomarkers, awareness, and inadequate evaluation (N Engl J Med. 2020;382:1244-56).

The 2008 U.S. health care costs for endometriosis were approximately $4,000 per affected woman, analogous to the costs for other chronic conditions such as type 2 diabetes, Crohn’s disease, and rheumatoid arthritis (Hum Reprod. 2012;27:1292-9). The management of symptoms further increases the financial burden because of the effect of the disease on physical, mental, sexual, and social well-being, as well as productivity (Health Qual Life Outcomes. 2019;17:123).

We have known the paradoxical relationship between the stage of endometriosis and symptoms: Women with low-stage disease may present with severe pain and/or infertility but those with advanced-stage disease may be asymptomatic. Endometriotic cells and tissue elicit a localized immune and inflammatory response with the production of cytokines, chemokines, and prostaglandins. Given the usual intra-abdominal location and the small size of implants, endometriosis requires a surgical diagnosis, ideally with histopathology for confirmation. However, imaging – transvaginal ultrasound or MRI – has more than 90% sensitivity and specificity for identifying endometriomas (Cochrane Database Syst Rev. 2016;2[2]:CD009591).

The effect of endometriosis on fertility, particularly in women with minimal to mild stages, is not clear, and many studies have been retrospective. Tubal factor infertility can be a result of endometriosis. Per the 2020 Cochrane Database Systemic Reviews (2020 Oct;2020[10]:CD011031), “Compared to diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis; no data were reported on live birth. There is moderate-quality evidence that laparoscopic surgery increases viable intrauterine pregnancy rates confirmed by ultrasound compared to diagnostic laparoscopy only.” In women undergoing IVF, more advanced stages of endometriosis have reduced pregnancy outcomes as shown in recent meta-analyses (Obstet Gynecol. 2015;125:79-88).

The revised ASRM (rASRM) surgical staging classification of endometriosis has been widely used to describe the degree, although it poorly correlates with fertility potential (Fertil Steril. 2012;98:591-8). Women diagnosed with endometriosis may benefit from the Endometriosis Fertility Index (EFI), published in 2010 as a useful scoring system to predict postoperative non-IVF pregnancy rates (both by natural means and intrauterine insemination) based on patient characteristics, rASRM staging and “least function” score of the adnexa (Fertil Steril. 2010;94:1609-15).

Compared with diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis. “Further research is needed considering the management of different subtypes of endometriosis and comparing laparoscopic interventions with lifestyle and medical interventions (Cochrane Database Syst Rev. 2020 Oct;2020[10]:CD011031).”

The treatment of endometriosis is directly related to the desire for and timing of fertility since therapy is often contraceptive, as opposed to surgery. Because endometriosis is exacerbated by estradiol, the mainstay of medical therapy is initially combined hormonal or progestin-only contraception as a means of reducing pelvic pain by reducing estradiol production and action, respectively. GnRH-agonist suppression of follicle stimulation hormone and luteinizing hormone remains the standard for inactivating endogenous estradiol. In 2018, the U.S. Food and Drug Administration approved elagolix for the treatment of pain associated with endometriosis – the first pill specifically approved for endometriosis pain relief. An off-label approach for women is letrozole, the aromatase inhibitor, to reduce circulating estradiol levels. Unfortunately, estradiol suppression cannot be used solely long term without add-back therapy, because of the risk of bone loss and vasomotor symptoms.

Excision of endometriomas adversely affects ovarian follicular reserve (as indicated by lower levels of anti-müllerian hormone and reduced ovarian antral follicle counts on ultrasound). For women who want to preserve their fertility, the potential benefits of surgery should be weighed against these negative effects. Surgical treatment of endometriosis in women without other identifiable infertility factors may improve rates of spontaneous pregnancy. In women with moderate to severe endometriosis, intrauterine insemination with ovarian stimulation may be of value, particularly with preceding GnRH-agonist therapy (J Endometr Pelvic Pain Disord. 2018;10[3]:158-73).

Despite the reduction in IVF outcomes in women with moderate to severe endometriosis, it remains unclear whether surgery improves the likelihood of pregnancy with IVF as does the concurrent use of prolonged GnRH agonist during IVF stimulation. (Fertil Steril. 2012;98:591-8).

Summary

• Medical therapy alone does not appear to improve fertility in endometriosis.
• Surgical treatment of endometriosis improves natural fertility, particularly in lower-stage endometriosis.
• EFI is a useful tool to predict postoperative natural fertility and assess the need for IVF.
• Despite advanced endometriosis reducing IVF outcomes, surgery or medical pretreatment to increase IVF success remains unproven.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Pain is classified as chronic when it lasts or recurs for more than 3-6 months (“Classification of chronic pain” 2nd ed. Seattle: IASP Press, 1994). This universally accepted definition does not distinguish between physical and emotional pain. Categorically, pain is pain. Two prevalent chronic gynecologic diseases are closely related medically and emotionally. Forty percent to 50% of women with endometriosis have infertility; 30%-50% of women with infertility are found to have coexisting endometriosis. The approach to both is, typically, symptomatic treatment. In this month’s column, I examine the relationship between these ailments and how we can advise women on management.

Endometriosis is simply defined as the displacement of normal endometrial glands and stroma from their natural anatomical location to elsewhere in the body. With the recent identification of the disease in the spleen, endometriosis has been found in every organ system. Endometriosis is identified in 6%-10% of the general female population. The prevalence ranges from 2% to 11% among asymptomatic women and from 5% to 21% in women hospitalized for pelvic pain (Best Pract Res Clin Obstet Gynaecol. 2018;51:1-15). Compared with fertile women, infertile women are six to eight times more likely to have endometriosis (Fertil Steril. 2012;98:591-8).

Retrograde menstruation is the presumed theory for the origins of endometriosis, that is, the reflux of menstrual debris containing active endometrial cells through the fallopian tubes into the peritoneal cavity (Am J Obstet Gynecol. 1927;14:422-69). Because of the varied etiologies of the most common symptoms of endometriosis, dysmenorrhea, dyspareunia, dyschezia, and infertility, women visit, on average, seven physicians before being diagnosed (Fertil Steril. 2011;96:366). The delay in promptly identifying endometriosis is further impaired by the lack of specific biomarkers, awareness, and inadequate evaluation (N Engl J Med. 2020;382:1244-56).

The 2008 U.S. health care costs for endometriosis were approximately $4,000 per affected woman, analogous to the costs for other chronic conditions such as type 2 diabetes, Crohn’s disease, and rheumatoid arthritis (Hum Reprod. 2012;27:1292-9). The management of symptoms further increases the financial burden because of the effect of the disease on physical, mental, sexual, and social well-being, as well as productivity (Health Qual Life Outcomes. 2019;17:123).

We have known the paradoxical relationship between the stage of endometriosis and symptoms: Women with low-stage disease may present with severe pain and/or infertility but those with advanced-stage disease may be asymptomatic. Endometriotic cells and tissue elicit a localized immune and inflammatory response with the production of cytokines, chemokines, and prostaglandins. Given the usual intra-abdominal location and the small size of implants, endometriosis requires a surgical diagnosis, ideally with histopathology for confirmation. However, imaging – transvaginal ultrasound or MRI – has more than 90% sensitivity and specificity for identifying endometriomas (Cochrane Database Syst Rev. 2016;2[2]:CD009591).

The effect of endometriosis on fertility, particularly in women with minimal to mild stages, is not clear, and many studies have been retrospective. Tubal factor infertility can be a result of endometriosis. Per the 2020 Cochrane Database Systemic Reviews (2020 Oct;2020[10]:CD011031), “Compared to diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis; no data were reported on live birth. There is moderate-quality evidence that laparoscopic surgery increases viable intrauterine pregnancy rates confirmed by ultrasound compared to diagnostic laparoscopy only.” In women undergoing IVF, more advanced stages of endometriosis have reduced pregnancy outcomes as shown in recent meta-analyses (Obstet Gynecol. 2015;125:79-88).

The revised ASRM (rASRM) surgical staging classification of endometriosis has been widely used to describe the degree, although it poorly correlates with fertility potential (Fertil Steril. 2012;98:591-8). Women diagnosed with endometriosis may benefit from the Endometriosis Fertility Index (EFI), published in 2010 as a useful scoring system to predict postoperative non-IVF pregnancy rates (both by natural means and intrauterine insemination) based on patient characteristics, rASRM staging and “least function” score of the adnexa (Fertil Steril. 2010;94:1609-15).

Compared with diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis. “Further research is needed considering the management of different subtypes of endometriosis and comparing laparoscopic interventions with lifestyle and medical interventions (Cochrane Database Syst Rev. 2020 Oct;2020[10]:CD011031).”

The treatment of endometriosis is directly related to the desire for and timing of fertility since therapy is often contraceptive, as opposed to surgery. Because endometriosis is exacerbated by estradiol, the mainstay of medical therapy is initially combined hormonal or progestin-only contraception as a means of reducing pelvic pain by reducing estradiol production and action, respectively. GnRH-agonist suppression of follicle stimulation hormone and luteinizing hormone remains the standard for inactivating endogenous estradiol. In 2018, the U.S. Food and Drug Administration approved elagolix for the treatment of pain associated with endometriosis – the first pill specifically approved for endometriosis pain relief. An off-label approach for women is letrozole, the aromatase inhibitor, to reduce circulating estradiol levels. Unfortunately, estradiol suppression cannot be used solely long term without add-back therapy, because of the risk of bone loss and vasomotor symptoms.

Excision of endometriomas adversely affects ovarian follicular reserve (as indicated by lower levels of anti-müllerian hormone and reduced ovarian antral follicle counts on ultrasound). For women who want to preserve their fertility, the potential benefits of surgery should be weighed against these negative effects. Surgical treatment of endometriosis in women without other identifiable infertility factors may improve rates of spontaneous pregnancy. In women with moderate to severe endometriosis, intrauterine insemination with ovarian stimulation may be of value, particularly with preceding GnRH-agonist therapy (J Endometr Pelvic Pain Disord. 2018;10[3]:158-73).

Despite the reduction in IVF outcomes in women with moderate to severe endometriosis, it remains unclear whether surgery improves the likelihood of pregnancy with IVF as does the concurrent use of prolonged GnRH agonist during IVF stimulation. (Fertil Steril. 2012;98:591-8).

Summary

• Medical therapy alone does not appear to improve fertility in endometriosis.
• Surgical treatment of endometriosis improves natural fertility, particularly in lower-stage endometriosis.
• EFI is a useful tool to predict postoperative natural fertility and assess the need for IVF.
• Despite advanced endometriosis reducing IVF outcomes, surgery or medical pretreatment to increase IVF success remains unproven.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

A 6-year-old girl presents with breast development. Her medical history is unremarkable. The parents are of average height, and the mother reports her thelarche was age 11 years. The girl is at the 97th percentile for her height and 90th percentile for her weight. She has Tanner stage 3 breast development and Tanner stage 2 pubic hair development. She has grown slightly more than 3 inches over the past year. How should she be evaluated and managed (N Engl J Med. 2008;358:2366-77)?

The premature onset of puberty, i.e., precocious puberty (PP), can be an emotionally traumatic event for the child and parents. Over the past century, improvements in public health and nutrition, and, more recently, increased obesity, have been associated with earlier puberty and the dominant factor has been attributed to genetics (Curr Opin Endocrinol Diabetes Obes. 2018;25[1]:49-54). This month’s article will focus on understanding what is considered “early” puberty, evaluating for causes, and managing precocious puberty.

More commonly seen in girls than boys, PP is defined as the onset of secondary sexual characteristics before age 7.5 years in Black and Hispanic girls, and prior to 8 years in White girls, which is 2-2.5 standard deviations below the average age of pubertal onset in healthy children (J Pediatr Adolesc Gynecol. 2019;32:455-9). As a comparison, PP is diagnosed with onset before age 9 years in boys. For White compared with Black girls, the average timing of thelarche is age 10 vs. 9.5 years, peak growth velocity is age 11.5, menarche is age 12.5 vs. 12, while completion of puberty is near age 14.5 vs. 13.5, respectively (J Pediatr. 1985;107:317). Fortunately, most girls with PP have common variants rather than serious pathology.
 

Classification: Central (CPP) vs. peripheral (PPP)

CPP is gonadotropin dependent, meaning the hypothalamic-pituitary-ovarian axis (HPO) is prematurely activated resulting in the normal progression of puberty.

PPP is gonadotropin independent, caused by sex steroid secretion from any source – ovaries, adrenal gland, exogenous or ectopic production, e.g., germ-cell tumor. This results in a disordered progression of pubertal milestones.

Whereas CPP is typically isosexual development, i.e., consistent with the child’s gender, PPP can be isosexual or contrasexual, e.g., virilization of girls. A third classification is “benign or nonprogressive pubertal variants” manifesting as isolated premature thelarche or adrenarche.
 

Causes (see table)

CPP. Idiopathic causes account for 80%-90% of presentations in girls and 25%-80% in boys. Remarkably, international and domestic adoption, as well as a family history of PP increases the likelihood of CPP in girls. Other etiologies include CNS lesions, e.g., hamartomas, which are the most common cause of PP in young children. MRI with contrast has been the traditional mode of diagnosis for CNS tumors, yet the yield is dubious in girls above age 6. Genetic causes are found in only a small percentage of PP cases. Rarely, CPP can result from gonadotropin-secreting tumors because of elevated luteinizing hormone levels.

McCune-Albright syndrome is rare and presents with the classic triad of PPP, skin pigmentation called café-au-lait, and fibrous dysplasia of bone. The pathophysiology of McCune-Albright syndrome is autoactivation of the G-protein leading to activation of ovarian tissue that results in formation of large ovarian cysts and extreme elevations in serum estradiol as well as the potential production of other hormones, e.g., thyrotoxicosis, excess growth hormone (acromegaly), and Cushing syndrome.

Premature thelarche. Premature thelarche typically occurs in girls between the ages of 1 and 3 years and is limited to breast enlargement. While no cause has been determined, the plausible explanations include partial activation of the HPO axis, endocrine-disrupting chemicals (EDCs), or a genetic origin. A small percentage of these girls progress to CPP.

EDCs have been considered as potential influencers of early puberty, but no consensus has been established. (Examples of EDCs in the environment include air, soil, or water supply along with food sources, personal care products, and manufactured products that can affect the endocrine system.)

Premature adenarche. Premature adrenarche presents with adult body odor and/or body hair (pubic and/or axillary) in girls who have an elevated body mass index, most commonly at the ages of 6-7 years. The presumed mechanism is normal maturation of the adrenal gland with resultant elevation of circulating androgens. Bone age may be mildly accelerated and DHEAS is prematurely elevated for age. These girls appear to be at increased risk for polycystic ovary syndrome.

Evaluation

The initial step in the evaluation of PP is to determine whether the cause is CPP or PPP; the latter includes distinguishing isosexual from contrasexual development. A thorough history (growth, headaches, behavior or visual change, seizures, abdominal pain), physical exam, including Tanner staging, and bone age is required. However, with isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for pubertal progression is likely sufficient.

For CPP, the diagnosis is based on serum LH, whether random levels or elevations follow GnRH stimulation. Puberty milestones progress normally although adrenarche is not consistently apparent. For girls younger than age 6, a brain MRI is recommended but not in asymptomatic older girls with CPP. LH and FSH along with estradiol or testosterone, the latter especially in boys, are the first line of serum testing. Serum TSH is recommended for suspicion of primary hypothyroidism. In girls with premature adrenarche, a bone age, testosterone, DHEAS, and 17-OHP to rule out adrenal hyperplasia should be obtained. Pelvic ultrasound may be a useful adjunct to assess uterine volume and/or ovarian cysts/tumors.

Rapidity of onset can also lead the evaluation since a normal growth chart and skeletal maturation suggests a benign pubertal variant whereas a more rapid rate can signal CPP or PPP. Of note, health care providers should ensure prescription, over-the-counter oral or topical sources of hormones, and EDCs are ruled out.
 

Consequences

An association between childhood sexual abuse and earlier pubertal onset has been cited. These girls may be at increased risk for psychosocial difficulties, menstrual and fertility problems, and even reproductive cancers because of prolonged exposure to sex hormones (J Adolesc Health. 2016;60[1]:65-71).

Treatment

The mainstay of CPP treatment is maximizing adult height, typically through the use of a GnRH agonist for HPO suppression from pituitary downregulation. For girls above age 8 years, attempts at improving adult height have not shown a benefit.

In girls with PPP, treatment is directed at the prevailing pathology. Interestingly, early PPP can activate the HPO axis thereby converting to “secondary” CPP. In PPP, McCune-Albright syndrome treatment targets reducing circulating estrogens through letrozole or tamoxifen as well as addressing other autoactivated hormone production. Ovarian and adrenal tumors, albeit rare, can cause PP; therefore, surgical excision is the goal of treatment.

PP should be approached with equal concerns about the physical and emotional effects while including the family to help them understand the pathophysiology and psychosocial risks.
 

Dr. Mark P. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

A 6-year-old girl presents with breast development. Her medical history is unremarkable. The parents are of average height, and the mother reports her thelarche was age 11 years. The girl is at the 97th percentile for her height and 90th percentile for her weight. She has Tanner stage 3 breast development and Tanner stage 2 pubic hair development. She has grown slightly more than 3 inches over the past year. How should she be evaluated and managed (N Engl J Med. 2008;358:2366-77)?

The premature onset of puberty, i.e., precocious puberty (PP), can be an emotionally traumatic event for the child and parents. Over the past century, improvements in public health and nutrition, and, more recently, increased obesity, have been associated with earlier puberty and the dominant factor has been attributed to genetics (Curr Opin Endocrinol Diabetes Obes. 2018;25[1]:49-54). This month’s article will focus on understanding what is considered “early” puberty, evaluating for causes, and managing precocious puberty.

More commonly seen in girls than boys, PP is defined as the onset of secondary sexual characteristics before age 7.5 years in Black and Hispanic girls, and prior to 8 years in White girls, which is 2-2.5 standard deviations below the average age of pubertal onset in healthy children (J Pediatr Adolesc Gynecol. 2019;32:455-9). As a comparison, PP is diagnosed with onset before age 9 years in boys. For White compared with Black girls, the average timing of thelarche is age 10 vs. 9.5 years, peak growth velocity is age 11.5, menarche is age 12.5 vs. 12, while completion of puberty is near age 14.5 vs. 13.5, respectively (J Pediatr. 1985;107:317). Fortunately, most girls with PP have common variants rather than serious pathology.
 

Classification: Central (CPP) vs. peripheral (PPP)

CPP is gonadotropin dependent, meaning the hypothalamic-pituitary-ovarian axis (HPO) is prematurely activated resulting in the normal progression of puberty.

PPP is gonadotropin independent, caused by sex steroid secretion from any source – ovaries, adrenal gland, exogenous or ectopic production, e.g., germ-cell tumor. This results in a disordered progression of pubertal milestones.

Whereas CPP is typically isosexual development, i.e., consistent with the child’s gender, PPP can be isosexual or contrasexual, e.g., virilization of girls. A third classification is “benign or nonprogressive pubertal variants” manifesting as isolated premature thelarche or adrenarche.
 

Causes (see table)

CPP. Idiopathic causes account for 80%-90% of presentations in girls and 25%-80% in boys. Remarkably, international and domestic adoption, as well as a family history of PP increases the likelihood of CPP in girls. Other etiologies include CNS lesions, e.g., hamartomas, which are the most common cause of PP in young children. MRI with contrast has been the traditional mode of diagnosis for CNS tumors, yet the yield is dubious in girls above age 6. Genetic causes are found in only a small percentage of PP cases. Rarely, CPP can result from gonadotropin-secreting tumors because of elevated luteinizing hormone levels.

McCune-Albright syndrome is rare and presents with the classic triad of PPP, skin pigmentation called café-au-lait, and fibrous dysplasia of bone. The pathophysiology of McCune-Albright syndrome is autoactivation of the G-protein leading to activation of ovarian tissue that results in formation of large ovarian cysts and extreme elevations in serum estradiol as well as the potential production of other hormones, e.g., thyrotoxicosis, excess growth hormone (acromegaly), and Cushing syndrome.

Premature thelarche. Premature thelarche typically occurs in girls between the ages of 1 and 3 years and is limited to breast enlargement. While no cause has been determined, the plausible explanations include partial activation of the HPO axis, endocrine-disrupting chemicals (EDCs), or a genetic origin. A small percentage of these girls progress to CPP.

EDCs have been considered as potential influencers of early puberty, but no consensus has been established. (Examples of EDCs in the environment include air, soil, or water supply along with food sources, personal care products, and manufactured products that can affect the endocrine system.)

Premature adenarche. Premature adrenarche presents with adult body odor and/or body hair (pubic and/or axillary) in girls who have an elevated body mass index, most commonly at the ages of 6-7 years. The presumed mechanism is normal maturation of the adrenal gland with resultant elevation of circulating androgens. Bone age may be mildly accelerated and DHEAS is prematurely elevated for age. These girls appear to be at increased risk for polycystic ovary syndrome.

Evaluation

The initial step in the evaluation of PP is to determine whether the cause is CPP or PPP; the latter includes distinguishing isosexual from contrasexual development. A thorough history (growth, headaches, behavior or visual change, seizures, abdominal pain), physical exam, including Tanner staging, and bone age is required. However, with isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for pubertal progression is likely sufficient.

For CPP, the diagnosis is based on serum LH, whether random levels or elevations follow GnRH stimulation. Puberty milestones progress normally although adrenarche is not consistently apparent. For girls younger than age 6, a brain MRI is recommended but not in asymptomatic older girls with CPP. LH and FSH along with estradiol or testosterone, the latter especially in boys, are the first line of serum testing. Serum TSH is recommended for suspicion of primary hypothyroidism. In girls with premature adrenarche, a bone age, testosterone, DHEAS, and 17-OHP to rule out adrenal hyperplasia should be obtained. Pelvic ultrasound may be a useful adjunct to assess uterine volume and/or ovarian cysts/tumors.

Rapidity of onset can also lead the evaluation since a normal growth chart and skeletal maturation suggests a benign pubertal variant whereas a more rapid rate can signal CPP or PPP. Of note, health care providers should ensure prescription, over-the-counter oral or topical sources of hormones, and EDCs are ruled out.
 

Consequences

An association between childhood sexual abuse and earlier pubertal onset has been cited. These girls may be at increased risk for psychosocial difficulties, menstrual and fertility problems, and even reproductive cancers because of prolonged exposure to sex hormones (J Adolesc Health. 2016;60[1]:65-71).

Treatment

The mainstay of CPP treatment is maximizing adult height, typically through the use of a GnRH agonist for HPO suppression from pituitary downregulation. For girls above age 8 years, attempts at improving adult height have not shown a benefit.

In girls with PPP, treatment is directed at the prevailing pathology. Interestingly, early PPP can activate the HPO axis thereby converting to “secondary” CPP. In PPP, McCune-Albright syndrome treatment targets reducing circulating estrogens through letrozole or tamoxifen as well as addressing other autoactivated hormone production. Ovarian and adrenal tumors, albeit rare, can cause PP; therefore, surgical excision is the goal of treatment.

PP should be approached with equal concerns about the physical and emotional effects while including the family to help them understand the pathophysiology and psychosocial risks.
 

Dr. Mark P. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

A 6-year-old girl presents with breast development. Her medical history is unremarkable. The parents are of average height, and the mother reports her thelarche was age 11 years. The girl is at the 97th percentile for her height and 90th percentile for her weight. She has Tanner stage 3 breast development and Tanner stage 2 pubic hair development. She has grown slightly more than 3 inches over the past year. How should she be evaluated and managed (N Engl J Med. 2008;358:2366-77)?

The premature onset of puberty, i.e., precocious puberty (PP), can be an emotionally traumatic event for the child and parents. Over the past century, improvements in public health and nutrition, and, more recently, increased obesity, have been associated with earlier puberty and the dominant factor has been attributed to genetics (Curr Opin Endocrinol Diabetes Obes. 2018;25[1]:49-54). This month’s article will focus on understanding what is considered “early” puberty, evaluating for causes, and managing precocious puberty.

More commonly seen in girls than boys, PP is defined as the onset of secondary sexual characteristics before age 7.5 years in Black and Hispanic girls, and prior to 8 years in White girls, which is 2-2.5 standard deviations below the average age of pubertal onset in healthy children (J Pediatr Adolesc Gynecol. 2019;32:455-9). As a comparison, PP is diagnosed with onset before age 9 years in boys. For White compared with Black girls, the average timing of thelarche is age 10 vs. 9.5 years, peak growth velocity is age 11.5, menarche is age 12.5 vs. 12, while completion of puberty is near age 14.5 vs. 13.5, respectively (J Pediatr. 1985;107:317). Fortunately, most girls with PP have common variants rather than serious pathology.
 

Classification: Central (CPP) vs. peripheral (PPP)

CPP is gonadotropin dependent, meaning the hypothalamic-pituitary-ovarian axis (HPO) is prematurely activated resulting in the normal progression of puberty.

PPP is gonadotropin independent, caused by sex steroid secretion from any source – ovaries, adrenal gland, exogenous or ectopic production, e.g., germ-cell tumor. This results in a disordered progression of pubertal milestones.

Whereas CPP is typically isosexual development, i.e., consistent with the child’s gender, PPP can be isosexual or contrasexual, e.g., virilization of girls. A third classification is “benign or nonprogressive pubertal variants” manifesting as isolated premature thelarche or adrenarche.
 

Causes (see table)

CPP. Idiopathic causes account for 80%-90% of presentations in girls and 25%-80% in boys. Remarkably, international and domestic adoption, as well as a family history of PP increases the likelihood of CPP in girls. Other etiologies include CNS lesions, e.g., hamartomas, which are the most common cause of PP in young children. MRI with contrast has been the traditional mode of diagnosis for CNS tumors, yet the yield is dubious in girls above age 6. Genetic causes are found in only a small percentage of PP cases. Rarely, CPP can result from gonadotropin-secreting tumors because of elevated luteinizing hormone levels.

McCune-Albright syndrome is rare and presents with the classic triad of PPP, skin pigmentation called café-au-lait, and fibrous dysplasia of bone. The pathophysiology of McCune-Albright syndrome is autoactivation of the G-protein leading to activation of ovarian tissue that results in formation of large ovarian cysts and extreme elevations in serum estradiol as well as the potential production of other hormones, e.g., thyrotoxicosis, excess growth hormone (acromegaly), and Cushing syndrome.

Premature thelarche. Premature thelarche typically occurs in girls between the ages of 1 and 3 years and is limited to breast enlargement. While no cause has been determined, the plausible explanations include partial activation of the HPO axis, endocrine-disrupting chemicals (EDCs), or a genetic origin. A small percentage of these girls progress to CPP.

EDCs have been considered as potential influencers of early puberty, but no consensus has been established. (Examples of EDCs in the environment include air, soil, or water supply along with food sources, personal care products, and manufactured products that can affect the endocrine system.)

Premature adenarche. Premature adrenarche presents with adult body odor and/or body hair (pubic and/or axillary) in girls who have an elevated body mass index, most commonly at the ages of 6-7 years. The presumed mechanism is normal maturation of the adrenal gland with resultant elevation of circulating androgens. Bone age may be mildly accelerated and DHEAS is prematurely elevated for age. These girls appear to be at increased risk for polycystic ovary syndrome.

Evaluation

The initial step in the evaluation of PP is to determine whether the cause is CPP or PPP; the latter includes distinguishing isosexual from contrasexual development. A thorough history (growth, headaches, behavior or visual change, seizures, abdominal pain), physical exam, including Tanner staging, and bone age is required. However, with isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for pubertal progression is likely sufficient.

For CPP, the diagnosis is based on serum LH, whether random levels or elevations follow GnRH stimulation. Puberty milestones progress normally although adrenarche is not consistently apparent. For girls younger than age 6, a brain MRI is recommended but not in asymptomatic older girls with CPP. LH and FSH along with estradiol or testosterone, the latter especially in boys, are the first line of serum testing. Serum TSH is recommended for suspicion of primary hypothyroidism. In girls with premature adrenarche, a bone age, testosterone, DHEAS, and 17-OHP to rule out adrenal hyperplasia should be obtained. Pelvic ultrasound may be a useful adjunct to assess uterine volume and/or ovarian cysts/tumors.

Rapidity of onset can also lead the evaluation since a normal growth chart and skeletal maturation suggests a benign pubertal variant whereas a more rapid rate can signal CPP or PPP. Of note, health care providers should ensure prescription, over-the-counter oral or topical sources of hormones, and EDCs are ruled out.
 

Consequences

An association between childhood sexual abuse and earlier pubertal onset has been cited. These girls may be at increased risk for psychosocial difficulties, menstrual and fertility problems, and even reproductive cancers because of prolonged exposure to sex hormones (J Adolesc Health. 2016;60[1]:65-71).

Treatment

The mainstay of CPP treatment is maximizing adult height, typically through the use of a GnRH agonist for HPO suppression from pituitary downregulation. For girls above age 8 years, attempts at improving adult height have not shown a benefit.

In girls with PPP, treatment is directed at the prevailing pathology. Interestingly, early PPP can activate the HPO axis thereby converting to “secondary” CPP. In PPP, McCune-Albright syndrome treatment targets reducing circulating estrogens through letrozole or tamoxifen as well as addressing other autoactivated hormone production. Ovarian and adrenal tumors, albeit rare, can cause PP; therefore, surgical excision is the goal of treatment.

PP should be approached with equal concerns about the physical and emotional effects while including the family to help them understand the pathophysiology and psychosocial risks.
 

Dr. Mark P. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

The American Society for Reproductive Medicine’s classification system for müllerian anomalies was the standard until the revision in 2021 by ASRM, which updated and expanded the classification presenting nine classes and imaging criteria: müllerian agenesis, cervical agenesis, unicornuate, uterus didelphys, bicornuate, septate, longitudinal vaginal septum, transverse vaginal septum, and complex anomalies. This month’s article addresses müllerian anomalies from embryology to treatment options.

The early embryo has the capability of developing a wolffian (internal male) or müllerian (internal female) system. Unless anti-müllerian hormone (formerly müllerian-inhibiting substance) is produced, the embryo develops a female reproductive system beginning with two lateral uterine anlagen that fuse in the midline and canalize. Müllerian anomalies occur because of accidents during fusion and canalization (see Table).

The incidence of müllerian anomalies is difficult to discern, given the potential for a normal reproductive outcome precluding an evaluation and based on the population studied. Müllerian anomalies are found in approximately 4.3% of fertile women, 3.5%-8% of infertile patients, 12.3%-13% of those with recurrent pregnancy losses, and 24.5% of patients with miscarriage and infertility. Of the müllerian anomalies, the most common is septate (35%), followed by bicornuate (26%), arcuate (18%), unicornuate (10%), didelphys (8%), and agenesis (3%) (Hum Reprod Update. 2001;7[2]:161; Hum Reprod Update. 2011;17[6]:761-71).

In 20%-30% of patients with müllerian anomalies, particularly in women with a unicornuate uterus, renal anomalies exist that are typically ipsilateral to the absent or rudimentary contralateral uterine horn (J Pediatr Adolesc Gynecol. 2021;34[2]:154-60). As there is no definitive evidence to suggest an association between a septate uterus and renal anomalies, the renal system evaluation can be deferred in this population (Fertil Steril. 2021 Nov;116[5]:1238-52).
 

Diagnosis

2-D ultrasound can be a screen for müllerian anomalies and genitourinary anatomic variants. The diagnostic accuracy of 3-D ultrasound with müllerian anomalies is reported to be 97.6% with sensitivity and specificity of 98.3% and 99.4%, respectively (Hum. Reprod. 2016;31[1]:2-7). As a result, office 3-D has essentially replaced MRI in the diagnosis of müllerian anomalies (Ultrasound Obstet Gynecol. 2015 Nov;46[5]:616-22), with one exception because of the avoidance of a transvaginal probe in the non–sexually active adult and younger adolescent/child. MRI is reserved for diagnosing complex müllerian anomalies or if there is a diagnostic challenge.

Criteria to diagnose müllerian anomalies by radiology begins with the “reference line,” i.e., a line joining both tubal ostia (interostial line). A septate uterus is diagnosed if the distance from the interostial line to the cephalad endometrium is more than 1 cm, otherwise it is considered normal or arcuate based on its appearance. An arcuate uterus has not been associated with impaired reproduction and can be viewed as a normal variant. Alternatively, a bicornuate uterus is diagnosed when the external fundal indentation is more than 1 cm (Fertil Steril. 2021 Nov;116[5]:1238-52).
 

Clinical course

Women with müllerian anomalies may experience pelvic pain and prolonged and/or abnormal bleeding at the time of menarche. While the ability to conceive may not be impaired from müllerian anomalies with the possible exception of the septate uterus, the pregnancy course can be affected, i.e., recurrent pregnancy loss, preterm birth, perinatal mortality, and malpresentation in labor (Reprod Biomed Online. 2014;29[6]:665). In women with septate, bicornuate, and uterine didelphys, fetal growth restriction appears to be increased. Spontaneous abortion rates of 32% and preterm birth rates of 28% have been reported in patients with uterus didelphys (Obstet Gynecol. 1990;75[6]:906).

Special consideration of the unicornuate is given because of the potential for a rudimentary horn that may communicate with the main uterine cavity and/or have functional endometrium which places the woman at risk of an ectopic pregnancy in the smaller horn. Patients with a unicornuate uterus are at higher risk for preterm labor and breech presentation. An obstructed (noncommunicating) functional rudimentary horn is a risk for endometriosis with cyclic pain because of outflow tract obstruction and an ectopic pregnancy prompting consideration for hemihysterectomy based on symptoms.
 

The septate uterus – old dogma revisited

The incidence of uterine septa is approximately 1-15 per 1,000. As the most common müllerian anomaly, the septate uterus has traditionally been associated with an increased risk for spontaneous abortion (21%-44%) and preterm birth (12%-33%). The live birth rate ranges from 50% to 72% (Hum Reprod Update. 2001;7[2]:161-74). A uterine septum is believed to develop as a result of failure of resorption of the tissue connecting the two paramesonephric (müllerian) ducts prior to the 20th embryonic week.

Incising the uterine septum (metroplasty) dates back to 1884 when Ruge described a blind transcervical metroplasty in a woman with two previous miscarriages who, postoperatively, delivered a healthy baby. In the early 1900s, Tompkins reported an abdominal metroplasty (Fertil Stertil. 2021;115:1140-2). The decision to proceed with metroplasty is based on only established observational studies (Fertil Steril. 2016;106:530-40). Until recently, the majority of studies suggested that metroplasty is associated with decreased spontaneous abortion rates and improved obstetrical outcomes. A retrospective case series of 361 patients with a septate uterus who had primary infertility of >2 years’ duration, a history of 1-2 spontaneous abortions, or recurrent pregnancy loss suggested a significant improvement in the live birth rate and reduction in miscarriage (Arch Gynecol Obstet. 2003;268:289-92). A meta-analysis found that the overall pregnancy rate after septum incision was 67.8% and the live-birth rate was 53.5% (J Minim Invas Gynecol. 2013;20:22-42).

Recently, two multinational studies question the prevailing dogma (Fertil Steril. 2021 Sep;116[3]:693-4). Both studies could not demonstrate any increase in live birth rate, reduction in preterm birth, or in pregnancy loss after metroplasty. A significant limitation was the lack of a uniform consensus on the definition of the septate uterus and allowing the discretion of the physician to diagnosis a septum (Hum Reprod. 2020;35:1578-88; Hum Reprod. 2021;36:1260-7).

Hysteroscopic metroplasty is not without complications. Uterine rupture during pregnancy or delivery, while rare, may be linked to significant entry into the myometrium and/or overzealous cauterization and perforation, which emphasizes the importance of appropriate techniques.
 

Conclusion

A diagnosis of müllerian anomalies justifies a comprehensive consultation with the patient given the risk of pregnancy complications. Management of the septate uterus has become controversial. In a patient with infertility, prior pregnancy loss, or poor obstetrical outcome, it is reasonable to consider metroplasty; otherwise, expectant management is an option.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Email him at [email protected].

The American Society for Reproductive Medicine’s classification system for müllerian anomalies was the standard until the revision in 2021 by ASRM, which updated and expanded the classification presenting nine classes and imaging criteria: müllerian agenesis, cervical agenesis, unicornuate, uterus didelphys, bicornuate, septate, longitudinal vaginal septum, transverse vaginal septum, and complex anomalies. This month’s article addresses müllerian anomalies from embryology to treatment options.

The early embryo has the capability of developing a wolffian (internal male) or müllerian (internal female) system. Unless anti-müllerian hormone (formerly müllerian-inhibiting substance) is produced, the embryo develops a female reproductive system beginning with two lateral uterine anlagen that fuse in the midline and canalize. Müllerian anomalies occur because of accidents during fusion and canalization (see Table).

The incidence of müllerian anomalies is difficult to discern, given the potential for a normal reproductive outcome precluding an evaluation and based on the population studied. Müllerian anomalies are found in approximately 4.3% of fertile women, 3.5%-8% of infertile patients, 12.3%-13% of those with recurrent pregnancy losses, and 24.5% of patients with miscarriage and infertility. Of the müllerian anomalies, the most common is septate (35%), followed by bicornuate (26%), arcuate (18%), unicornuate (10%), didelphys (8%), and agenesis (3%) (Hum Reprod Update. 2001;7[2]:161; Hum Reprod Update. 2011;17[6]:761-71).

In 20%-30% of patients with müllerian anomalies, particularly in women with a unicornuate uterus, renal anomalies exist that are typically ipsilateral to the absent or rudimentary contralateral uterine horn (J Pediatr Adolesc Gynecol. 2021;34[2]:154-60). As there is no definitive evidence to suggest an association between a septate uterus and renal anomalies, the renal system evaluation can be deferred in this population (Fertil Steril. 2021 Nov;116[5]:1238-52).
 

Diagnosis

2-D ultrasound can be a screen for müllerian anomalies and genitourinary anatomic variants. The diagnostic accuracy of 3-D ultrasound with müllerian anomalies is reported to be 97.6% with sensitivity and specificity of 98.3% and 99.4%, respectively (Hum. Reprod. 2016;31[1]:2-7). As a result, office 3-D has essentially replaced MRI in the diagnosis of müllerian anomalies (Ultrasound Obstet Gynecol. 2015 Nov;46[5]:616-22), with one exception because of the avoidance of a transvaginal probe in the non–sexually active adult and younger adolescent/child. MRI is reserved for diagnosing complex müllerian anomalies or if there is a diagnostic challenge.

Criteria to diagnose müllerian anomalies by radiology begins with the “reference line,” i.e., a line joining both tubal ostia (interostial line). A septate uterus is diagnosed if the distance from the interostial line to the cephalad endometrium is more than 1 cm, otherwise it is considered normal or arcuate based on its appearance. An arcuate uterus has not been associated with impaired reproduction and can be viewed as a normal variant. Alternatively, a bicornuate uterus is diagnosed when the external fundal indentation is more than 1 cm (Fertil Steril. 2021 Nov;116[5]:1238-52).
 

Clinical course

Women with müllerian anomalies may experience pelvic pain and prolonged and/or abnormal bleeding at the time of menarche. While the ability to conceive may not be impaired from müllerian anomalies with the possible exception of the septate uterus, the pregnancy course can be affected, i.e., recurrent pregnancy loss, preterm birth, perinatal mortality, and malpresentation in labor (Reprod Biomed Online. 2014;29[6]:665). In women with septate, bicornuate, and uterine didelphys, fetal growth restriction appears to be increased. Spontaneous abortion rates of 32% and preterm birth rates of 28% have been reported in patients with uterus didelphys (Obstet Gynecol. 1990;75[6]:906).

Special consideration of the unicornuate is given because of the potential for a rudimentary horn that may communicate with the main uterine cavity and/or have functional endometrium which places the woman at risk of an ectopic pregnancy in the smaller horn. Patients with a unicornuate uterus are at higher risk for preterm labor and breech presentation. An obstructed (noncommunicating) functional rudimentary horn is a risk for endometriosis with cyclic pain because of outflow tract obstruction and an ectopic pregnancy prompting consideration for hemihysterectomy based on symptoms.
 

The septate uterus – old dogma revisited

The incidence of uterine septa is approximately 1-15 per 1,000. As the most common müllerian anomaly, the septate uterus has traditionally been associated with an increased risk for spontaneous abortion (21%-44%) and preterm birth (12%-33%). The live birth rate ranges from 50% to 72% (Hum Reprod Update. 2001;7[2]:161-74). A uterine septum is believed to develop as a result of failure of resorption of the tissue connecting the two paramesonephric (müllerian) ducts prior to the 20th embryonic week.

Incising the uterine septum (metroplasty) dates back to 1884 when Ruge described a blind transcervical metroplasty in a woman with two previous miscarriages who, postoperatively, delivered a healthy baby. In the early 1900s, Tompkins reported an abdominal metroplasty (Fertil Stertil. 2021;115:1140-2). The decision to proceed with metroplasty is based on only established observational studies (Fertil Steril. 2016;106:530-40). Until recently, the majority of studies suggested that metroplasty is associated with decreased spontaneous abortion rates and improved obstetrical outcomes. A retrospective case series of 361 patients with a septate uterus who had primary infertility of >2 years’ duration, a history of 1-2 spontaneous abortions, or recurrent pregnancy loss suggested a significant improvement in the live birth rate and reduction in miscarriage (Arch Gynecol Obstet. 2003;268:289-92). A meta-analysis found that the overall pregnancy rate after septum incision was 67.8% and the live-birth rate was 53.5% (J Minim Invas Gynecol. 2013;20:22-42).

Recently, two multinational studies question the prevailing dogma (Fertil Steril. 2021 Sep;116[3]:693-4). Both studies could not demonstrate any increase in live birth rate, reduction in preterm birth, or in pregnancy loss after metroplasty. A significant limitation was the lack of a uniform consensus on the definition of the septate uterus and allowing the discretion of the physician to diagnosis a septum (Hum Reprod. 2020;35:1578-88; Hum Reprod. 2021;36:1260-7).

Hysteroscopic metroplasty is not without complications. Uterine rupture during pregnancy or delivery, while rare, may be linked to significant entry into the myometrium and/or overzealous cauterization and perforation, which emphasizes the importance of appropriate techniques.
 

Conclusion

A diagnosis of müllerian anomalies justifies a comprehensive consultation with the patient given the risk of pregnancy complications. Management of the septate uterus has become controversial. In a patient with infertility, prior pregnancy loss, or poor obstetrical outcome, it is reasonable to consider metroplasty; otherwise, expectant management is an option.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Email him at [email protected].

The American Society for Reproductive Medicine’s classification system for müllerian anomalies was the standard until the revision in 2021 by ASRM, which updated and expanded the classification presenting nine classes and imaging criteria: müllerian agenesis, cervical agenesis, unicornuate, uterus didelphys, bicornuate, septate, longitudinal vaginal septum, transverse vaginal septum, and complex anomalies. This month’s article addresses müllerian anomalies from embryology to treatment options.

The early embryo has the capability of developing a wolffian (internal male) or müllerian (internal female) system. Unless anti-müllerian hormone (formerly müllerian-inhibiting substance) is produced, the embryo develops a female reproductive system beginning with two lateral uterine anlagen that fuse in the midline and canalize. Müllerian anomalies occur because of accidents during fusion and canalization (see Table).

The incidence of müllerian anomalies is difficult to discern, given the potential for a normal reproductive outcome precluding an evaluation and based on the population studied. Müllerian anomalies are found in approximately 4.3% of fertile women, 3.5%-8% of infertile patients, 12.3%-13% of those with recurrent pregnancy losses, and 24.5% of patients with miscarriage and infertility. Of the müllerian anomalies, the most common is septate (35%), followed by bicornuate (26%), arcuate (18%), unicornuate (10%), didelphys (8%), and agenesis (3%) (Hum Reprod Update. 2001;7[2]:161; Hum Reprod Update. 2011;17[6]:761-71).

In 20%-30% of patients with müllerian anomalies, particularly in women with a unicornuate uterus, renal anomalies exist that are typically ipsilateral to the absent or rudimentary contralateral uterine horn (J Pediatr Adolesc Gynecol. 2021;34[2]:154-60). As there is no definitive evidence to suggest an association between a septate uterus and renal anomalies, the renal system evaluation can be deferred in this population (Fertil Steril. 2021 Nov;116[5]:1238-52).
 

Diagnosis

2-D ultrasound can be a screen for müllerian anomalies and genitourinary anatomic variants. The diagnostic accuracy of 3-D ultrasound with müllerian anomalies is reported to be 97.6% with sensitivity and specificity of 98.3% and 99.4%, respectively (Hum. Reprod. 2016;31[1]:2-7). As a result, office 3-D has essentially replaced MRI in the diagnosis of müllerian anomalies (Ultrasound Obstet Gynecol. 2015 Nov;46[5]:616-22), with one exception because of the avoidance of a transvaginal probe in the non–sexually active adult and younger adolescent/child. MRI is reserved for diagnosing complex müllerian anomalies or if there is a diagnostic challenge.

Criteria to diagnose müllerian anomalies by radiology begins with the “reference line,” i.e., a line joining both tubal ostia (interostial line). A septate uterus is diagnosed if the distance from the interostial line to the cephalad endometrium is more than 1 cm, otherwise it is considered normal or arcuate based on its appearance. An arcuate uterus has not been associated with impaired reproduction and can be viewed as a normal variant. Alternatively, a bicornuate uterus is diagnosed when the external fundal indentation is more than 1 cm (Fertil Steril. 2021 Nov;116[5]:1238-52).
 

Clinical course

Women with müllerian anomalies may experience pelvic pain and prolonged and/or abnormal bleeding at the time of menarche. While the ability to conceive may not be impaired from müllerian anomalies with the possible exception of the septate uterus, the pregnancy course can be affected, i.e., recurrent pregnancy loss, preterm birth, perinatal mortality, and malpresentation in labor (Reprod Biomed Online. 2014;29[6]:665). In women with septate, bicornuate, and uterine didelphys, fetal growth restriction appears to be increased. Spontaneous abortion rates of 32% and preterm birth rates of 28% have been reported in patients with uterus didelphys (Obstet Gynecol. 1990;75[6]:906).

Special consideration of the unicornuate is given because of the potential for a rudimentary horn that may communicate with the main uterine cavity and/or have functional endometrium which places the woman at risk of an ectopic pregnancy in the smaller horn. Patients with a unicornuate uterus are at higher risk for preterm labor and breech presentation. An obstructed (noncommunicating) functional rudimentary horn is a risk for endometriosis with cyclic pain because of outflow tract obstruction and an ectopic pregnancy prompting consideration for hemihysterectomy based on symptoms.
 

The septate uterus – old dogma revisited

The incidence of uterine septa is approximately 1-15 per 1,000. As the most common müllerian anomaly, the septate uterus has traditionally been associated with an increased risk for spontaneous abortion (21%-44%) and preterm birth (12%-33%). The live birth rate ranges from 50% to 72% (Hum Reprod Update. 2001;7[2]:161-74). A uterine septum is believed to develop as a result of failure of resorption of the tissue connecting the two paramesonephric (müllerian) ducts prior to the 20th embryonic week.

Incising the uterine septum (metroplasty) dates back to 1884 when Ruge described a blind transcervical metroplasty in a woman with two previous miscarriages who, postoperatively, delivered a healthy baby. In the early 1900s, Tompkins reported an abdominal metroplasty (Fertil Stertil. 2021;115:1140-2). The decision to proceed with metroplasty is based on only established observational studies (Fertil Steril. 2016;106:530-40). Until recently, the majority of studies suggested that metroplasty is associated with decreased spontaneous abortion rates and improved obstetrical outcomes. A retrospective case series of 361 patients with a septate uterus who had primary infertility of >2 years’ duration, a history of 1-2 spontaneous abortions, or recurrent pregnancy loss suggested a significant improvement in the live birth rate and reduction in miscarriage (Arch Gynecol Obstet. 2003;268:289-92). A meta-analysis found that the overall pregnancy rate after septum incision was 67.8% and the live-birth rate was 53.5% (J Minim Invas Gynecol. 2013;20:22-42).

Recently, two multinational studies question the prevailing dogma (Fertil Steril. 2021 Sep;116[3]:693-4). Both studies could not demonstrate any increase in live birth rate, reduction in preterm birth, or in pregnancy loss after metroplasty. A significant limitation was the lack of a uniform consensus on the definition of the septate uterus and allowing the discretion of the physician to diagnosis a septum (Hum Reprod. 2020;35:1578-88; Hum Reprod. 2021;36:1260-7).

Hysteroscopic metroplasty is not without complications. Uterine rupture during pregnancy or delivery, while rare, may be linked to significant entry into the myometrium and/or overzealous cauterization and perforation, which emphasizes the importance of appropriate techniques.
 

Conclusion

A diagnosis of müllerian anomalies justifies a comprehensive consultation with the patient given the risk of pregnancy complications. Management of the septate uterus has become controversial. In a patient with infertility, prior pregnancy loss, or poor obstetrical outcome, it is reasonable to consider metroplasty; otherwise, expectant management is an option.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Email him at [email protected].

In the presentation of secondary amenorrhea, pregnancy is the No. 1 differential diagnosis. Once this has been excluded, an algorithm is initiated to determine the etiology, including an assessment of the hypothalamic-pituitary-ovarian axis. While the early onset of ovarian failure can be physically and psychologically disrupting, the effect on fertility is an especially devastating event. Previously identified by terms including premature ovarian failure and premature menopause, “primary ovarian insufficiency” (POI) is now the preferred designation. This month’s article will address the diagnosis, evaluation, and management of POI.

The definition of POI is the development of primary hypogonadism before the age of 40 years. Spontaneous POI occurs in approximately 1 in 250 women by age 35 years and 1 in 100 by age 40 years. After excluding pregnancy, the clinician should determine signs and symptoms that can lead to expedited and cost-efficient testing.

Consequences

POI is an important risk factor for bone loss and osteoporosis, especially in young women who develop ovarian dysfunction before they achieve peak adult bone mass. At the time of diagnosis of POI, a bone density test (dual-energy x-ray absorptiometry) should be obtained. Women with POI may also develop depression and anxiety as well as experience an increased risk for cardiovascular morbidity and mortality, possibly related to endothelial dysfunction.

Young women with spontaneous POI are at increased risk of developing autoimmune adrenal insufficiency (AAI), a potentially fatal disorder. Consequently, to diagnose AAI, serum adrenal cortical and 21-hydroxylase antibodies should be measured in all women who have a karyotype of 46,XX and experience spontaneous POI. Women with AAI have a 50% risk of developing adrenal insufficiency. Despite initial normal adrenal function, women with positive adrenal cortical antibodies should be followed annually.
 

Causes (see table for a more complete list)

Iatrogenic

Known causes of POI include chemotherapy/radiation often in the setting of cancer treatment. The three most commonly used drugs, cyclophosphamide, cisplatin, and doxorubicin, cause POI by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. The most damaging agents are alkylating drugs. A cyclophosphamide equivalent dose calculator has been established for ovarian failure risk stratification from chemotherapy based on the cumulative dose of alkylating agents received.

One study estimated the radiosensitivity of the oocyte to be less than 2 Gy. Based upon this estimate, the authors calculated the dose of radiotherapy that would result in immediate and permanent ovarian failure in 97.5% of patients as follows:

• 20.3 Gy at birth
• 18.4 Gy at age 10 years
• 16.5 Gy at age 20 years
• 14.3 Gy at age 30 years

Genetic

Approximately 10% of cases are familial. A family history of POI raises concern for a fragile X premutation. Fragile X syndrome is an X-linked form of intellectual disability that is one of the most common causes of mental retardation worldwide. There is a strong relationship between age at menopause, including POI, and premutations for fragile X syndrome. The American College of Obstetricians and Gynecologists recommends that women with POI or an elevated follicle-stimulating hormone (FSH) level before age 40 years without known cause be screened for FMR1 premutations. Approximately 6% of cases of POI are associated with premutations in the FMR1 gene.

Turner syndrome is one of the most common causes of POI and results from the lack of a second X chromosome. The most common chromosomal defect in humans, TS occurs in up to 1.5% of conceptions, 10% of spontaneous abortions, and 1 of 2,500 live births.

Serum antiadrenal and/or anti–21-hydroxylase antibodies and antithyroid antiperoxidase antibodies, can aid in the diagnosis of adrenal gland, ovary, and thyroid autoimmune causes, which is found in 4% of women with spontaneous POI. Testing for the presence of 21-hydroxylase autoantibodies or adrenal autoantibodies is sufficient to make the diagnosis of autoimmune oophoritis in women with proven spontaneous POI.

The etiology of POI remains unknown in approximately 75%-90% of cases. However, studies using whole exome or whole genome sequencing have identified genetic variants in approximately 30%-35% of these patients.
 

Risk factors

Factors that are thought to play a role in determining the age of menopause, include genetics (e.g., FMR1 premutation and mosaic Turner syndrome), ethnicity (earlier among Hispanic women and later in Japanese American women when compared with White women), and smoking (reduced by approximately 2 years ).

Regarding ovarian aging, the holy grail of the reproductive life span is to predict menopause. While the definitive age eludes us, anti-Müllerian hormone levels appear to show promise. An ultrasensitive anti-Müllerian hormone assay (< 0.01 ng/mL) predicted a 79% probability of menopause within 12 months for women aged 51 and above; the probability was 51% for women below age 48.
 

Diagnosis

The three P’s of secondary amenorrhea are physiological, pharmacological, or pathological and can guide the clinician to a targeted evaluation. Physiological causes are pregnancy, the first 6 months of continuous breastfeeding (from elevated prolactin), and natural menopause. Pharmacological etiologies, excluding hormonal treatment that suppresses ovulation (combined oral contraceptives, gonadotropin-releasing hormone agonist/antagonist, or danazol), include agents that inhibit dopamine thereby increasing serum prolactin, such as metoclopramide; phenothiazine antipsychotics, such as haloperidol; and tardive dystonia dopamine-depleting medications, such as reserpine. Pathological causes include pituitary adenomas, thyroid disease, functional hypothalamic amenorrhea from changes in weight, exercise regimen, and stress.

Management

About 50%-75% of women with 46,XX spontaneous POI experience intermittent ovarian function and 5%-10% of women remain able to conceive. Anecdotally, a 32-year-old woman presented to me with primary infertility, secondary amenorrhea, and suspected POI based on vasomotor symptoms and elevated FSH levels. Pelvic ultrasound showed a hemorrhagic cyst, suspicious for a corpus luteum. Two weeks thereafter she reported a positive home urine human chorionic gonadotropin test and ultimately delivered twins. Her diagnosis of POI with amenorrhea remained postpartum.

Unless there is an absolute contraindication, estrogen therapy should be prescribed to women with POI to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy as well as to maintain sexual health and quality of life. For those with an intact uterus, women should receive progesterone because of the risk of endometrial hyperplasia from unopposed estrogen. Rather than oral estrogen, the use of transdermal or vaginal delivery of estrogen is a more physiological approach and provides lower risks of venous thromboembolism and gallbladder disease. Of note, standard postmenopausal hormone therapy, which has a much lower dose of estrogen than combined estrogen-progestin contraceptives, does not provide effective contraception. Per ACOG, systemic hormone treatment should be prescribed until age 50-51 years to all women with POI.

For fertility, women with spontaneous POI can be offered oocyte or embryo donation. The uterus does not age reproductively, unlike oocytes, therefore women can achieve reasonable pregnancy success rates through egg donation despite experiencing menopause.
 

Future potential options

Female germline stem cells have been isolated from neonatal mice and transplanted into sterile adult mice, who then were able to produce offspring. In a second study, oogonial stem cells were isolated from neonatal and adult mouse ovaries; pups were subsequently born from the oocytes. Further experiments are needed before the implications for humans can be determined.

Emotionally traumatic for most women, POI disrupts life plans, hopes, and dreams of raising a family. The approach to the patient with POI involves the above evidence-based testing along with empathy from the health care provider.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

In the presentation of secondary amenorrhea, pregnancy is the No. 1 differential diagnosis. Once this has been excluded, an algorithm is initiated to determine the etiology, including an assessment of the hypothalamic-pituitary-ovarian axis. While the early onset of ovarian failure can be physically and psychologically disrupting, the effect on fertility is an especially devastating event. Previously identified by terms including premature ovarian failure and premature menopause, “primary ovarian insufficiency” (POI) is now the preferred designation. This month’s article will address the diagnosis, evaluation, and management of POI.

The definition of POI is the development of primary hypogonadism before the age of 40 years. Spontaneous POI occurs in approximately 1 in 250 women by age 35 years and 1 in 100 by age 40 years. After excluding pregnancy, the clinician should determine signs and symptoms that can lead to expedited and cost-efficient testing.

Consequences

POI is an important risk factor for bone loss and osteoporosis, especially in young women who develop ovarian dysfunction before they achieve peak adult bone mass. At the time of diagnosis of POI, a bone density test (dual-energy x-ray absorptiometry) should be obtained. Women with POI may also develop depression and anxiety as well as experience an increased risk for cardiovascular morbidity and mortality, possibly related to endothelial dysfunction.

Young women with spontaneous POI are at increased risk of developing autoimmune adrenal insufficiency (AAI), a potentially fatal disorder. Consequently, to diagnose AAI, serum adrenal cortical and 21-hydroxylase antibodies should be measured in all women who have a karyotype of 46,XX and experience spontaneous POI. Women with AAI have a 50% risk of developing adrenal insufficiency. Despite initial normal adrenal function, women with positive adrenal cortical antibodies should be followed annually.
 

Causes (see table for a more complete list)

Iatrogenic

Known causes of POI include chemotherapy/radiation often in the setting of cancer treatment. The three most commonly used drugs, cyclophosphamide, cisplatin, and doxorubicin, cause POI by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. The most damaging agents are alkylating drugs. A cyclophosphamide equivalent dose calculator has been established for ovarian failure risk stratification from chemotherapy based on the cumulative dose of alkylating agents received.

One study estimated the radiosensitivity of the oocyte to be less than 2 Gy. Based upon this estimate, the authors calculated the dose of radiotherapy that would result in immediate and permanent ovarian failure in 97.5% of patients as follows:

• 20.3 Gy at birth
• 18.4 Gy at age 10 years
• 16.5 Gy at age 20 years
• 14.3 Gy at age 30 years

Genetic

Approximately 10% of cases are familial. A family history of POI raises concern for a fragile X premutation. Fragile X syndrome is an X-linked form of intellectual disability that is one of the most common causes of mental retardation worldwide. There is a strong relationship between age at menopause, including POI, and premutations for fragile X syndrome. The American College of Obstetricians and Gynecologists recommends that women with POI or an elevated follicle-stimulating hormone (FSH) level before age 40 years without known cause be screened for FMR1 premutations. Approximately 6% of cases of POI are associated with premutations in the FMR1 gene.

Turner syndrome is one of the most common causes of POI and results from the lack of a second X chromosome. The most common chromosomal defect in humans, TS occurs in up to 1.5% of conceptions, 10% of spontaneous abortions, and 1 of 2,500 live births.

Serum antiadrenal and/or anti–21-hydroxylase antibodies and antithyroid antiperoxidase antibodies, can aid in the diagnosis of adrenal gland, ovary, and thyroid autoimmune causes, which is found in 4% of women with spontaneous POI. Testing for the presence of 21-hydroxylase autoantibodies or adrenal autoantibodies is sufficient to make the diagnosis of autoimmune oophoritis in women with proven spontaneous POI.

The etiology of POI remains unknown in approximately 75%-90% of cases. However, studies using whole exome or whole genome sequencing have identified genetic variants in approximately 30%-35% of these patients.
 

Risk factors

Factors that are thought to play a role in determining the age of menopause, include genetics (e.g., FMR1 premutation and mosaic Turner syndrome), ethnicity (earlier among Hispanic women and later in Japanese American women when compared with White women), and smoking (reduced by approximately 2 years ).

Regarding ovarian aging, the holy grail of the reproductive life span is to predict menopause. While the definitive age eludes us, anti-Müllerian hormone levels appear to show promise. An ultrasensitive anti-Müllerian hormone assay (< 0.01 ng/mL) predicted a 79% probability of menopause within 12 months for women aged 51 and above; the probability was 51% for women below age 48.
 

Diagnosis

The three P’s of secondary amenorrhea are physiological, pharmacological, or pathological and can guide the clinician to a targeted evaluation. Physiological causes are pregnancy, the first 6 months of continuous breastfeeding (from elevated prolactin), and natural menopause. Pharmacological etiologies, excluding hormonal treatment that suppresses ovulation (combined oral contraceptives, gonadotropin-releasing hormone agonist/antagonist, or danazol), include agents that inhibit dopamine thereby increasing serum prolactin, such as metoclopramide; phenothiazine antipsychotics, such as haloperidol; and tardive dystonia dopamine-depleting medications, such as reserpine. Pathological causes include pituitary adenomas, thyroid disease, functional hypothalamic amenorrhea from changes in weight, exercise regimen, and stress.

Management

About 50%-75% of women with 46,XX spontaneous POI experience intermittent ovarian function and 5%-10% of women remain able to conceive. Anecdotally, a 32-year-old woman presented to me with primary infertility, secondary amenorrhea, and suspected POI based on vasomotor symptoms and elevated FSH levels. Pelvic ultrasound showed a hemorrhagic cyst, suspicious for a corpus luteum. Two weeks thereafter she reported a positive home urine human chorionic gonadotropin test and ultimately delivered twins. Her diagnosis of POI with amenorrhea remained postpartum.

Unless there is an absolute contraindication, estrogen therapy should be prescribed to women with POI to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy as well as to maintain sexual health and quality of life. For those with an intact uterus, women should receive progesterone because of the risk of endometrial hyperplasia from unopposed estrogen. Rather than oral estrogen, the use of transdermal or vaginal delivery of estrogen is a more physiological approach and provides lower risks of venous thromboembolism and gallbladder disease. Of note, standard postmenopausal hormone therapy, which has a much lower dose of estrogen than combined estrogen-progestin contraceptives, does not provide effective contraception. Per ACOG, systemic hormone treatment should be prescribed until age 50-51 years to all women with POI.

For fertility, women with spontaneous POI can be offered oocyte or embryo donation. The uterus does not age reproductively, unlike oocytes, therefore women can achieve reasonable pregnancy success rates through egg donation despite experiencing menopause.
 

Future potential options

Female germline stem cells have been isolated from neonatal mice and transplanted into sterile adult mice, who then were able to produce offspring. In a second study, oogonial stem cells were isolated from neonatal and adult mouse ovaries; pups were subsequently born from the oocytes. Further experiments are needed before the implications for humans can be determined.

Emotionally traumatic for most women, POI disrupts life plans, hopes, and dreams of raising a family. The approach to the patient with POI involves the above evidence-based testing along with empathy from the health care provider.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

In the presentation of secondary amenorrhea, pregnancy is the No. 1 differential diagnosis. Once this has been excluded, an algorithm is initiated to determine the etiology, including an assessment of the hypothalamic-pituitary-ovarian axis. While the early onset of ovarian failure can be physically and psychologically disrupting, the effect on fertility is an especially devastating event. Previously identified by terms including premature ovarian failure and premature menopause, “primary ovarian insufficiency” (POI) is now the preferred designation. This month’s article will address the diagnosis, evaluation, and management of POI.

The definition of POI is the development of primary hypogonadism before the age of 40 years. Spontaneous POI occurs in approximately 1 in 250 women by age 35 years and 1 in 100 by age 40 years. After excluding pregnancy, the clinician should determine signs and symptoms that can lead to expedited and cost-efficient testing.

Consequences

POI is an important risk factor for bone loss and osteoporosis, especially in young women who develop ovarian dysfunction before they achieve peak adult bone mass. At the time of diagnosis of POI, a bone density test (dual-energy x-ray absorptiometry) should be obtained. Women with POI may also develop depression and anxiety as well as experience an increased risk for cardiovascular morbidity and mortality, possibly related to endothelial dysfunction.

Young women with spontaneous POI are at increased risk of developing autoimmune adrenal insufficiency (AAI), a potentially fatal disorder. Consequently, to diagnose AAI, serum adrenal cortical and 21-hydroxylase antibodies should be measured in all women who have a karyotype of 46,XX and experience spontaneous POI. Women with AAI have a 50% risk of developing adrenal insufficiency. Despite initial normal adrenal function, women with positive adrenal cortical antibodies should be followed annually.
 

Causes (see table for a more complete list)

Iatrogenic

Known causes of POI include chemotherapy/radiation often in the setting of cancer treatment. The three most commonly used drugs, cyclophosphamide, cisplatin, and doxorubicin, cause POI by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. The most damaging agents are alkylating drugs. A cyclophosphamide equivalent dose calculator has been established for ovarian failure risk stratification from chemotherapy based on the cumulative dose of alkylating agents received.

One study estimated the radiosensitivity of the oocyte to be less than 2 Gy. Based upon this estimate, the authors calculated the dose of radiotherapy that would result in immediate and permanent ovarian failure in 97.5% of patients as follows:

• 20.3 Gy at birth
• 18.4 Gy at age 10 years
• 16.5 Gy at age 20 years
• 14.3 Gy at age 30 years

Genetic

Approximately 10% of cases are familial. A family history of POI raises concern for a fragile X premutation. Fragile X syndrome is an X-linked form of intellectual disability that is one of the most common causes of mental retardation worldwide. There is a strong relationship between age at menopause, including POI, and premutations for fragile X syndrome. The American College of Obstetricians and Gynecologists recommends that women with POI or an elevated follicle-stimulating hormone (FSH) level before age 40 years without known cause be screened for FMR1 premutations. Approximately 6% of cases of POI are associated with premutations in the FMR1 gene.

Turner syndrome is one of the most common causes of POI and results from the lack of a second X chromosome. The most common chromosomal defect in humans, TS occurs in up to 1.5% of conceptions, 10% of spontaneous abortions, and 1 of 2,500 live births.

Serum antiadrenal and/or anti–21-hydroxylase antibodies and antithyroid antiperoxidase antibodies, can aid in the diagnosis of adrenal gland, ovary, and thyroid autoimmune causes, which is found in 4% of women with spontaneous POI. Testing for the presence of 21-hydroxylase autoantibodies or adrenal autoantibodies is sufficient to make the diagnosis of autoimmune oophoritis in women with proven spontaneous POI.

The etiology of POI remains unknown in approximately 75%-90% of cases. However, studies using whole exome or whole genome sequencing have identified genetic variants in approximately 30%-35% of these patients.
 

Risk factors

Factors that are thought to play a role in determining the age of menopause, include genetics (e.g., FMR1 premutation and mosaic Turner syndrome), ethnicity (earlier among Hispanic women and later in Japanese American women when compared with White women), and smoking (reduced by approximately 2 years ).

Regarding ovarian aging, the holy grail of the reproductive life span is to predict menopause. While the definitive age eludes us, anti-Müllerian hormone levels appear to show promise. An ultrasensitive anti-Müllerian hormone assay (< 0.01 ng/mL) predicted a 79% probability of menopause within 12 months for women aged 51 and above; the probability was 51% for women below age 48.
 

Diagnosis

The three P’s of secondary amenorrhea are physiological, pharmacological, or pathological and can guide the clinician to a targeted evaluation. Physiological causes are pregnancy, the first 6 months of continuous breastfeeding (from elevated prolactin), and natural menopause. Pharmacological etiologies, excluding hormonal treatment that suppresses ovulation (combined oral contraceptives, gonadotropin-releasing hormone agonist/antagonist, or danazol), include agents that inhibit dopamine thereby increasing serum prolactin, such as metoclopramide; phenothiazine antipsychotics, such as haloperidol; and tardive dystonia dopamine-depleting medications, such as reserpine. Pathological causes include pituitary adenomas, thyroid disease, functional hypothalamic amenorrhea from changes in weight, exercise regimen, and stress.

Management

About 50%-75% of women with 46,XX spontaneous POI experience intermittent ovarian function and 5%-10% of women remain able to conceive. Anecdotally, a 32-year-old woman presented to me with primary infertility, secondary amenorrhea, and suspected POI based on vasomotor symptoms and elevated FSH levels. Pelvic ultrasound showed a hemorrhagic cyst, suspicious for a corpus luteum. Two weeks thereafter she reported a positive home urine human chorionic gonadotropin test and ultimately delivered twins. Her diagnosis of POI with amenorrhea remained postpartum.

Unless there is an absolute contraindication, estrogen therapy should be prescribed to women with POI to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy as well as to maintain sexual health and quality of life. For those with an intact uterus, women should receive progesterone because of the risk of endometrial hyperplasia from unopposed estrogen. Rather than oral estrogen, the use of transdermal or vaginal delivery of estrogen is a more physiological approach and provides lower risks of venous thromboembolism and gallbladder disease. Of note, standard postmenopausal hormone therapy, which has a much lower dose of estrogen than combined estrogen-progestin contraceptives, does not provide effective contraception. Per ACOG, systemic hormone treatment should be prescribed until age 50-51 years to all women with POI.

For fertility, women with spontaneous POI can be offered oocyte or embryo donation. The uterus does not age reproductively, unlike oocytes, therefore women can achieve reasonable pregnancy success rates through egg donation despite experiencing menopause.
 

Future potential options

Female germline stem cells have been isolated from neonatal mice and transplanted into sterile adult mice, who then were able to produce offspring. In a second study, oogonial stem cells were isolated from neonatal and adult mouse ovaries; pups were subsequently born from the oocytes. Further experiments are needed before the implications for humans can be determined.

Emotionally traumatic for most women, POI disrupts life plans, hopes, and dreams of raising a family. The approach to the patient with POI involves the above evidence-based testing along with empathy from the health care provider.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Despite the original intent of permanent contraception, tubal sterilization regret is experienced by 2%-26% of women as demonstrated by the United States Collaborative Review of Sterilization “CREST” 14-year study (Obstet Gynecol. 1999 Jun;93[6]:889-95). Regret appears to be higher in the United States than Europe and in resource-limited countries and is more common in women who are less than age 30, African-American, and unmarried. Nevertheless, requests for tubal reversal are estimated to be between 1% and 4% (Contraception. 1981 Jun;23[6]:579-89). The alternative option for fertility is in vitro fertilization (IVF) and this month’s column considers the pros and cons of both methods.

The procedure of tubal reanastomosis involves removing abnormal tissue and reapproximating the healthy tubal segments with attention to minimize adhesion formation through continued gentle irrigation. The surgery involves microsuturing using 6-0 to 10-0 sutures. Tubal patency can be confirmed during the procedure and with a subsequent hysterosalpingogram. While time from sterilization and the type of sterilization technique are factors that may influence the success rate of tubal reanastomosis, the age of the woman is the most predictive for pregnancy outcome.

In the original CREST study, the risk of ectopic pregnancy following tubal reanastomosis was contingent on the method of sterilization: Bipolar electrosurgery resulted in the highest probability of ectopic pregnancy (17.1 per 1,000 procedures at 10 years after permanent contraception), while postpartum partial salpingectomy resulted in the lowest (1.5 per 1,000 procedures at 10 years after permanent contraception) (N Engl J Med. 1997;336[11]:762). Comparatively, the ectopic pregnancy rate during an IVF cycle was 1.9% for pregnancies from transfers of fresh cleavage embryo, followed by transfers of frozen cleavage embryo (1.7%), transfers of fresh blastocyst (1.3%), and transfers of frozen blastocyst (0.8%) (Hum Reprod. 2015;30[9]:2048-54).

Reports vary regarding pregnancy rates from tubal reanastomosis. Prior use of rings and clips for sterilization appear to yield the highest outcomes as opposed to the use of electrocautery. In one large Canadian cohort study of over 300,000 women, those aged 15-30 years, 30-33 years, and 34-49 years had a conception rate of 73%, 64%, and 46%, respectively (Obstet Gynecol. 2003;101[4]:677-84). Most pregnancies were within 2 years after reversal and 48% of women achieved a delivery. Of interest, 23% of patients subsequently underwent another sterilization.

An Australian study of nearly 2,000 women found an overall cumulative live-delivery rate of 20% within the first year after reversal, 40% at 2 years, 51% at 5 years, and 52% at 10 years. As expected, the 5-year cumulative live-delivery rate was significantly lower in women who were aged 40-44 years (26%), compared with younger women. For all women below age 40 years, the live-delivery rate was approximately 50% within 5 years after tubal reanastomosis, while the rate halves after the age of 40 (Fertil Steril. 2015 Oct;104[4]:921-6).

To compare tubal reanastomosis with IVF, a retrospective cohort study of 163 patients demonstrated the cumulative delivery rate over 72 months was comparable for IVF vs. sterilization reversal (52% vs. 60%). The only significant difference was in a subset of patients aged <37 years (52% after IVF and 72% after reversal) and the lower cost of surgery. The authors advocated laparoscopic sterilization reversal in women younger than 37 years who have ≥4 cm of residual tube with IVF as the better alternative for all other women (Hum Reprod. 2007;22[10]:2660).

Indeed, tubal length is another important factor in successful reversal. The pregnancy rate after tubal anastomosis is 75% in women with tubal length of 4 cm or more, but only 19% in those with shorter tubes (Fertil Steril. 1987;48[1]:13-7). The literature does suggest equivalent pregnancy rates after laparoscopic tubal anastomosis and conventional microsurgical anastomosis. Although the laparoscopic approach may be more economical, it is more demanding technically than an open microsurgical procedure.

Tubal reanastomosis can also be performed using robot-assisted laparoscopy. In preliminary studies, robotic surgery appears to have a similar success rate and a shorter recovery time, but longer operative times and higher costs (Obstet Gynecol. 2007;109[6]:1375; Fertil Steril. 2008;90[4]:1175).

To educate women on the success of IVF based on individual characteristics, a valuable tool to approximate the cumulative outcome for a live birth following one cycle of IVF is offered by the Society for Assisted Reproductive Technology. To clarify, a cycle of IVF consists of one egg retrieval and the ultimate transfer of all embryos produced, i.e., fresh and frozen. The website also includes estimations of success following a second and third IVF cycle.

The woman’s age is a significant predictor of IVF success. Ovarian aging is currently best measured by combining chronologic age, antral follicle count (AFC) by transvaginal pelvic ultrasound, and serum anti-Müllerian hormone (AMH). Natural fecundity begins to decline, on average, above age 32-33 years. An AFC less than 11 reflects diminished ovarian reserve (DOR) and less than 6 is severe. AMH levels below 1.6 ng/mL have been shown to reduce the number of eggs retrieved with IVF, while levels below 0.4 ng/mL are very low. Very low AMH levels negatively affect the outcome of IVF cycles as demonstrated in the SART data study from a population of women with a mean age of 39.4 years: Cycle cancellation was 54%; of all retrieval attempts, no oocytes were obtained in 5.4%, and no embryo transfer occurred in 25.1% of cycles; the live birth rate per embryo transfer was 20.5% (9.5% per cycle start and 16.3% per retrieval) from a mean age of 36.8 years (Fertil Steril. 2016 Feb;105[2]:385-93.e3). The predictive ability of AMH on the live birth rate from IVF cycles was also shown in a study of over 85,000 women (Fertil Steril. 2018;109:258-65).

While low AMH has been shown to lessen a successful outcome from IVF, there appears to be no difference in natural pregnancy rates in women aged 30-44 years irrespective of AMH levels (JAMA. 2017;318[14]:1367-76). Of importance, the use of AMH in a population at low risk for DOR will yield a larger number of false-positive results (i.e., characterizing a woman as DOR when in fact she has normal ovarian reserve). Further, users of hormonal contraceptives have a 25.2% lower mean AMH level than nonusers.

When a patient is considering tubal reanastomosis vs. IVF, a useful acronym to remember is to check “AGE” – the A is for AMH because severely diminished ovarian reserve will reduce success with IVF as shown by the SART calculator; the G represents guy, i.e., ensuring a reasonably normal sperm analysis; and E stands for eggs representing ovulation function. In a woman who is anovulatory and who will require fertility medication, it would be reasonable to consider IVF given the need for ovarian stimulation. As in females, advanced paternal age has demonstrated a decline in fertility and sperm analysis parameters. Men above age 45 take approximately five times as long to achieve a pregnancy, compared with men less than 25 years of age. Further, there is evidence for advanced paternal age increasing risk of miscarriage, preterm birth, and birth defects. Men older than 40-45 years have twice the risk of an autistic child and five times the risk of having a child with schizophrenia (Transl Psychiatry 2017;7: e1019; Am J Psychiatry. 2002;159:1528-33).

To conclude, the data support consideration for sterilization reversal in women less than age 37 years with more than 4 cm of residual functional fallopian tube and the prior use of rings or clip sterilization. In other women, IVF may be the better option, particularly when ovulation dysfunction and/or male factor is present. IVF also offers the advantage of maintaining contraception and gender determination. However, given that AMH does not appear to reduce natural fertility, unlike during its effect during an IVF cycle, the option of tubal reversal may be more favorable in women with severe DOR.

Dr. Trolice is director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Despite the original intent of permanent contraception, tubal sterilization regret is experienced by 2%-26% of women as demonstrated by the United States Collaborative Review of Sterilization “CREST” 14-year study (Obstet Gynecol. 1999 Jun;93[6]:889-95). Regret appears to be higher in the United States than Europe and in resource-limited countries and is more common in women who are less than age 30, African-American, and unmarried. Nevertheless, requests for tubal reversal are estimated to be between 1% and 4% (Contraception. 1981 Jun;23[6]:579-89). The alternative option for fertility is in vitro fertilization (IVF) and this month’s column considers the pros and cons of both methods.

The procedure of tubal reanastomosis involves removing abnormal tissue and reapproximating the healthy tubal segments with attention to minimize adhesion formation through continued gentle irrigation. The surgery involves microsuturing using 6-0 to 10-0 sutures. Tubal patency can be confirmed during the procedure and with a subsequent hysterosalpingogram. While time from sterilization and the type of sterilization technique are factors that may influence the success rate of tubal reanastomosis, the age of the woman is the most predictive for pregnancy outcome.

In the original CREST study, the risk of ectopic pregnancy following tubal reanastomosis was contingent on the method of sterilization: Bipolar electrosurgery resulted in the highest probability of ectopic pregnancy (17.1 per 1,000 procedures at 10 years after permanent contraception), while postpartum partial salpingectomy resulted in the lowest (1.5 per 1,000 procedures at 10 years after permanent contraception) (N Engl J Med. 1997;336[11]:762). Comparatively, the ectopic pregnancy rate during an IVF cycle was 1.9% for pregnancies from transfers of fresh cleavage embryo, followed by transfers of frozen cleavage embryo (1.7%), transfers of fresh blastocyst (1.3%), and transfers of frozen blastocyst (0.8%) (Hum Reprod. 2015;30[9]:2048-54).

Reports vary regarding pregnancy rates from tubal reanastomosis. Prior use of rings and clips for sterilization appear to yield the highest outcomes as opposed to the use of electrocautery. In one large Canadian cohort study of over 300,000 women, those aged 15-30 years, 30-33 years, and 34-49 years had a conception rate of 73%, 64%, and 46%, respectively (Obstet Gynecol. 2003;101[4]:677-84). Most pregnancies were within 2 years after reversal and 48% of women achieved a delivery. Of interest, 23% of patients subsequently underwent another sterilization.

An Australian study of nearly 2,000 women found an overall cumulative live-delivery rate of 20% within the first year after reversal, 40% at 2 years, 51% at 5 years, and 52% at 10 years. As expected, the 5-year cumulative live-delivery rate was significantly lower in women who were aged 40-44 years (26%), compared with younger women. For all women below age 40 years, the live-delivery rate was approximately 50% within 5 years after tubal reanastomosis, while the rate halves after the age of 40 (Fertil Steril. 2015 Oct;104[4]:921-6).

To compare tubal reanastomosis with IVF, a retrospective cohort study of 163 patients demonstrated the cumulative delivery rate over 72 months was comparable for IVF vs. sterilization reversal (52% vs. 60%). The only significant difference was in a subset of patients aged <37 years (52% after IVF and 72% after reversal) and the lower cost of surgery. The authors advocated laparoscopic sterilization reversal in women younger than 37 years who have ≥4 cm of residual tube with IVF as the better alternative for all other women (Hum Reprod. 2007;22[10]:2660).

Indeed, tubal length is another important factor in successful reversal. The pregnancy rate after tubal anastomosis is 75% in women with tubal length of 4 cm or more, but only 19% in those with shorter tubes (Fertil Steril. 1987;48[1]:13-7). The literature does suggest equivalent pregnancy rates after laparoscopic tubal anastomosis and conventional microsurgical anastomosis. Although the laparoscopic approach may be more economical, it is more demanding technically than an open microsurgical procedure.

Tubal reanastomosis can also be performed using robot-assisted laparoscopy. In preliminary studies, robotic surgery appears to have a similar success rate and a shorter recovery time, but longer operative times and higher costs (Obstet Gynecol. 2007;109[6]:1375; Fertil Steril. 2008;90[4]:1175).

To educate women on the success of IVF based on individual characteristics, a valuable tool to approximate the cumulative outcome for a live birth following one cycle of IVF is offered by the Society for Assisted Reproductive Technology. To clarify, a cycle of IVF consists of one egg retrieval and the ultimate transfer of all embryos produced, i.e., fresh and frozen. The website also includes estimations of success following a second and third IVF cycle.

The woman’s age is a significant predictor of IVF success. Ovarian aging is currently best measured by combining chronologic age, antral follicle count (AFC) by transvaginal pelvic ultrasound, and serum anti-Müllerian hormone (AMH). Natural fecundity begins to decline, on average, above age 32-33 years. An AFC less than 11 reflects diminished ovarian reserve (DOR) and less than 6 is severe. AMH levels below 1.6 ng/mL have been shown to reduce the number of eggs retrieved with IVF, while levels below 0.4 ng/mL are very low. Very low AMH levels negatively affect the outcome of IVF cycles as demonstrated in the SART data study from a population of women with a mean age of 39.4 years: Cycle cancellation was 54%; of all retrieval attempts, no oocytes were obtained in 5.4%, and no embryo transfer occurred in 25.1% of cycles; the live birth rate per embryo transfer was 20.5% (9.5% per cycle start and 16.3% per retrieval) from a mean age of 36.8 years (Fertil Steril. 2016 Feb;105[2]:385-93.e3). The predictive ability of AMH on the live birth rate from IVF cycles was also shown in a study of over 85,000 women (Fertil Steril. 2018;109:258-65).

While low AMH has been shown to lessen a successful outcome from IVF, there appears to be no difference in natural pregnancy rates in women aged 30-44 years irrespective of AMH levels (JAMA. 2017;318[14]:1367-76). Of importance, the use of AMH in a population at low risk for DOR will yield a larger number of false-positive results (i.e., characterizing a woman as DOR when in fact she has normal ovarian reserve). Further, users of hormonal contraceptives have a 25.2% lower mean AMH level than nonusers.

When a patient is considering tubal reanastomosis vs. IVF, a useful acronym to remember is to check “AGE” – the A is for AMH because severely diminished ovarian reserve will reduce success with IVF as shown by the SART calculator; the G represents guy, i.e., ensuring a reasonably normal sperm analysis; and E stands for eggs representing ovulation function. In a woman who is anovulatory and who will require fertility medication, it would be reasonable to consider IVF given the need for ovarian stimulation. As in females, advanced paternal age has demonstrated a decline in fertility and sperm analysis parameters. Men above age 45 take approximately five times as long to achieve a pregnancy, compared with men less than 25 years of age. Further, there is evidence for advanced paternal age increasing risk of miscarriage, preterm birth, and birth defects. Men older than 40-45 years have twice the risk of an autistic child and five times the risk of having a child with schizophrenia (Transl Psychiatry 2017;7: e1019; Am J Psychiatry. 2002;159:1528-33).

To conclude, the data support consideration for sterilization reversal in women less than age 37 years with more than 4 cm of residual functional fallopian tube and the prior use of rings or clip sterilization. In other women, IVF may be the better option, particularly when ovulation dysfunction and/or male factor is present. IVF also offers the advantage of maintaining contraception and gender determination. However, given that AMH does not appear to reduce natural fertility, unlike during its effect during an IVF cycle, the option of tubal reversal may be more favorable in women with severe DOR.

Dr. Trolice is director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Despite the original intent of permanent contraception, tubal sterilization regret is experienced by 2%-26% of women as demonstrated by the United States Collaborative Review of Sterilization “CREST” 14-year study (Obstet Gynecol. 1999 Jun;93[6]:889-95). Regret appears to be higher in the United States than Europe and in resource-limited countries and is more common in women who are less than age 30, African-American, and unmarried. Nevertheless, requests for tubal reversal are estimated to be between 1% and 4% (Contraception. 1981 Jun;23[6]:579-89). The alternative option for fertility is in vitro fertilization (IVF) and this month’s column considers the pros and cons of both methods.

The procedure of tubal reanastomosis involves removing abnormal tissue and reapproximating the healthy tubal segments with attention to minimize adhesion formation through continued gentle irrigation. The surgery involves microsuturing using 6-0 to 10-0 sutures. Tubal patency can be confirmed during the procedure and with a subsequent hysterosalpingogram. While time from sterilization and the type of sterilization technique are factors that may influence the success rate of tubal reanastomosis, the age of the woman is the most predictive for pregnancy outcome.

In the original CREST study, the risk of ectopic pregnancy following tubal reanastomosis was contingent on the method of sterilization: Bipolar electrosurgery resulted in the highest probability of ectopic pregnancy (17.1 per 1,000 procedures at 10 years after permanent contraception), while postpartum partial salpingectomy resulted in the lowest (1.5 per 1,000 procedures at 10 years after permanent contraception) (N Engl J Med. 1997;336[11]:762). Comparatively, the ectopic pregnancy rate during an IVF cycle was 1.9% for pregnancies from transfers of fresh cleavage embryo, followed by transfers of frozen cleavage embryo (1.7%), transfers of fresh blastocyst (1.3%), and transfers of frozen blastocyst (0.8%) (Hum Reprod. 2015;30[9]:2048-54).

Reports vary regarding pregnancy rates from tubal reanastomosis. Prior use of rings and clips for sterilization appear to yield the highest outcomes as opposed to the use of electrocautery. In one large Canadian cohort study of over 300,000 women, those aged 15-30 years, 30-33 years, and 34-49 years had a conception rate of 73%, 64%, and 46%, respectively (Obstet Gynecol. 2003;101[4]:677-84). Most pregnancies were within 2 years after reversal and 48% of women achieved a delivery. Of interest, 23% of patients subsequently underwent another sterilization.

An Australian study of nearly 2,000 women found an overall cumulative live-delivery rate of 20% within the first year after reversal, 40% at 2 years, 51% at 5 years, and 52% at 10 years. As expected, the 5-year cumulative live-delivery rate was significantly lower in women who were aged 40-44 years (26%), compared with younger women. For all women below age 40 years, the live-delivery rate was approximately 50% within 5 years after tubal reanastomosis, while the rate halves after the age of 40 (Fertil Steril. 2015 Oct;104[4]:921-6).

To compare tubal reanastomosis with IVF, a retrospective cohort study of 163 patients demonstrated the cumulative delivery rate over 72 months was comparable for IVF vs. sterilization reversal (52% vs. 60%). The only significant difference was in a subset of patients aged <37 years (52% after IVF and 72% after reversal) and the lower cost of surgery. The authors advocated laparoscopic sterilization reversal in women younger than 37 years who have ≥4 cm of residual tube with IVF as the better alternative for all other women (Hum Reprod. 2007;22[10]:2660).

Indeed, tubal length is another important factor in successful reversal. The pregnancy rate after tubal anastomosis is 75% in women with tubal length of 4 cm or more, but only 19% in those with shorter tubes (Fertil Steril. 1987;48[1]:13-7). The literature does suggest equivalent pregnancy rates after laparoscopic tubal anastomosis and conventional microsurgical anastomosis. Although the laparoscopic approach may be more economical, it is more demanding technically than an open microsurgical procedure.

Tubal reanastomosis can also be performed using robot-assisted laparoscopy. In preliminary studies, robotic surgery appears to have a similar success rate and a shorter recovery time, but longer operative times and higher costs (Obstet Gynecol. 2007;109[6]:1375; Fertil Steril. 2008;90[4]:1175).

To educate women on the success of IVF based on individual characteristics, a valuable tool to approximate the cumulative outcome for a live birth following one cycle of IVF is offered by the Society for Assisted Reproductive Technology. To clarify, a cycle of IVF consists of one egg retrieval and the ultimate transfer of all embryos produced, i.e., fresh and frozen. The website also includes estimations of success following a second and third IVF cycle.

The woman’s age is a significant predictor of IVF success. Ovarian aging is currently best measured by combining chronologic age, antral follicle count (AFC) by transvaginal pelvic ultrasound, and serum anti-Müllerian hormone (AMH). Natural fecundity begins to decline, on average, above age 32-33 years. An AFC less than 11 reflects diminished ovarian reserve (DOR) and less than 6 is severe. AMH levels below 1.6 ng/mL have been shown to reduce the number of eggs retrieved with IVF, while levels below 0.4 ng/mL are very low. Very low AMH levels negatively affect the outcome of IVF cycles as demonstrated in the SART data study from a population of women with a mean age of 39.4 years: Cycle cancellation was 54%; of all retrieval attempts, no oocytes were obtained in 5.4%, and no embryo transfer occurred in 25.1% of cycles; the live birth rate per embryo transfer was 20.5% (9.5% per cycle start and 16.3% per retrieval) from a mean age of 36.8 years (Fertil Steril. 2016 Feb;105[2]:385-93.e3). The predictive ability of AMH on the live birth rate from IVF cycles was also shown in a study of over 85,000 women (Fertil Steril. 2018;109:258-65).

While low AMH has been shown to lessen a successful outcome from IVF, there appears to be no difference in natural pregnancy rates in women aged 30-44 years irrespective of AMH levels (JAMA. 2017;318[14]:1367-76). Of importance, the use of AMH in a population at low risk for DOR will yield a larger number of false-positive results (i.e., characterizing a woman as DOR when in fact she has normal ovarian reserve). Further, users of hormonal contraceptives have a 25.2% lower mean AMH level than nonusers.

When a patient is considering tubal reanastomosis vs. IVF, a useful acronym to remember is to check “AGE” – the A is for AMH because severely diminished ovarian reserve will reduce success with IVF as shown by the SART calculator; the G represents guy, i.e., ensuring a reasonably normal sperm analysis; and E stands for eggs representing ovulation function. In a woman who is anovulatory and who will require fertility medication, it would be reasonable to consider IVF given the need for ovarian stimulation. As in females, advanced paternal age has demonstrated a decline in fertility and sperm analysis parameters. Men above age 45 take approximately five times as long to achieve a pregnancy, compared with men less than 25 years of age. Further, there is evidence for advanced paternal age increasing risk of miscarriage, preterm birth, and birth defects. Men older than 40-45 years have twice the risk of an autistic child and five times the risk of having a child with schizophrenia (Transl Psychiatry 2017;7: e1019; Am J Psychiatry. 2002;159:1528-33).

To conclude, the data support consideration for sterilization reversal in women less than age 37 years with more than 4 cm of residual functional fallopian tube and the prior use of rings or clip sterilization. In other women, IVF may be the better option, particularly when ovulation dysfunction and/or male factor is present. IVF also offers the advantage of maintaining contraception and gender determination. However, given that AMH does not appear to reduce natural fertility, unlike during its effect during an IVF cycle, the option of tubal reversal may be more favorable in women with severe DOR.

Dr. Trolice is director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Because of the increasing popularity and success of in vitro fertilization, the field of reproductive endocrinology and infertility has steadily morphed toward the treatment of infertility. Nevertheless, a physician board certified in reproductive endocrinology and infertility is the referring physician of choice regarding prolactin disorders and gynecologists should be familiar with the symptoms and sequela of prolactin elevations. This month’s column will address when to obtain a serum prolactin and how to appropriately manage hyperprolactinemia.

Of all the anterior pituitary hormones (adrenocorticotropic hormone, follicle-stimulating hormone, growth hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone ), prolactin is the only one under tonic inhibition by dopamine. Disturbances in this dopaminergic pathway result in elevated serum prolactin. The normal range for prolactin is approximately 5-20 ng/mL.

In the nonpregnant state, little is known regarding the purpose of prolactin, which is produced by the anterior pituitary cluster of cells called lactotrophs. To prepare the breast for postpartum lactation, increases in prolactin are necessary and sustained throughout pregnancy. Second to pregnancy, amenorrhea can occur in 10%-20% of cases of hyperprolactinemia. Outside of pregnancy, elevations in prolactin result in hypogonadism, through gonadotropin-releasing hormone suppression, resulting in infertility (48%), headache (39%), oligomenorrhea (29%) and galactorrhea (24%).¹ Most hypogonadal symptoms are more likely to occur with prolactin levels greater than 100 ng/mL, whereas infertility and ovulation dysfunction can occur with mild to moderate hyperprolactinemia, respectively. Prolonged amenorrhea can risk bone mineral density loss.

While the focus of our discussion is the effect of prolactin on women, men with hyperprolactinemia can experience hypogonadotropic hypogonadism with resultant decreased libido, impotence, infertility, gynecomastia, or, rarely, galactorrhea.²

The three Ps – physiological, pharmacologic, pathological

Physiological causes of hyperprolactinemia include rising estradiol during the late follicular phase and into the secretory phase of the menstrual cycle or while taking combined oral contraception, nipple stimulation, pregnancy, lactation, meals, sleep, and stress.

Drugs can interrupt the dopaminergic pathway, thereby elevating serum prolactin but usually not above 100 ng/mL, except for the antipsychotic drug risperidone, which can cause marked elevation up to 300 or even 400 ng/mL. Medications that can cause hyperprolactinemia are estrogens, neuroleptic drugs such as risperidone, metoclopramide, antidepressant drugs, cimetidine, methyldopa, and verapamil.

A pituitary MRI can diagnose an adenoma, that is, a collection of cells in the pituitary that are responsible for hyperprolactinemia and is named based on its size. Microadenomas are less than 1 cm and are typically associated with serum prolactin values below 200 ng/mL. Macroadenomas can worsen while a patient is on combined oral contraception and during pregnancy; fortunately, this is not the case with a microadenoma.

Hypothyroidism can elevate serum prolactin since thyrotropin releasing hormone is known to stimulate prolactin secretion.³ Consequently, when a patient presents with both hypothyroidism and hyperprolactinemia, thyroid replacement should be initiated for thyroid regulation and potential restoration of prolactin levels. If hyperprolactinemia persists, then further evaluation is required. Chronic renal impairment can also elevate prolactin levels due to decreased clearance.
 

Management

The appropriate evaluation of hyperprolactinemia consists of a history to disclose medications, identify galactorrhea, and visual changes. Because of an adenoma compressing the optic chiasm, partial blindness may occur where vision is lost in the outer half of both the right and left visual field, called bitemporal hemianopsia. Mild elevations in prolactin should be tested at a time when physiological influences are at a minimum, that is, during menses, fasting, and in late morning.⁴ Persistent elevations should be appropriately evaluated rather than by using the empiric “shotgun” approach of prescribing a dopamine agonist. Laboratory testing for repeated elevations in prolactin includes a pituitary MRI looking for a mass in the hypothalamic-pituitary region that interrupts dopamine suppression.

Treatment of hyperprolactinemia begins with a dopamine agonist and is indicated when there is hypogonadism or intolerable galactorrhea. Cabergoline is the first choice because of effectiveness (reduced adenoma size in greater than 90% of patients) and lesser side effects, particularly nausea, than bromocriptine. Dopamine agonists, such as bromocriptine and cabergoline, belong to the category of ergot-derived dopamine agonists and have been used to treat Parkinson’s disease. At high doses used to treat Parkinson’s, cabergoline is associated with an increased risk of valvular heart disease. In the United States, pergolide was voluntarily withdrawn from the market in March 2007 because of this risk. At the lower doses generally used for the treatment of hyperprolactinemia, cabergoline is probably not associated with excess risk.⁵

Newer dopamine agonists are known as nonergot. These are pramipexole, ropinirole, rotigotine, and apomorphine. They have not been associated with a risk of heart damage and can be prescribed.

The initial prescribing dose of cabergoline should be 0.25 mg twice a week or 0.5 mg once a week. If bromocriptine is used, the starting dose is 1.25 mg after dinner or at bedtime for 1 week, then increasing to 1.25 mg twice a day (after breakfast and after dinner or at bedtime to reduce nausea and fatigue). After 1 month of a dopamine agonist, the patient should be evaluated for side effects and a serum prolactin level should be obtained. With a normal prolactin level, gonadal function will probably return within a few months. The dopamine agonist should typically be discontinued with pregnancy as pregnancy increases prolactin physiologically.

Treatment of a macroadenoma is essential when the tumor is large enough to cause neurologic symptoms, such as visual impairment or headache, and is preferable when it is invasive or when there are enlarging microadenomas since they are likely to continue to grow and become symptomatic. About 95% of microadenomas have not been shown to increase in size during 4-6 years of observation.⁶

Transsphenoidal surgery should be considered when there is:

• Persistent hyperprolactinemia and/or size of the adenoma, with associated symptoms or signs despite several months of dopamine agonist treatment at high doses.
• Presence of a giant lactotroph adenoma (e.g., >3 cm) with pregnancy desired including those whose adenoma responds to a dopamine agonist – to avoid significant growth during pregnancy while off medication.

Data from over 6,000 pregnancies suggest that the administration of bromocriptine during the first month of pregnancy does not harm the fetus.⁷

Discontinuing treatment

Three scenarios may allow for cessation of dopamine agonist therapy. The first is when a patient has had a normal serum prolactin test following 2 years of low-dose dopamine agonist. Another is the patient who had hyperprolactinemia and a microadenoma that responded to treatment with a normal prolactin level and no further evidence of an adenoma by MRI for at least 2 years. Lastly, the patient who had a macroadenoma prior to treatment and a subsequent normal serum prolactin level without an adenoma for at least 2 years.

Like the management of thyroid dysfunction, our field must be aware of prolactin disorders for early detection, prompt referral, and appropriate management to minimize long-term consequences.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Bayrak A et al. Fertil Steril. 2005 Jul;84(1):181-5.

2. Carter JN et al. N Engl J Med. 1978 Oct 19;299(16):847-52.

3. Sachson R et al. N Engl J Med. 1972;287:972.

4. Singh SP and Singh TP. Ann Endocrinol (Paris). 1984;45(2):137-41.

5. Valassi E et al. J Clin Endocrinol Metab. 2010 Mar;95(3):1025-33.

6. Sisam DA et al. Fertil Steril. 1987 Jul;48(1):67-71.

7. Molitch ME. Best Pract Res Clin Endocrinol Metab. 2011 Dec;25(6):885-96.

Because of the increasing popularity and success of in vitro fertilization, the field of reproductive endocrinology and infertility has steadily morphed toward the treatment of infertility. Nevertheless, a physician board certified in reproductive endocrinology and infertility is the referring physician of choice regarding prolactin disorders and gynecologists should be familiar with the symptoms and sequela of prolactin elevations. This month’s column will address when to obtain a serum prolactin and how to appropriately manage hyperprolactinemia.

Of all the anterior pituitary hormones (adrenocorticotropic hormone, follicle-stimulating hormone, growth hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone ), prolactin is the only one under tonic inhibition by dopamine. Disturbances in this dopaminergic pathway result in elevated serum prolactin. The normal range for prolactin is approximately 5-20 ng/mL.

In the nonpregnant state, little is known regarding the purpose of prolactin, which is produced by the anterior pituitary cluster of cells called lactotrophs. To prepare the breast for postpartum lactation, increases in prolactin are necessary and sustained throughout pregnancy. Second to pregnancy, amenorrhea can occur in 10%-20% of cases of hyperprolactinemia. Outside of pregnancy, elevations in prolactin result in hypogonadism, through gonadotropin-releasing hormone suppression, resulting in infertility (48%), headache (39%), oligomenorrhea (29%) and galactorrhea (24%).¹ Most hypogonadal symptoms are more likely to occur with prolactin levels greater than 100 ng/mL, whereas infertility and ovulation dysfunction can occur with mild to moderate hyperprolactinemia, respectively. Prolonged amenorrhea can risk bone mineral density loss.

While the focus of our discussion is the effect of prolactin on women, men with hyperprolactinemia can experience hypogonadotropic hypogonadism with resultant decreased libido, impotence, infertility, gynecomastia, or, rarely, galactorrhea.²

The three Ps – physiological, pharmacologic, pathological

Physiological causes of hyperprolactinemia include rising estradiol during the late follicular phase and into the secretory phase of the menstrual cycle or while taking combined oral contraception, nipple stimulation, pregnancy, lactation, meals, sleep, and stress.

Drugs can interrupt the dopaminergic pathway, thereby elevating serum prolactin but usually not above 100 ng/mL, except for the antipsychotic drug risperidone, which can cause marked elevation up to 300 or even 400 ng/mL. Medications that can cause hyperprolactinemia are estrogens, neuroleptic drugs such as risperidone, metoclopramide, antidepressant drugs, cimetidine, methyldopa, and verapamil.

A pituitary MRI can diagnose an adenoma, that is, a collection of cells in the pituitary that are responsible for hyperprolactinemia and is named based on its size. Microadenomas are less than 1 cm and are typically associated with serum prolactin values below 200 ng/mL. Macroadenomas can worsen while a patient is on combined oral contraception and during pregnancy; fortunately, this is not the case with a microadenoma.

Hypothyroidism can elevate serum prolactin since thyrotropin releasing hormone is known to stimulate prolactin secretion.³ Consequently, when a patient presents with both hypothyroidism and hyperprolactinemia, thyroid replacement should be initiated for thyroid regulation and potential restoration of prolactin levels. If hyperprolactinemia persists, then further evaluation is required. Chronic renal impairment can also elevate prolactin levels due to decreased clearance.
 

Management

The appropriate evaluation of hyperprolactinemia consists of a history to disclose medications, identify galactorrhea, and visual changes. Because of an adenoma compressing the optic chiasm, partial blindness may occur where vision is lost in the outer half of both the right and left visual field, called bitemporal hemianopsia. Mild elevations in prolactin should be tested at a time when physiological influences are at a minimum, that is, during menses, fasting, and in late morning.⁴ Persistent elevations should be appropriately evaluated rather than by using the empiric “shotgun” approach of prescribing a dopamine agonist. Laboratory testing for repeated elevations in prolactin includes a pituitary MRI looking for a mass in the hypothalamic-pituitary region that interrupts dopamine suppression.

Treatment of hyperprolactinemia begins with a dopamine agonist and is indicated when there is hypogonadism or intolerable galactorrhea. Cabergoline is the first choice because of effectiveness (reduced adenoma size in greater than 90% of patients) and lesser side effects, particularly nausea, than bromocriptine. Dopamine agonists, such as bromocriptine and cabergoline, belong to the category of ergot-derived dopamine agonists and have been used to treat Parkinson’s disease. At high doses used to treat Parkinson’s, cabergoline is associated with an increased risk of valvular heart disease. In the United States, pergolide was voluntarily withdrawn from the market in March 2007 because of this risk. At the lower doses generally used for the treatment of hyperprolactinemia, cabergoline is probably not associated with excess risk.⁵

Newer dopamine agonists are known as nonergot. These are pramipexole, ropinirole, rotigotine, and apomorphine. They have not been associated with a risk of heart damage and can be prescribed.

The initial prescribing dose of cabergoline should be 0.25 mg twice a week or 0.5 mg once a week. If bromocriptine is used, the starting dose is 1.25 mg after dinner or at bedtime for 1 week, then increasing to 1.25 mg twice a day (after breakfast and after dinner or at bedtime to reduce nausea and fatigue). After 1 month of a dopamine agonist, the patient should be evaluated for side effects and a serum prolactin level should be obtained. With a normal prolactin level, gonadal function will probably return within a few months. The dopamine agonist should typically be discontinued with pregnancy as pregnancy increases prolactin physiologically.

Treatment of a macroadenoma is essential when the tumor is large enough to cause neurologic symptoms, such as visual impairment or headache, and is preferable when it is invasive or when there are enlarging microadenomas since they are likely to continue to grow and become symptomatic. About 95% of microadenomas have not been shown to increase in size during 4-6 years of observation.⁶

Transsphenoidal surgery should be considered when there is:

• Persistent hyperprolactinemia and/or size of the adenoma, with associated symptoms or signs despite several months of dopamine agonist treatment at high doses.
• Presence of a giant lactotroph adenoma (e.g., >3 cm) with pregnancy desired including those whose adenoma responds to a dopamine agonist – to avoid significant growth during pregnancy while off medication.

Data from over 6,000 pregnancies suggest that the administration of bromocriptine during the first month of pregnancy does not harm the fetus.⁷

Discontinuing treatment

Three scenarios may allow for cessation of dopamine agonist therapy. The first is when a patient has had a normal serum prolactin test following 2 years of low-dose dopamine agonist. Another is the patient who had hyperprolactinemia and a microadenoma that responded to treatment with a normal prolactin level and no further evidence of an adenoma by MRI for at least 2 years. Lastly, the patient who had a macroadenoma prior to treatment and a subsequent normal serum prolactin level without an adenoma for at least 2 years.

Like the management of thyroid dysfunction, our field must be aware of prolactin disorders for early detection, prompt referral, and appropriate management to minimize long-term consequences.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Bayrak A et al. Fertil Steril. 2005 Jul;84(1):181-5.

2. Carter JN et al. N Engl J Med. 1978 Oct 19;299(16):847-52.

3. Sachson R et al. N Engl J Med. 1972;287:972.

4. Singh SP and Singh TP. Ann Endocrinol (Paris). 1984;45(2):137-41.

5. Valassi E et al. J Clin Endocrinol Metab. 2010 Mar;95(3):1025-33.

6. Sisam DA et al. Fertil Steril. 1987 Jul;48(1):67-71.

7. Molitch ME. Best Pract Res Clin Endocrinol Metab. 2011 Dec;25(6):885-96.

Because of the increasing popularity and success of in vitro fertilization, the field of reproductive endocrinology and infertility has steadily morphed toward the treatment of infertility. Nevertheless, a physician board certified in reproductive endocrinology and infertility is the referring physician of choice regarding prolactin disorders and gynecologists should be familiar with the symptoms and sequela of prolactin elevations. This month’s column will address when to obtain a serum prolactin and how to appropriately manage hyperprolactinemia.

Of all the anterior pituitary hormones (adrenocorticotropic hormone, follicle-stimulating hormone, growth hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone ), prolactin is the only one under tonic inhibition by dopamine. Disturbances in this dopaminergic pathway result in elevated serum prolactin. The normal range for prolactin is approximately 5-20 ng/mL.

In the nonpregnant state, little is known regarding the purpose of prolactin, which is produced by the anterior pituitary cluster of cells called lactotrophs. To prepare the breast for postpartum lactation, increases in prolactin are necessary and sustained throughout pregnancy. Second to pregnancy, amenorrhea can occur in 10%-20% of cases of hyperprolactinemia. Outside of pregnancy, elevations in prolactin result in hypogonadism, through gonadotropin-releasing hormone suppression, resulting in infertility (48%), headache (39%), oligomenorrhea (29%) and galactorrhea (24%).¹ Most hypogonadal symptoms are more likely to occur with prolactin levels greater than 100 ng/mL, whereas infertility and ovulation dysfunction can occur with mild to moderate hyperprolactinemia, respectively. Prolonged amenorrhea can risk bone mineral density loss.

While the focus of our discussion is the effect of prolactin on women, men with hyperprolactinemia can experience hypogonadotropic hypogonadism with resultant decreased libido, impotence, infertility, gynecomastia, or, rarely, galactorrhea.²

The three Ps – physiological, pharmacologic, pathological

Physiological causes of hyperprolactinemia include rising estradiol during the late follicular phase and into the secretory phase of the menstrual cycle or while taking combined oral contraception, nipple stimulation, pregnancy, lactation, meals, sleep, and stress.

Drugs can interrupt the dopaminergic pathway, thereby elevating serum prolactin but usually not above 100 ng/mL, except for the antipsychotic drug risperidone, which can cause marked elevation up to 300 or even 400 ng/mL. Medications that can cause hyperprolactinemia are estrogens, neuroleptic drugs such as risperidone, metoclopramide, antidepressant drugs, cimetidine, methyldopa, and verapamil.

A pituitary MRI can diagnose an adenoma, that is, a collection of cells in the pituitary that are responsible for hyperprolactinemia and is named based on its size. Microadenomas are less than 1 cm and are typically associated with serum prolactin values below 200 ng/mL. Macroadenomas can worsen while a patient is on combined oral contraception and during pregnancy; fortunately, this is not the case with a microadenoma.

Hypothyroidism can elevate serum prolactin since thyrotropin releasing hormone is known to stimulate prolactin secretion.³ Consequently, when a patient presents with both hypothyroidism and hyperprolactinemia, thyroid replacement should be initiated for thyroid regulation and potential restoration of prolactin levels. If hyperprolactinemia persists, then further evaluation is required. Chronic renal impairment can also elevate prolactin levels due to decreased clearance.
 

Management

The appropriate evaluation of hyperprolactinemia consists of a history to disclose medications, identify galactorrhea, and visual changes. Because of an adenoma compressing the optic chiasm, partial blindness may occur where vision is lost in the outer half of both the right and left visual field, called bitemporal hemianopsia. Mild elevations in prolactin should be tested at a time when physiological influences are at a minimum, that is, during menses, fasting, and in late morning.⁴ Persistent elevations should be appropriately evaluated rather than by using the empiric “shotgun” approach of prescribing a dopamine agonist. Laboratory testing for repeated elevations in prolactin includes a pituitary MRI looking for a mass in the hypothalamic-pituitary region that interrupts dopamine suppression.

Treatment of hyperprolactinemia begins with a dopamine agonist and is indicated when there is hypogonadism or intolerable galactorrhea. Cabergoline is the first choice because of effectiveness (reduced adenoma size in greater than 90% of patients) and lesser side effects, particularly nausea, than bromocriptine. Dopamine agonists, such as bromocriptine and cabergoline, belong to the category of ergot-derived dopamine agonists and have been used to treat Parkinson’s disease. At high doses used to treat Parkinson’s, cabergoline is associated with an increased risk of valvular heart disease. In the United States, pergolide was voluntarily withdrawn from the market in March 2007 because of this risk. At the lower doses generally used for the treatment of hyperprolactinemia, cabergoline is probably not associated with excess risk.⁵

Newer dopamine agonists are known as nonergot. These are pramipexole, ropinirole, rotigotine, and apomorphine. They have not been associated with a risk of heart damage and can be prescribed.

The initial prescribing dose of cabergoline should be 0.25 mg twice a week or 0.5 mg once a week. If bromocriptine is used, the starting dose is 1.25 mg after dinner or at bedtime for 1 week, then increasing to 1.25 mg twice a day (after breakfast and after dinner or at bedtime to reduce nausea and fatigue). After 1 month of a dopamine agonist, the patient should be evaluated for side effects and a serum prolactin level should be obtained. With a normal prolactin level, gonadal function will probably return within a few months. The dopamine agonist should typically be discontinued with pregnancy as pregnancy increases prolactin physiologically.

Treatment of a macroadenoma is essential when the tumor is large enough to cause neurologic symptoms, such as visual impairment or headache, and is preferable when it is invasive or when there are enlarging microadenomas since they are likely to continue to grow and become symptomatic. About 95% of microadenomas have not been shown to increase in size during 4-6 years of observation.⁶

Transsphenoidal surgery should be considered when there is:

• Persistent hyperprolactinemia and/or size of the adenoma, with associated symptoms or signs despite several months of dopamine agonist treatment at high doses.
• Presence of a giant lactotroph adenoma (e.g., >3 cm) with pregnancy desired including those whose adenoma responds to a dopamine agonist – to avoid significant growth during pregnancy while off medication.

Data from over 6,000 pregnancies suggest that the administration of bromocriptine during the first month of pregnancy does not harm the fetus.⁷

Discontinuing treatment

Three scenarios may allow for cessation of dopamine agonist therapy. The first is when a patient has had a normal serum prolactin test following 2 years of low-dose dopamine agonist. Another is the patient who had hyperprolactinemia and a microadenoma that responded to treatment with a normal prolactin level and no further evidence of an adenoma by MRI for at least 2 years. Lastly, the patient who had a macroadenoma prior to treatment and a subsequent normal serum prolactin level without an adenoma for at least 2 years.

Like the management of thyroid dysfunction, our field must be aware of prolactin disorders for early detection, prompt referral, and appropriate management to minimize long-term consequences.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Bayrak A et al. Fertil Steril. 2005 Jul;84(1):181-5.

2. Carter JN et al. N Engl J Med. 1978 Oct 19;299(16):847-52.

3. Sachson R et al. N Engl J Med. 1972;287:972.

4. Singh SP and Singh TP. Ann Endocrinol (Paris). 1984;45(2):137-41.

5. Valassi E et al. J Clin Endocrinol Metab. 2010 Mar;95(3):1025-33.

6. Sisam DA et al. Fertil Steril. 1987 Jul;48(1):67-71.

7. Molitch ME. Best Pract Res Clin Endocrinol Metab. 2011 Dec;25(6):885-96.

Physicians who care for women having difficulty conceiving must understand the devastation their patients feel while knowing how to define infertility, when (and when not) to advise an evaluation, and offer evidence-based treatment options. Analogous to a mother desiring an antibiotic prescription for her child’s common cold, infertility patients can be desperate for an evaluation and treatment, despite the lack of an indication. This month’s article addresses the diagnosis and management of unexplained infertility.

The chronological age of a woman is the leading prognostic factor for successful reproduction. The definition of infertility remains 1 year of an inability to conceive in a couple who have no demonstrable risk factors, such as ovulation dysfunction, prior infertility, or known male factor. In women less than age 30, monthly fecundity rates are between 20% and 37% during the first 3 months of trying to conceive. The chance of success increases to 80% after 1 year and 90% after 2 years of trying to conceive, according to the American Society of Reproductive Medicine. Nevertheless, following unsuccessful attempts at conception by a couple, the physician should offer an evaluation based on the woman’s age – 1 year for women less than age 35, 6 months for women aged 35-39, and 3 months for women aged 40 and older. Testing can be initiated earlier if there are predisposing factors impairing fertility.

The basic infertility evaluation consists of a thorough history of the couple, a review of medical records, and an assessment of ovulation, fallopian tube patency, and sperm parameters on analysis. In the interest of efficiency, given that couples are typically anxious, these three areas can be evaluated within 1 month. In years past, a diagnostic laparoscopy was considered the gold standard of necessity to provide the diagnosis of exclusion, that is, unexplained infertility. This surgical procedure has fallen out of favor given the low diagnostic yield in a woman with a normal hysterosalpingogram, pelvic ultrasound, and no risk for a pelvic factor; for example, prior abdominal myomectomy, bowel surgery, or strong suspicion for endometriosis based on symptoms including significant pelvic pain affecting activities of daily living.

Initial laboratory testing should be judiciously ordered by recommending only those that will affect management, that is, prenatal labs to assess immunity to rubella and varicella along with a baseline thyroid-stimulating hormone, CBC, blood type, and Rh and antibody screen. In a woman with monthly ovulatory menstrual cycles and no signs of hirsutism or galactorrhea, the clinical utility of obtaining follicle-stimulating hormone, luteinizing hormone (LH), estradiol, prolactin, total and free testosterone, and dehydroepiandrosterone lack evidence. Further, a random anti-Müllerian hormone (without prior chemotherapy, radiation, or ovarian surgery) lacks value as the natural pregnancy rate does not appear to be affected, although low AMH has been associated with an increased risk for miscarriage.

Although not typically screened, measles can cause significant complications in pregnancy including an increased risk of maternal hospitalization and pneumonia, as well as miscarriage, stillbirth, low birth weight, and increased risk of preterm delivery.

Education is an important tool to guide patients and begins with an explanation of urine LH timed intercourse. From the onset of the LH surge, the oocyte is released in 24-36 hours, i.e., the actual day of ovulation is estimated to be the day after the urine LH surge. The “fertile window” appears to be the 5 days before plus the day of ovulation but the highest chance of conception occurs within the 2 days before and including the day of ovulation.

Empiric treatment may be offered when no demonstrable etiology has been identified, lifestyle factors have been addressed (for example, elevated female body mass index, tobacco use by the couple), and medical conditions have been optimized. Reproductive capability declines with continued attempts at conception such that, by 2 years, the approximate monthly fecundity rate is 3%-4%.

The first-line treatment of unexplained infertility is clomiphene citrate (CC) with intrauterine insemination. Letrozole, while not Food and Drug Administration approved for infertility treatment, has been shown in multiple studies to be equally effective as CC and to have a good safety profile. In a recent study, the cumulative live-birth rate over three cycles with CC and IUI, compared with expectant management was 31% versus 9%, respectively. Further, multiple studies failed to show a difference in pregnancy outcomes when comparing CC and IUI with letrozole and IUI.

It is vital to note that, for women who ovulate, studies do not support the use of CC without the addition of intrauterine insemination (IUI). The monthly fecundity rate of a cycle of CC without IUI is similar to natural conception attempts with urine LH timed intercourse, that is, without ovarian stimulation.
 

Recommendations (along with the level of evidence) from ASRM guidelines

• 1. Natural cycle, that is, without ovarian stimulation, timed with IUI is equivalent to expectant management (strong)
• 2. CC or letrozole with timed intercourse is no more effective than a natural cycle (good)
• 3. Pregnancy rates using gonadotropins with timed intercourse have not been shown to be superior to oral ovarian stimulating medications but risks multiple gestation (insufficient)
• 4. CC plus standard-dose gonadotropins results in higher pregnancy rates, there is good evidence for an increased risk of multiple gestation (fair)
• 5. Treatment with gonadotropins alone with IUI is superior to CC or letrozole with IUI; the risk of a multiple gestation rate remains significant (insufficient)
• 6. IUI can be performed between 0 and 36 hours following human chorionic gonadotropin trigger and performing one IUI in a cycle has equivalent success as two (fair)
• 7. Immediate IVF in women older than 38 years may be associated with a higher pregnancy rate and shorter time to pregnancy, compared with ovarian stimulation/IUI cycles before IVF (good)

Conclusion

It is recommended that couples with unexplained infertility initially undergo a course (typically three or four cycles) of ovarian stimulation with IUI using oral agents (CC or letrozole). For those unsuccessful with ovarian stimulation and IUI treatments with oral agents, in vitro fertilization is recommended rather than ovarian stimulation and IUI with gonadotropins to reduce the risk of a multiple gestation.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Email him at [email protected].

Physicians who care for women having difficulty conceiving must understand the devastation their patients feel while knowing how to define infertility, when (and when not) to advise an evaluation, and offer evidence-based treatment options. Analogous to a mother desiring an antibiotic prescription for her child’s common cold, infertility patients can be desperate for an evaluation and treatment, despite the lack of an indication. This month’s article addresses the diagnosis and management of unexplained infertility.

The chronological age of a woman is the leading prognostic factor for successful reproduction. The definition of infertility remains 1 year of an inability to conceive in a couple who have no demonstrable risk factors, such as ovulation dysfunction, prior infertility, or known male factor. In women less than age 30, monthly fecundity rates are between 20% and 37% during the first 3 months of trying to conceive. The chance of success increases to 80% after 1 year and 90% after 2 years of trying to conceive, according to the American Society of Reproductive Medicine. Nevertheless, following unsuccessful attempts at conception by a couple, the physician should offer an evaluation based on the woman’s age – 1 year for women less than age 35, 6 months for women aged 35-39, and 3 months for women aged 40 and older. Testing can be initiated earlier if there are predisposing factors impairing fertility.

The basic infertility evaluation consists of a thorough history of the couple, a review of medical records, and an assessment of ovulation, fallopian tube patency, and sperm parameters on analysis. In the interest of efficiency, given that couples are typically anxious, these three areas can be evaluated within 1 month. In years past, a diagnostic laparoscopy was considered the gold standard of necessity to provide the diagnosis of exclusion, that is, unexplained infertility. This surgical procedure has fallen out of favor given the low diagnostic yield in a woman with a normal hysterosalpingogram, pelvic ultrasound, and no risk for a pelvic factor; for example, prior abdominal myomectomy, bowel surgery, or strong suspicion for endometriosis based on symptoms including significant pelvic pain affecting activities of daily living.

Initial laboratory testing should be judiciously ordered by recommending only those that will affect management, that is, prenatal labs to assess immunity to rubella and varicella along with a baseline thyroid-stimulating hormone, CBC, blood type, and Rh and antibody screen. In a woman with monthly ovulatory menstrual cycles and no signs of hirsutism or galactorrhea, the clinical utility of obtaining follicle-stimulating hormone, luteinizing hormone (LH), estradiol, prolactin, total and free testosterone, and dehydroepiandrosterone lack evidence. Further, a random anti-Müllerian hormone (without prior chemotherapy, radiation, or ovarian surgery) lacks value as the natural pregnancy rate does not appear to be affected, although low AMH has been associated with an increased risk for miscarriage.

Although not typically screened, measles can cause significant complications in pregnancy including an increased risk of maternal hospitalization and pneumonia, as well as miscarriage, stillbirth, low birth weight, and increased risk of preterm delivery.

Education is an important tool to guide patients and begins with an explanation of urine LH timed intercourse. From the onset of the LH surge, the oocyte is released in 24-36 hours, i.e., the actual day of ovulation is estimated to be the day after the urine LH surge. The “fertile window” appears to be the 5 days before plus the day of ovulation but the highest chance of conception occurs within the 2 days before and including the day of ovulation.

Empiric treatment may be offered when no demonstrable etiology has been identified, lifestyle factors have been addressed (for example, elevated female body mass index, tobacco use by the couple), and medical conditions have been optimized. Reproductive capability declines with continued attempts at conception such that, by 2 years, the approximate monthly fecundity rate is 3%-4%.

The first-line treatment of unexplained infertility is clomiphene citrate (CC) with intrauterine insemination. Letrozole, while not Food and Drug Administration approved for infertility treatment, has been shown in multiple studies to be equally effective as CC and to have a good safety profile. In a recent study, the cumulative live-birth rate over three cycles with CC and IUI, compared with expectant management was 31% versus 9%, respectively. Further, multiple studies failed to show a difference in pregnancy outcomes when comparing CC and IUI with letrozole and IUI.

It is vital to note that, for women who ovulate, studies do not support the use of CC without the addition of intrauterine insemination (IUI). The monthly fecundity rate of a cycle of CC without IUI is similar to natural conception attempts with urine LH timed intercourse, that is, without ovarian stimulation.
 

Recommendations (along with the level of evidence) from ASRM guidelines

• 1. Natural cycle, that is, without ovarian stimulation, timed with IUI is equivalent to expectant management (strong)
• 2. CC or letrozole with timed intercourse is no more effective than a natural cycle (good)
• 3. Pregnancy rates using gonadotropins with timed intercourse have not been shown to be superior to oral ovarian stimulating medications but risks multiple gestation (insufficient)
• 4. CC plus standard-dose gonadotropins results in higher pregnancy rates, there is good evidence for an increased risk of multiple gestation (fair)
• 5. Treatment with gonadotropins alone with IUI is superior to CC or letrozole with IUI; the risk of a multiple gestation rate remains significant (insufficient)
• 6. IUI can be performed between 0 and 36 hours following human chorionic gonadotropin trigger and performing one IUI in a cycle has equivalent success as two (fair)
• 7. Immediate IVF in women older than 38 years may be associated with a higher pregnancy rate and shorter time to pregnancy, compared with ovarian stimulation/IUI cycles before IVF (good)

Conclusion

It is recommended that couples with unexplained infertility initially undergo a course (typically three or four cycles) of ovarian stimulation with IUI using oral agents (CC or letrozole). For those unsuccessful with ovarian stimulation and IUI treatments with oral agents, in vitro fertilization is recommended rather than ovarian stimulation and IUI with gonadotropins to reduce the risk of a multiple gestation.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Email him at [email protected].

Physicians who care for women having difficulty conceiving must understand the devastation their patients feel while knowing how to define infertility, when (and when not) to advise an evaluation, and offer evidence-based treatment options. Analogous to a mother desiring an antibiotic prescription for her child’s common cold, infertility patients can be desperate for an evaluation and treatment, despite the lack of an indication. This month’s article addresses the diagnosis and management of unexplained infertility.

The chronological age of a woman is the leading prognostic factor for successful reproduction. The definition of infertility remains 1 year of an inability to conceive in a couple who have no demonstrable risk factors, such as ovulation dysfunction, prior infertility, or known male factor. In women less than age 30, monthly fecundity rates are between 20% and 37% during the first 3 months of trying to conceive. The chance of success increases to 80% after 1 year and 90% after 2 years of trying to conceive, according to the American Society of Reproductive Medicine. Nevertheless, following unsuccessful attempts at conception by a couple, the physician should offer an evaluation based on the woman’s age – 1 year for women less than age 35, 6 months for women aged 35-39, and 3 months for women aged 40 and older. Testing can be initiated earlier if there are predisposing factors impairing fertility.

The basic infertility evaluation consists of a thorough history of the couple, a review of medical records, and an assessment of ovulation, fallopian tube patency, and sperm parameters on analysis. In the interest of efficiency, given that couples are typically anxious, these three areas can be evaluated within 1 month. In years past, a diagnostic laparoscopy was considered the gold standard of necessity to provide the diagnosis of exclusion, that is, unexplained infertility. This surgical procedure has fallen out of favor given the low diagnostic yield in a woman with a normal hysterosalpingogram, pelvic ultrasound, and no risk for a pelvic factor; for example, prior abdominal myomectomy, bowel surgery, or strong suspicion for endometriosis based on symptoms including significant pelvic pain affecting activities of daily living.

Initial laboratory testing should be judiciously ordered by recommending only those that will affect management, that is, prenatal labs to assess immunity to rubella and varicella along with a baseline thyroid-stimulating hormone, CBC, blood type, and Rh and antibody screen. In a woman with monthly ovulatory menstrual cycles and no signs of hirsutism or galactorrhea, the clinical utility of obtaining follicle-stimulating hormone, luteinizing hormone (LH), estradiol, prolactin, total and free testosterone, and dehydroepiandrosterone lack evidence. Further, a random anti-Müllerian hormone (without prior chemotherapy, radiation, or ovarian surgery) lacks value as the natural pregnancy rate does not appear to be affected, although low AMH has been associated with an increased risk for miscarriage.

Although not typically screened, measles can cause significant complications in pregnancy including an increased risk of maternal hospitalization and pneumonia, as well as miscarriage, stillbirth, low birth weight, and increased risk of preterm delivery.

Education is an important tool to guide patients and begins with an explanation of urine LH timed intercourse. From the onset of the LH surge, the oocyte is released in 24-36 hours, i.e., the actual day of ovulation is estimated to be the day after the urine LH surge. The “fertile window” appears to be the 5 days before plus the day of ovulation but the highest chance of conception occurs within the 2 days before and including the day of ovulation.

Empiric treatment may be offered when no demonstrable etiology has been identified, lifestyle factors have been addressed (for example, elevated female body mass index, tobacco use by the couple), and medical conditions have been optimized. Reproductive capability declines with continued attempts at conception such that, by 2 years, the approximate monthly fecundity rate is 3%-4%.

The first-line treatment of unexplained infertility is clomiphene citrate (CC) with intrauterine insemination. Letrozole, while not Food and Drug Administration approved for infertility treatment, has been shown in multiple studies to be equally effective as CC and to have a good safety profile. In a recent study, the cumulative live-birth rate over three cycles with CC and IUI, compared with expectant management was 31% versus 9%, respectively. Further, multiple studies failed to show a difference in pregnancy outcomes when comparing CC and IUI with letrozole and IUI.

It is vital to note that, for women who ovulate, studies do not support the use of CC without the addition of intrauterine insemination (IUI). The monthly fecundity rate of a cycle of CC without IUI is similar to natural conception attempts with urine LH timed intercourse, that is, without ovarian stimulation.
 

Recommendations (along with the level of evidence) from ASRM guidelines

• 1. Natural cycle, that is, without ovarian stimulation, timed with IUI is equivalent to expectant management (strong)
• 2. CC or letrozole with timed intercourse is no more effective than a natural cycle (good)
• 3. Pregnancy rates using gonadotropins with timed intercourse have not been shown to be superior to oral ovarian stimulating medications but risks multiple gestation (insufficient)
• 4. CC plus standard-dose gonadotropins results in higher pregnancy rates, there is good evidence for an increased risk of multiple gestation (fair)
• 5. Treatment with gonadotropins alone with IUI is superior to CC or letrozole with IUI; the risk of a multiple gestation rate remains significant (insufficient)
• 6. IUI can be performed between 0 and 36 hours following human chorionic gonadotropin trigger and performing one IUI in a cycle has equivalent success as two (fair)
• 7. Immediate IVF in women older than 38 years may be associated with a higher pregnancy rate and shorter time to pregnancy, compared with ovarian stimulation/IUI cycles before IVF (good)

Conclusion

It is recommended that couples with unexplained infertility initially undergo a course (typically three or four cycles) of ovarian stimulation with IUI using oral agents (CC or letrozole). For those unsuccessful with ovarian stimulation and IUI treatments with oral agents, in vitro fertilization is recommended rather than ovarian stimulation and IUI with gonadotropins to reduce the risk of a multiple gestation.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Email him at [email protected].