John F. Randolph Jr, MD

A. Clomiphene is superior to metformin in achieving live births in infertile women with polycystic ovary syndrome (PCOS), but carries a higher risk of multiple gestation.

Expert Commentary

Frontline therapy for ovulation induction in women with PCOS has evolved from clomiphene to metformin, particularly since Palomba and colleagues¹ noted comparable ovulation rates and improved conception rates when metformin was given. This new report by Legro and colleagues from the Cooperative Multicenter Reproductive Medicine Network resoundingly contradicts that more limited report and reasserts the primacy of clomiphene in ovulation induction for PCOS. It is reminiscent of the Women’s Health Initiative, in that a well-designed large clinical trial has yielded findings opposite those theorized by investigators.

Legro and colleagues also report a reassuringly low multiple-pregnancy rate in the treatment groups that included clomiphene citrate, and no multiples in the metformin-only group. In addition, they demonstrate a clear, deleterious effect of extreme obesity (body mass index [BMI] greater than 35) on the efficacy of clomiphene and metformin individually and of the 2 agents combined.

Distinctive features of this trial

It is worth noting that the trial by Legro and colleagues contrasts the study by Palomba and associates in 2 critical design characteristics. First, Palomba and associates included only women with a BMI less than 30, whereas Legro and colleagues included a range of body sizes: Only 30% of participants were less than obese and nearly half were massively obese.

Second, the Palomba study was conducted in Italy, presumably in a more homogeneous population than the multiethnic, multicenter trial by Legro and colleagues. However, in the latter trial, even the subgroup analysis for the 179 subjects with a BMI less than 30 demonstrated the same relative proportions of ovulation and conception as the overall trial, albeit with higher rates than in heavier women.

The 2 studies also used slightly different criteria to document ovulation, and the study by Legro and colleagues used the more robust outcome of live birth rate as a primary endpoint—a much more clinically useful measure.

Nonetheless, these differences are insufficient to explain the striking contrast between the data from Legro and colleagues and virtually all of the limited recent work in this area, calling into question the recent move toward metformin as primary frontline therapy. The size, design, and multicenter nature of this trial demand that we consider it the primary source for level I evidence on the subject.

The greater the obesity, the lower the fertility

Perhaps an equally important finding of this study is the diminished response to metformin, clomiphene, or both in women with a BMI of 35 or above. This suggests that aggressive therapy up front may be warranted in these patients in addition to a coordinated plan of dietary and exercise therapy.

Bottom line: Use clomiphene first

This study points us back to the long-standing practice of using clomiphene citrate as frontline therapy for ovulation induction in women with PCOS, with the additional caveat that body size is a critical modifier of this therapy. However, the cumulative ovulation rate of about 40% and cumulative conception rate of about 20% in women with a BMI less than 35 taking metformin make that drug a reasonable frontline option for couples very concerned about multiple gestation or significant side effects with clomiphene.

A. Clomiphene is superior to metformin in achieving live births in infertile women with polycystic ovary syndrome (PCOS), but carries a higher risk of multiple gestation.

Expert Commentary

Frontline therapy for ovulation induction in women with PCOS has evolved from clomiphene to metformin, particularly since Palomba and colleagues¹ noted comparable ovulation rates and improved conception rates when metformin was given. This new report by Legro and colleagues from the Cooperative Multicenter Reproductive Medicine Network resoundingly contradicts that more limited report and reasserts the primacy of clomiphene in ovulation induction for PCOS. It is reminiscent of the Women’s Health Initiative, in that a well-designed large clinical trial has yielded findings opposite those theorized by investigators.

Legro and colleagues also report a reassuringly low multiple-pregnancy rate in the treatment groups that included clomiphene citrate, and no multiples in the metformin-only group. In addition, they demonstrate a clear, deleterious effect of extreme obesity (body mass index [BMI] greater than 35) on the efficacy of clomiphene and metformin individually and of the 2 agents combined.

Distinctive features of this trial

It is worth noting that the trial by Legro and colleagues contrasts the study by Palomba and associates in 2 critical design characteristics. First, Palomba and associates included only women with a BMI less than 30, whereas Legro and colleagues included a range of body sizes: Only 30% of participants were less than obese and nearly half were massively obese.

Second, the Palomba study was conducted in Italy, presumably in a more homogeneous population than the multiethnic, multicenter trial by Legro and colleagues. However, in the latter trial, even the subgroup analysis for the 179 subjects with a BMI less than 30 demonstrated the same relative proportions of ovulation and conception as the overall trial, albeit with higher rates than in heavier women.

The 2 studies also used slightly different criteria to document ovulation, and the study by Legro and colleagues used the more robust outcome of live birth rate as a primary endpoint—a much more clinically useful measure.

Nonetheless, these differences are insufficient to explain the striking contrast between the data from Legro and colleagues and virtually all of the limited recent work in this area, calling into question the recent move toward metformin as primary frontline therapy. The size, design, and multicenter nature of this trial demand that we consider it the primary source for level I evidence on the subject.

The greater the obesity, the lower the fertility

Perhaps an equally important finding of this study is the diminished response to metformin, clomiphene, or both in women with a BMI of 35 or above. This suggests that aggressive therapy up front may be warranted in these patients in addition to a coordinated plan of dietary and exercise therapy.

Bottom line: Use clomiphene first

This study points us back to the long-standing practice of using clomiphene citrate as frontline therapy for ovulation induction in women with PCOS, with the additional caveat that body size is a critical modifier of this therapy. However, the cumulative ovulation rate of about 40% and cumulative conception rate of about 20% in women with a BMI less than 35 taking metformin make that drug a reasonable frontline option for couples very concerned about multiple gestation or significant side effects with clomiphene.

A. Clomiphene is superior to metformin in achieving live births in infertile women with polycystic ovary syndrome (PCOS), but carries a higher risk of multiple gestation.

Expert Commentary

Frontline therapy for ovulation induction in women with PCOS has evolved from clomiphene to metformin, particularly since Palomba and colleagues¹ noted comparable ovulation rates and improved conception rates when metformin was given. This new report by Legro and colleagues from the Cooperative Multicenter Reproductive Medicine Network resoundingly contradicts that more limited report and reasserts the primacy of clomiphene in ovulation induction for PCOS. It is reminiscent of the Women’s Health Initiative, in that a well-designed large clinical trial has yielded findings opposite those theorized by investigators.

Legro and colleagues also report a reassuringly low multiple-pregnancy rate in the treatment groups that included clomiphene citrate, and no multiples in the metformin-only group. In addition, they demonstrate a clear, deleterious effect of extreme obesity (body mass index [BMI] greater than 35) on the efficacy of clomiphene and metformin individually and of the 2 agents combined.

Distinctive features of this trial

It is worth noting that the trial by Legro and colleagues contrasts the study by Palomba and associates in 2 critical design characteristics. First, Palomba and associates included only women with a BMI less than 30, whereas Legro and colleagues included a range of body sizes: Only 30% of participants were less than obese and nearly half were massively obese.

Second, the Palomba study was conducted in Italy, presumably in a more homogeneous population than the multiethnic, multicenter trial by Legro and colleagues. However, in the latter trial, even the subgroup analysis for the 179 subjects with a BMI less than 30 demonstrated the same relative proportions of ovulation and conception as the overall trial, albeit with higher rates than in heavier women.

The 2 studies also used slightly different criteria to document ovulation, and the study by Legro and colleagues used the more robust outcome of live birth rate as a primary endpoint—a much more clinically useful measure.

Nonetheless, these differences are insufficient to explain the striking contrast between the data from Legro and colleagues and virtually all of the limited recent work in this area, calling into question the recent move toward metformin as primary frontline therapy. The size, design, and multicenter nature of this trial demand that we consider it the primary source for level I evidence on the subject.

The greater the obesity, the lower the fertility

Perhaps an equally important finding of this study is the diminished response to metformin, clomiphene, or both in women with a BMI of 35 or above. This suggests that aggressive therapy up front may be warranted in these patients in addition to a coordinated plan of dietary and exercise therapy.

Bottom line: Use clomiphene first

This study points us back to the long-standing practice of using clomiphene citrate as frontline therapy for ovulation induction in women with PCOS, with the additional caveat that body size is a critical modifier of this therapy. However, the cumulative ovulation rate of about 40% and cumulative conception rate of about 20% in women with a BMI less than 35 taking metformin make that drug a reasonable frontline option for couples very concerned about multiple gestation or significant side effects with clomiphene.

• Metformin as frontline treatment for ovulation induction and other PCOS-related disorders
• New PCOS diagnostic criteria

It seems that most advances in the field of infertility entail high-tech, high-risk therapies and expensive diagnostics that are the domain of subspecialists. But this year brought compelling evidence of a better “low-tech” treatment for a common dilemma that has challenged generalists and subspecialists alike for decades: PCOS-related infertility.

A more effective primary-care based strategy is all the more welcome because the difficulties encountered in helping women with PCOS achieve pregnancy have prompted many generalists to routinely refer these patients to subspecialty care.

There’s more: The same new findings that generalists can apply to management of infertility also apply to other PCOS-caused problems: abnormal bleeding, obesity, and cosmetic concerns.

The new research on PCOS also points out our need to stay up-to-date on the current definition and diagnostic criteria for PCOS—both have changed within the past 2 years.

In addition, as a follow-up to my comments in this column a year ago: new and exciting information on oogonial stem cells, though not of immediate clinical utility, may nevertheless be of interest for patients who desire to preserve their fertility.

Try metformin first for PCOS-related infertility

Palomba S, Orio F Jr, Falbo A, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4068–4074.

This study heralds a shift away from our typical approach. It argues that a trial of metformin for up to 6 months prior to an alternative strategy is very reasonable, and easily managed by any ObGyn.

Metformin has been utilized increasingly over the past decade to improve ovulation and conception rates in women with PCOS who wish to conceive. Traditionally, primary therapy has involved ovulation induction, initially with clomiphene citrate, frequently followed by gonadotropins due to failure of the initial therapy. Palomba and colleagues conducted the first well-designed, well-controlled head-to-head trial of metformin versus clomiphene citrate as frontline therapy to induce ovulation.

A total of 100 women with nonobese PCOS were randomly assigned to metformin (850 mg twice a day) or clomiphene citrate (150 mg on days 3–7 of each cycle) for 6 months. The main outcome measures were ovulation, pregnancy, abortion, and live-birth rates. More than 200 potential conception cycles were studied in each group.

Although metformin and clomiphene resulted in statistically similar rates of ovulation in the treatment groups (about 2 out of 3 cycles), there was a big difference in the pregnancy rates. The percycle pregnancy rate was twice as high in the metformin group (15.1% vs 7.2%, P=.009). The cumulative pregnancy rate was also far higher in the metformin group (68.9% vs 34.0%, P<.001), and the abortion rate was much lower (9.7% vs 37.5%).

Metformin’s benefits increase over time

Equally interesting was the progressive increase in both ovulation and conception rates in the metformin group during the course of the 6-month trial, compared with a progressive decrease in both the ovulation and conception rates in the clomiphene group—suggesting a cumulative benefit with ongoing metformin therapy. Although the trial was conducted in nonobese PCOS patients, it is reasonable to extrapolate the approach to the larger sub-group of women with PCOS who are obese.

Side effects. Metformin is relatively safe and well tolerated, except for a small percentage of women with intractable gastrointestinal (GI) side effects. The risk of multiple gestations does not increase.

Metformin for hirsutism and abnormal bleeding

While the Palomba study deals specifically with treatment of PCOS to induce pregnancy, the metabolic implications of inducing normal ovulation make this strategy applicable to the treatment of PCOS in women who are not attempting conception. It now appears reasonable to consider the use of metformin to help manage other issues such as hirsutism and abnormal bleeding, particularly when more conventional therapies have been insufficient.

Treatment tips

I now use metformin as first-line therapy in all patients with a confirmed diagnosis of PCOS regardless of the reason for therapy.

• Minimal pretreatment screening is appropriate to rule out thyroid or pituitary disorders, unsuspected renal disease, or actual diabetes mellitus.
• I titrate the dose over several weeks from an initial 500 mg daily with food to a target of 1,500 mg daily to help reduce GI symptoms.
• I prefer the extended-release preparation for its ease of use and (anecdotally) fewer side effects.

 

When to start additional therapy. If regular menses do not occur within 3 months on metformin alone, I add additional therapy as indicated.

A new way to define PCOS

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19–25.

The addition of ultrasonographic criteria for the diagnosis has effectively nearly doubled the prevalence of PCOS in the United States—and justifies the use of ultrasound to make the diagnosis.

In conjunction with the shift toward metformin as first-line therapy for ovulation induction in women with PCOS, it is important that ObGyns incorporate the latest clinical criteria for the diagnosis of PCOS.

3 clinical indicators

The “Rotterdam Criteria” from the 2003 Consensus Conference require 2 out of 3 clinical indicators to make the diagnosis:

1. Oligo- or anovulation,
2. Clinical and/or biochemical signs of hyperandrogenism, and
3. Polycystic ovaries as evidenced on ultrasound or histology. Ultrasound criteria for polycystic ovaries are specific: increased stroma-to-follicle ratio with multiple subcapsular early antral follicles.

It is also important to note that the diagnosis is primarily clinical, not biochemical, thereby shifting the emphasis to history, physical examination and ultrasound. It also requires the exclusion of other endocrinologic diseases such as thyroid or prolactin disorders, Cushing’s syndrome, or adult onset congenital adrenal hyperplasia.

The addition of ultrasonographic criteria for the diagnosis has effectively nearly doubled the prevalence of PCOS in the United States—and justifies the use of ultrasound to make the diagnosis.

When to use ultrasound in the diagnosis of PCOS

If you suspect PCOS but the patient has only oligo/anovulation or evidence of hyperandrogenism, it is quite reasonable to use vaginal ultrasound to establish the diagnosis, if the strict sonographic criteria are met.

If she has both oligo/anovulation and evidence of hyperandrogenism, however, the diagnosis is established and ultrasound is not necessary.

More promise for fertility preservation

Johnson J, Bagley J, Skaznik-Wikiel M, et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell. 2005;122:303–315.

For women interested in preserving their fertility, this finding suggests the possibility of harvesting and storing oogonial stem cells from a simple blood draw.

In a follow-up from Jonathan Tilly’s lab as reported in this column last year, this paper describes the latest advance in the oogonial stem cell story. The authors report that both bone marrow transplantation and peripheral blood transplantation restored oocytes in the ovaries of mice sterilized with chemotherapy. While the reproductive competence of the restored oocytes has not yet been determined, these findings suggest that germ line stem cells may reside in bone marrow and circulate in the blood stream.

Although a great deal of work is required to verify these findings and demonstrate them in humans, they highlight the astounding progress in the field of stem cell biology and emphasize the promise for fertility preservation in the future.

The author reports no financial relationships relevant to this article.

• Metformin as frontline treatment for ovulation induction and other PCOS-related disorders
• New PCOS diagnostic criteria

It seems that most advances in the field of infertility entail high-tech, high-risk therapies and expensive diagnostics that are the domain of subspecialists. But this year brought compelling evidence of a better “low-tech” treatment for a common dilemma that has challenged generalists and subspecialists alike for decades: PCOS-related infertility.

A more effective primary-care based strategy is all the more welcome because the difficulties encountered in helping women with PCOS achieve pregnancy have prompted many generalists to routinely refer these patients to subspecialty care.

There’s more: The same new findings that generalists can apply to management of infertility also apply to other PCOS-caused problems: abnormal bleeding, obesity, and cosmetic concerns.

The new research on PCOS also points out our need to stay up-to-date on the current definition and diagnostic criteria for PCOS—both have changed within the past 2 years.

In addition, as a follow-up to my comments in this column a year ago: new and exciting information on oogonial stem cells, though not of immediate clinical utility, may nevertheless be of interest for patients who desire to preserve their fertility.

Try metformin first for PCOS-related infertility

Palomba S, Orio F Jr, Falbo A, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4068–4074.

This study heralds a shift away from our typical approach. It argues that a trial of metformin for up to 6 months prior to an alternative strategy is very reasonable, and easily managed by any ObGyn.

Metformin has been utilized increasingly over the past decade to improve ovulation and conception rates in women with PCOS who wish to conceive. Traditionally, primary therapy has involved ovulation induction, initially with clomiphene citrate, frequently followed by gonadotropins due to failure of the initial therapy. Palomba and colleagues conducted the first well-designed, well-controlled head-to-head trial of metformin versus clomiphene citrate as frontline therapy to induce ovulation.

A total of 100 women with nonobese PCOS were randomly assigned to metformin (850 mg twice a day) or clomiphene citrate (150 mg on days 3–7 of each cycle) for 6 months. The main outcome measures were ovulation, pregnancy, abortion, and live-birth rates. More than 200 potential conception cycles were studied in each group.

Although metformin and clomiphene resulted in statistically similar rates of ovulation in the treatment groups (about 2 out of 3 cycles), there was a big difference in the pregnancy rates. The percycle pregnancy rate was twice as high in the metformin group (15.1% vs 7.2%, P=.009). The cumulative pregnancy rate was also far higher in the metformin group (68.9% vs 34.0%, P<.001), and the abortion rate was much lower (9.7% vs 37.5%).

Metformin’s benefits increase over time

Equally interesting was the progressive increase in both ovulation and conception rates in the metformin group during the course of the 6-month trial, compared with a progressive decrease in both the ovulation and conception rates in the clomiphene group—suggesting a cumulative benefit with ongoing metformin therapy. Although the trial was conducted in nonobese PCOS patients, it is reasonable to extrapolate the approach to the larger sub-group of women with PCOS who are obese.

Side effects. Metformin is relatively safe and well tolerated, except for a small percentage of women with intractable gastrointestinal (GI) side effects. The risk of multiple gestations does not increase.

Metformin for hirsutism and abnormal bleeding

While the Palomba study deals specifically with treatment of PCOS to induce pregnancy, the metabolic implications of inducing normal ovulation make this strategy applicable to the treatment of PCOS in women who are not attempting conception. It now appears reasonable to consider the use of metformin to help manage other issues such as hirsutism and abnormal bleeding, particularly when more conventional therapies have been insufficient.

Treatment tips

I now use metformin as first-line therapy in all patients with a confirmed diagnosis of PCOS regardless of the reason for therapy.

• Minimal pretreatment screening is appropriate to rule out thyroid or pituitary disorders, unsuspected renal disease, or actual diabetes mellitus.
• I titrate the dose over several weeks from an initial 500 mg daily with food to a target of 1,500 mg daily to help reduce GI symptoms.
• I prefer the extended-release preparation for its ease of use and (anecdotally) fewer side effects.

 

When to start additional therapy. If regular menses do not occur within 3 months on metformin alone, I add additional therapy as indicated.

A new way to define PCOS

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19–25.

The addition of ultrasonographic criteria for the diagnosis has effectively nearly doubled the prevalence of PCOS in the United States—and justifies the use of ultrasound to make the diagnosis.

In conjunction with the shift toward metformin as first-line therapy for ovulation induction in women with PCOS, it is important that ObGyns incorporate the latest clinical criteria for the diagnosis of PCOS.

3 clinical indicators

The “Rotterdam Criteria” from the 2003 Consensus Conference require 2 out of 3 clinical indicators to make the diagnosis:

1. Oligo- or anovulation,
2. Clinical and/or biochemical signs of hyperandrogenism, and
3. Polycystic ovaries as evidenced on ultrasound or histology. Ultrasound criteria for polycystic ovaries are specific: increased stroma-to-follicle ratio with multiple subcapsular early antral follicles.

It is also important to note that the diagnosis is primarily clinical, not biochemical, thereby shifting the emphasis to history, physical examination and ultrasound. It also requires the exclusion of other endocrinologic diseases such as thyroid or prolactin disorders, Cushing’s syndrome, or adult onset congenital adrenal hyperplasia.

The addition of ultrasonographic criteria for the diagnosis has effectively nearly doubled the prevalence of PCOS in the United States—and justifies the use of ultrasound to make the diagnosis.

When to use ultrasound in the diagnosis of PCOS

If you suspect PCOS but the patient has only oligo/anovulation or evidence of hyperandrogenism, it is quite reasonable to use vaginal ultrasound to establish the diagnosis, if the strict sonographic criteria are met.

If she has both oligo/anovulation and evidence of hyperandrogenism, however, the diagnosis is established and ultrasound is not necessary.

More promise for fertility preservation

Johnson J, Bagley J, Skaznik-Wikiel M, et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell. 2005;122:303–315.

For women interested in preserving their fertility, this finding suggests the possibility of harvesting and storing oogonial stem cells from a simple blood draw.

In a follow-up from Jonathan Tilly’s lab as reported in this column last year, this paper describes the latest advance in the oogonial stem cell story. The authors report that both bone marrow transplantation and peripheral blood transplantation restored oocytes in the ovaries of mice sterilized with chemotherapy. While the reproductive competence of the restored oocytes has not yet been determined, these findings suggest that germ line stem cells may reside in bone marrow and circulate in the blood stream.

Although a great deal of work is required to verify these findings and demonstrate them in humans, they highlight the astounding progress in the field of stem cell biology and emphasize the promise for fertility preservation in the future.

The author reports no financial relationships relevant to this article.

• Metformin as frontline treatment for ovulation induction and other PCOS-related disorders
• New PCOS diagnostic criteria

It seems that most advances in the field of infertility entail high-tech, high-risk therapies and expensive diagnostics that are the domain of subspecialists. But this year brought compelling evidence of a better “low-tech” treatment for a common dilemma that has challenged generalists and subspecialists alike for decades: PCOS-related infertility.

A more effective primary-care based strategy is all the more welcome because the difficulties encountered in helping women with PCOS achieve pregnancy have prompted many generalists to routinely refer these patients to subspecialty care.

There’s more: The same new findings that generalists can apply to management of infertility also apply to other PCOS-caused problems: abnormal bleeding, obesity, and cosmetic concerns.

The new research on PCOS also points out our need to stay up-to-date on the current definition and diagnostic criteria for PCOS—both have changed within the past 2 years.

In addition, as a follow-up to my comments in this column a year ago: new and exciting information on oogonial stem cells, though not of immediate clinical utility, may nevertheless be of interest for patients who desire to preserve their fertility.

Try metformin first for PCOS-related infertility

Palomba S, Orio F Jr, Falbo A, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4068–4074.

This study heralds a shift away from our typical approach. It argues that a trial of metformin for up to 6 months prior to an alternative strategy is very reasonable, and easily managed by any ObGyn.

Metformin has been utilized increasingly over the past decade to improve ovulation and conception rates in women with PCOS who wish to conceive. Traditionally, primary therapy has involved ovulation induction, initially with clomiphene citrate, frequently followed by gonadotropins due to failure of the initial therapy. Palomba and colleagues conducted the first well-designed, well-controlled head-to-head trial of metformin versus clomiphene citrate as frontline therapy to induce ovulation.

A total of 100 women with nonobese PCOS were randomly assigned to metformin (850 mg twice a day) or clomiphene citrate (150 mg on days 3–7 of each cycle) for 6 months. The main outcome measures were ovulation, pregnancy, abortion, and live-birth rates. More than 200 potential conception cycles were studied in each group.

Although metformin and clomiphene resulted in statistically similar rates of ovulation in the treatment groups (about 2 out of 3 cycles), there was a big difference in the pregnancy rates. The percycle pregnancy rate was twice as high in the metformin group (15.1% vs 7.2%, P=.009). The cumulative pregnancy rate was also far higher in the metformin group (68.9% vs 34.0%, P<.001), and the abortion rate was much lower (9.7% vs 37.5%).

Metformin’s benefits increase over time

Equally interesting was the progressive increase in both ovulation and conception rates in the metformin group during the course of the 6-month trial, compared with a progressive decrease in both the ovulation and conception rates in the clomiphene group—suggesting a cumulative benefit with ongoing metformin therapy. Although the trial was conducted in nonobese PCOS patients, it is reasonable to extrapolate the approach to the larger sub-group of women with PCOS who are obese.

Side effects. Metformin is relatively safe and well tolerated, except for a small percentage of women with intractable gastrointestinal (GI) side effects. The risk of multiple gestations does not increase.

Metformin for hirsutism and abnormal bleeding

While the Palomba study deals specifically with treatment of PCOS to induce pregnancy, the metabolic implications of inducing normal ovulation make this strategy applicable to the treatment of PCOS in women who are not attempting conception. It now appears reasonable to consider the use of metformin to help manage other issues such as hirsutism and abnormal bleeding, particularly when more conventional therapies have been insufficient.

Treatment tips

I now use metformin as first-line therapy in all patients with a confirmed diagnosis of PCOS regardless of the reason for therapy.

• Minimal pretreatment screening is appropriate to rule out thyroid or pituitary disorders, unsuspected renal disease, or actual diabetes mellitus.
• I titrate the dose over several weeks from an initial 500 mg daily with food to a target of 1,500 mg daily to help reduce GI symptoms.
• I prefer the extended-release preparation for its ease of use and (anecdotally) fewer side effects.

 

When to start additional therapy. If regular menses do not occur within 3 months on metformin alone, I add additional therapy as indicated.

A new way to define PCOS

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19–25.

The addition of ultrasonographic criteria for the diagnosis has effectively nearly doubled the prevalence of PCOS in the United States—and justifies the use of ultrasound to make the diagnosis.

In conjunction with the shift toward metformin as first-line therapy for ovulation induction in women with PCOS, it is important that ObGyns incorporate the latest clinical criteria for the diagnosis of PCOS.

3 clinical indicators

The “Rotterdam Criteria” from the 2003 Consensus Conference require 2 out of 3 clinical indicators to make the diagnosis:

1. Oligo- or anovulation,
2. Clinical and/or biochemical signs of hyperandrogenism, and
3. Polycystic ovaries as evidenced on ultrasound or histology. Ultrasound criteria for polycystic ovaries are specific: increased stroma-to-follicle ratio with multiple subcapsular early antral follicles.

It is also important to note that the diagnosis is primarily clinical, not biochemical, thereby shifting the emphasis to history, physical examination and ultrasound. It also requires the exclusion of other endocrinologic diseases such as thyroid or prolactin disorders, Cushing’s syndrome, or adult onset congenital adrenal hyperplasia.

The addition of ultrasonographic criteria for the diagnosis has effectively nearly doubled the prevalence of PCOS in the United States—and justifies the use of ultrasound to make the diagnosis.

When to use ultrasound in the diagnosis of PCOS

If you suspect PCOS but the patient has only oligo/anovulation or evidence of hyperandrogenism, it is quite reasonable to use vaginal ultrasound to establish the diagnosis, if the strict sonographic criteria are met.

If she has both oligo/anovulation and evidence of hyperandrogenism, however, the diagnosis is established and ultrasound is not necessary.

More promise for fertility preservation

Johnson J, Bagley J, Skaznik-Wikiel M, et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell. 2005;122:303–315.

For women interested in preserving their fertility, this finding suggests the possibility of harvesting and storing oogonial stem cells from a simple blood draw.

In a follow-up from Jonathan Tilly’s lab as reported in this column last year, this paper describes the latest advance in the oogonial stem cell story. The authors report that both bone marrow transplantation and peripheral blood transplantation restored oocytes in the ovaries of mice sterilized with chemotherapy. While the reproductive competence of the restored oocytes has not yet been determined, these findings suggest that germ line stem cells may reside in bone marrow and circulate in the blood stream.

Although a great deal of work is required to verify these findings and demonstrate them in humans, they highlight the astounding progress in the field of stem cell biology and emphasize the promise for fertility preservation in the future.

The author reports no financial relationships relevant to this article.

As predicted in this column a year ago, 2004 saw the emergence of human oocyte cryopreservation as a hot topic. Now, it is generally agreed that human oocyte cryopreservation is a technique that can be applied to clinical practice in certain circumstances, although general application will be hotly debated pending further adequate clinical trials.

Be prepared for questions when the marketing starts

We can expect younger patients wishing to preserve reproductive capacity to ask our advice on freezing their eggs. (This technology is of limited applicability to the average reproductive-aged woman). The official position of the American Society for Reproductive Medicine is that, until outcome data are available, it is too early to incorporate this practice into general use.

However, a growing number of assisted reproductive technology (ART) centers will be offering—and marketing—the procedure.

Related to the growing interest in preserving female fertility so that women can delay childbearing: a momentous discovery reported in 2004 suggests that our time-honored dogma on growth of new human oocytes may be wrong.

In addition, 2 laboratory studies suggest a future for assisted reproductive technologies, when every embryo is assessed for its likelihood to result in a healthy infant.

These reports demonstrate the excitement of translational research in bringing basic discoveries into the clinical arena. They highlight the incredible development of both stem cell biology and nanotechnology, and suggest how such fields are rapidly becoming relevant in the modern practice of infertility. While it is difficult to predict an accurate timeline, or certainty, of the application of these discoveries to a modern infertility practice, it is safe to say that these and similar discoveries will influence our usual practice in the foreseeable future.

Oocytes unlimited after all?

Johnson J, Canning J, Kaneko T, Pru J, Tilly J. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428:145–150.

Along-held belief is that women reach their peak oocyte number at midgestation, and that number continuously declines until oocytes are depleted, sometime after menopause. This study from Jonathan Tilly’s group at Harvard Medical School presents evidence for germline stem cells in the ovaries of mice capable of replenishing oocytes into adult life. Removal of these germline stem cells caused a rapid depletion of primordial follicles, suggesting that the primordial follicle reserve was continuously replenished from germline stem cells.

While it is quite a leap to assume that human ovaries contain similar germline stem cells, the possibility that reproductive age woman may be able to develop new oocytes is truly exciting. If such oogonial stem cells exist in women—and could be harvested and cryopreserved, as mature oocytes are now being harvested and preserved—it opens the possibility that a renewable supply of oocytes may be available for women who wish to preserve the capacity to reproduce.

Practical implications

Whether for personal use following cancer therapy or oophorectomy, or as a source of oocytes for donation to women who have lost ovarian function, the potential holds great promise. However, extensive further work is required, not the least of which is independent verification of Dr. Tilly’s findings and the extension of that discovery to women.

For the practicing obstetrician/gynecologist fielding a question about “growing new eggs” from a savvy patient surfing the Net, know that the concept has a scientific basis but is definitely not ready for prime time.

New standard ahead for embryo assessment

In vivo assessment without injury

Kulkarni RN, Roper MG, Dahlgren G, Shih DQ, Kauri LM, Peters JL, Stoffel M, Kennedy RT. Islet secretory defect in insulin receptor substrate 1 null mice is linked with reduced calcium signaling and expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SECA)-2b and -3. Diabetes. 2004;53:1517–1525.

The assessment of human embryos for their viability and the likelihood of implanting and developing into a healthy baby has been a challenge for in vitro fertilization programs worldwide. Recent interest has focused on removing single cells from embryos and performing genetic studies. However, this is expensive, time consuming, and runs the risk of damaging embryos in the process of removing single blastomeres.

This study by Kennedy and colleagues, while not immediately applicable to human ART programs, demonstrates a technique for monitoring the secretion products from individual pancreatic beta cells. Using microelectrodes placed adjacent to individually cultured beta cells, insulin secretion from each cell was estimated by measuring the number of exocytotic events in normal and IRS-1 knock-out mice. The in vivo measurement of specific secretion products from individual cells without injuring them is an exciting example of the miniaturization of clinical science.

 

Practical implications

The extension of this technique to the safe assessment of human embryos in vivo while they are in culture is logical and opens up an entire area of both investigation and potential clinical practice. If the metabolic activity of the individual embryos indicates the likelihood of implantation and development, then this could become a new standard in the assessment of every embryo resulting from an ART cycle.

Much work will be required to translate this exciting new technique to human embryos, but it does offer a logical approach to the longstanding problem of embryo assessment.

Real-time assessment

Schuster TG, Cho B, Keller LM, Takayama S, Smith GD. Isolation of motile spermatozoa from semen samples using microfluidics. Reproductive Biomedicine Online. 2004;1(Jul-Aug):75–81.

One of the challenges of assessing individual human embryos in vivo is the dilution effect on any secretion products secreted from an embryo into the relatively vast amount of media in a traditional ART Petri dish. This report describes the first of a series of microfluidic devices designed to separate motile from nonmotile spermatozoa in very small volumes. Such devices can be used to isolate motile sperm from nonmotile sperm and debris for ART procedures when numbers are exceptionally low.

However, similar microfluidic devices are being developed to include tiny chambers that could be used to contain individual human embryos receiving a constant stream of nutrient media with a constant output of spent media and secretory products. In conjunction with the capacity to analyze such tiny amounts of secretory products in vivo from individual cells, this suggests a system for evaluating all human embryos in modern microchambers and continually monitoring for appropriate secretion and subsequent selection for optimal reproductive capacity.

Practical implications

The promise of real-time embryo assessment is certainly upon us, though much work needs to be done to develop these microfluidic incubation chambers before they will be clinically applicable.

For the practicing Ob/Gyn, it is useful to know that the era of preimplantation evaluation of all embryos is not far off. Whether that will translate into fewer fetal/neonatal defects remains to be seen.

The author reports no financial relationships relevant to this article.

As predicted in this column a year ago, 2004 saw the emergence of human oocyte cryopreservation as a hot topic. Now, it is generally agreed that human oocyte cryopreservation is a technique that can be applied to clinical practice in certain circumstances, although general application will be hotly debated pending further adequate clinical trials.

Be prepared for questions when the marketing starts

We can expect younger patients wishing to preserve reproductive capacity to ask our advice on freezing their eggs. (This technology is of limited applicability to the average reproductive-aged woman). The official position of the American Society for Reproductive Medicine is that, until outcome data are available, it is too early to incorporate this practice into general use.

However, a growing number of assisted reproductive technology (ART) centers will be offering—and marketing—the procedure.

Related to the growing interest in preserving female fertility so that women can delay childbearing: a momentous discovery reported in 2004 suggests that our time-honored dogma on growth of new human oocytes may be wrong.

In addition, 2 laboratory studies suggest a future for assisted reproductive technologies, when every embryo is assessed for its likelihood to result in a healthy infant.

These reports demonstrate the excitement of translational research in bringing basic discoveries into the clinical arena. They highlight the incredible development of both stem cell biology and nanotechnology, and suggest how such fields are rapidly becoming relevant in the modern practice of infertility. While it is difficult to predict an accurate timeline, or certainty, of the application of these discoveries to a modern infertility practice, it is safe to say that these and similar discoveries will influence our usual practice in the foreseeable future.

Oocytes unlimited after all?

Johnson J, Canning J, Kaneko T, Pru J, Tilly J. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428:145–150.

Along-held belief is that women reach their peak oocyte number at midgestation, and that number continuously declines until oocytes are depleted, sometime after menopause. This study from Jonathan Tilly’s group at Harvard Medical School presents evidence for germline stem cells in the ovaries of mice capable of replenishing oocytes into adult life. Removal of these germline stem cells caused a rapid depletion of primordial follicles, suggesting that the primordial follicle reserve was continuously replenished from germline stem cells.

While it is quite a leap to assume that human ovaries contain similar germline stem cells, the possibility that reproductive age woman may be able to develop new oocytes is truly exciting. If such oogonial stem cells exist in women—and could be harvested and cryopreserved, as mature oocytes are now being harvested and preserved—it opens the possibility that a renewable supply of oocytes may be available for women who wish to preserve the capacity to reproduce.

Practical implications

Whether for personal use following cancer therapy or oophorectomy, or as a source of oocytes for donation to women who have lost ovarian function, the potential holds great promise. However, extensive further work is required, not the least of which is independent verification of Dr. Tilly’s findings and the extension of that discovery to women.

For the practicing obstetrician/gynecologist fielding a question about “growing new eggs” from a savvy patient surfing the Net, know that the concept has a scientific basis but is definitely not ready for prime time.

New standard ahead for embryo assessment

In vivo assessment without injury

Kulkarni RN, Roper MG, Dahlgren G, Shih DQ, Kauri LM, Peters JL, Stoffel M, Kennedy RT. Islet secretory defect in insulin receptor substrate 1 null mice is linked with reduced calcium signaling and expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SECA)-2b and -3. Diabetes. 2004;53:1517–1525.

The assessment of human embryos for their viability and the likelihood of implanting and developing into a healthy baby has been a challenge for in vitro fertilization programs worldwide. Recent interest has focused on removing single cells from embryos and performing genetic studies. However, this is expensive, time consuming, and runs the risk of damaging embryos in the process of removing single blastomeres.

This study by Kennedy and colleagues, while not immediately applicable to human ART programs, demonstrates a technique for monitoring the secretion products from individual pancreatic beta cells. Using microelectrodes placed adjacent to individually cultured beta cells, insulin secretion from each cell was estimated by measuring the number of exocytotic events in normal and IRS-1 knock-out mice. The in vivo measurement of specific secretion products from individual cells without injuring them is an exciting example of the miniaturization of clinical science.

 

Practical implications

The extension of this technique to the safe assessment of human embryos in vivo while they are in culture is logical and opens up an entire area of both investigation and potential clinical practice. If the metabolic activity of the individual embryos indicates the likelihood of implantation and development, then this could become a new standard in the assessment of every embryo resulting from an ART cycle.

Much work will be required to translate this exciting new technique to human embryos, but it does offer a logical approach to the longstanding problem of embryo assessment.

Real-time assessment

Schuster TG, Cho B, Keller LM, Takayama S, Smith GD. Isolation of motile spermatozoa from semen samples using microfluidics. Reproductive Biomedicine Online. 2004;1(Jul-Aug):75–81.

One of the challenges of assessing individual human embryos in vivo is the dilution effect on any secretion products secreted from an embryo into the relatively vast amount of media in a traditional ART Petri dish. This report describes the first of a series of microfluidic devices designed to separate motile from nonmotile spermatozoa in very small volumes. Such devices can be used to isolate motile sperm from nonmotile sperm and debris for ART procedures when numbers are exceptionally low.

However, similar microfluidic devices are being developed to include tiny chambers that could be used to contain individual human embryos receiving a constant stream of nutrient media with a constant output of spent media and secretory products. In conjunction with the capacity to analyze such tiny amounts of secretory products in vivo from individual cells, this suggests a system for evaluating all human embryos in modern microchambers and continually monitoring for appropriate secretion and subsequent selection for optimal reproductive capacity.

Practical implications

The promise of real-time embryo assessment is certainly upon us, though much work needs to be done to develop these microfluidic incubation chambers before they will be clinically applicable.

For the practicing Ob/Gyn, it is useful to know that the era of preimplantation evaluation of all embryos is not far off. Whether that will translate into fewer fetal/neonatal defects remains to be seen.

The author reports no financial relationships relevant to this article.

As predicted in this column a year ago, 2004 saw the emergence of human oocyte cryopreservation as a hot topic. Now, it is generally agreed that human oocyte cryopreservation is a technique that can be applied to clinical practice in certain circumstances, although general application will be hotly debated pending further adequate clinical trials.

Be prepared for questions when the marketing starts

We can expect younger patients wishing to preserve reproductive capacity to ask our advice on freezing their eggs. (This technology is of limited applicability to the average reproductive-aged woman). The official position of the American Society for Reproductive Medicine is that, until outcome data are available, it is too early to incorporate this practice into general use.

However, a growing number of assisted reproductive technology (ART) centers will be offering—and marketing—the procedure.

Related to the growing interest in preserving female fertility so that women can delay childbearing: a momentous discovery reported in 2004 suggests that our time-honored dogma on growth of new human oocytes may be wrong.

In addition, 2 laboratory studies suggest a future for assisted reproductive technologies, when every embryo is assessed for its likelihood to result in a healthy infant.

These reports demonstrate the excitement of translational research in bringing basic discoveries into the clinical arena. They highlight the incredible development of both stem cell biology and nanotechnology, and suggest how such fields are rapidly becoming relevant in the modern practice of infertility. While it is difficult to predict an accurate timeline, or certainty, of the application of these discoveries to a modern infertility practice, it is safe to say that these and similar discoveries will influence our usual practice in the foreseeable future.

Oocytes unlimited after all?

Johnson J, Canning J, Kaneko T, Pru J, Tilly J. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428:145–150.

Along-held belief is that women reach their peak oocyte number at midgestation, and that number continuously declines until oocytes are depleted, sometime after menopause. This study from Jonathan Tilly’s group at Harvard Medical School presents evidence for germline stem cells in the ovaries of mice capable of replenishing oocytes into adult life. Removal of these germline stem cells caused a rapid depletion of primordial follicles, suggesting that the primordial follicle reserve was continuously replenished from germline stem cells.

While it is quite a leap to assume that human ovaries contain similar germline stem cells, the possibility that reproductive age woman may be able to develop new oocytes is truly exciting. If such oogonial stem cells exist in women—and could be harvested and cryopreserved, as mature oocytes are now being harvested and preserved—it opens the possibility that a renewable supply of oocytes may be available for women who wish to preserve the capacity to reproduce.

Practical implications

Whether for personal use following cancer therapy or oophorectomy, or as a source of oocytes for donation to women who have lost ovarian function, the potential holds great promise. However, extensive further work is required, not the least of which is independent verification of Dr. Tilly’s findings and the extension of that discovery to women.

For the practicing obstetrician/gynecologist fielding a question about “growing new eggs” from a savvy patient surfing the Net, know that the concept has a scientific basis but is definitely not ready for prime time.

New standard ahead for embryo assessment

In vivo assessment without injury

Kulkarni RN, Roper MG, Dahlgren G, Shih DQ, Kauri LM, Peters JL, Stoffel M, Kennedy RT. Islet secretory defect in insulin receptor substrate 1 null mice is linked with reduced calcium signaling and expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SECA)-2b and -3. Diabetes. 2004;53:1517–1525.

The assessment of human embryos for their viability and the likelihood of implanting and developing into a healthy baby has been a challenge for in vitro fertilization programs worldwide. Recent interest has focused on removing single cells from embryos and performing genetic studies. However, this is expensive, time consuming, and runs the risk of damaging embryos in the process of removing single blastomeres.

This study by Kennedy and colleagues, while not immediately applicable to human ART programs, demonstrates a technique for monitoring the secretion products from individual pancreatic beta cells. Using microelectrodes placed adjacent to individually cultured beta cells, insulin secretion from each cell was estimated by measuring the number of exocytotic events in normal and IRS-1 knock-out mice. The in vivo measurement of specific secretion products from individual cells without injuring them is an exciting example of the miniaturization of clinical science.

 

Practical implications

The extension of this technique to the safe assessment of human embryos in vivo while they are in culture is logical and opens up an entire area of both investigation and potential clinical practice. If the metabolic activity of the individual embryos indicates the likelihood of implantation and development, then this could become a new standard in the assessment of every embryo resulting from an ART cycle.

Much work will be required to translate this exciting new technique to human embryos, but it does offer a logical approach to the longstanding problem of embryo assessment.

Real-time assessment

Schuster TG, Cho B, Keller LM, Takayama S, Smith GD. Isolation of motile spermatozoa from semen samples using microfluidics. Reproductive Biomedicine Online. 2004;1(Jul-Aug):75–81.

One of the challenges of assessing individual human embryos in vivo is the dilution effect on any secretion products secreted from an embryo into the relatively vast amount of media in a traditional ART Petri dish. This report describes the first of a series of microfluidic devices designed to separate motile from nonmotile spermatozoa in very small volumes. Such devices can be used to isolate motile sperm from nonmotile sperm and debris for ART procedures when numbers are exceptionally low.

However, similar microfluidic devices are being developed to include tiny chambers that could be used to contain individual human embryos receiving a constant stream of nutrient media with a constant output of spent media and secretory products. In conjunction with the capacity to analyze such tiny amounts of secretory products in vivo from individual cells, this suggests a system for evaluating all human embryos in modern microchambers and continually monitoring for appropriate secretion and subsequent selection for optimal reproductive capacity.

Practical implications

The promise of real-time embryo assessment is certainly upon us, though much work needs to be done to develop these microfluidic incubation chambers before they will be clinically applicable.

For the practicing Ob/Gyn, it is useful to know that the era of preimplantation evaluation of all embryos is not far off. Whether that will translate into fewer fetal/neonatal defects remains to be seen.

The author reports no financial relationships relevant to this article.

Advancements during the year 2003 propelled infertility therapy further than ever along its 20-year evolution toward extensive use of assisted reproductive technologies (ART) and the introduction of diagnostic genetics. Refreshingly, social and ethical implications were viewed with greater recognition that we must deal effectively with the repercussions of technical progress.

Basic evaluation still key; early referral appropriate. For the practicing Ob/Gyn already confused by the bewildering and growing array of options presented to patients, these changes do not mean that a basic infertility evaluation and primary therapy are inappropriate. However, early referral to a trusted, experienced infertility specialist before invasive diagnostic studies such as laparoscopy or aggressive therapies is now most appropriate.

This Update reviews trends in reproductive medicine that herald both clinical and social transformations.

Oocyte cryopreservation: Ready for prime time

Porcu E. Human oocyte cryopreservation: from basic research to clinical application. Tap Pharmaceuticals Endowed Lecture presented at: American Society for Reproductive Medicine 59th Annual Meeting; October 15, 2003; San Antonio, Tex.

Growing concern over the past decade about age-related infertility due to progressive loss of oocyte number and quality has prompted rapidly expanding use of donated oocytes from younger women. Due to technical difficulties in cryopreserving oocytes, it has not been clinically feasible to save eggs from young women for later use or for donation to other women from “egg banks,” as has been done with sperm for many years.

In a presentation on the research program in oocyte freezing at the University of Bologna, Italy, Dr. Eleonora Porcu elaborated on the last decade’s progress. She described progressively improving clinical pregnancy rates from cryopreserved eggs, and commented that clinical experience to date is sufficient to begin offering this option to women generally.

A growing number of centers are offering oocyte cryopreservation, although outcome data for specific centers are limited and no national aggregate data are yet available.

Cryopreservation will beat the biological clock. Although immediate clinical use of this technology will be directed to young women at risk for loss of ovarian function due to cancer therapy or oophorectomy, the social implications could be comparable to the introduction of effective contraception in the 1960s.

Just as oral contraceptives allowed women to delay childbearing and yet be sexually active, oocyte cryopreservation may allow women to delay childbearing without fear that the “biological clock” will strike midnight before they have had children.

More older mothers, more concerns. While demand for this service is undetermined, and many biological and financial issues remain to be delineated, this process will continue the trend to later childbearing and older mothers, with all their attendant social and medical concerns.

Prepare to provide referral services. It will be increasingly important for physicians to be aware of the availability of such services and to have a ready source of referral for their patients interested in pursuing oocyte cryopreservation.

On the horizon: Unlimited supply of gametes. In a scientifically related but much less clinically applicable presentation at the same meeting, Susan Rothmann, Roger Gosden, and Pasquale Patrizio described the status of research in germ-line stem cells and reviewed the evidence for oogonial stem cells in human ovaries and the efforts to isolate and cryopreserve such stem cells.

Although much work needs to be done before spermatogonial and oogonial stem cells can be isolated and stored from patients, this work holds the promise that storage of germ-line stem cells may provide an unlimited future supply of gametes for use in later reproduction.

Related Reading

Porcu E. Oocyte freezing. Semin Reprod Med. 2001;19:221-230.

Advances in genetic diagnosis will enable transfer of ‘normal’ embryos only

Wilton L, Voullaire L, Sargeant P, Williamson R, McBain J. Preimplantation aneuploidy screening using comparative genomic hybridization or fluorescence in situ hybridization of embryos from patients with recurrent implantation failure. Fertil Steril. 2003;80:860-868.

One of the hottest topics today in reproductive medicine is the increasing availability of preimplantation diagnosis to determine if embryos are genetically normal. This Australian study compared 2 methods of genetic evaluation for their sensitivity in identifying abnormalities and in predicting subsequent implantation and pregnancy rates. The investigators concluded that comparative genomic hybridization was more effective than fluorescence in situ hybridization in identifying chromosomally normal embryos.

Improved techniques will be universally applied, to maximize the likelihood of a positive outcome from any intervention.

Improved techniques will be used for all ART embryos. Although the specifics of individual laboratory techniques are of limited interest to the general Ob/Gyn, the study emphasizes a growing trend in ART that will have far-reaching consequences. Currently, preimplantation genetic diagnosis is offered to couples with known genetic defects and to an increasing number of older couples at greater risk of producing embryos with genetic abnormalities.

 

As the techniques improve in reliability, applicability, and cost-effectiveness, they will be universally applied to all embryos resulting from ART procedures, to the extent that only genetically “normal” embryos will be transferred. This has the potential to drive all infertility therapy in the direction of ART, to maximize the likelihood of a positive outcome from any intervention.

Surgery, superovulation will dwindle. The necessity of infertility surgery will continue to diminish and use of superovulation as an isolated therapy will disappear, since the number and quality of resulting fetuses cannot be controlled.

CDC study: Insured patients may opt for fewer embryos

Reynolds MA, Schieve LA, Jeng G, Peterson HB. Does insurance coverage decrease the risk for multiple births associated with assisted reproductive technology? Fertil Steril. 2003;80:16-23.

Multiple births have soared over the past generation, primarily because of ART, specifically superovulation and in vitro fertilization. The initial emphasis was simply to achieve pregnancy, but now, the medical and financial risks related to multiple gestation are a target of concern. Strategies to decrease multiple pregnancies and yet maintain high pregnancy rates are now a health policy priority.

CDC examines assisted reproduction outcomes in insured vs noninsured states. This CDC study compared ART practices and outcomes in 3 states with mandated ART insurance coverage (Illinois, Massachusetts, and Rhode Island) to 3 states without such mandated coverage (Indiana, Michigan, and New Jersey). Outcome measures were number of embryos transferred, multiple-birth rate, triplet or higher order birth rate, and triplet or higher order gestation rate. The study utilized data from the national registry for 1998.

A smaller proportion of procedures included transfer of 3 or more embryos in 2 of the 3 states with mandated insurance (Massachusetts, 64% and Rhode Island, 74%) than in the noninsurance states (82%), and the multiple-birth rate was lower in 1 of the mandated states (Massachusetts, 38%) than in the nonmandated states (43%). A trend toward fewer triplet or higher order births was seen in all mandated states, but was statistically significant only in Massachusetts.

Implication: Insurance may be a tool to reduce multiple births. While the magnitude of the differences in the number of embryos transferred and the multiple-birth rate was not great, this study does suggest that insurance coverage may be an effective way to modify practice patterns and outcomes. Higher order multiple-birth rates are substantially lower in countries with national health insurance and restrictions on the number of embryos transferred. In the United States, where most states have not mandated ART insurance and there is no restriction on number of embryos transferred, the decision and risks are assumed by the patient and practitioner.

The natural tendency is to maximize the yield from an expensive procedure, and accept the increased risk.

Without insurance, the motivation is maximum yield. Unlike health decisions where cost is less central, the natural tendency is to try to maximize the yield from a single expensive procedure and accept the increased risk. This study suggests that reducing personal financial risk can modify those decisions.

Would long-term savings offset higher insurance costs? The move to find ways to reduce the rate of multiple gestations is welcome news for the practicing Ob/Gyn. While any attempt to increase health-care coverage may seem counterintuitive in an era of escalating health costs, a subsequent reduction in the multiple-birth rate would provide long-term savings by reducing the number of multiple gestations and their well-documented increase in premature deliveries and long-term costs.

Be alert for cost-analysis studies in the upcoming year.

Dr. Randolph reports no affiliations or financial arrangements with any companies whose products are mentioned in this article.

Advancements during the year 2003 propelled infertility therapy further than ever along its 20-year evolution toward extensive use of assisted reproductive technologies (ART) and the introduction of diagnostic genetics. Refreshingly, social and ethical implications were viewed with greater recognition that we must deal effectively with the repercussions of technical progress.

Basic evaluation still key; early referral appropriate. For the practicing Ob/Gyn already confused by the bewildering and growing array of options presented to patients, these changes do not mean that a basic infertility evaluation and primary therapy are inappropriate. However, early referral to a trusted, experienced infertility specialist before invasive diagnostic studies such as laparoscopy or aggressive therapies is now most appropriate.

This Update reviews trends in reproductive medicine that herald both clinical and social transformations.

Oocyte cryopreservation: Ready for prime time

Porcu E. Human oocyte cryopreservation: from basic research to clinical application. Tap Pharmaceuticals Endowed Lecture presented at: American Society for Reproductive Medicine 59th Annual Meeting; October 15, 2003; San Antonio, Tex.

Growing concern over the past decade about age-related infertility due to progressive loss of oocyte number and quality has prompted rapidly expanding use of donated oocytes from younger women. Due to technical difficulties in cryopreserving oocytes, it has not been clinically feasible to save eggs from young women for later use or for donation to other women from “egg banks,” as has been done with sperm for many years.

In a presentation on the research program in oocyte freezing at the University of Bologna, Italy, Dr. Eleonora Porcu elaborated on the last decade’s progress. She described progressively improving clinical pregnancy rates from cryopreserved eggs, and commented that clinical experience to date is sufficient to begin offering this option to women generally.

A growing number of centers are offering oocyte cryopreservation, although outcome data for specific centers are limited and no national aggregate data are yet available.

Cryopreservation will beat the biological clock. Although immediate clinical use of this technology will be directed to young women at risk for loss of ovarian function due to cancer therapy or oophorectomy, the social implications could be comparable to the introduction of effective contraception in the 1960s.

Just as oral contraceptives allowed women to delay childbearing and yet be sexually active, oocyte cryopreservation may allow women to delay childbearing without fear that the “biological clock” will strike midnight before they have had children.

More older mothers, more concerns. While demand for this service is undetermined, and many biological and financial issues remain to be delineated, this process will continue the trend to later childbearing and older mothers, with all their attendant social and medical concerns.

Prepare to provide referral services. It will be increasingly important for physicians to be aware of the availability of such services and to have a ready source of referral for their patients interested in pursuing oocyte cryopreservation.

On the horizon: Unlimited supply of gametes. In a scientifically related but much less clinically applicable presentation at the same meeting, Susan Rothmann, Roger Gosden, and Pasquale Patrizio described the status of research in germ-line stem cells and reviewed the evidence for oogonial stem cells in human ovaries and the efforts to isolate and cryopreserve such stem cells.

Although much work needs to be done before spermatogonial and oogonial stem cells can be isolated and stored from patients, this work holds the promise that storage of germ-line stem cells may provide an unlimited future supply of gametes for use in later reproduction.

Related Reading

Porcu E. Oocyte freezing. Semin Reprod Med. 2001;19:221-230.

Advances in genetic diagnosis will enable transfer of ‘normal’ embryos only

Wilton L, Voullaire L, Sargeant P, Williamson R, McBain J. Preimplantation aneuploidy screening using comparative genomic hybridization or fluorescence in situ hybridization of embryos from patients with recurrent implantation failure. Fertil Steril. 2003;80:860-868.

One of the hottest topics today in reproductive medicine is the increasing availability of preimplantation diagnosis to determine if embryos are genetically normal. This Australian study compared 2 methods of genetic evaluation for their sensitivity in identifying abnormalities and in predicting subsequent implantation and pregnancy rates. The investigators concluded that comparative genomic hybridization was more effective than fluorescence in situ hybridization in identifying chromosomally normal embryos.

Improved techniques will be universally applied, to maximize the likelihood of a positive outcome from any intervention.

Improved techniques will be used for all ART embryos. Although the specifics of individual laboratory techniques are of limited interest to the general Ob/Gyn, the study emphasizes a growing trend in ART that will have far-reaching consequences. Currently, preimplantation genetic diagnosis is offered to couples with known genetic defects and to an increasing number of older couples at greater risk of producing embryos with genetic abnormalities.

 

As the techniques improve in reliability, applicability, and cost-effectiveness, they will be universally applied to all embryos resulting from ART procedures, to the extent that only genetically “normal” embryos will be transferred. This has the potential to drive all infertility therapy in the direction of ART, to maximize the likelihood of a positive outcome from any intervention.

Surgery, superovulation will dwindle. The necessity of infertility surgery will continue to diminish and use of superovulation as an isolated therapy will disappear, since the number and quality of resulting fetuses cannot be controlled.

CDC study: Insured patients may opt for fewer embryos

Reynolds MA, Schieve LA, Jeng G, Peterson HB. Does insurance coverage decrease the risk for multiple births associated with assisted reproductive technology? Fertil Steril. 2003;80:16-23.

Multiple births have soared over the past generation, primarily because of ART, specifically superovulation and in vitro fertilization. The initial emphasis was simply to achieve pregnancy, but now, the medical and financial risks related to multiple gestation are a target of concern. Strategies to decrease multiple pregnancies and yet maintain high pregnancy rates are now a health policy priority.

CDC examines assisted reproduction outcomes in insured vs noninsured states. This CDC study compared ART practices and outcomes in 3 states with mandated ART insurance coverage (Illinois, Massachusetts, and Rhode Island) to 3 states without such mandated coverage (Indiana, Michigan, and New Jersey). Outcome measures were number of embryos transferred, multiple-birth rate, triplet or higher order birth rate, and triplet or higher order gestation rate. The study utilized data from the national registry for 1998.

A smaller proportion of procedures included transfer of 3 or more embryos in 2 of the 3 states with mandated insurance (Massachusetts, 64% and Rhode Island, 74%) than in the noninsurance states (82%), and the multiple-birth rate was lower in 1 of the mandated states (Massachusetts, 38%) than in the nonmandated states (43%). A trend toward fewer triplet or higher order births was seen in all mandated states, but was statistically significant only in Massachusetts.

Implication: Insurance may be a tool to reduce multiple births. While the magnitude of the differences in the number of embryos transferred and the multiple-birth rate was not great, this study does suggest that insurance coverage may be an effective way to modify practice patterns and outcomes. Higher order multiple-birth rates are substantially lower in countries with national health insurance and restrictions on the number of embryos transferred. In the United States, where most states have not mandated ART insurance and there is no restriction on number of embryos transferred, the decision and risks are assumed by the patient and practitioner.

The natural tendency is to maximize the yield from an expensive procedure, and accept the increased risk.

Without insurance, the motivation is maximum yield. Unlike health decisions where cost is less central, the natural tendency is to try to maximize the yield from a single expensive procedure and accept the increased risk. This study suggests that reducing personal financial risk can modify those decisions.

Would long-term savings offset higher insurance costs? The move to find ways to reduce the rate of multiple gestations is welcome news for the practicing Ob/Gyn. While any attempt to increase health-care coverage may seem counterintuitive in an era of escalating health costs, a subsequent reduction in the multiple-birth rate would provide long-term savings by reducing the number of multiple gestations and their well-documented increase in premature deliveries and long-term costs.

Be alert for cost-analysis studies in the upcoming year.

Dr. Randolph reports no affiliations or financial arrangements with any companies whose products are mentioned in this article.

Advancements during the year 2003 propelled infertility therapy further than ever along its 20-year evolution toward extensive use of assisted reproductive technologies (ART) and the introduction of diagnostic genetics. Refreshingly, social and ethical implications were viewed with greater recognition that we must deal effectively with the repercussions of technical progress.

Basic evaluation still key; early referral appropriate. For the practicing Ob/Gyn already confused by the bewildering and growing array of options presented to patients, these changes do not mean that a basic infertility evaluation and primary therapy are inappropriate. However, early referral to a trusted, experienced infertility specialist before invasive diagnostic studies such as laparoscopy or aggressive therapies is now most appropriate.

This Update reviews trends in reproductive medicine that herald both clinical and social transformations.

Oocyte cryopreservation: Ready for prime time

Porcu E. Human oocyte cryopreservation: from basic research to clinical application. Tap Pharmaceuticals Endowed Lecture presented at: American Society for Reproductive Medicine 59th Annual Meeting; October 15, 2003; San Antonio, Tex.

Growing concern over the past decade about age-related infertility due to progressive loss of oocyte number and quality has prompted rapidly expanding use of donated oocytes from younger women. Due to technical difficulties in cryopreserving oocytes, it has not been clinically feasible to save eggs from young women for later use or for donation to other women from “egg banks,” as has been done with sperm for many years.

In a presentation on the research program in oocyte freezing at the University of Bologna, Italy, Dr. Eleonora Porcu elaborated on the last decade’s progress. She described progressively improving clinical pregnancy rates from cryopreserved eggs, and commented that clinical experience to date is sufficient to begin offering this option to women generally.

A growing number of centers are offering oocyte cryopreservation, although outcome data for specific centers are limited and no national aggregate data are yet available.

Cryopreservation will beat the biological clock. Although immediate clinical use of this technology will be directed to young women at risk for loss of ovarian function due to cancer therapy or oophorectomy, the social implications could be comparable to the introduction of effective contraception in the 1960s.

Just as oral contraceptives allowed women to delay childbearing and yet be sexually active, oocyte cryopreservation may allow women to delay childbearing without fear that the “biological clock” will strike midnight before they have had children.

More older mothers, more concerns. While demand for this service is undetermined, and many biological and financial issues remain to be delineated, this process will continue the trend to later childbearing and older mothers, with all their attendant social and medical concerns.

Prepare to provide referral services. It will be increasingly important for physicians to be aware of the availability of such services and to have a ready source of referral for their patients interested in pursuing oocyte cryopreservation.

On the horizon: Unlimited supply of gametes. In a scientifically related but much less clinically applicable presentation at the same meeting, Susan Rothmann, Roger Gosden, and Pasquale Patrizio described the status of research in germ-line stem cells and reviewed the evidence for oogonial stem cells in human ovaries and the efforts to isolate and cryopreserve such stem cells.

Although much work needs to be done before spermatogonial and oogonial stem cells can be isolated and stored from patients, this work holds the promise that storage of germ-line stem cells may provide an unlimited future supply of gametes for use in later reproduction.

Related Reading

Porcu E. Oocyte freezing. Semin Reprod Med. 2001;19:221-230.

Advances in genetic diagnosis will enable transfer of ‘normal’ embryos only

Wilton L, Voullaire L, Sargeant P, Williamson R, McBain J. Preimplantation aneuploidy screening using comparative genomic hybridization or fluorescence in situ hybridization of embryos from patients with recurrent implantation failure. Fertil Steril. 2003;80:860-868.

One of the hottest topics today in reproductive medicine is the increasing availability of preimplantation diagnosis to determine if embryos are genetically normal. This Australian study compared 2 methods of genetic evaluation for their sensitivity in identifying abnormalities and in predicting subsequent implantation and pregnancy rates. The investigators concluded that comparative genomic hybridization was more effective than fluorescence in situ hybridization in identifying chromosomally normal embryos.

Improved techniques will be universally applied, to maximize the likelihood of a positive outcome from any intervention.

Improved techniques will be used for all ART embryos. Although the specifics of individual laboratory techniques are of limited interest to the general Ob/Gyn, the study emphasizes a growing trend in ART that will have far-reaching consequences. Currently, preimplantation genetic diagnosis is offered to couples with known genetic defects and to an increasing number of older couples at greater risk of producing embryos with genetic abnormalities.

 

As the techniques improve in reliability, applicability, and cost-effectiveness, they will be universally applied to all embryos resulting from ART procedures, to the extent that only genetically “normal” embryos will be transferred. This has the potential to drive all infertility therapy in the direction of ART, to maximize the likelihood of a positive outcome from any intervention.

Surgery, superovulation will dwindle. The necessity of infertility surgery will continue to diminish and use of superovulation as an isolated therapy will disappear, since the number and quality of resulting fetuses cannot be controlled.

CDC study: Insured patients may opt for fewer embryos

Reynolds MA, Schieve LA, Jeng G, Peterson HB. Does insurance coverage decrease the risk for multiple births associated with assisted reproductive technology? Fertil Steril. 2003;80:16-23.

Multiple births have soared over the past generation, primarily because of ART, specifically superovulation and in vitro fertilization. The initial emphasis was simply to achieve pregnancy, but now, the medical and financial risks related to multiple gestation are a target of concern. Strategies to decrease multiple pregnancies and yet maintain high pregnancy rates are now a health policy priority.

CDC examines assisted reproduction outcomes in insured vs noninsured states. This CDC study compared ART practices and outcomes in 3 states with mandated ART insurance coverage (Illinois, Massachusetts, and Rhode Island) to 3 states without such mandated coverage (Indiana, Michigan, and New Jersey). Outcome measures were number of embryos transferred, multiple-birth rate, triplet or higher order birth rate, and triplet or higher order gestation rate. The study utilized data from the national registry for 1998.

A smaller proportion of procedures included transfer of 3 or more embryos in 2 of the 3 states with mandated insurance (Massachusetts, 64% and Rhode Island, 74%) than in the noninsurance states (82%), and the multiple-birth rate was lower in 1 of the mandated states (Massachusetts, 38%) than in the nonmandated states (43%). A trend toward fewer triplet or higher order births was seen in all mandated states, but was statistically significant only in Massachusetts.

Implication: Insurance may be a tool to reduce multiple births. While the magnitude of the differences in the number of embryos transferred and the multiple-birth rate was not great, this study does suggest that insurance coverage may be an effective way to modify practice patterns and outcomes. Higher order multiple-birth rates are substantially lower in countries with national health insurance and restrictions on the number of embryos transferred. In the United States, where most states have not mandated ART insurance and there is no restriction on number of embryos transferred, the decision and risks are assumed by the patient and practitioner.

The natural tendency is to maximize the yield from an expensive procedure, and accept the increased risk.

Without insurance, the motivation is maximum yield. Unlike health decisions where cost is less central, the natural tendency is to try to maximize the yield from a single expensive procedure and accept the increased risk. This study suggests that reducing personal financial risk can modify those decisions.

Would long-term savings offset higher insurance costs? The move to find ways to reduce the rate of multiple gestations is welcome news for the practicing Ob/Gyn. While any attempt to increase health-care coverage may seem counterintuitive in an era of escalating health costs, a subsequent reduction in the multiple-birth rate would provide long-term savings by reducing the number of multiple gestations and their well-documented increase in premature deliveries and long-term costs.

Be alert for cost-analysis studies in the upcoming year.

Dr. Randolph reports no affiliations or financial arrangements with any companies whose products are mentioned in this article.