Women's Health

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

Cigarette smoking has been linked to the diagnosis of bacterial vaginosis (BV) and other genital infections including herpes simplex virus type 2, Chlamydia trachomatis, and oral and genital human papillomavirus (HPV).  Nicotine’s major metabolite, cotinine, has been found to concentrate in cervical mucus.

In 2014, researchers from Montana State University confirmed that the composition of the vaginal microbiota is “strongly associated with smoking.” They reported that women whose vaginal microbiota lacked significant numbers of Lactobacillus spp were 25-fold more likely to report current smoking than those with microbiota dominated by Lactobacillus crispatus (L crispatus). The researchers note that most Lactobacillus spp are thought to provide broad-spectrum protection to pathogenic infections by reducing vaginal pH.

But what is the mechanistic link between smoking and its effects on the vaginal microenvironment? The researchers conducted further study to assess the metabolome, a set of small molecule chemicals that includes host and microbial-produced and modified biomolecules as well as exogenous chemicals. The metabolome is an important characteristic of the vaginal microenvironment; the researchers say; differences in some metabolites are associated with functional variations of the vaginal microbiota. 

The analysis revealed samples clustered into 3 community state types (CSTs): CST-I (L crispatus dominated), CST-III (L iners dominated) and CST-IV (low Lactobacillus). Overall, smoking did not affect the vaginal metabolome after controlling for CSTs, but the researchers identified “an extensive and diverse range” of vaginal metabolites for which profiles were affected by both the microbiology and smoking status. They found 607 compounds in 36 women, including 12 metabolites that differed significantly between smokers and nonsmokers. Bacterial composition was the most pronounced driver of the vaginal metabolome, they say, associated with changes in 57% of all metabolites. As expected, nicotine, cotinine, and hydroxycotinine were markedly elevated in smokers’ vaginas.

Another “key finding,” the researchers say, was a significant increase in the abundance of various biogenic amines among smokers, far more pronounced in women with a low level of Lactobacillus. Biogenic amines are essential, they note, to mammalian and bacterial physiology. (Several are implicated in the “fishy” odor of BV.)

Their study serves as a pilot study, the researchers say, for future examinations of the connections between smoking and poor gynecologic and reproductive health outcomes.

Cigarette smoking has been linked to the diagnosis of bacterial vaginosis (BV) and other genital infections including herpes simplex virus type 2, Chlamydia trachomatis, and oral and genital human papillomavirus (HPV).  Nicotine’s major metabolite, cotinine, has been found to concentrate in cervical mucus.

In 2014, researchers from Montana State University confirmed that the composition of the vaginal microbiota is “strongly associated with smoking.” They reported that women whose vaginal microbiota lacked significant numbers of Lactobacillus spp were 25-fold more likely to report current smoking than those with microbiota dominated by Lactobacillus crispatus (L crispatus). The researchers note that most Lactobacillus spp are thought to provide broad-spectrum protection to pathogenic infections by reducing vaginal pH.

But what is the mechanistic link between smoking and its effects on the vaginal microenvironment? The researchers conducted further study to assess the metabolome, a set of small molecule chemicals that includes host and microbial-produced and modified biomolecules as well as exogenous chemicals. The metabolome is an important characteristic of the vaginal microenvironment; the researchers say; differences in some metabolites are associated with functional variations of the vaginal microbiota. 

The analysis revealed samples clustered into 3 community state types (CSTs): CST-I (L crispatus dominated), CST-III (L iners dominated) and CST-IV (low Lactobacillus). Overall, smoking did not affect the vaginal metabolome after controlling for CSTs, but the researchers identified “an extensive and diverse range” of vaginal metabolites for which profiles were affected by both the microbiology and smoking status. They found 607 compounds in 36 women, including 12 metabolites that differed significantly between smokers and nonsmokers. Bacterial composition was the most pronounced driver of the vaginal metabolome, they say, associated with changes in 57% of all metabolites. As expected, nicotine, cotinine, and hydroxycotinine were markedly elevated in smokers’ vaginas.

Another “key finding,” the researchers say, was a significant increase in the abundance of various biogenic amines among smokers, far more pronounced in women with a low level of Lactobacillus. Biogenic amines are essential, they note, to mammalian and bacterial physiology. (Several are implicated in the “fishy” odor of BV.)

Their study serves as a pilot study, the researchers say, for future examinations of the connections between smoking and poor gynecologic and reproductive health outcomes.

Cigarette smoking has been linked to the diagnosis of bacterial vaginosis (BV) and other genital infections including herpes simplex virus type 2, Chlamydia trachomatis, and oral and genital human papillomavirus (HPV).  Nicotine’s major metabolite, cotinine, has been found to concentrate in cervical mucus.

In 2014, researchers from Montana State University confirmed that the composition of the vaginal microbiota is “strongly associated with smoking.” They reported that women whose vaginal microbiota lacked significant numbers of Lactobacillus spp were 25-fold more likely to report current smoking than those with microbiota dominated by Lactobacillus crispatus (L crispatus). The researchers note that most Lactobacillus spp are thought to provide broad-spectrum protection to pathogenic infections by reducing vaginal pH.

But what is the mechanistic link between smoking and its effects on the vaginal microenvironment? The researchers conducted further study to assess the metabolome, a set of small molecule chemicals that includes host and microbial-produced and modified biomolecules as well as exogenous chemicals. The metabolome is an important characteristic of the vaginal microenvironment; the researchers say; differences in some metabolites are associated with functional variations of the vaginal microbiota. 

The analysis revealed samples clustered into 3 community state types (CSTs): CST-I (L crispatus dominated), CST-III (L iners dominated) and CST-IV (low Lactobacillus). Overall, smoking did not affect the vaginal metabolome after controlling for CSTs, but the researchers identified “an extensive and diverse range” of vaginal metabolites for which profiles were affected by both the microbiology and smoking status. They found 607 compounds in 36 women, including 12 metabolites that differed significantly between smokers and nonsmokers. Bacterial composition was the most pronounced driver of the vaginal metabolome, they say, associated with changes in 57% of all metabolites. As expected, nicotine, cotinine, and hydroxycotinine were markedly elevated in smokers’ vaginas.

Another “key finding,” the researchers say, was a significant increase in the abundance of various biogenic amines among smokers, far more pronounced in women with a low level of Lactobacillus. Biogenic amines are essential, they note, to mammalian and bacterial physiology. (Several are implicated in the “fishy” odor of BV.)

Their study serves as a pilot study, the researchers say, for future examinations of the connections between smoking and poor gynecologic and reproductive health outcomes.

Here are 5 articles from the May issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Subclinical hypothyroidism boosts immediate risk of heart failure

To take the posttest, go to: https://bit.ly/2IK0YiL
Expires January 24, 2020

2. Meta-analysis supports aspirin to reduce cardiovascular events

To take the posttest, go to: https://bit.ly/2GJLgSB
Expires January 24, 2020

3. Age of migraine onset may affect stroke risk

To take the posttest, go to: https://bit.ly/2ZAJ5YR
Expires January 24, 2020

4. Women with RA have reduced chance of live birth after assisted reproduction treatment

To take the posttest, go to: https://bit.ly/2VvKRLF
Expires January 27, 2020

5. New SLE disease activity measure beats SLEDAI-2K

To take the posttest, go to: https://bit.ly/2W8SVPA
Expires January 31, 2020

Here are 5 articles from the May issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Subclinical hypothyroidism boosts immediate risk of heart failure

To take the posttest, go to: https://bit.ly/2IK0YiL
Expires January 24, 2020

2. Meta-analysis supports aspirin to reduce cardiovascular events

To take the posttest, go to: https://bit.ly/2GJLgSB
Expires January 24, 2020

3. Age of migraine onset may affect stroke risk

To take the posttest, go to: https://bit.ly/2ZAJ5YR
Expires January 24, 2020

4. Women with RA have reduced chance of live birth after assisted reproduction treatment

To take the posttest, go to: https://bit.ly/2VvKRLF
Expires January 27, 2020

5. New SLE disease activity measure beats SLEDAI-2K

To take the posttest, go to: https://bit.ly/2W8SVPA
Expires January 31, 2020

Here are 5 articles from the May issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Subclinical hypothyroidism boosts immediate risk of heart failure

To take the posttest, go to: https://bit.ly/2IK0YiL
Expires January 24, 2020

2. Meta-analysis supports aspirin to reduce cardiovascular events

To take the posttest, go to: https://bit.ly/2GJLgSB
Expires January 24, 2020

3. Age of migraine onset may affect stroke risk

To take the posttest, go to: https://bit.ly/2ZAJ5YR
Expires January 24, 2020

4. Women with RA have reduced chance of live birth after assisted reproduction treatment

To take the posttest, go to: https://bit.ly/2VvKRLF
Expires January 27, 2020

5. New SLE disease activity measure beats SLEDAI-2K

To take the posttest, go to: https://bit.ly/2W8SVPA
Expires January 31, 2020

The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m², a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”

Alexander Raths/Fotolia

My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.¹ If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.

What are compounded bioidentical hormones?

The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.

An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.

How do they differ from synthetic hormones?

Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.

Critics of CBHT, which includes the North American Menopause Society² and the American College of Obstetricians and Gynecologists,³ highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.

What drives patients’ decision to use compounded bioidentical hormones?

After the Womens’ Health Initiative study was published in 2002⁵, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.

But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.⁶ Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).

Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.

Are bioidentical hormones safe with respect to cancer risk?

Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.

How should we counsel patients?

Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.

We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at [email protected].

References:

1. Maturitas. 2014 Jan;77(1):4-6.

2. Menopause. 2014 Dec;21(12):1298-300.

3. Fertil Steril. 2012 Aug;98(2):308-12.

4. Report: Limited FDA survey of compounded drug products (Silver Spring, Md.: U.S. Food and Drug Administration, 2009).

5. JAMA. 2002;288(3):321-33.

6. BMC Womens Health. 2017 Oct 2;17(1):97.

The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m², a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”

Alexander Raths/Fotolia

My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.¹ If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.

What are compounded bioidentical hormones?

The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.

An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.

How do they differ from synthetic hormones?

Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.

Critics of CBHT, which includes the North American Menopause Society² and the American College of Obstetricians and Gynecologists,³ highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.

What drives patients’ decision to use compounded bioidentical hormones?

After the Womens’ Health Initiative study was published in 2002⁵, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.

But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.⁶ Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).

Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.

Are bioidentical hormones safe with respect to cancer risk?

Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.

How should we counsel patients?

Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.

We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at [email protected].

References:

1. Maturitas. 2014 Jan;77(1):4-6.

2. Menopause. 2014 Dec;21(12):1298-300.

3. Fertil Steril. 2012 Aug;98(2):308-12.

4. Report: Limited FDA survey of compounded drug products (Silver Spring, Md.: U.S. Food and Drug Administration, 2009).

5. JAMA. 2002;288(3):321-33.

6. BMC Womens Health. 2017 Oct 2;17(1):97.

The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m², a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”

Alexander Raths/Fotolia

My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.¹ If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.

What are compounded bioidentical hormones?

The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.

An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.

How do they differ from synthetic hormones?

Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.

Critics of CBHT, which includes the North American Menopause Society² and the American College of Obstetricians and Gynecologists,³ highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.

What drives patients’ decision to use compounded bioidentical hormones?

After the Womens’ Health Initiative study was published in 2002⁵, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.

But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.⁶ Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).

Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.

Are bioidentical hormones safe with respect to cancer risk?

Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.

How should we counsel patients?

Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.

We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at [email protected].

References:

1. Maturitas. 2014 Jan;77(1):4-6.

2. Menopause. 2014 Dec;21(12):1298-300.

3. Fertil Steril. 2012 Aug;98(2):308-12.

4. Report: Limited FDA survey of compounded drug products (Silver Spring, Md.: U.S. Food and Drug Administration, 2009).

5. JAMA. 2002;288(3):321-33.

6. BMC Womens Health. 2017 Oct 2;17(1):97.

LOS ANGELES – In patients with end-stage renal disease, women older than 50 years have a significantly higher mortality, compared with their male counterparts, results from an analysis of national data showed.

“The racial and ethnic disparities in the prevalence, treatment, risks, and outcomes of [hypertension] in patients with CKD [chronic kidney disease], are well recognized,” the study’s senior author, Ricardo Correa, MD, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “Whites have better control of blood pressure, compared with Hispanics or African Americans with CKD, for example. On the other hand, gender differences in the outcome of blood pressure control and mortality across the different CKD stages have been very poorly studied, with conflicting results.”

The importance of gender difference has been mostly the focus in cardiovascular diseases, he continued, with compelling data revealing a higher incidence in men than in women of similar age, and a menopause-associated increase in cardiovascular disease in women.

“Whether the same can be said for hypertension, remains to be elucidated,” said Dr. Correa, an endocrinologist who directs the diabetes and metabolism fellowship at the University of Arizona in Phoenix.

In what he said is the first study of its kind, Dr. Correa and his colleagues set out to determine if gender in the U.S. population and menopausal age affect the inpatient survival rate in hypertensive patients across different stages of CKD. They drew from the 2005-2012 National Inpatient Sample to identify 2,121,750 hospitalized hypertensive patients and compared a number of factors between men and women, including crude mortality and mortality per CKD stage, menopausal age, length of stay, and total hospital charges.

Of the 2,121,750 patients, 1,092,931 (52%) were men and 1,028,819 (48%) were women; their mean age was 65 years. Among women, 32% had stage 3 CKD, 15% had stage 4 disease, 3% had stage 5 CKD, and 54% had end-stage renal disease (ESRD). Among men, 33% had stage 3 CKD, 13% had stage 4 disease, 3% had stage 5 CKD, and 51% had ESRD. The researchers observed that in-hospital crude mortality was significantly higher for men, compared with a matched group of women at CKD stages 3 and 4 (3.09% vs. 3.29% for CDK 3; P less than .0001 and 4.05% vs. 4.36% for CDK 4; P = .0004), yet was nonsignificant among those with ESRD (4.68% vs. 4.83%; P = .45).

“One could hypothesize that cardiac remodeling in hemodialysis women may be different than that in hemodialysis men to the extent that it affects mortality,” Dr. Correa said. “However, it is unclear if the survival benefit for dialysis men is owing to the possibility of a selection bias or not. Dialysis women may not be receiving equal access to cardiovascular procedures or surgical interventions (arteriovenous fistula, for example) or women may not be offered adequate hemodialysis to the same extent as men are. Further investigations regarding sex-based differences in dialysis treatment are required.”

He acknowledged certain limitations of the study, including its observational design. “We lacked detailed information regarding the cause of death, dialysis efficiency, types of dialysis accesses, and left ventricular hypertrophy measurements. We did not account for transitions between different hemodialysis modalities [and] we do not have information about distances or traveling time to dialysis units.”

The study’s first author was Kelvin Tran, MD. The researchers reported having no financial disclosures.

[email protected]

LOS ANGELES – In patients with end-stage renal disease, women older than 50 years have a significantly higher mortality, compared with their male counterparts, results from an analysis of national data showed.

“The racial and ethnic disparities in the prevalence, treatment, risks, and outcomes of [hypertension] in patients with CKD [chronic kidney disease], are well recognized,” the study’s senior author, Ricardo Correa, MD, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “Whites have better control of blood pressure, compared with Hispanics or African Americans with CKD, for example. On the other hand, gender differences in the outcome of blood pressure control and mortality across the different CKD stages have been very poorly studied, with conflicting results.”

The importance of gender difference has been mostly the focus in cardiovascular diseases, he continued, with compelling data revealing a higher incidence in men than in women of similar age, and a menopause-associated increase in cardiovascular disease in women.

“Whether the same can be said for hypertension, remains to be elucidated,” said Dr. Correa, an endocrinologist who directs the diabetes and metabolism fellowship at the University of Arizona in Phoenix.

In what he said is the first study of its kind, Dr. Correa and his colleagues set out to determine if gender in the U.S. population and menopausal age affect the inpatient survival rate in hypertensive patients across different stages of CKD. They drew from the 2005-2012 National Inpatient Sample to identify 2,121,750 hospitalized hypertensive patients and compared a number of factors between men and women, including crude mortality and mortality per CKD stage, menopausal age, length of stay, and total hospital charges.

Of the 2,121,750 patients, 1,092,931 (52%) were men and 1,028,819 (48%) were women; their mean age was 65 years. Among women, 32% had stage 3 CKD, 15% had stage 4 disease, 3% had stage 5 CKD, and 54% had end-stage renal disease (ESRD). Among men, 33% had stage 3 CKD, 13% had stage 4 disease, 3% had stage 5 CKD, and 51% had ESRD. The researchers observed that in-hospital crude mortality was significantly higher for men, compared with a matched group of women at CKD stages 3 and 4 (3.09% vs. 3.29% for CDK 3; P less than .0001 and 4.05% vs. 4.36% for CDK 4; P = .0004), yet was nonsignificant among those with ESRD (4.68% vs. 4.83%; P = .45).

“One could hypothesize that cardiac remodeling in hemodialysis women may be different than that in hemodialysis men to the extent that it affects mortality,” Dr. Correa said. “However, it is unclear if the survival benefit for dialysis men is owing to the possibility of a selection bias or not. Dialysis women may not be receiving equal access to cardiovascular procedures or surgical interventions (arteriovenous fistula, for example) or women may not be offered adequate hemodialysis to the same extent as men are. Further investigations regarding sex-based differences in dialysis treatment are required.”

He acknowledged certain limitations of the study, including its observational design. “We lacked detailed information regarding the cause of death, dialysis efficiency, types of dialysis accesses, and left ventricular hypertrophy measurements. We did not account for transitions between different hemodialysis modalities [and] we do not have information about distances or traveling time to dialysis units.”

The study’s first author was Kelvin Tran, MD. The researchers reported having no financial disclosures.

[email protected]

LOS ANGELES – In patients with end-stage renal disease, women older than 50 years have a significantly higher mortality, compared with their male counterparts, results from an analysis of national data showed.

“The racial and ethnic disparities in the prevalence, treatment, risks, and outcomes of [hypertension] in patients with CKD [chronic kidney disease], are well recognized,” the study’s senior author, Ricardo Correa, MD, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “Whites have better control of blood pressure, compared with Hispanics or African Americans with CKD, for example. On the other hand, gender differences in the outcome of blood pressure control and mortality across the different CKD stages have been very poorly studied, with conflicting results.”

The importance of gender difference has been mostly the focus in cardiovascular diseases, he continued, with compelling data revealing a higher incidence in men than in women of similar age, and a menopause-associated increase in cardiovascular disease in women.

“Whether the same can be said for hypertension, remains to be elucidated,” said Dr. Correa, an endocrinologist who directs the diabetes and metabolism fellowship at the University of Arizona in Phoenix.

In what he said is the first study of its kind, Dr. Correa and his colleagues set out to determine if gender in the U.S. population and menopausal age affect the inpatient survival rate in hypertensive patients across different stages of CKD. They drew from the 2005-2012 National Inpatient Sample to identify 2,121,750 hospitalized hypertensive patients and compared a number of factors between men and women, including crude mortality and mortality per CKD stage, menopausal age, length of stay, and total hospital charges.

Of the 2,121,750 patients, 1,092,931 (52%) were men and 1,028,819 (48%) were women; their mean age was 65 years. Among women, 32% had stage 3 CKD, 15% had stage 4 disease, 3% had stage 5 CKD, and 54% had end-stage renal disease (ESRD). Among men, 33% had stage 3 CKD, 13% had stage 4 disease, 3% had stage 5 CKD, and 51% had ESRD. The researchers observed that in-hospital crude mortality was significantly higher for men, compared with a matched group of women at CKD stages 3 and 4 (3.09% vs. 3.29% for CDK 3; P less than .0001 and 4.05% vs. 4.36% for CDK 4; P = .0004), yet was nonsignificant among those with ESRD (4.68% vs. 4.83%; P = .45).

“One could hypothesize that cardiac remodeling in hemodialysis women may be different than that in hemodialysis men to the extent that it affects mortality,” Dr. Correa said. “However, it is unclear if the survival benefit for dialysis men is owing to the possibility of a selection bias or not. Dialysis women may not be receiving equal access to cardiovascular procedures or surgical interventions (arteriovenous fistula, for example) or women may not be offered adequate hemodialysis to the same extent as men are. Further investigations regarding sex-based differences in dialysis treatment are required.”

He acknowledged certain limitations of the study, including its observational design. “We lacked detailed information regarding the cause of death, dialysis efficiency, types of dialysis accesses, and left ventricular hypertrophy measurements. We did not account for transitions between different hemodialysis modalities [and] we do not have information about distances or traveling time to dialysis units.”

The study’s first author was Kelvin Tran, MD. The researchers reported having no financial disclosures.

[email protected]

Two federal judges have temporarily barred the Trump administration from making changes to the Title X program that would restrict funding from clinics that provide abortion counseling or that refer patients for abortion services.

jsmith/iStockphoto

U.S. District Judge Stanley Bastian for the District of Eastern Washington on April 25 approved a temporary nationwide ban against the program changes in response to legal a challenge by Washington state. The same day, U.S. District Judge for the District of Oregon Michael J. McShane also preliminarily barred the restrictions from taking effect in response to a legal challenge by the American Medical Association and the Planned Parenthood Federation of America.

Judge McShane called the program restrictions “arbitrary and capricious,” and wrote that the rules ignore comprehensive, ethical, and evidence-based health care, and impermissibly interfere with the patient-doctor relationship. Judge Bastian agreed, writing in his order that the plaintiffs have demonstrated that the restrictions violate the central purpose of Title X, which is to equalize access to comprehensive, evidence-based, and voluntary family planning.

“Plaintiffs have demonstrated they are likely to suffer irreparable harm in the absence of a preliminary injunction by presenting facts and argument that the final rule may or likely will: seriously disrupt or destroy the existing network of Title X providers in both the State of Washington and throughout the entire nation,” Judge Bastian wrote in his order.

Changes to the Title X program – scheduled to take effect May 3 – would have made health clinics ineligible for Title X funding if they offer, promote, or support abortion as a method of family planning. Title X grants generally go to health centers that provide reproductive health care – such as STD-testing, cancer screenings, and contraception – to low-income families. Under the rule, the government would withdraw financial assistance to clinics if they allow counseling or referrals associated with abortion, regardless of whether the money is used for other health care services.

HHS officials said that the final rule will provide for clear financial and physical separation between Title X and non–Title X activities, reduce confusion on the part of Title X clinics and the public about permissible Title X activities, and improve program transparency by requiring more complete reporting by grantees about their partnerships with referral agencies.

Two federal judges have temporarily barred the Trump administration from making changes to the Title X program that would restrict funding from clinics that provide abortion counseling or that refer patients for abortion services.

jsmith/iStockphoto

U.S. District Judge Stanley Bastian for the District of Eastern Washington on April 25 approved a temporary nationwide ban against the program changes in response to legal a challenge by Washington state. The same day, U.S. District Judge for the District of Oregon Michael J. McShane also preliminarily barred the restrictions from taking effect in response to a legal challenge by the American Medical Association and the Planned Parenthood Federation of America.

Judge McShane called the program restrictions “arbitrary and capricious,” and wrote that the rules ignore comprehensive, ethical, and evidence-based health care, and impermissibly interfere with the patient-doctor relationship. Judge Bastian agreed, writing in his order that the plaintiffs have demonstrated that the restrictions violate the central purpose of Title X, which is to equalize access to comprehensive, evidence-based, and voluntary family planning.

“Plaintiffs have demonstrated they are likely to suffer irreparable harm in the absence of a preliminary injunction by presenting facts and argument that the final rule may or likely will: seriously disrupt or destroy the existing network of Title X providers in both the State of Washington and throughout the entire nation,” Judge Bastian wrote in his order.

Changes to the Title X program – scheduled to take effect May 3 – would have made health clinics ineligible for Title X funding if they offer, promote, or support abortion as a method of family planning. Title X grants generally go to health centers that provide reproductive health care – such as STD-testing, cancer screenings, and contraception – to low-income families. Under the rule, the government would withdraw financial assistance to clinics if they allow counseling or referrals associated with abortion, regardless of whether the money is used for other health care services.

HHS officials said that the final rule will provide for clear financial and physical separation between Title X and non–Title X activities, reduce confusion on the part of Title X clinics and the public about permissible Title X activities, and improve program transparency by requiring more complete reporting by grantees about their partnerships with referral agencies.

Two federal judges have temporarily barred the Trump administration from making changes to the Title X program that would restrict funding from clinics that provide abortion counseling or that refer patients for abortion services.

jsmith/iStockphoto

U.S. District Judge Stanley Bastian for the District of Eastern Washington on April 25 approved a temporary nationwide ban against the program changes in response to legal a challenge by Washington state. The same day, U.S. District Judge for the District of Oregon Michael J. McShane also preliminarily barred the restrictions from taking effect in response to a legal challenge by the American Medical Association and the Planned Parenthood Federation of America.

Judge McShane called the program restrictions “arbitrary and capricious,” and wrote that the rules ignore comprehensive, ethical, and evidence-based health care, and impermissibly interfere with the patient-doctor relationship. Judge Bastian agreed, writing in his order that the plaintiffs have demonstrated that the restrictions violate the central purpose of Title X, which is to equalize access to comprehensive, evidence-based, and voluntary family planning.

“Plaintiffs have demonstrated they are likely to suffer irreparable harm in the absence of a preliminary injunction by presenting facts and argument that the final rule may or likely will: seriously disrupt or destroy the existing network of Title X providers in both the State of Washington and throughout the entire nation,” Judge Bastian wrote in his order.

Changes to the Title X program – scheduled to take effect May 3 – would have made health clinics ineligible for Title X funding if they offer, promote, or support abortion as a method of family planning. Title X grants generally go to health centers that provide reproductive health care – such as STD-testing, cancer screenings, and contraception – to low-income families. Under the rule, the government would withdraw financial assistance to clinics if they allow counseling or referrals associated with abortion, regardless of whether the money is used for other health care services.

HHS officials said that the final rule will provide for clear financial and physical separation between Title X and non–Title X activities, reduce confusion on the part of Title X clinics and the public about permissible Title X activities, and improve program transparency by requiring more complete reporting by grantees about their partnerships with referral agencies.

A treat-to-target approach using total hip T scores could help guide decisions about how long women with osteoporosis should stay on bone-building therapy, according to Serge Ferrari, MD, and his colleagues.

Using 10 years of follow-up data from 1,343 women who took denosumab in the FREEDOM trial, Dr. Ferrari and his colleagues determined that a T score of at least –2.5 would be an appropriate target for this decision.

“A T-score unit increase of 1.0 was associated with a significant reduction in fracture risk for T scores up to, but no greater than, –2.0, suggesting that a T-score threshold of at least –2.0 would be an appropriate target for therapy to maximize treatment,” said Dr. Ferrari of the University of Geneva and his colleagues. “Further improvements in bone mineral density were not associated with major additional changes in 1-year nonvertebral fracture incidence.”

The findings “highlight the importance of the relationship between hip T score and fracture risk, which is maintained during long-term therapy with denosumab. Regular monitoring of bone mineral density during therapy may be useful to determine when fracture risk has reached a minimal threshold; treatment could therefore be suspended and/or consolidated, as in the case of a reversible therapy such as denosumab.”

[email protected]

SOURCE: Ferrari S et al. J Bone Miner Res. 2019 Mar 28. doi: 10.1002/jbmr.3722.

A treat-to-target approach using total hip T scores could help guide decisions about how long women with osteoporosis should stay on bone-building therapy, according to Serge Ferrari, MD, and his colleagues.

Using 10 years of follow-up data from 1,343 women who took denosumab in the FREEDOM trial, Dr. Ferrari and his colleagues determined that a T score of at least –2.5 would be an appropriate target for this decision.

“A T-score unit increase of 1.0 was associated with a significant reduction in fracture risk for T scores up to, but no greater than, –2.0, suggesting that a T-score threshold of at least –2.0 would be an appropriate target for therapy to maximize treatment,” said Dr. Ferrari of the University of Geneva and his colleagues. “Further improvements in bone mineral density were not associated with major additional changes in 1-year nonvertebral fracture incidence.”

The findings “highlight the importance of the relationship between hip T score and fracture risk, which is maintained during long-term therapy with denosumab. Regular monitoring of bone mineral density during therapy may be useful to determine when fracture risk has reached a minimal threshold; treatment could therefore be suspended and/or consolidated, as in the case of a reversible therapy such as denosumab.”

[email protected]

SOURCE: Ferrari S et al. J Bone Miner Res. 2019 Mar 28. doi: 10.1002/jbmr.3722.

A treat-to-target approach using total hip T scores could help guide decisions about how long women with osteoporosis should stay on bone-building therapy, according to Serge Ferrari, MD, and his colleagues.

Using 10 years of follow-up data from 1,343 women who took denosumab in the FREEDOM trial, Dr. Ferrari and his colleagues determined that a T score of at least –2.5 would be an appropriate target for this decision.

“A T-score unit increase of 1.0 was associated with a significant reduction in fracture risk for T scores up to, but no greater than, –2.0, suggesting that a T-score threshold of at least –2.0 would be an appropriate target for therapy to maximize treatment,” said Dr. Ferrari of the University of Geneva and his colleagues. “Further improvements in bone mineral density were not associated with major additional changes in 1-year nonvertebral fracture incidence.”

The findings “highlight the importance of the relationship between hip T score and fracture risk, which is maintained during long-term therapy with denosumab. Regular monitoring of bone mineral density during therapy may be useful to determine when fracture risk has reached a minimal threshold; treatment could therefore be suspended and/or consolidated, as in the case of a reversible therapy such as denosumab.”

[email protected]

SOURCE: Ferrari S et al. J Bone Miner Res. 2019 Mar 28. doi: 10.1002/jbmr.3722.

The introduction of human papillomavirus vaccination in the United States in 2006 was associated with a significant decrease in the rates of cervical intraepithelial neoplasia grades 2 and above (CIN2+) in younger women.

The overall rate of CIN2+ declined from an estimated 216,000 cases in 2008 – 55% of which were in women aged 18-29 years – to 196,000 cases in 2016, of which 36% were in women aged 18-29 years, according to analysis of data from the Human Papillomavirus Vaccine Impact Monitoring Program (MMWR. 2019 Apr 19;68:337-43.

In 2008, the highest rates of CIN2+ were seen in women aged 20-24 years and decreased with age, but in 2016, the highest rates were in women aged 25-29 years. The rates of CIN2+ declined significantly in women aged 18-19 years from 2008-2016, but increased in women aged 40-64 years.

In 2008 and 2016, around three-quarters of all CIN2+ cases were attributable to HPV types that are targeted by the HPV vaccine. However the rates of vaccine-preventable CIN2+ declined among women aged 18-24 years, from 52% in 2008 to 30% in 2016.

“Both the estimated number and rates of U.S. CIN2+ cases in this report must be interpreted in the context of cervical cancer prevention strategies, including HPV vaccination and cervical cancer screening,” wrote Nancy M. McClung, PhD, of the Epidemic Intelligence Service at the Centers for Disease Control and Prevention and coauthors.

Notably, the screening interval for cervical cancer was increased from yearly in 2008 to once in 3 years with cytology alone or once in 5 years with cytology plus HPV testing for women aged 30 or above in 2016.

“Older age at screening initiation, longer screening intervals, and more conservative management in young women might be expected to reduce the number of CIN2+ cases detected in younger age groups in whom lesions are most likely to regress and shift detection of some CIN2+ to older age groups, resulting in a transient increase in rates,” Dr. McClung and colleagues wrote.

However they noted that the decrease in HPV 16/18–attributable CIN2+ rates among younger age groups was likely a reflection of the impact of the introduction of the quadrivalent vaccine immunization program.

One author declared personal fees from Merck during the course of the study. No other conflicts of interest were declared.

SOURCE: McClung N et al. MMWR. 2019 Apr 19;68:337-43.

The introduction of human papillomavirus vaccination in the United States in 2006 was associated with a significant decrease in the rates of cervical intraepithelial neoplasia grades 2 and above (CIN2+) in younger women.

The overall rate of CIN2+ declined from an estimated 216,000 cases in 2008 – 55% of which were in women aged 18-29 years – to 196,000 cases in 2016, of which 36% were in women aged 18-29 years, according to analysis of data from the Human Papillomavirus Vaccine Impact Monitoring Program (MMWR. 2019 Apr 19;68:337-43.

In 2008, the highest rates of CIN2+ were seen in women aged 20-24 years and decreased with age, but in 2016, the highest rates were in women aged 25-29 years. The rates of CIN2+ declined significantly in women aged 18-19 years from 2008-2016, but increased in women aged 40-64 years.

In 2008 and 2016, around three-quarters of all CIN2+ cases were attributable to HPV types that are targeted by the HPV vaccine. However the rates of vaccine-preventable CIN2+ declined among women aged 18-24 years, from 52% in 2008 to 30% in 2016.

“Both the estimated number and rates of U.S. CIN2+ cases in this report must be interpreted in the context of cervical cancer prevention strategies, including HPV vaccination and cervical cancer screening,” wrote Nancy M. McClung, PhD, of the Epidemic Intelligence Service at the Centers for Disease Control and Prevention and coauthors.

Notably, the screening interval for cervical cancer was increased from yearly in 2008 to once in 3 years with cytology alone or once in 5 years with cytology plus HPV testing for women aged 30 or above in 2016.

“Older age at screening initiation, longer screening intervals, and more conservative management in young women might be expected to reduce the number of CIN2+ cases detected in younger age groups in whom lesions are most likely to regress and shift detection of some CIN2+ to older age groups, resulting in a transient increase in rates,” Dr. McClung and colleagues wrote.

However they noted that the decrease in HPV 16/18–attributable CIN2+ rates among younger age groups was likely a reflection of the impact of the introduction of the quadrivalent vaccine immunization program.

One author declared personal fees from Merck during the course of the study. No other conflicts of interest were declared.

SOURCE: McClung N et al. MMWR. 2019 Apr 19;68:337-43.

The introduction of human papillomavirus vaccination in the United States in 2006 was associated with a significant decrease in the rates of cervical intraepithelial neoplasia grades 2 and above (CIN2+) in younger women.

The overall rate of CIN2+ declined from an estimated 216,000 cases in 2008 – 55% of which were in women aged 18-29 years – to 196,000 cases in 2016, of which 36% were in women aged 18-29 years, according to analysis of data from the Human Papillomavirus Vaccine Impact Monitoring Program (MMWR. 2019 Apr 19;68:337-43.

In 2008, the highest rates of CIN2+ were seen in women aged 20-24 years and decreased with age, but in 2016, the highest rates were in women aged 25-29 years. The rates of CIN2+ declined significantly in women aged 18-19 years from 2008-2016, but increased in women aged 40-64 years.

In 2008 and 2016, around three-quarters of all CIN2+ cases were attributable to HPV types that are targeted by the HPV vaccine. However the rates of vaccine-preventable CIN2+ declined among women aged 18-24 years, from 52% in 2008 to 30% in 2016.

“Both the estimated number and rates of U.S. CIN2+ cases in this report must be interpreted in the context of cervical cancer prevention strategies, including HPV vaccination and cervical cancer screening,” wrote Nancy M. McClung, PhD, of the Epidemic Intelligence Service at the Centers for Disease Control and Prevention and coauthors.

Notably, the screening interval for cervical cancer was increased from yearly in 2008 to once in 3 years with cytology alone or once in 5 years with cytology plus HPV testing for women aged 30 or above in 2016.

“Older age at screening initiation, longer screening intervals, and more conservative management in young women might be expected to reduce the number of CIN2+ cases detected in younger age groups in whom lesions are most likely to regress and shift detection of some CIN2+ to older age groups, resulting in a transient increase in rates,” Dr. McClung and colleagues wrote.

However they noted that the decrease in HPV 16/18–attributable CIN2+ rates among younger age groups was likely a reflection of the impact of the introduction of the quadrivalent vaccine immunization program.

One author declared personal fees from Merck during the course of the study. No other conflicts of interest were declared.

SOURCE: McClung N et al. MMWR. 2019 Apr 19;68:337-43.

The Food and Drug Administration has ordered companies to immediately cease selling transvaginal mesh intended for pelvic organ prolapse (POP) repair.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The mandate came after Boston Scientific and Coloplast failed to provide adequate safety and efficacy information to the federal regulatory body in the wake of a 2016 reclassification to Class III (high-risk) devices, according to an FDA press statement. Both companies were required to submit a premarket approval application to continue marketing the mesh in the United States. Boston Scientific did file two PMAs, one for each of its transvaginal mesh products, but the FDA said the applications did not contain the required efficacy and safety data.

Both companies will have 10 days to submit their plan to withdraw these products from the market.

“In order for these mesh devices to stay on the market, we determined that we needed evidence that they worked better than surgery without the use of mesh to repair POP. That evidence was lacking in these premarket applications, and we couldn’t assure women that these devices were safe and effective long term,” said Jeffrey Shuren, MD, director of FDA’s Center for Devices and Radiological Health. “Patient safety is our highest priority, and women must have access to safe medical devices that provide relief from symptoms and better management of their medical conditions. The FDA has committed to taking forceful new actions to enhance device safety and encourage innovations that lead to safer medical devices, so that patients have access to safe and effective medical devices and the information they need to make informed decisions about their care.”

The deadline for submitting premarket approval applications for POP repair with transvaginal mesh was July 5, 2018. Manufacturers that did not file PMAs were required to pull their devices from the market. Those that did could keep selling the mesh while FDA reviewed their PMAs.

Boston Scientific submitted PMAs for its two devices, the Uphold LITE Vaginal Support System and the Xenform Soft Tissue Repair System. Coloplast filed a PMA for its device, Restorelle DirectFix Anterior. But in February, the FDA convened an advisory panel to discuss just how to evaluate the safety and efficacy of the products.

To prove efficacy, the panel concluded, transvaginal POP repair with mesh should be better than repair with native tissue at 36 months, and the safety should be superior to repair with native tissue repair. The FDA agreed. However, the submitted premarket approval application did not include these kinds of data. Therefore, the agency declined to approve the devices.

In addition to stopping U.S. sales, FDA has required Boston Scientific and Coloplast to continue safety and efficacy follow-up of all women included in their 522 studies.

Coloplast did not have a press or public statement on its website as of April 16. Boston Scientific did have one.

“Up to 50% of women in the U.S. will suffer from POP during their lives, and we believe these women should have access to safe and effective treatment options,” according to the statement. “As a global leader in the pelvic floor space, we remain steadfast in our commitment to helping women live better and healthier lives. We also remain confident in the benefits and safety of our treatments for POP, and we look forward to continuing to work with the FDA on our PMAs for the Uphold LITE Vaginal Support System and the Xenform Soft Tissue Repair Matrix, which are currently under review.”

The FDA statement also included advice to women who have had the mesh procedure for POP, and for their physicians

“Women who have had transvaginal mesh placed for the surgical repair of POP should continue with their annual and other routine check-ups and follow-up care. There is no need to take additional action if they are satisfied with their surgery and are not having complications or symptoms. Patients should notify their health care professionals if they have complications or symptoms, including persistent vaginal bleeding or discharge, pelvic or groin pain, or pain with sex. They should also let their health care professional know if they have surgical mesh, especially if they plan to have another surgery or other medical procedures. Women who were planning to have mesh placed transvaginally for the repair of POP should discuss other treatment options with their doctors.”

[email protected]

The Food and Drug Administration has ordered companies to immediately cease selling transvaginal mesh intended for pelvic organ prolapse (POP) repair.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The mandate came after Boston Scientific and Coloplast failed to provide adequate safety and efficacy information to the federal regulatory body in the wake of a 2016 reclassification to Class III (high-risk) devices, according to an FDA press statement. Both companies were required to submit a premarket approval application to continue marketing the mesh in the United States. Boston Scientific did file two PMAs, one for each of its transvaginal mesh products, but the FDA said the applications did not contain the required efficacy and safety data.

Both companies will have 10 days to submit their plan to withdraw these products from the market.

“In order for these mesh devices to stay on the market, we determined that we needed evidence that they worked better than surgery without the use of mesh to repair POP. That evidence was lacking in these premarket applications, and we couldn’t assure women that these devices were safe and effective long term,” said Jeffrey Shuren, MD, director of FDA’s Center for Devices and Radiological Health. “Patient safety is our highest priority, and women must have access to safe medical devices that provide relief from symptoms and better management of their medical conditions. The FDA has committed to taking forceful new actions to enhance device safety and encourage innovations that lead to safer medical devices, so that patients have access to safe and effective medical devices and the information they need to make informed decisions about their care.”

The deadline for submitting premarket approval applications for POP repair with transvaginal mesh was July 5, 2018. Manufacturers that did not file PMAs were required to pull their devices from the market. Those that did could keep selling the mesh while FDA reviewed their PMAs.

Boston Scientific submitted PMAs for its two devices, the Uphold LITE Vaginal Support System and the Xenform Soft Tissue Repair System. Coloplast filed a PMA for its device, Restorelle DirectFix Anterior. But in February, the FDA convened an advisory panel to discuss just how to evaluate the safety and efficacy of the products.

To prove efficacy, the panel concluded, transvaginal POP repair with mesh should be better than repair with native tissue at 36 months, and the safety should be superior to repair with native tissue repair. The FDA agreed. However, the submitted premarket approval application did not include these kinds of data. Therefore, the agency declined to approve the devices.

In addition to stopping U.S. sales, FDA has required Boston Scientific and Coloplast to continue safety and efficacy follow-up of all women included in their 522 studies.

Coloplast did not have a press or public statement on its website as of April 16. Boston Scientific did have one.

“Up to 50% of women in the U.S. will suffer from POP during their lives, and we believe these women should have access to safe and effective treatment options,” according to the statement. “As a global leader in the pelvic floor space, we remain steadfast in our commitment to helping women live better and healthier lives. We also remain confident in the benefits and safety of our treatments for POP, and we look forward to continuing to work with the FDA on our PMAs for the Uphold LITE Vaginal Support System and the Xenform Soft Tissue Repair Matrix, which are currently under review.”

The FDA statement also included advice to women who have had the mesh procedure for POP, and for their physicians

“Women who have had transvaginal mesh placed for the surgical repair of POP should continue with their annual and other routine check-ups and follow-up care. There is no need to take additional action if they are satisfied with their surgery and are not having complications or symptoms. Patients should notify their health care professionals if they have complications or symptoms, including persistent vaginal bleeding or discharge, pelvic or groin pain, or pain with sex. They should also let their health care professional know if they have surgical mesh, especially if they plan to have another surgery or other medical procedures. Women who were planning to have mesh placed transvaginally for the repair of POP should discuss other treatment options with their doctors.”

[email protected]

The Food and Drug Administration has ordered companies to immediately cease selling transvaginal mesh intended for pelvic organ prolapse (POP) repair.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The mandate came after Boston Scientific and Coloplast failed to provide adequate safety and efficacy information to the federal regulatory body in the wake of a 2016 reclassification to Class III (high-risk) devices, according to an FDA press statement. Both companies were required to submit a premarket approval application to continue marketing the mesh in the United States. Boston Scientific did file two PMAs, one for each of its transvaginal mesh products, but the FDA said the applications did not contain the required efficacy and safety data.

Both companies will have 10 days to submit their plan to withdraw these products from the market.

“In order for these mesh devices to stay on the market, we determined that we needed evidence that they worked better than surgery without the use of mesh to repair POP. That evidence was lacking in these premarket applications, and we couldn’t assure women that these devices were safe and effective long term,” said Jeffrey Shuren, MD, director of FDA’s Center for Devices and Radiological Health. “Patient safety is our highest priority, and women must have access to safe medical devices that provide relief from symptoms and better management of their medical conditions. The FDA has committed to taking forceful new actions to enhance device safety and encourage innovations that lead to safer medical devices, so that patients have access to safe and effective medical devices and the information they need to make informed decisions about their care.”

The deadline for submitting premarket approval applications for POP repair with transvaginal mesh was July 5, 2018. Manufacturers that did not file PMAs were required to pull their devices from the market. Those that did could keep selling the mesh while FDA reviewed their PMAs.

Boston Scientific submitted PMAs for its two devices, the Uphold LITE Vaginal Support System and the Xenform Soft Tissue Repair System. Coloplast filed a PMA for its device, Restorelle DirectFix Anterior. But in February, the FDA convened an advisory panel to discuss just how to evaluate the safety and efficacy of the products.

To prove efficacy, the panel concluded, transvaginal POP repair with mesh should be better than repair with native tissue at 36 months, and the safety should be superior to repair with native tissue repair. The FDA agreed. However, the submitted premarket approval application did not include these kinds of data. Therefore, the agency declined to approve the devices.

In addition to stopping U.S. sales, FDA has required Boston Scientific and Coloplast to continue safety and efficacy follow-up of all women included in their 522 studies.

Coloplast did not have a press or public statement on its website as of April 16. Boston Scientific did have one.

“Up to 50% of women in the U.S. will suffer from POP during their lives, and we believe these women should have access to safe and effective treatment options,” according to the statement. “As a global leader in the pelvic floor space, we remain steadfast in our commitment to helping women live better and healthier lives. We also remain confident in the benefits and safety of our treatments for POP, and we look forward to continuing to work with the FDA on our PMAs for the Uphold LITE Vaginal Support System and the Xenform Soft Tissue Repair Matrix, which are currently under review.”

The FDA statement also included advice to women who have had the mesh procedure for POP, and for their physicians

“Women who have had transvaginal mesh placed for the surgical repair of POP should continue with their annual and other routine check-ups and follow-up care. There is no need to take additional action if they are satisfied with their surgery and are not having complications or symptoms. Patients should notify their health care professionals if they have complications or symptoms, including persistent vaginal bleeding or discharge, pelvic or groin pain, or pain with sex. They should also let their health care professional know if they have surgical mesh, especially if they plan to have another surgery or other medical procedures. Women who were planning to have mesh placed transvaginally for the repair of POP should discuss other treatment options with their doctors.”

[email protected]