Reproductive Endocrinology

A new study ties the odds of conception to the advantages of the neighborhood a woman lives in.

In a cohort of more than 6,000 women who were trying to get pregnant without fertility treatments, the probability of conception was reduced 21%-23% per menstrual cycle when comparing the most disadvantaged neighborhoods with the least disadvantaged.

“When disadvantaged neighborhood status was categorized within each state (as opposed to nationally), the results were slightly larger in magnitude,” wrote authors of the study published online in JAMA Network Open.

Among 6,356 participants, 3,725 pregnancies were observed for 27,427 menstrual cycles of follow-up. Average age was 30, and most participants were non-Hispanic White (5,297 [83.3%]) and had not previously given birth (4,179 [65.7%]).

When the researchers compared the top and bottom deciles of disadvantaged neighborhood status, adjusted fecundability ratios (the per-cycle probability of conception) were 0.79 (95% confidence interval [CI], 0.66-0.96) for national-level area deprivation index (ADI) rankings and 0.77 (95% CI, 0.65-0.92) for within-state ADI rankings. ADI score includes population indicators related to educational attainment, housing, employment, and poverty.

“These findings suggest that investments in disadvantaged neighborhoods may yield positive cobenefits for fertility,” the authors wrote.

The researchers used the Pregnancy Study Online, for which baseline data were collected from women in the United States from June 19, 2013, through April 12, 2019.

In the United States, 10%-15% of reproductive-aged couples experience infertility, defined as the inability to conceive after a year of unprotected intercourse.
 

Reason behind the numbers unclear

Mark Hornstein, MD, director in the reproductive endocrinology division of Brigham and Women’s Hospital and professor at Harvard Medical School, both in Boston, said in an interview that this study gives the “what” but the “why” is harder to pinpoint.

What is not known, he said, is what kind of access the women had to fertility counseling or treatment.

The association between fertility and neighborhood advantage status is very plausible given the well-established links between disadvantaged regions and poorer health outcomes, he said, adding that the authors make a good case for their conclusions in the paper.

The authors ruled out many potential confounders, such as age of the women, reproductive history, multivitamin use, education level, household income, and frequency of intercourse, and still there was a difference between disadvantaged and advantaged neighborhoods, he noted.

Dr. Hornstein said his own research team has found that lack of knowledge about insurance coverage regarding infertility services may keep women from seeking the services.

“One of the things I worry about it access,” he said. “[The study authors] didn’t really look at that. They just looked at what the chances were that they got pregnant. But they didn’t say how many of those women had a workup, an evaluation, for why they were having difficulty, if they were, or had treatment. So I don’t know if some or all or none of that difference that they saw from the highest neighborhood health score to the most disadvantaged – if that was from inherent problems in the area, access to the best health care, or some combination.”
 

Discussions have focused on changing personal behaviors

Discussions on improving fertility often center on changing personal behaviors, the authors noted. “However, structural, political, and environmental factors may also play a substantial role,” they wrote.

The findings are in line with previous research on the effect of stress on in vitro outcomes, they pointed out. “Perceived stress has been associated with poorer in vitro fertilization outcomes and reduced fecundability among couples attempting spontaneous conception,” the authors noted.

Studies also have shown that living in a disadvantaged neighborhood is linked with comorbidities during pregnancy, such as increased risks of gestational hypertension (risk ratio for lowest vs. highest quartile: 1.24 [95% CI, 1.14-1.35]) and poor gestational weight gain (relative risk for lowest vs. highest quartile: 1.1 [95% CI, 1.1-1.2]).

In addition, policies such as those that support civil rights, protect the environment, and invest in underresourced communities have been shown to improve health markers such as life expectancy.

Policy decisions can also perpetuate a cycle of stress, they wrote. Disadvantaged communities may have more air pollution, which has been shown to have negative effects on fertility. Unemployment has been linked with decreased population-level fertility rates. Lack of green space may result in fewer areas to reduce stress.

A study coauthor reported grants from the National Institutes of Health during the conduct of the study; nonfinancial support from Swiss Precision Diagnostics GmbH, Labcorp, Kindara.com, and FertilityFriend.com; and consulting for AbbVie outside the submitted work. No other author disclosures were reported. Dr. Hornstein reported no relevant financial relationships.

A new study ties the odds of conception to the advantages of the neighborhood a woman lives in.

In a cohort of more than 6,000 women who were trying to get pregnant without fertility treatments, the probability of conception was reduced 21%-23% per menstrual cycle when comparing the most disadvantaged neighborhoods with the least disadvantaged.

“When disadvantaged neighborhood status was categorized within each state (as opposed to nationally), the results were slightly larger in magnitude,” wrote authors of the study published online in JAMA Network Open.

Among 6,356 participants, 3,725 pregnancies were observed for 27,427 menstrual cycles of follow-up. Average age was 30, and most participants were non-Hispanic White (5,297 [83.3%]) and had not previously given birth (4,179 [65.7%]).

When the researchers compared the top and bottom deciles of disadvantaged neighborhood status, adjusted fecundability ratios (the per-cycle probability of conception) were 0.79 (95% confidence interval [CI], 0.66-0.96) for national-level area deprivation index (ADI) rankings and 0.77 (95% CI, 0.65-0.92) for within-state ADI rankings. ADI score includes population indicators related to educational attainment, housing, employment, and poverty.

“These findings suggest that investments in disadvantaged neighborhoods may yield positive cobenefits for fertility,” the authors wrote.

The researchers used the Pregnancy Study Online, for which baseline data were collected from women in the United States from June 19, 2013, through April 12, 2019.

In the United States, 10%-15% of reproductive-aged couples experience infertility, defined as the inability to conceive after a year of unprotected intercourse.
 

Reason behind the numbers unclear

Mark Hornstein, MD, director in the reproductive endocrinology division of Brigham and Women’s Hospital and professor at Harvard Medical School, both in Boston, said in an interview that this study gives the “what” but the “why” is harder to pinpoint.

What is not known, he said, is what kind of access the women had to fertility counseling or treatment.

The association between fertility and neighborhood advantage status is very plausible given the well-established links between disadvantaged regions and poorer health outcomes, he said, adding that the authors make a good case for their conclusions in the paper.

The authors ruled out many potential confounders, such as age of the women, reproductive history, multivitamin use, education level, household income, and frequency of intercourse, and still there was a difference between disadvantaged and advantaged neighborhoods, he noted.

Dr. Hornstein said his own research team has found that lack of knowledge about insurance coverage regarding infertility services may keep women from seeking the services.

“One of the things I worry about it access,” he said. “[The study authors] didn’t really look at that. They just looked at what the chances were that they got pregnant. But they didn’t say how many of those women had a workup, an evaluation, for why they were having difficulty, if they were, or had treatment. So I don’t know if some or all or none of that difference that they saw from the highest neighborhood health score to the most disadvantaged – if that was from inherent problems in the area, access to the best health care, or some combination.”
 

Discussions have focused on changing personal behaviors

Discussions on improving fertility often center on changing personal behaviors, the authors noted. “However, structural, political, and environmental factors may also play a substantial role,” they wrote.

The findings are in line with previous research on the effect of stress on in vitro outcomes, they pointed out. “Perceived stress has been associated with poorer in vitro fertilization outcomes and reduced fecundability among couples attempting spontaneous conception,” the authors noted.

Studies also have shown that living in a disadvantaged neighborhood is linked with comorbidities during pregnancy, such as increased risks of gestational hypertension (risk ratio for lowest vs. highest quartile: 1.24 [95% CI, 1.14-1.35]) and poor gestational weight gain (relative risk for lowest vs. highest quartile: 1.1 [95% CI, 1.1-1.2]).

In addition, policies such as those that support civil rights, protect the environment, and invest in underresourced communities have been shown to improve health markers such as life expectancy.

Policy decisions can also perpetuate a cycle of stress, they wrote. Disadvantaged communities may have more air pollution, which has been shown to have negative effects on fertility. Unemployment has been linked with decreased population-level fertility rates. Lack of green space may result in fewer areas to reduce stress.

A study coauthor reported grants from the National Institutes of Health during the conduct of the study; nonfinancial support from Swiss Precision Diagnostics GmbH, Labcorp, Kindara.com, and FertilityFriend.com; and consulting for AbbVie outside the submitted work. No other author disclosures were reported. Dr. Hornstein reported no relevant financial relationships.

A new study ties the odds of conception to the advantages of the neighborhood a woman lives in.

In a cohort of more than 6,000 women who were trying to get pregnant without fertility treatments, the probability of conception was reduced 21%-23% per menstrual cycle when comparing the most disadvantaged neighborhoods with the least disadvantaged.

“When disadvantaged neighborhood status was categorized within each state (as opposed to nationally), the results were slightly larger in magnitude,” wrote authors of the study published online in JAMA Network Open.

Among 6,356 participants, 3,725 pregnancies were observed for 27,427 menstrual cycles of follow-up. Average age was 30, and most participants were non-Hispanic White (5,297 [83.3%]) and had not previously given birth (4,179 [65.7%]).

When the researchers compared the top and bottom deciles of disadvantaged neighborhood status, adjusted fecundability ratios (the per-cycle probability of conception) were 0.79 (95% confidence interval [CI], 0.66-0.96) for national-level area deprivation index (ADI) rankings and 0.77 (95% CI, 0.65-0.92) for within-state ADI rankings. ADI score includes population indicators related to educational attainment, housing, employment, and poverty.

“These findings suggest that investments in disadvantaged neighborhoods may yield positive cobenefits for fertility,” the authors wrote.

The researchers used the Pregnancy Study Online, for which baseline data were collected from women in the United States from June 19, 2013, through April 12, 2019.

In the United States, 10%-15% of reproductive-aged couples experience infertility, defined as the inability to conceive after a year of unprotected intercourse.
 

Reason behind the numbers unclear

Mark Hornstein, MD, director in the reproductive endocrinology division of Brigham and Women’s Hospital and professor at Harvard Medical School, both in Boston, said in an interview that this study gives the “what” but the “why” is harder to pinpoint.

What is not known, he said, is what kind of access the women had to fertility counseling or treatment.

The association between fertility and neighborhood advantage status is very plausible given the well-established links between disadvantaged regions and poorer health outcomes, he said, adding that the authors make a good case for their conclusions in the paper.

The authors ruled out many potential confounders, such as age of the women, reproductive history, multivitamin use, education level, household income, and frequency of intercourse, and still there was a difference between disadvantaged and advantaged neighborhoods, he noted.

Dr. Hornstein said his own research team has found that lack of knowledge about insurance coverage regarding infertility services may keep women from seeking the services.

“One of the things I worry about it access,” he said. “[The study authors] didn’t really look at that. They just looked at what the chances were that they got pregnant. But they didn’t say how many of those women had a workup, an evaluation, for why they were having difficulty, if they were, or had treatment. So I don’t know if some or all or none of that difference that they saw from the highest neighborhood health score to the most disadvantaged – if that was from inherent problems in the area, access to the best health care, or some combination.”
 

Discussions have focused on changing personal behaviors

Discussions on improving fertility often center on changing personal behaviors, the authors noted. “However, structural, political, and environmental factors may also play a substantial role,” they wrote.

The findings are in line with previous research on the effect of stress on in vitro outcomes, they pointed out. “Perceived stress has been associated with poorer in vitro fertilization outcomes and reduced fecundability among couples attempting spontaneous conception,” the authors noted.

Studies also have shown that living in a disadvantaged neighborhood is linked with comorbidities during pregnancy, such as increased risks of gestational hypertension (risk ratio for lowest vs. highest quartile: 1.24 [95% CI, 1.14-1.35]) and poor gestational weight gain (relative risk for lowest vs. highest quartile: 1.1 [95% CI, 1.1-1.2]).

In addition, policies such as those that support civil rights, protect the environment, and invest in underresourced communities have been shown to improve health markers such as life expectancy.

Policy decisions can also perpetuate a cycle of stress, they wrote. Disadvantaged communities may have more air pollution, which has been shown to have negative effects on fertility. Unemployment has been linked with decreased population-level fertility rates. Lack of green space may result in fewer areas to reduce stress.

A study coauthor reported grants from the National Institutes of Health during the conduct of the study; nonfinancial support from Swiss Precision Diagnostics GmbH, Labcorp, Kindara.com, and FertilityFriend.com; and consulting for AbbVie outside the submitted work. No other author disclosures were reported. Dr. Hornstein reported no relevant financial relationships.

Boys with obesity have lower testicular volume, compared with their normal-weight counterparts, suggesting the potential for fertility problems in adulthood, new data suggest.

Testicular volume is a fertility marker directly related to sperm count that has halved in the past 40 years worldwide for unknown reasons. At the same time, childhood obesity has risen dramatically and infertility appears to have risen as well, Rossella Cannarella, MD, of the department of endocrinology and andrology, University of Catania (Italy), said at the annual meeting of the Endocrine Society.

According to recent Italian studies, between 14% and 23% of young men aged 18-19 had testicular hypotrophy. “Worryingly, we don’t know the reason for this hypotrophy. And therefore, they are at risk for future infertility,” Dr. Cannarella said during a press briefing.

Her study, which included a total of 264 male children and adolescents, also linked lower testicular volume to hyperinsulinemia and insulin resistance. “The testis is not quiescent in childhood and is sensitive to the hormone insulin. Obesity and metabolic impairment actually can have an effect and negative impact on Sertoli cell proliferation,” Dr. Cannarella said.
 

Screen testicular volume at all visits

If other studies confirm these results, she said that pediatricians should begin routinely assessing testicular volume at all visits as is now done with height and weight to identify early deflection of the testicular growth curve.

In addition, “include male infertility as a possible consequence of obesity in counseling of male obese children,” she advised.

Asked to comment, Amin Sedaghat Herati, MD, director of male infertility and men’s health at Johns Hopkins Hospital, and assistant professor of urology at Johns Hopkins Medicine, both in Baltimore, said in an interview: “I think what’s really interesting about this study is the association that they’ve made between testicular volume and obesity.”

But, he noted, “it does not implicate necessarily the development of infertility. It’s an extrapolation. So it’s a step towards the link between obesity and infertility, and it’s an important study to establish the association, but changes in testicular volume and even changes in semen panel don’t necessarily indicate fertility or infertility.”

The findings are “consistent with what we know as far as what obesity can potentially do to the activity of the cells in the testes. The authors are postulating that it’s more the support cells, called Sertoli cells, but I would say it’s probably all of the cells that are being affected by obesity and specifically elevated leptin levels,” Dr. Herati said.

He agrees with the recommendation that pediatricians screen all boys for testicular volume. “I agree it’s a good idea so they don’t miss any cases in which the testes don’t develop the way they should or any other conditions,” Dr. Herati said. “I think in general it’s a good practice, especially in the peripubertal stage, to make sure that kids are on the same growth curve and that they’re meeting their Tanner staging. [Pediatricians] should be looking at the size of the testes and tracking, maybe not at every visit, but at least on an annual basis.”

And, he noted, “I think any study that establishes a link that we can point to when we’re educating patients and parents is important.”
 

Links found between overweight/obesity, testicular hypotrophy

The study population included 61 male children and adolescents with normal weight, 53 with overweight, and 150 with obesity. Insulin resistance (Homeostatic Model Assessment for Insulin Resistance index ≥ 2.5) was present in 97 participants, 22 had prediabetes, and 3 had type 2 diabetes. Clinical data were collected retrospectively.

Among the boys aged 9-14 years, those with overweight and obesity had significantly lower testicular volume, compared with those of normal weight.

Those who were in Tanner Stage 1 were more likely to have overweight and obesity than those with normal weight, suggesting that “overweight and obese adolescents start puberty later than those of normal weight,” Dr. Cannarella said.

In the 14- to 16-year-old age group, those with insulin resistance had lower testicular volume, compared with those without insulin resistance (HOMA index < 2.5). The number of insulin-resistant adolescents was greater than that of controls in the Tanner stage 2 group.

In both the prepubertal (< 9 years) and pubertal (14-16 years) groups, hyperinsulinemia was associated with lower levels of testicular volume.

Hyperinsulinemia did not influence the timing of puberty onset.
 

No way to quantify the effect of obesity on fertility just yet

During a press briefing, Dr. Cannarella commented that obesity is likely just one of several factors influencing what appears to be an increase in male infertility over time. “It isn’t of course the only reason, but many factors in our environment have drastically changed, compared to 40 years ago, including the prevalence of heavy metals and endocrine disruptors, and of course, the change in habits and higher prevalence of metabolic disease. All of this has an impact on the proliferation of Sertoli cells in childhood and this may explain the trend toward the decline of sperm concentration and count.”

Longitudinal data are needed to establish cause and effect, she noted. “We need longitudinal studies that link the degrees of testicular volume with the degree of the sperm concentration and count starting from childhood and ending with the adult age. This is the missing link so far.”

Dr. Cannarella has reported no relevant financial relationships. Dr. Herati has reported being an advisor for Dadi, LiNA Medical, and Teleflex.

A version of this article first appeared on Medscape.com.

Boys with obesity have lower testicular volume, compared with their normal-weight counterparts, suggesting the potential for fertility problems in adulthood, new data suggest.

Testicular volume is a fertility marker directly related to sperm count that has halved in the past 40 years worldwide for unknown reasons. At the same time, childhood obesity has risen dramatically and infertility appears to have risen as well, Rossella Cannarella, MD, of the department of endocrinology and andrology, University of Catania (Italy), said at the annual meeting of the Endocrine Society.

According to recent Italian studies, between 14% and 23% of young men aged 18-19 had testicular hypotrophy. “Worryingly, we don’t know the reason for this hypotrophy. And therefore, they are at risk for future infertility,” Dr. Cannarella said during a press briefing.

Her study, which included a total of 264 male children and adolescents, also linked lower testicular volume to hyperinsulinemia and insulin resistance. “The testis is not quiescent in childhood and is sensitive to the hormone insulin. Obesity and metabolic impairment actually can have an effect and negative impact on Sertoli cell proliferation,” Dr. Cannarella said.
 

Screen testicular volume at all visits

If other studies confirm these results, she said that pediatricians should begin routinely assessing testicular volume at all visits as is now done with height and weight to identify early deflection of the testicular growth curve.

In addition, “include male infertility as a possible consequence of obesity in counseling of male obese children,” she advised.

Asked to comment, Amin Sedaghat Herati, MD, director of male infertility and men’s health at Johns Hopkins Hospital, and assistant professor of urology at Johns Hopkins Medicine, both in Baltimore, said in an interview: “I think what’s really interesting about this study is the association that they’ve made between testicular volume and obesity.”

But, he noted, “it does not implicate necessarily the development of infertility. It’s an extrapolation. So it’s a step towards the link between obesity and infertility, and it’s an important study to establish the association, but changes in testicular volume and even changes in semen panel don’t necessarily indicate fertility or infertility.”

The findings are “consistent with what we know as far as what obesity can potentially do to the activity of the cells in the testes. The authors are postulating that it’s more the support cells, called Sertoli cells, but I would say it’s probably all of the cells that are being affected by obesity and specifically elevated leptin levels,” Dr. Herati said.

He agrees with the recommendation that pediatricians screen all boys for testicular volume. “I agree it’s a good idea so they don’t miss any cases in which the testes don’t develop the way they should or any other conditions,” Dr. Herati said. “I think in general it’s a good practice, especially in the peripubertal stage, to make sure that kids are on the same growth curve and that they’re meeting their Tanner staging. [Pediatricians] should be looking at the size of the testes and tracking, maybe not at every visit, but at least on an annual basis.”

And, he noted, “I think any study that establishes a link that we can point to when we’re educating patients and parents is important.”
 

Links found between overweight/obesity, testicular hypotrophy

The study population included 61 male children and adolescents with normal weight, 53 with overweight, and 150 with obesity. Insulin resistance (Homeostatic Model Assessment for Insulin Resistance index ≥ 2.5) was present in 97 participants, 22 had prediabetes, and 3 had type 2 diabetes. Clinical data were collected retrospectively.

Among the boys aged 9-14 years, those with overweight and obesity had significantly lower testicular volume, compared with those of normal weight.

Those who were in Tanner Stage 1 were more likely to have overweight and obesity than those with normal weight, suggesting that “overweight and obese adolescents start puberty later than those of normal weight,” Dr. Cannarella said.

In the 14- to 16-year-old age group, those with insulin resistance had lower testicular volume, compared with those without insulin resistance (HOMA index < 2.5). The number of insulin-resistant adolescents was greater than that of controls in the Tanner stage 2 group.

In both the prepubertal (< 9 years) and pubertal (14-16 years) groups, hyperinsulinemia was associated with lower levels of testicular volume.

Hyperinsulinemia did not influence the timing of puberty onset.
 

No way to quantify the effect of obesity on fertility just yet

During a press briefing, Dr. Cannarella commented that obesity is likely just one of several factors influencing what appears to be an increase in male infertility over time. “It isn’t of course the only reason, but many factors in our environment have drastically changed, compared to 40 years ago, including the prevalence of heavy metals and endocrine disruptors, and of course, the change in habits and higher prevalence of metabolic disease. All of this has an impact on the proliferation of Sertoli cells in childhood and this may explain the trend toward the decline of sperm concentration and count.”

Longitudinal data are needed to establish cause and effect, she noted. “We need longitudinal studies that link the degrees of testicular volume with the degree of the sperm concentration and count starting from childhood and ending with the adult age. This is the missing link so far.”

Dr. Cannarella has reported no relevant financial relationships. Dr. Herati has reported being an advisor for Dadi, LiNA Medical, and Teleflex.

A version of this article first appeared on Medscape.com.

Boys with obesity have lower testicular volume, compared with their normal-weight counterparts, suggesting the potential for fertility problems in adulthood, new data suggest.

Testicular volume is a fertility marker directly related to sperm count that has halved in the past 40 years worldwide for unknown reasons. At the same time, childhood obesity has risen dramatically and infertility appears to have risen as well, Rossella Cannarella, MD, of the department of endocrinology and andrology, University of Catania (Italy), said at the annual meeting of the Endocrine Society.

According to recent Italian studies, between 14% and 23% of young men aged 18-19 had testicular hypotrophy. “Worryingly, we don’t know the reason for this hypotrophy. And therefore, they are at risk for future infertility,” Dr. Cannarella said during a press briefing.

Her study, which included a total of 264 male children and adolescents, also linked lower testicular volume to hyperinsulinemia and insulin resistance. “The testis is not quiescent in childhood and is sensitive to the hormone insulin. Obesity and metabolic impairment actually can have an effect and negative impact on Sertoli cell proliferation,” Dr. Cannarella said.
 

Screen testicular volume at all visits

If other studies confirm these results, she said that pediatricians should begin routinely assessing testicular volume at all visits as is now done with height and weight to identify early deflection of the testicular growth curve.

In addition, “include male infertility as a possible consequence of obesity in counseling of male obese children,” she advised.

Asked to comment, Amin Sedaghat Herati, MD, director of male infertility and men’s health at Johns Hopkins Hospital, and assistant professor of urology at Johns Hopkins Medicine, both in Baltimore, said in an interview: “I think what’s really interesting about this study is the association that they’ve made between testicular volume and obesity.”

But, he noted, “it does not implicate necessarily the development of infertility. It’s an extrapolation. So it’s a step towards the link between obesity and infertility, and it’s an important study to establish the association, but changes in testicular volume and even changes in semen panel don’t necessarily indicate fertility or infertility.”

The findings are “consistent with what we know as far as what obesity can potentially do to the activity of the cells in the testes. The authors are postulating that it’s more the support cells, called Sertoli cells, but I would say it’s probably all of the cells that are being affected by obesity and specifically elevated leptin levels,” Dr. Herati said.

He agrees with the recommendation that pediatricians screen all boys for testicular volume. “I agree it’s a good idea so they don’t miss any cases in which the testes don’t develop the way they should or any other conditions,” Dr. Herati said. “I think in general it’s a good practice, especially in the peripubertal stage, to make sure that kids are on the same growth curve and that they’re meeting their Tanner staging. [Pediatricians] should be looking at the size of the testes and tracking, maybe not at every visit, but at least on an annual basis.”

And, he noted, “I think any study that establishes a link that we can point to when we’re educating patients and parents is important.”
 

Links found between overweight/obesity, testicular hypotrophy

The study population included 61 male children and adolescents with normal weight, 53 with overweight, and 150 with obesity. Insulin resistance (Homeostatic Model Assessment for Insulin Resistance index ≥ 2.5) was present in 97 participants, 22 had prediabetes, and 3 had type 2 diabetes. Clinical data were collected retrospectively.

Among the boys aged 9-14 years, those with overweight and obesity had significantly lower testicular volume, compared with those of normal weight.

Those who were in Tanner Stage 1 were more likely to have overweight and obesity than those with normal weight, suggesting that “overweight and obese adolescents start puberty later than those of normal weight,” Dr. Cannarella said.

In the 14- to 16-year-old age group, those with insulin resistance had lower testicular volume, compared with those without insulin resistance (HOMA index < 2.5). The number of insulin-resistant adolescents was greater than that of controls in the Tanner stage 2 group.

In both the prepubertal (< 9 years) and pubertal (14-16 years) groups, hyperinsulinemia was associated with lower levels of testicular volume.

Hyperinsulinemia did not influence the timing of puberty onset.
 

No way to quantify the effect of obesity on fertility just yet

During a press briefing, Dr. Cannarella commented that obesity is likely just one of several factors influencing what appears to be an increase in male infertility over time. “It isn’t of course the only reason, but many factors in our environment have drastically changed, compared to 40 years ago, including the prevalence of heavy metals and endocrine disruptors, and of course, the change in habits and higher prevalence of metabolic disease. All of this has an impact on the proliferation of Sertoli cells in childhood and this may explain the trend toward the decline of sperm concentration and count.”

Longitudinal data are needed to establish cause and effect, she noted. “We need longitudinal studies that link the degrees of testicular volume with the degree of the sperm concentration and count starting from childhood and ending with the adult age. This is the missing link so far.”

Dr. Cannarella has reported no relevant financial relationships. Dr. Herati has reported being an advisor for Dadi, LiNA Medical, and Teleflex.

A version of this article first appeared on Medscape.com.

Infertility, pregnancy loss, and stillbirth increased women’s later risk of both nonfatal and fatal stroke, based on data from more than 600,000 women.

“To date, multiple studies have generated an expanding body of evidence on the association between pregnancy complications (e.g., gestational diabetes and preeclampsia) and the long-term risk of stroke, but studies on associations with infertility, miscarriage, or stillbirth have produced mixed evidence,” Chen Liang, a PhD candidate at the University of Queensland, Brisbane, Australia, and colleagues wrote.

In a study published in the BMJ, the researchers reviewed data from eight observational cohort studies across seven countries (Australia, China, Japan, the Netherlands, Sweden, the United Kingdom, and the United States). The participants were part of the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium established in 2021. Most observational studies included in the analysis began between 1990 and 2000.

The study population included 618,851 women aged 32-73 years at baseline for whom data on infertility, miscarriage, or stillbirth, were available. The primary outcome was the association of infertility, recurrent miscarriage, and stillbirth with risk of first fatal or nonfatal stroke, and the results were further stratified by subtype. Stroke was identified through self-reports, linked hospital data, national patient registers, or death registry data. Baseline was defined as the first incidence of infertility, miscarriage, or stillbirth. The exception was the National Survey of Health and Development, a British birth cohort started in 1946, that collected data retrospectively.

The median follow-up period was 13 years for nonfatal stroke and 9.4 years for fatal stroke.

Overall, 17.2%, 16.6%, and 4.6% of the women experienced infertility, miscarriage, and stillbirth, respectively.

Women with a history of infertility had a significantly higher nonfatal stroke risk, compared with those without infertility (hazard ratio, 1.14). Further analysis by stroke subtypes showed an increased association between miscarriage and ischemic stroke (HR, 1.15).

Those with a history of miscarriage also had an increased risk of nonfatal stroke, compared with those without miscarriages (HR, 1.11). In the miscarriage group, the risk of stroke increased with the number of miscarriages, with adjusted HRs of 1.07, 1.12, and 1.35 for women with one, two, and three or more miscarriages, respectively. When stratified by stroke subtype, women with three or more miscarriages were more likely than women with no miscarriages to experience ischemic and hemorrhagic nonfatal strokes.

Associations were similar between miscarriage history and fatal stroke risk. Women with one, two, and three or more miscarriages had increased risk of fatal stroke, compared with those with no miscarriages (aHR, 1.08, 1.26, and 1.82, respectively, and women with three or more miscarriages had a higher risk of ischemic and hemorrhagic stroke (aHR, 1.83 and 1.84, respectively).

Women with a history of stillbirth had an approximately 31% increased risk of nonfatal stroke, compared with those with no history of stillbirth, with aHRs similar for single and recurrent stillbirths (1.32 and 1.29, respectively). Ischemic nonfatal stroke risk was higher in women with any stillbirth, compared with those without stillbirth (aHR, 1.77). Fatal stroke risk also was higher in women with any stillbirth, compared with those without, and this risk increased with the number of stillbirths (HR, 0.97 and HR, 1.26 for those with one stillbirth and two or more, respectively).

“The increased risk of stroke associated with infertility or recurrent stillbirths was mainly driven by a single subtype of stroke (nonfatal ischemic stroke or fatal hemorrhagic stroke, respectively), whereas the risk of stroke associated with recurrent miscarriages was driven by both subtypes,” the researchers wrote.

The researchers cited endothelial dysfunction as a potential underlying mechanism for increased stroke risk associated with pregnancy complications. “Endothelial dysfunction might lead to pregnancy loss through placentation-related defects, persist after a complicated pregnancy, and contribute to the development of stroke through reduced vasodilation, proinflammatory status, and prothrombic properties,” and that history of recurrent pregnancy loss might be a female-specific risk factor for stroke.

To mitigate this risk, they advised early monitoring of women with a history of recurrent miscarriages and stillbirths for stroke risk factors such as high blood pressure, blood sugar levels, and lipid levels.

The study findings were limited by several factors including the use of questionnaires to collect information on infertility, miscarriage, and stillbirth, and the potential variation in definitions of infertility, miscarriage, and stillbirth across the included studies, and a lack of data on the effect of different causes or treatments based on reproductive histories, the researchers noted. Other limitations include incomplete data on stroke subtypes and inability to adjust for all covariates such as thyroid disorders and endometriosis. However, the results were strengthened by the large study size and geographically and racially diverse population, extend the current knowledge on associations between infertility, miscarriage, and stillbirth with stroke, and highlight the need for more research on underlying mechanisms.
 

Data support gender-specific stroke risk stratification

“Studies that seek to understand gender differences and disparities in adverse outcomes, such as stroke risk, are extremely important given that women historically were excluded from research studies,” Catherine M. Albright, MD, of the University of Washington, Seattle, said in an interview. “By doing these studies, we are able to better risk stratify people in order to better predict and modify risks,” added Dr. Albright, who was not involved in the current study.

“It is well known than adverse pregnancy outcomes such as hypertension in pregnancy, fetal growth restriction, and preterm birth, lead to increased risk of cardiovascular disease and stroke later in life, so the general findings of an association between other adverse reproductive and pregnancy outcomes leads to increased stroke risk are not surprising,” she said.

“The take-home message is that outcomes for pregnancy really do provide a window to future health,” said Dr. Albright. “For clinicians, especially non-ob.gyns., knowing a complete pregnancy history for any new patient is important and can help risk-stratify patients, especially as we continue to gain knowledge like what is shown in this study.”

However, “this study did not evaluate why individual patients may have had infertility, recurrent pregnancy loss, or stillbirth, so research to look further into this association to determine if there is an underlying medical condition that could be treated and therefore possibly reduce both pregnancy complications and future stroke risks would be important,” Dr. Albright noted.

The study was supported by the Australian National Health and Medical Research Council Centres of Research Excellence; one corresponding author was supported by an Australian National Health and Medical Research Council Investigator grant. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

Infertility, pregnancy loss, and stillbirth increased women’s later risk of both nonfatal and fatal stroke, based on data from more than 600,000 women.

“To date, multiple studies have generated an expanding body of evidence on the association between pregnancy complications (e.g., gestational diabetes and preeclampsia) and the long-term risk of stroke, but studies on associations with infertility, miscarriage, or stillbirth have produced mixed evidence,” Chen Liang, a PhD candidate at the University of Queensland, Brisbane, Australia, and colleagues wrote.

In a study published in the BMJ, the researchers reviewed data from eight observational cohort studies across seven countries (Australia, China, Japan, the Netherlands, Sweden, the United Kingdom, and the United States). The participants were part of the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium established in 2021. Most observational studies included in the analysis began between 1990 and 2000.

The study population included 618,851 women aged 32-73 years at baseline for whom data on infertility, miscarriage, or stillbirth, were available. The primary outcome was the association of infertility, recurrent miscarriage, and stillbirth with risk of first fatal or nonfatal stroke, and the results were further stratified by subtype. Stroke was identified through self-reports, linked hospital data, national patient registers, or death registry data. Baseline was defined as the first incidence of infertility, miscarriage, or stillbirth. The exception was the National Survey of Health and Development, a British birth cohort started in 1946, that collected data retrospectively.

The median follow-up period was 13 years for nonfatal stroke and 9.4 years for fatal stroke.

Overall, 17.2%, 16.6%, and 4.6% of the women experienced infertility, miscarriage, and stillbirth, respectively.

Women with a history of infertility had a significantly higher nonfatal stroke risk, compared with those without infertility (hazard ratio, 1.14). Further analysis by stroke subtypes showed an increased association between miscarriage and ischemic stroke (HR, 1.15).

Those with a history of miscarriage also had an increased risk of nonfatal stroke, compared with those without miscarriages (HR, 1.11). In the miscarriage group, the risk of stroke increased with the number of miscarriages, with adjusted HRs of 1.07, 1.12, and 1.35 for women with one, two, and three or more miscarriages, respectively. When stratified by stroke subtype, women with three or more miscarriages were more likely than women with no miscarriages to experience ischemic and hemorrhagic nonfatal strokes.

Associations were similar between miscarriage history and fatal stroke risk. Women with one, two, and three or more miscarriages had increased risk of fatal stroke, compared with those with no miscarriages (aHR, 1.08, 1.26, and 1.82, respectively, and women with three or more miscarriages had a higher risk of ischemic and hemorrhagic stroke (aHR, 1.83 and 1.84, respectively).

Women with a history of stillbirth had an approximately 31% increased risk of nonfatal stroke, compared with those with no history of stillbirth, with aHRs similar for single and recurrent stillbirths (1.32 and 1.29, respectively). Ischemic nonfatal stroke risk was higher in women with any stillbirth, compared with those without stillbirth (aHR, 1.77). Fatal stroke risk also was higher in women with any stillbirth, compared with those without, and this risk increased with the number of stillbirths (HR, 0.97 and HR, 1.26 for those with one stillbirth and two or more, respectively).

“The increased risk of stroke associated with infertility or recurrent stillbirths was mainly driven by a single subtype of stroke (nonfatal ischemic stroke or fatal hemorrhagic stroke, respectively), whereas the risk of stroke associated with recurrent miscarriages was driven by both subtypes,” the researchers wrote.

The researchers cited endothelial dysfunction as a potential underlying mechanism for increased stroke risk associated with pregnancy complications. “Endothelial dysfunction might lead to pregnancy loss through placentation-related defects, persist after a complicated pregnancy, and contribute to the development of stroke through reduced vasodilation, proinflammatory status, and prothrombic properties,” and that history of recurrent pregnancy loss might be a female-specific risk factor for stroke.

To mitigate this risk, they advised early monitoring of women with a history of recurrent miscarriages and stillbirths for stroke risk factors such as high blood pressure, blood sugar levels, and lipid levels.

The study findings were limited by several factors including the use of questionnaires to collect information on infertility, miscarriage, and stillbirth, and the potential variation in definitions of infertility, miscarriage, and stillbirth across the included studies, and a lack of data on the effect of different causes or treatments based on reproductive histories, the researchers noted. Other limitations include incomplete data on stroke subtypes and inability to adjust for all covariates such as thyroid disorders and endometriosis. However, the results were strengthened by the large study size and geographically and racially diverse population, extend the current knowledge on associations between infertility, miscarriage, and stillbirth with stroke, and highlight the need for more research on underlying mechanisms.
 

Data support gender-specific stroke risk stratification

“Studies that seek to understand gender differences and disparities in adverse outcomes, such as stroke risk, are extremely important given that women historically were excluded from research studies,” Catherine M. Albright, MD, of the University of Washington, Seattle, said in an interview. “By doing these studies, we are able to better risk stratify people in order to better predict and modify risks,” added Dr. Albright, who was not involved in the current study.

“It is well known than adverse pregnancy outcomes such as hypertension in pregnancy, fetal growth restriction, and preterm birth, lead to increased risk of cardiovascular disease and stroke later in life, so the general findings of an association between other adverse reproductive and pregnancy outcomes leads to increased stroke risk are not surprising,” she said.

“The take-home message is that outcomes for pregnancy really do provide a window to future health,” said Dr. Albright. “For clinicians, especially non-ob.gyns., knowing a complete pregnancy history for any new patient is important and can help risk-stratify patients, especially as we continue to gain knowledge like what is shown in this study.”

However, “this study did not evaluate why individual patients may have had infertility, recurrent pregnancy loss, or stillbirth, so research to look further into this association to determine if there is an underlying medical condition that could be treated and therefore possibly reduce both pregnancy complications and future stroke risks would be important,” Dr. Albright noted.

The study was supported by the Australian National Health and Medical Research Council Centres of Research Excellence; one corresponding author was supported by an Australian National Health and Medical Research Council Investigator grant. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

Infertility, pregnancy loss, and stillbirth increased women’s later risk of both nonfatal and fatal stroke, based on data from more than 600,000 women.

“To date, multiple studies have generated an expanding body of evidence on the association between pregnancy complications (e.g., gestational diabetes and preeclampsia) and the long-term risk of stroke, but studies on associations with infertility, miscarriage, or stillbirth have produced mixed evidence,” Chen Liang, a PhD candidate at the University of Queensland, Brisbane, Australia, and colleagues wrote.

In a study published in the BMJ, the researchers reviewed data from eight observational cohort studies across seven countries (Australia, China, Japan, the Netherlands, Sweden, the United Kingdom, and the United States). The participants were part of the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium established in 2021. Most observational studies included in the analysis began between 1990 and 2000.

The study population included 618,851 women aged 32-73 years at baseline for whom data on infertility, miscarriage, or stillbirth, were available. The primary outcome was the association of infertility, recurrent miscarriage, and stillbirth with risk of first fatal or nonfatal stroke, and the results were further stratified by subtype. Stroke was identified through self-reports, linked hospital data, national patient registers, or death registry data. Baseline was defined as the first incidence of infertility, miscarriage, or stillbirth. The exception was the National Survey of Health and Development, a British birth cohort started in 1946, that collected data retrospectively.

The median follow-up period was 13 years for nonfatal stroke and 9.4 years for fatal stroke.

Overall, 17.2%, 16.6%, and 4.6% of the women experienced infertility, miscarriage, and stillbirth, respectively.

Women with a history of infertility had a significantly higher nonfatal stroke risk, compared with those without infertility (hazard ratio, 1.14). Further analysis by stroke subtypes showed an increased association between miscarriage and ischemic stroke (HR, 1.15).

Those with a history of miscarriage also had an increased risk of nonfatal stroke, compared with those without miscarriages (HR, 1.11). In the miscarriage group, the risk of stroke increased with the number of miscarriages, with adjusted HRs of 1.07, 1.12, and 1.35 for women with one, two, and three or more miscarriages, respectively. When stratified by stroke subtype, women with three or more miscarriages were more likely than women with no miscarriages to experience ischemic and hemorrhagic nonfatal strokes.

Associations were similar between miscarriage history and fatal stroke risk. Women with one, two, and three or more miscarriages had increased risk of fatal stroke, compared with those with no miscarriages (aHR, 1.08, 1.26, and 1.82, respectively, and women with three or more miscarriages had a higher risk of ischemic and hemorrhagic stroke (aHR, 1.83 and 1.84, respectively).

Women with a history of stillbirth had an approximately 31% increased risk of nonfatal stroke, compared with those with no history of stillbirth, with aHRs similar for single and recurrent stillbirths (1.32 and 1.29, respectively). Ischemic nonfatal stroke risk was higher in women with any stillbirth, compared with those without stillbirth (aHR, 1.77). Fatal stroke risk also was higher in women with any stillbirth, compared with those without, and this risk increased with the number of stillbirths (HR, 0.97 and HR, 1.26 for those with one stillbirth and two or more, respectively).

“The increased risk of stroke associated with infertility or recurrent stillbirths was mainly driven by a single subtype of stroke (nonfatal ischemic stroke or fatal hemorrhagic stroke, respectively), whereas the risk of stroke associated with recurrent miscarriages was driven by both subtypes,” the researchers wrote.

The researchers cited endothelial dysfunction as a potential underlying mechanism for increased stroke risk associated with pregnancy complications. “Endothelial dysfunction might lead to pregnancy loss through placentation-related defects, persist after a complicated pregnancy, and contribute to the development of stroke through reduced vasodilation, proinflammatory status, and prothrombic properties,” and that history of recurrent pregnancy loss might be a female-specific risk factor for stroke.

To mitigate this risk, they advised early monitoring of women with a history of recurrent miscarriages and stillbirths for stroke risk factors such as high blood pressure, blood sugar levels, and lipid levels.

The study findings were limited by several factors including the use of questionnaires to collect information on infertility, miscarriage, and stillbirth, and the potential variation in definitions of infertility, miscarriage, and stillbirth across the included studies, and a lack of data on the effect of different causes or treatments based on reproductive histories, the researchers noted. Other limitations include incomplete data on stroke subtypes and inability to adjust for all covariates such as thyroid disorders and endometriosis. However, the results were strengthened by the large study size and geographically and racially diverse population, extend the current knowledge on associations between infertility, miscarriage, and stillbirth with stroke, and highlight the need for more research on underlying mechanisms.
 

Data support gender-specific stroke risk stratification

“Studies that seek to understand gender differences and disparities in adverse outcomes, such as stroke risk, are extremely important given that women historically were excluded from research studies,” Catherine M. Albright, MD, of the University of Washington, Seattle, said in an interview. “By doing these studies, we are able to better risk stratify people in order to better predict and modify risks,” added Dr. Albright, who was not involved in the current study.

“It is well known than adverse pregnancy outcomes such as hypertension in pregnancy, fetal growth restriction, and preterm birth, lead to increased risk of cardiovascular disease and stroke later in life, so the general findings of an association between other adverse reproductive and pregnancy outcomes leads to increased stroke risk are not surprising,” she said.

“The take-home message is that outcomes for pregnancy really do provide a window to future health,” said Dr. Albright. “For clinicians, especially non-ob.gyns., knowing a complete pregnancy history for any new patient is important and can help risk-stratify patients, especially as we continue to gain knowledge like what is shown in this study.”

However, “this study did not evaluate why individual patients may have had infertility, recurrent pregnancy loss, or stillbirth, so research to look further into this association to determine if there is an underlying medical condition that could be treated and therefore possibly reduce both pregnancy complications and future stroke risks would be important,” Dr. Albright noted.

The study was supported by the Australian National Health and Medical Research Council Centres of Research Excellence; one corresponding author was supported by an Australian National Health and Medical Research Council Investigator grant. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MADRID – During the International Scientific Symposium “New Frontiers in Scientific Research” that recently took place in Barcelona, specialists analyzed the role of the very-low-calorie ketogenic diet. This analysis was in relation to three comorbidities that have a higher incidence among overweight and obese patients: polycystic ovary syndrome, nonalcoholic fatty liver disease, and type 2 diabetes. The experts’ aim? To analyze and update the latest evidence on the benefits of this dietary choice.

Polycystic ovary syndrome

Alessandra Gambineri, MD, PhD, associate professor at the department of medicine and surgery (DIMEC) at the University of Bologna, Italy, addressed the link between obesity and polycystic ovary syndrome, which she described as a chronic disease that affects about 10% of women of childbearing age and that presents diverse phenotypes with different characteristics.

“The pathophysiology of this syndrome is characterized by the interaction of three factors: androgen excess, adipose tissue dysfunction, and insulin resistance. These factors interact with each other and are expressed differently in each phenotype,” said Dr. Gambineri.

She indicated that adipose tissue dysfunction is central to this pathology. This centrality results from its association with secretions, such as free fatty acids, proinflammatory cytokines, certain adipokines that promote insulin resistance, glucocorticosteroids, androgens, and oxidative stress.

“Similarly, the oxidative stress that characterizes this syndrome is increasingly present in obese individuals,” said Dr. Gambineri. “This oxidative stress also produces ovary hypotoxicity that aggravates ovulatory function. In this context, the very-low-calorie ketogenic diet can be useful in several ways: weight reduction; promoting the loss of mainly visceral/abdominal fat; decreasing lipotoxicity; and improving inflammation, hyperinsulinemia, and insulin resistance.”

This was the path followed to carry out a study that aimed to analyze the effects of the very-low-calorie ketogenic diet on manifestations of polycystic ovary syndrome in the obesity phenotype. Dr. Gambineri presented its results.

“The objective was to compare the effects of a very-low-calorie ketogenic diet and the standard low-calorie (hypocaloric) diet as a control group,” she said. “The effects studied include body weight, insulin resistance, menstrual cycle, ovulation, ovarian morphology, and hyperandrogenism in a population of 30 obese women with polycystic ovary syndrome and insulin resistance.”

Study participants had a diagnosis of polycystic ovary syndrome as defined by the National Institutes of Health criteria and were aged 18-45 years. These women were randomly assigned to two groups of equal size: experimental (very-low-calorie ketogenic diet) and control (hypocaloric diet). “The women assigned to the experimental group followed the ketogenic stage for eight weeks and then moved to the second, low-calorie diet phase for an additional eight weeks, while those in the control group (hypocaloric diet) followed the low-calorie diet for all 16 weeks.”

The primary outcomes were changes in weight and body composition, specifically fat mass and lean mass, measured by bioimpedance. “The changes observed in the following aspects were considered secondary outcomes: abdominal fat distribution, metabolic parameters, ovulation, ovarian morphology, hirsutism, hyperandrogenism, psychological well-being, and psychological distress,” said Dr. Gambineri. “Any reduction in the ovarian stroma, the area where androgens are synthesized, was also analyzed.”

The study authors found that although BMI decreased in both groups, this reduction was greater in the group that followed the very-low-calorie ketogenic diet. Significant weight loss was observed in both groups, 12.4 kg versus 4.7 kg. Significant differences were also observed in waist circumference (−8.1% in the experimental group vs. −2.2% in the control group), fat mass (−15.1% vs. −8.5%), and free testosterone (−30.3% vs. +10.6%). Only the experimental group saw a reduction in insulin.

“A key point regarding hyperandrogenism, especially regarding what’s referred to as free testosterone, there was only a significant reduction in the very-low-calorie ketogenic diet group,” said Dr. Gambineri. “This reduction was especially evident in the first part of the study, coinciding with the ketogenic period. The reason for this effect lies in the significant increase in the concentration of sex hormone-binding globulins, SHB6. Said globulins bind to the testosterone present in female blood, producing a reduction in free testosterone, a very important effect considering that this syndrome is an androgenic disorder. Furthermore, current treatments for polycystic ovary syndrome do not reduce free testosterone as much as this dietary approach does.”

For the specialist, among all these positive effects in these patients, perhaps most important is the notable improvement that occurs in ovulation. “At the beginning of the study, only 38.5% of the participants in the experimental group and 14.3% of those in the control group had ovulatory cycles. After the intervention, 84.6% managed to ovulate, compared to 35.7% who achieved this goal in the other group.”

Dr. Gambineri suggested that this method is “valid for reducing fat mass and rapidly improving hyperandrogenism and ovulatory dysfunction in women with obesity and polycystic ovary syndrome.”
 

Reversing type 2 diabetes?

Daniela Sofrà, MD, an endocrinologist specializing in diabetology at La Source Clinic, Lausanne, Switzerland, reviewed the current evidence on the role of the very-low-calorie ketogenic diet in the management of type 2 diabetes.

“It’s time to rethink diabetes treatment and focus efforts on managing obesity as an associated factor,” she said. “One of the hypotheses being examined in this regard is the twin cycle, which postulates that type 2 diabetes is the result of excess fat in the liver. This in turn is associated with insulin resistance with pancreas dysfunction.”

Dr. Sofrà added that there is a study documenting for the first time the reversibility of the morphology of the diabetic pancreas after caloric restriction with the very-low-calorie ketogenic diet. “The reason for this effect is the use of visceral and intrahepatic fat, which can lead to the remission of the clinical manifestation of type 2 diabetes, understanding as such the definition made by the American Diabetes Association: glycosylated hemoglobin < 6.5% without pharmacological therapy.”

Specifically, the results of this research showed that after following the very-low-calorie ketogenic diet and achieving a 15% weight loss (mean weight loss of the participants), liver glucose levels returned to normal levels within 7 days. Beta cell function returned to near normal within 8 weeks.

“Subsequent studies have shown the durability of remission of type 2 diabetes, thanks to the reactivation of the insulin-secreting function of beta cells that had become dedifferentiated in the face of chronic nutrient excess. Specifically, 6 out of 10 patients maintained glycosylated hemoglobin < 6% after 6 months without the need for pharmacological therapy,” Dr. Sofrà added.

Likewise, she highlighted that the probability of achieving remission is mainly determined by the duration of the disease. “The years with diabetes are one of the main predictors of the response that the patient will have with this dietary intervention. Studies have shown that remission is possible in patients with diabetes for less than 6 years, although there are other projects that indicate that it can be achieved with up to 10 years’ duration.”

Based on these data, Dr. Sofrà emphasized the pleiotropic effects of the very-low-calorie ketogenic diet on glycemic control, favoring the possible remission of diabetes or the reduction of drugs, as well as the reduction of the HOMA-IR index (insulin resistance) and waist circumference in people with type 2 diabetes.
 

Nonalcoholic fatty liver disease

The third comorbidity of obesity that may benefit from the very-low-calorie ketogenic diet is hepatic steatosis, or nonalcoholic fatty liver disease, said Hardy Walle, MD, an internal medicine specialist and director/founder of the Bodymed center, Kirkel, Germany, and one of the authors of this research.

“Recent research shows that ectopic fat and nonalcoholic fatty liver disease could be considered a cause, or at least one of the causes, of most of the diseases that affect the population as a consequence of overweight and obesity,” said Dr. Walle. “Some authors have stated that without fatty liver, there is no type 2 diabetes.”

Dr. Walle pointed out that between 30% and 40% of the adult population has nonalcoholic fatty liver disease, a percentage that increases considerably in people with obesity, reaching 70% prevalence and increasing, in the case of type 2 diabetes, to almost 90%. “Even normal weight does not rule out fatty liver; in fact, about 15% of people with nonalcoholic fatty liver disease are not overweight.”

In a setting where there are no approved drugs for the treatment of fatty liver (the current standard approach focuses on lifestyle interventions), a short-term hypocaloric diet (or liver fasting) is considered an effective method for management of this pathology. This principle was demonstrated by a study by the Saarland University, Saarbrücken, Germany, that Dr. Walle used to illustrate this statement.

“The participants (60 patients with hepatic steatosis) followed a hypocaloric diet (less than 1,000 kcal/day) for 14 days with a formula rich in protein and fiber specially developed for the treatment of nonalcoholic fatty liver disease. A fibroscan was then performed with controlled attenuation parameter measurement to quantify fatty liver disease. The results showed not only a significant improvement in nonalcoholic fatty liver disease parameters but also a marked improvement in all relevant metabolic parameters (serum lipids, liver enzymes),” explained Dr. Walle.

“This evidence leads us to affirm that the concept of hepatic fasting (by means of a hypocaloric diet) marks a point of reference for a future treatment approach for nonalcoholic fatty liver disease,” he concluded.

The study that Dr. Gambineri presented was carried out with the collaboration of the Pronokal Group (Nestlé Health Science). Dr. Gambineri, Dr. Sofrà, and Dr. Walle disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MADRID – During the International Scientific Symposium “New Frontiers in Scientific Research” that recently took place in Barcelona, specialists analyzed the role of the very-low-calorie ketogenic diet. This analysis was in relation to three comorbidities that have a higher incidence among overweight and obese patients: polycystic ovary syndrome, nonalcoholic fatty liver disease, and type 2 diabetes. The experts’ aim? To analyze and update the latest evidence on the benefits of this dietary choice.

Polycystic ovary syndrome

Alessandra Gambineri, MD, PhD, associate professor at the department of medicine and surgery (DIMEC) at the University of Bologna, Italy, addressed the link between obesity and polycystic ovary syndrome, which she described as a chronic disease that affects about 10% of women of childbearing age and that presents diverse phenotypes with different characteristics.

“The pathophysiology of this syndrome is characterized by the interaction of three factors: androgen excess, adipose tissue dysfunction, and insulin resistance. These factors interact with each other and are expressed differently in each phenotype,” said Dr. Gambineri.

She indicated that adipose tissue dysfunction is central to this pathology. This centrality results from its association with secretions, such as free fatty acids, proinflammatory cytokines, certain adipokines that promote insulin resistance, glucocorticosteroids, androgens, and oxidative stress.

“Similarly, the oxidative stress that characterizes this syndrome is increasingly present in obese individuals,” said Dr. Gambineri. “This oxidative stress also produces ovary hypotoxicity that aggravates ovulatory function. In this context, the very-low-calorie ketogenic diet can be useful in several ways: weight reduction; promoting the loss of mainly visceral/abdominal fat; decreasing lipotoxicity; and improving inflammation, hyperinsulinemia, and insulin resistance.”

This was the path followed to carry out a study that aimed to analyze the effects of the very-low-calorie ketogenic diet on manifestations of polycystic ovary syndrome in the obesity phenotype. Dr. Gambineri presented its results.

“The objective was to compare the effects of a very-low-calorie ketogenic diet and the standard low-calorie (hypocaloric) diet as a control group,” she said. “The effects studied include body weight, insulin resistance, menstrual cycle, ovulation, ovarian morphology, and hyperandrogenism in a population of 30 obese women with polycystic ovary syndrome and insulin resistance.”

Study participants had a diagnosis of polycystic ovary syndrome as defined by the National Institutes of Health criteria and were aged 18-45 years. These women were randomly assigned to two groups of equal size: experimental (very-low-calorie ketogenic diet) and control (hypocaloric diet). “The women assigned to the experimental group followed the ketogenic stage for eight weeks and then moved to the second, low-calorie diet phase for an additional eight weeks, while those in the control group (hypocaloric diet) followed the low-calorie diet for all 16 weeks.”

The primary outcomes were changes in weight and body composition, specifically fat mass and lean mass, measured by bioimpedance. “The changes observed in the following aspects were considered secondary outcomes: abdominal fat distribution, metabolic parameters, ovulation, ovarian morphology, hirsutism, hyperandrogenism, psychological well-being, and psychological distress,” said Dr. Gambineri. “Any reduction in the ovarian stroma, the area where androgens are synthesized, was also analyzed.”

The study authors found that although BMI decreased in both groups, this reduction was greater in the group that followed the very-low-calorie ketogenic diet. Significant weight loss was observed in both groups, 12.4 kg versus 4.7 kg. Significant differences were also observed in waist circumference (−8.1% in the experimental group vs. −2.2% in the control group), fat mass (−15.1% vs. −8.5%), and free testosterone (−30.3% vs. +10.6%). Only the experimental group saw a reduction in insulin.

“A key point regarding hyperandrogenism, especially regarding what’s referred to as free testosterone, there was only a significant reduction in the very-low-calorie ketogenic diet group,” said Dr. Gambineri. “This reduction was especially evident in the first part of the study, coinciding with the ketogenic period. The reason for this effect lies in the significant increase in the concentration of sex hormone-binding globulins, SHB6. Said globulins bind to the testosterone present in female blood, producing a reduction in free testosterone, a very important effect considering that this syndrome is an androgenic disorder. Furthermore, current treatments for polycystic ovary syndrome do not reduce free testosterone as much as this dietary approach does.”

For the specialist, among all these positive effects in these patients, perhaps most important is the notable improvement that occurs in ovulation. “At the beginning of the study, only 38.5% of the participants in the experimental group and 14.3% of those in the control group had ovulatory cycles. After the intervention, 84.6% managed to ovulate, compared to 35.7% who achieved this goal in the other group.”

Dr. Gambineri suggested that this method is “valid for reducing fat mass and rapidly improving hyperandrogenism and ovulatory dysfunction in women with obesity and polycystic ovary syndrome.”
 

Reversing type 2 diabetes?

Daniela Sofrà, MD, an endocrinologist specializing in diabetology at La Source Clinic, Lausanne, Switzerland, reviewed the current evidence on the role of the very-low-calorie ketogenic diet in the management of type 2 diabetes.

“It’s time to rethink diabetes treatment and focus efforts on managing obesity as an associated factor,” she said. “One of the hypotheses being examined in this regard is the twin cycle, which postulates that type 2 diabetes is the result of excess fat in the liver. This in turn is associated with insulin resistance with pancreas dysfunction.”

Dr. Sofrà added that there is a study documenting for the first time the reversibility of the morphology of the diabetic pancreas after caloric restriction with the very-low-calorie ketogenic diet. “The reason for this effect is the use of visceral and intrahepatic fat, which can lead to the remission of the clinical manifestation of type 2 diabetes, understanding as such the definition made by the American Diabetes Association: glycosylated hemoglobin < 6.5% without pharmacological therapy.”

Specifically, the results of this research showed that after following the very-low-calorie ketogenic diet and achieving a 15% weight loss (mean weight loss of the participants), liver glucose levels returned to normal levels within 7 days. Beta cell function returned to near normal within 8 weeks.

“Subsequent studies have shown the durability of remission of type 2 diabetes, thanks to the reactivation of the insulin-secreting function of beta cells that had become dedifferentiated in the face of chronic nutrient excess. Specifically, 6 out of 10 patients maintained glycosylated hemoglobin < 6% after 6 months without the need for pharmacological therapy,” Dr. Sofrà added.

Likewise, she highlighted that the probability of achieving remission is mainly determined by the duration of the disease. “The years with diabetes are one of the main predictors of the response that the patient will have with this dietary intervention. Studies have shown that remission is possible in patients with diabetes for less than 6 years, although there are other projects that indicate that it can be achieved with up to 10 years’ duration.”

Based on these data, Dr. Sofrà emphasized the pleiotropic effects of the very-low-calorie ketogenic diet on glycemic control, favoring the possible remission of diabetes or the reduction of drugs, as well as the reduction of the HOMA-IR index (insulin resistance) and waist circumference in people with type 2 diabetes.
 

Nonalcoholic fatty liver disease

The third comorbidity of obesity that may benefit from the very-low-calorie ketogenic diet is hepatic steatosis, or nonalcoholic fatty liver disease, said Hardy Walle, MD, an internal medicine specialist and director/founder of the Bodymed center, Kirkel, Germany, and one of the authors of this research.

“Recent research shows that ectopic fat and nonalcoholic fatty liver disease could be considered a cause, or at least one of the causes, of most of the diseases that affect the population as a consequence of overweight and obesity,” said Dr. Walle. “Some authors have stated that without fatty liver, there is no type 2 diabetes.”

Dr. Walle pointed out that between 30% and 40% of the adult population has nonalcoholic fatty liver disease, a percentage that increases considerably in people with obesity, reaching 70% prevalence and increasing, in the case of type 2 diabetes, to almost 90%. “Even normal weight does not rule out fatty liver; in fact, about 15% of people with nonalcoholic fatty liver disease are not overweight.”

In a setting where there are no approved drugs for the treatment of fatty liver (the current standard approach focuses on lifestyle interventions), a short-term hypocaloric diet (or liver fasting) is considered an effective method for management of this pathology. This principle was demonstrated by a study by the Saarland University, Saarbrücken, Germany, that Dr. Walle used to illustrate this statement.

“The participants (60 patients with hepatic steatosis) followed a hypocaloric diet (less than 1,000 kcal/day) for 14 days with a formula rich in protein and fiber specially developed for the treatment of nonalcoholic fatty liver disease. A fibroscan was then performed with controlled attenuation parameter measurement to quantify fatty liver disease. The results showed not only a significant improvement in nonalcoholic fatty liver disease parameters but also a marked improvement in all relevant metabolic parameters (serum lipids, liver enzymes),” explained Dr. Walle.

“This evidence leads us to affirm that the concept of hepatic fasting (by means of a hypocaloric diet) marks a point of reference for a future treatment approach for nonalcoholic fatty liver disease,” he concluded.

The study that Dr. Gambineri presented was carried out with the collaboration of the Pronokal Group (Nestlé Health Science). Dr. Gambineri, Dr. Sofrà, and Dr. Walle disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MADRID – During the International Scientific Symposium “New Frontiers in Scientific Research” that recently took place in Barcelona, specialists analyzed the role of the very-low-calorie ketogenic diet. This analysis was in relation to three comorbidities that have a higher incidence among overweight and obese patients: polycystic ovary syndrome, nonalcoholic fatty liver disease, and type 2 diabetes. The experts’ aim? To analyze and update the latest evidence on the benefits of this dietary choice.

Polycystic ovary syndrome

Alessandra Gambineri, MD, PhD, associate professor at the department of medicine and surgery (DIMEC) at the University of Bologna, Italy, addressed the link between obesity and polycystic ovary syndrome, which she described as a chronic disease that affects about 10% of women of childbearing age and that presents diverse phenotypes with different characteristics.

“The pathophysiology of this syndrome is characterized by the interaction of three factors: androgen excess, adipose tissue dysfunction, and insulin resistance. These factors interact with each other and are expressed differently in each phenotype,” said Dr. Gambineri.

She indicated that adipose tissue dysfunction is central to this pathology. This centrality results from its association with secretions, such as free fatty acids, proinflammatory cytokines, certain adipokines that promote insulin resistance, glucocorticosteroids, androgens, and oxidative stress.

“Similarly, the oxidative stress that characterizes this syndrome is increasingly present in obese individuals,” said Dr. Gambineri. “This oxidative stress also produces ovary hypotoxicity that aggravates ovulatory function. In this context, the very-low-calorie ketogenic diet can be useful in several ways: weight reduction; promoting the loss of mainly visceral/abdominal fat; decreasing lipotoxicity; and improving inflammation, hyperinsulinemia, and insulin resistance.”

This was the path followed to carry out a study that aimed to analyze the effects of the very-low-calorie ketogenic diet on manifestations of polycystic ovary syndrome in the obesity phenotype. Dr. Gambineri presented its results.

“The objective was to compare the effects of a very-low-calorie ketogenic diet and the standard low-calorie (hypocaloric) diet as a control group,” she said. “The effects studied include body weight, insulin resistance, menstrual cycle, ovulation, ovarian morphology, and hyperandrogenism in a population of 30 obese women with polycystic ovary syndrome and insulin resistance.”

Study participants had a diagnosis of polycystic ovary syndrome as defined by the National Institutes of Health criteria and were aged 18-45 years. These women were randomly assigned to two groups of equal size: experimental (very-low-calorie ketogenic diet) and control (hypocaloric diet). “The women assigned to the experimental group followed the ketogenic stage for eight weeks and then moved to the second, low-calorie diet phase for an additional eight weeks, while those in the control group (hypocaloric diet) followed the low-calorie diet for all 16 weeks.”

The primary outcomes were changes in weight and body composition, specifically fat mass and lean mass, measured by bioimpedance. “The changes observed in the following aspects were considered secondary outcomes: abdominal fat distribution, metabolic parameters, ovulation, ovarian morphology, hirsutism, hyperandrogenism, psychological well-being, and psychological distress,” said Dr. Gambineri. “Any reduction in the ovarian stroma, the area where androgens are synthesized, was also analyzed.”

The study authors found that although BMI decreased in both groups, this reduction was greater in the group that followed the very-low-calorie ketogenic diet. Significant weight loss was observed in both groups, 12.4 kg versus 4.7 kg. Significant differences were also observed in waist circumference (−8.1% in the experimental group vs. −2.2% in the control group), fat mass (−15.1% vs. −8.5%), and free testosterone (−30.3% vs. +10.6%). Only the experimental group saw a reduction in insulin.

“A key point regarding hyperandrogenism, especially regarding what’s referred to as free testosterone, there was only a significant reduction in the very-low-calorie ketogenic diet group,” said Dr. Gambineri. “This reduction was especially evident in the first part of the study, coinciding with the ketogenic period. The reason for this effect lies in the significant increase in the concentration of sex hormone-binding globulins, SHB6. Said globulins bind to the testosterone present in female blood, producing a reduction in free testosterone, a very important effect considering that this syndrome is an androgenic disorder. Furthermore, current treatments for polycystic ovary syndrome do not reduce free testosterone as much as this dietary approach does.”

For the specialist, among all these positive effects in these patients, perhaps most important is the notable improvement that occurs in ovulation. “At the beginning of the study, only 38.5% of the participants in the experimental group and 14.3% of those in the control group had ovulatory cycles. After the intervention, 84.6% managed to ovulate, compared to 35.7% who achieved this goal in the other group.”

Dr. Gambineri suggested that this method is “valid for reducing fat mass and rapidly improving hyperandrogenism and ovulatory dysfunction in women with obesity and polycystic ovary syndrome.”
 

Reversing type 2 diabetes?

Daniela Sofrà, MD, an endocrinologist specializing in diabetology at La Source Clinic, Lausanne, Switzerland, reviewed the current evidence on the role of the very-low-calorie ketogenic diet in the management of type 2 diabetes.

“It’s time to rethink diabetes treatment and focus efforts on managing obesity as an associated factor,” she said. “One of the hypotheses being examined in this regard is the twin cycle, which postulates that type 2 diabetes is the result of excess fat in the liver. This in turn is associated with insulin resistance with pancreas dysfunction.”

Dr. Sofrà added that there is a study documenting for the first time the reversibility of the morphology of the diabetic pancreas after caloric restriction with the very-low-calorie ketogenic diet. “The reason for this effect is the use of visceral and intrahepatic fat, which can lead to the remission of the clinical manifestation of type 2 diabetes, understanding as such the definition made by the American Diabetes Association: glycosylated hemoglobin < 6.5% without pharmacological therapy.”

Specifically, the results of this research showed that after following the very-low-calorie ketogenic diet and achieving a 15% weight loss (mean weight loss of the participants), liver glucose levels returned to normal levels within 7 days. Beta cell function returned to near normal within 8 weeks.

“Subsequent studies have shown the durability of remission of type 2 diabetes, thanks to the reactivation of the insulin-secreting function of beta cells that had become dedifferentiated in the face of chronic nutrient excess. Specifically, 6 out of 10 patients maintained glycosylated hemoglobin < 6% after 6 months without the need for pharmacological therapy,” Dr. Sofrà added.

Likewise, she highlighted that the probability of achieving remission is mainly determined by the duration of the disease. “The years with diabetes are one of the main predictors of the response that the patient will have with this dietary intervention. Studies have shown that remission is possible in patients with diabetes for less than 6 years, although there are other projects that indicate that it can be achieved with up to 10 years’ duration.”

Based on these data, Dr. Sofrà emphasized the pleiotropic effects of the very-low-calorie ketogenic diet on glycemic control, favoring the possible remission of diabetes or the reduction of drugs, as well as the reduction of the HOMA-IR index (insulin resistance) and waist circumference in people with type 2 diabetes.
 

Nonalcoholic fatty liver disease

The third comorbidity of obesity that may benefit from the very-low-calorie ketogenic diet is hepatic steatosis, or nonalcoholic fatty liver disease, said Hardy Walle, MD, an internal medicine specialist and director/founder of the Bodymed center, Kirkel, Germany, and one of the authors of this research.

“Recent research shows that ectopic fat and nonalcoholic fatty liver disease could be considered a cause, or at least one of the causes, of most of the diseases that affect the population as a consequence of overweight and obesity,” said Dr. Walle. “Some authors have stated that without fatty liver, there is no type 2 diabetes.”

Dr. Walle pointed out that between 30% and 40% of the adult population has nonalcoholic fatty liver disease, a percentage that increases considerably in people with obesity, reaching 70% prevalence and increasing, in the case of type 2 diabetes, to almost 90%. “Even normal weight does not rule out fatty liver; in fact, about 15% of people with nonalcoholic fatty liver disease are not overweight.”

In a setting where there are no approved drugs for the treatment of fatty liver (the current standard approach focuses on lifestyle interventions), a short-term hypocaloric diet (or liver fasting) is considered an effective method for management of this pathology. This principle was demonstrated by a study by the Saarland University, Saarbrücken, Germany, that Dr. Walle used to illustrate this statement.

“The participants (60 patients with hepatic steatosis) followed a hypocaloric diet (less than 1,000 kcal/day) for 14 days with a formula rich in protein and fiber specially developed for the treatment of nonalcoholic fatty liver disease. A fibroscan was then performed with controlled attenuation parameter measurement to quantify fatty liver disease. The results showed not only a significant improvement in nonalcoholic fatty liver disease parameters but also a marked improvement in all relevant metabolic parameters (serum lipids, liver enzymes),” explained Dr. Walle.

“This evidence leads us to affirm that the concept of hepatic fasting (by means of a hypocaloric diet) marks a point of reference for a future treatment approach for nonalcoholic fatty liver disease,” he concluded.

The study that Dr. Gambineri presented was carried out with the collaboration of the Pronokal Group (Nestlé Health Science). Dr. Gambineri, Dr. Sofrà, and Dr. Walle disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A phase 3 trial has associated the neurokinin-3 (NK3)–receptor inhibitor fezolinetant, an oral therapy taken once daily, with substantial control over the symptoms of menopause, according to results of the randomized SKYLIGHT 2 trial.

The nonhormonal therapy has the potential to address an important unmet need, Genevieve Neal-Perry, MD, PhD, said at the annual meeting of the Endocrine Society.

The health risks of hormone therapy (HT) have “caused quite a few women to consider whether hormone replacement is right for them, and, in addition, there are other individuals who have hormone-responsive cancers or other disorders that might prohibit them [from using HT],” Dr. Neal-Perry said.

The NK3 receptor stimulates the thermoregulatory center in the hypothalamus. By blocking the NK3 receptor, vasodilation and other downstream effects are inhibited, explained Dr. Neal-Perry. She credited relatively recent advances in understanding the mechanisms of menopausal symptoms for identifying this and other potentially targetable mediators.

SKYLIGHT 2 trial: Two phases

In the double-blind multinational phase 3 SKYLIGHT 2 trial, 484 otherwise healthy symptomatic menopausal women were randomized to 30 mg of fezolinetant, 45 mg of fezolinetant, or placebo. The 120 participating centers were in North American and Europe.

In the first phase, safety and efficacy were evaluated over 12 weeks. In a second extension phase, placebo patients were rerandomized to one of the fezolinetant study doses. Those on active therapy remained in their assigned groups. All patients were then followed for an additional 40 weeks.

The coprimary endpoints were frequency and severity of moderate to severe vasomotor symptoms as reported by patients using an electronic diary. There were several secondary endpoints, including patient-reported outcomes regarding sleep quality.

As expected from other controlled trials, placebo patients achieved about a 40% reduction in moderate to severe vasomotor symptom frequency over the first 12 weeks. Relative to placebo, symptom frequency declined more quickly and steeply on fezolinetant. By week 12, both achieved reductions of about 60%. Statistical P values for the differences in the three arms were not provided, but Dr. Neal-Perry reported they were significant.

Vasomotor severity, like frequency, is reduced

The change in vasomotor severity, which subjects in the trial rated as better or worse, was also significant. The differences in the severity curves were less, but they separated in favor of the two active treatment arms by about 2 weeks, and the curves continued to show an advantage for fezolinetant over both the first 12 weeks and then the remaining 40 weeks.

Overall, the decline in vasomotor symptom frequency remained on a persistent downward slope on both doses of fezolinetant for the full 52 weeks of the study, so that the reduction at 52 weeks was on the order of 25% greater than that seen at 12 weeks.

At 52 weeks, “you can see that individuals on placebo who were crossed over to an active treatment had a significant reduction in their hot flashes and look very much like those who were randomized to fezolinetant at the beginning of the study,” said Dr. Neal-Perry, who is chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

Other outcomes also favored fezolinetant over placebo. For example, a reduction in sleep disturbance observed at 12 weeks was sustained over the full 52 weeks of the study. The reduction in sleep symptoms appeared to be slightly greater on the higher dose, but the benefit at 52 weeks among patients after the crossover was similar on either active arm.

No serious side effects identified

There were no serious drug-related treatment-emergent adverse events in any treatment group. One patient in the placebo arm (< 1%), two patients in the 30-mg fezolinetant arm (1.2%), and five patients in the 45-mg arm (3%) discontinued therapy for an adverse event considered to be treatment related.

“The most common side effect associated with fezolinetant was headache. There were no other side effects that led patients to pull out of the study,” Dr. Neal-Perry reported at the meeting, which was held in Atlanta and virtually.

According to Dr. Neal-Perry the vasomotor symptoms relative to menopause, which occur in almost all women, are moderate to severe in an estimated 35%-45%. Some groups, such as those with an elevated body mass index and African Americans, appear to be at even greater risk. Study enrollment was specifically designed to include these high-risk groups, but the subgroup efficacy data have not yet been analyzed.

Other drugs with a similar mechanism of action have not been brought forward because of concern about elevated liver enzymes, but Dr. Neal-Perry said that this does not appear to be an issue for fezolinetant, which was designed with greater specificity for the NK3 target than previous treatments.

If fezolinetant is approved, Dr. Neal-Perry expects this agent to fulfill an important unmet need because of the limitations of other nonhormonal solutions for control of menopause symptoms.

HT alternatives limited

For control of many menopause symptoms, particularly hot flashes, hormone therapy (HT) is the most efficacious, but Richard J. Santen, MD, emeritus professor and an endocrinologist at the University of Virginia, Charlottesville, agreed there is a need for alternatives.

In addition to those who have contraindications for HT, Dr. Santen said in an interview that this option is not acceptable to others “for a variety of reasons.” The problem is that the alternatives are limited.

“The SSRI agents and gabapentin are alternative nonhormonal agents, but they have side effects and are not as effective,” he said. Hot flashes “can be a major disruptor of quality of life,” so he is intrigued with the positive results achieved with fezolinetant.

“A new drug such as reported at the Endocrine Society meeting would be an important new addition to the armamentarium,” he said.

Dr. Neal-Perry reports no conflicts of interest.

A phase 3 trial has associated the neurokinin-3 (NK3)–receptor inhibitor fezolinetant, an oral therapy taken once daily, with substantial control over the symptoms of menopause, according to results of the randomized SKYLIGHT 2 trial.

The nonhormonal therapy has the potential to address an important unmet need, Genevieve Neal-Perry, MD, PhD, said at the annual meeting of the Endocrine Society.

The health risks of hormone therapy (HT) have “caused quite a few women to consider whether hormone replacement is right for them, and, in addition, there are other individuals who have hormone-responsive cancers or other disorders that might prohibit them [from using HT],” Dr. Neal-Perry said.

The NK3 receptor stimulates the thermoregulatory center in the hypothalamus. By blocking the NK3 receptor, vasodilation and other downstream effects are inhibited, explained Dr. Neal-Perry. She credited relatively recent advances in understanding the mechanisms of menopausal symptoms for identifying this and other potentially targetable mediators.

SKYLIGHT 2 trial: Two phases

In the double-blind multinational phase 3 SKYLIGHT 2 trial, 484 otherwise healthy symptomatic menopausal women were randomized to 30 mg of fezolinetant, 45 mg of fezolinetant, or placebo. The 120 participating centers were in North American and Europe.

In the first phase, safety and efficacy were evaluated over 12 weeks. In a second extension phase, placebo patients were rerandomized to one of the fezolinetant study doses. Those on active therapy remained in their assigned groups. All patients were then followed for an additional 40 weeks.

The coprimary endpoints were frequency and severity of moderate to severe vasomotor symptoms as reported by patients using an electronic diary. There were several secondary endpoints, including patient-reported outcomes regarding sleep quality.

As expected from other controlled trials, placebo patients achieved about a 40% reduction in moderate to severe vasomotor symptom frequency over the first 12 weeks. Relative to placebo, symptom frequency declined more quickly and steeply on fezolinetant. By week 12, both achieved reductions of about 60%. Statistical P values for the differences in the three arms were not provided, but Dr. Neal-Perry reported they were significant.

Vasomotor severity, like frequency, is reduced

The change in vasomotor severity, which subjects in the trial rated as better or worse, was also significant. The differences in the severity curves were less, but they separated in favor of the two active treatment arms by about 2 weeks, and the curves continued to show an advantage for fezolinetant over both the first 12 weeks and then the remaining 40 weeks.

Overall, the decline in vasomotor symptom frequency remained on a persistent downward slope on both doses of fezolinetant for the full 52 weeks of the study, so that the reduction at 52 weeks was on the order of 25% greater than that seen at 12 weeks.

At 52 weeks, “you can see that individuals on placebo who were crossed over to an active treatment had a significant reduction in their hot flashes and look very much like those who were randomized to fezolinetant at the beginning of the study,” said Dr. Neal-Perry, who is chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

Other outcomes also favored fezolinetant over placebo. For example, a reduction in sleep disturbance observed at 12 weeks was sustained over the full 52 weeks of the study. The reduction in sleep symptoms appeared to be slightly greater on the higher dose, but the benefit at 52 weeks among patients after the crossover was similar on either active arm.

No serious side effects identified

There were no serious drug-related treatment-emergent adverse events in any treatment group. One patient in the placebo arm (< 1%), two patients in the 30-mg fezolinetant arm (1.2%), and five patients in the 45-mg arm (3%) discontinued therapy for an adverse event considered to be treatment related.

“The most common side effect associated with fezolinetant was headache. There were no other side effects that led patients to pull out of the study,” Dr. Neal-Perry reported at the meeting, which was held in Atlanta and virtually.

According to Dr. Neal-Perry the vasomotor symptoms relative to menopause, which occur in almost all women, are moderate to severe in an estimated 35%-45%. Some groups, such as those with an elevated body mass index and African Americans, appear to be at even greater risk. Study enrollment was specifically designed to include these high-risk groups, but the subgroup efficacy data have not yet been analyzed.

Other drugs with a similar mechanism of action have not been brought forward because of concern about elevated liver enzymes, but Dr. Neal-Perry said that this does not appear to be an issue for fezolinetant, which was designed with greater specificity for the NK3 target than previous treatments.

If fezolinetant is approved, Dr. Neal-Perry expects this agent to fulfill an important unmet need because of the limitations of other nonhormonal solutions for control of menopause symptoms.

HT alternatives limited

For control of many menopause symptoms, particularly hot flashes, hormone therapy (HT) is the most efficacious, but Richard J. Santen, MD, emeritus professor and an endocrinologist at the University of Virginia, Charlottesville, agreed there is a need for alternatives.

In addition to those who have contraindications for HT, Dr. Santen said in an interview that this option is not acceptable to others “for a variety of reasons.” The problem is that the alternatives are limited.

“The SSRI agents and gabapentin are alternative nonhormonal agents, but they have side effects and are not as effective,” he said. Hot flashes “can be a major disruptor of quality of life,” so he is intrigued with the positive results achieved with fezolinetant.

“A new drug such as reported at the Endocrine Society meeting would be an important new addition to the armamentarium,” he said.

Dr. Neal-Perry reports no conflicts of interest.

A phase 3 trial has associated the neurokinin-3 (NK3)–receptor inhibitor fezolinetant, an oral therapy taken once daily, with substantial control over the symptoms of menopause, according to results of the randomized SKYLIGHT 2 trial.

The nonhormonal therapy has the potential to address an important unmet need, Genevieve Neal-Perry, MD, PhD, said at the annual meeting of the Endocrine Society.

The health risks of hormone therapy (HT) have “caused quite a few women to consider whether hormone replacement is right for them, and, in addition, there are other individuals who have hormone-responsive cancers or other disorders that might prohibit them [from using HT],” Dr. Neal-Perry said.

The NK3 receptor stimulates the thermoregulatory center in the hypothalamus. By blocking the NK3 receptor, vasodilation and other downstream effects are inhibited, explained Dr. Neal-Perry. She credited relatively recent advances in understanding the mechanisms of menopausal symptoms for identifying this and other potentially targetable mediators.

SKYLIGHT 2 trial: Two phases

In the double-blind multinational phase 3 SKYLIGHT 2 trial, 484 otherwise healthy symptomatic menopausal women were randomized to 30 mg of fezolinetant, 45 mg of fezolinetant, or placebo. The 120 participating centers were in North American and Europe.

In the first phase, safety and efficacy were evaluated over 12 weeks. In a second extension phase, placebo patients were rerandomized to one of the fezolinetant study doses. Those on active therapy remained in their assigned groups. All patients were then followed for an additional 40 weeks.

The coprimary endpoints were frequency and severity of moderate to severe vasomotor symptoms as reported by patients using an electronic diary. There were several secondary endpoints, including patient-reported outcomes regarding sleep quality.

As expected from other controlled trials, placebo patients achieved about a 40% reduction in moderate to severe vasomotor symptom frequency over the first 12 weeks. Relative to placebo, symptom frequency declined more quickly and steeply on fezolinetant. By week 12, both achieved reductions of about 60%. Statistical P values for the differences in the three arms were not provided, but Dr. Neal-Perry reported they were significant.

Vasomotor severity, like frequency, is reduced

The change in vasomotor severity, which subjects in the trial rated as better or worse, was also significant. The differences in the severity curves were less, but they separated in favor of the two active treatment arms by about 2 weeks, and the curves continued to show an advantage for fezolinetant over both the first 12 weeks and then the remaining 40 weeks.

Overall, the decline in vasomotor symptom frequency remained on a persistent downward slope on both doses of fezolinetant for the full 52 weeks of the study, so that the reduction at 52 weeks was on the order of 25% greater than that seen at 12 weeks.

At 52 weeks, “you can see that individuals on placebo who were crossed over to an active treatment had a significant reduction in their hot flashes and look very much like those who were randomized to fezolinetant at the beginning of the study,” said Dr. Neal-Perry, who is chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

Other outcomes also favored fezolinetant over placebo. For example, a reduction in sleep disturbance observed at 12 weeks was sustained over the full 52 weeks of the study. The reduction in sleep symptoms appeared to be slightly greater on the higher dose, but the benefit at 52 weeks among patients after the crossover was similar on either active arm.

No serious side effects identified

There were no serious drug-related treatment-emergent adverse events in any treatment group. One patient in the placebo arm (< 1%), two patients in the 30-mg fezolinetant arm (1.2%), and five patients in the 45-mg arm (3%) discontinued therapy for an adverse event considered to be treatment related.

“The most common side effect associated with fezolinetant was headache. There were no other side effects that led patients to pull out of the study,” Dr. Neal-Perry reported at the meeting, which was held in Atlanta and virtually.

According to Dr. Neal-Perry the vasomotor symptoms relative to menopause, which occur in almost all women, are moderate to severe in an estimated 35%-45%. Some groups, such as those with an elevated body mass index and African Americans, appear to be at even greater risk. Study enrollment was specifically designed to include these high-risk groups, but the subgroup efficacy data have not yet been analyzed.

Other drugs with a similar mechanism of action have not been brought forward because of concern about elevated liver enzymes, but Dr. Neal-Perry said that this does not appear to be an issue for fezolinetant, which was designed with greater specificity for the NK3 target than previous treatments.

If fezolinetant is approved, Dr. Neal-Perry expects this agent to fulfill an important unmet need because of the limitations of other nonhormonal solutions for control of menopause symptoms.

HT alternatives limited

For control of many menopause symptoms, particularly hot flashes, hormone therapy (HT) is the most efficacious, but Richard J. Santen, MD, emeritus professor and an endocrinologist at the University of Virginia, Charlottesville, agreed there is a need for alternatives.

In addition to those who have contraindications for HT, Dr. Santen said in an interview that this option is not acceptable to others “for a variety of reasons.” The problem is that the alternatives are limited.

“The SSRI agents and gabapentin are alternative nonhormonal agents, but they have side effects and are not as effective,” he said. Hot flashes “can be a major disruptor of quality of life,” so he is intrigued with the positive results achieved with fezolinetant.

“A new drug such as reported at the Endocrine Society meeting would be an important new addition to the armamentarium,” he said.

Dr. Neal-Perry reports no conflicts of interest.

Contrary to previous analyses, women without a history of psychiatric illness who take combined hormonal contraceptives do not have an increased risk for attempted suicide but may have a reduced risk with extended use, new research suggests.

In a study of more than 800 women younger than age 50 who attempted suicide and more than 3,000 age-matched peers, results showed those who took hormonal contraceptives had a 27% reduced risk for attempted suicide.

areeya_ann/Thinkstock

Further analysis showed this was confined to women without a history of psychiatric illness and the reduction in risk rose to 43% among those who took combined hormonal contraceptives rather than progestin-only versions.

The protective effect against attempted suicide increased further to 46% if ethinyl estradiol (EE)–containing preparations were used. Moreover, the beneficial effect of contraceptive use increased over time.

The main message is the “current use of hormonal contraceptives is not associated with an increased risk of attempted suicide in our population,” study presenter Elena Toffol, MD, PhD, department of public health, University of Helsinki, told meeting attendees at the European Psychiatric Association 2022 Congress.
 

Age range differences

Dr. Toffol said there could be “several reasons” why the results are different from those in previous studies, including that the researchers included a “larger age range.” She noted it is known that “older women have a lower rate of attempted suicide and use different types of contraceptives.”

Dr. Toffol said in an interview that, although it’s “hard to estimate any causality” because this is an observational study, it is “tempting to speculate, and it is plausible, that hormones partly play a role with some, but not all, women being more sensitive to hormonal influences.”

However, the results “may also reflect life choices or a protective life status; for example, more stable relationships or more conscious and health-focused behaviors,” she said.

“It may also be that the underlying characteristics of women who are prescribed or opt for certain types of contraceptives are somehow related to their suicidal risk,” she added.

In 2019, the global age-standardized suicide rate was 9.0 per 100,000, which translates into more than 700,000 deaths every year, Dr. Toffol noted.

However, she emphasized the World Health Organization has calculated that, for every adult who dies by suicide, more than 20 people attempt suicide. In addition, data from the U.S. Centers for Disease Control and Prevention indicate that attempted suicides are three times more common among young women than in men.

“What are the reasons for this gender gap?” Dr. Toffol asked during her presentation.

“It is known that the major risk factor for suicidal behavior is a psychiatric disorder, and in particular depression and mood disorders. And depression and mood disorders are more common in women than in men,” she said.

However, there is also “growing interest into the role of biological factors” in the risk for suicide, including hormones and hormonal contraception. Some studies have also suggested that there is an increased risk for depression and “both completed and attempted suicide” after starting hormonal contraception.

Dr. Toffol added that about 70% of European women use some form of contraception and, among Finnish women, 40% choose a hormonal contraceptive.
 

Nested analysis

The researchers conducted a nested case-control analysis combining 2017 national prescription data on 587,823 women aged 15-49 years with information from general and primary healthcare registers for the years 2018 to 2019.

They were able to identify 818 cases of attempted suicide among the women. These were matched 4:1 with 3,272 age-matched healthy women who acted as the control group. Use of hormonal contraceptives in the previous 180 days was determined for the whole cohort.

Among users of hormonal contraceptives, there were 344 attempted suicides in 2017, at an incidence rate of 0.59 per 1,000 person-years. This compared with 474 attempted suicides among nonusers, at an incidence rate of 0.81 per 1000 person-years.

Kaplan-Meier analysis showed there was a significant difference in rates for attempted suicide among hormonal contraceptive users versus nonusers, at an incidence rate ratio of 0.73 (P < .0001) – and the difference increased over time.

In addition, the incidence of attempted suicide decreased with increasing age, with the highest incidence rate in women aged 15-19 years (1.62 per 1,000 person-years).

Conditional logistic regression analysis that controlled for education, marital status, chronic disease, recent psychiatric hospitalization, and current use of psychotropic medication showed hormonal contraceptive use was not linked to an increased risk of attempted suicide overall, at an odds ratio of 0.79 (95% confidence interval, 0.56-1.11).

However, when they looked specifically at women without a history of psychiatric illness, the association became significant, at an OR of 0.73 for attempted suicide among hormonal contraceptive users (95% CI, 0.58-0.91), while the relationship remained nonsignificant in women with a history of psychiatric disorders.

Further analysis suggested the significant association was confined to women taking combined hormonal contraceptives, at an OR of 0.57 for suicide attempt versus nonusers (95% CI, 0.44-0.75), and those use EE-containing preparations (OR, 0.54; 95% CI, 0.40-0.73).

There was a suggestion in the data that hormonal contraceptives containing desogestrel or drospirenone alongside EE may offer the greatest reduction in attempted suicide risk, but that did not survive multivariate analysis.

Dr. Toffol also noted that they were not able to capture data on use of intrauterine devices in their analysis.

“There is a growing number of municipalities in Finland that are providing free-of-charge contraception to young women” that is often an intrauterine device, she said. The researchers hope to include these women in a future analysis.
 

‘Age matters’

Commenting on the findings, Alexis C. Edwards, PhD, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, said the current study’s findings “made a lot of sense.” Dr. Edwards wasn’t involved with this study but conducted a previous study of 216,702 Swedish women aged 15-22 years that showed use of combination or progestin-only oral contraceptives was associated with an increased risk for suicidal behavior.

She agreed with Dr. Toffol that the “much larger age range” in the new study may have played a role in showing the opposite result.

“The trajectory that we saw if we had been able to continue following the women for longer – which we couldn’t, due to limitations of the registries – [was that] using hormonal contraceptives was going to end up being protective, so I do think that it matters what age you’re looking at,” she said.

Dr. Edwards noted the takeaway from both studies “is that, even if there is a slight increase in risk from using hormonal contraceptives, it’s short lived and it’s probably specific to young women, which is important.”

She suggested the hormonal benefit from extended contraceptive use could come from the regulation of mood, as it offers a “more stable hormonal course than what their body might be putting them through in the absence of using the pill.”

Overall, it is “really lovely to see very well-executed studies on this, providing more empirical evidence on this question, because it is something that’s relevant to anyone who’s potentially going to be using hormonal contraception,” Dr. Edwards said.
 

Clinical implications?

Andrea Fiorillo, MD, PhD, department of psychiatry, University of Campania “Luigi Vanvitelli,” Naples, Italy, said in a press release that the “striking” findings of the current study need “careful evaluation.”

They also need to be replicated in “different cohorts of women and controlled for the impact of several psychosocial stressors, such as economic upheavals, social insecurity, and uncertainty due to the COVID pandemic,” said Dr. Fiorillo, who was not involved with the research.

Nevertheless, she believes the “clinical implications of the study are obvious and may help to destigmatize the use of hormonal contraceptives.”

The study was funded by the Jane and Aatos Erkko Foundation, the Avohoidon Tsukimis äätiö (Foundation for Primary Care Research), the Yrj ö Jahnsson Foundation, and the Finnish Cultural Foundation. No relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

Contrary to previous analyses, women without a history of psychiatric illness who take combined hormonal contraceptives do not have an increased risk for attempted suicide but may have a reduced risk with extended use, new research suggests.

In a study of more than 800 women younger than age 50 who attempted suicide and more than 3,000 age-matched peers, results showed those who took hormonal contraceptives had a 27% reduced risk for attempted suicide.

areeya_ann/Thinkstock

Further analysis showed this was confined to women without a history of psychiatric illness and the reduction in risk rose to 43% among those who took combined hormonal contraceptives rather than progestin-only versions.

The protective effect against attempted suicide increased further to 46% if ethinyl estradiol (EE)–containing preparations were used. Moreover, the beneficial effect of contraceptive use increased over time.

The main message is the “current use of hormonal contraceptives is not associated with an increased risk of attempted suicide in our population,” study presenter Elena Toffol, MD, PhD, department of public health, University of Helsinki, told meeting attendees at the European Psychiatric Association 2022 Congress.
 

Age range differences

Dr. Toffol said there could be “several reasons” why the results are different from those in previous studies, including that the researchers included a “larger age range.” She noted it is known that “older women have a lower rate of attempted suicide and use different types of contraceptives.”

Dr. Toffol said in an interview that, although it’s “hard to estimate any causality” because this is an observational study, it is “tempting to speculate, and it is plausible, that hormones partly play a role with some, but not all, women being more sensitive to hormonal influences.”

However, the results “may also reflect life choices or a protective life status; for example, more stable relationships or more conscious and health-focused behaviors,” she said.

“It may also be that the underlying characteristics of women who are prescribed or opt for certain types of contraceptives are somehow related to their suicidal risk,” she added.

In 2019, the global age-standardized suicide rate was 9.0 per 100,000, which translates into more than 700,000 deaths every year, Dr. Toffol noted.

However, she emphasized the World Health Organization has calculated that, for every adult who dies by suicide, more than 20 people attempt suicide. In addition, data from the U.S. Centers for Disease Control and Prevention indicate that attempted suicides are three times more common among young women than in men.

“What are the reasons for this gender gap?” Dr. Toffol asked during her presentation.

“It is known that the major risk factor for suicidal behavior is a psychiatric disorder, and in particular depression and mood disorders. And depression and mood disorders are more common in women than in men,” she said.

However, there is also “growing interest into the role of biological factors” in the risk for suicide, including hormones and hormonal contraception. Some studies have also suggested that there is an increased risk for depression and “both completed and attempted suicide” after starting hormonal contraception.

Dr. Toffol added that about 70% of European women use some form of contraception and, among Finnish women, 40% choose a hormonal contraceptive.
 

Nested analysis

The researchers conducted a nested case-control analysis combining 2017 national prescription data on 587,823 women aged 15-49 years with information from general and primary healthcare registers for the years 2018 to 2019.

They were able to identify 818 cases of attempted suicide among the women. These were matched 4:1 with 3,272 age-matched healthy women who acted as the control group. Use of hormonal contraceptives in the previous 180 days was determined for the whole cohort.

Among users of hormonal contraceptives, there were 344 attempted suicides in 2017, at an incidence rate of 0.59 per 1,000 person-years. This compared with 474 attempted suicides among nonusers, at an incidence rate of 0.81 per 1000 person-years.

Kaplan-Meier analysis showed there was a significant difference in rates for attempted suicide among hormonal contraceptive users versus nonusers, at an incidence rate ratio of 0.73 (P < .0001) – and the difference increased over time.

In addition, the incidence of attempted suicide decreased with increasing age, with the highest incidence rate in women aged 15-19 years (1.62 per 1,000 person-years).

Conditional logistic regression analysis that controlled for education, marital status, chronic disease, recent psychiatric hospitalization, and current use of psychotropic medication showed hormonal contraceptive use was not linked to an increased risk of attempted suicide overall, at an odds ratio of 0.79 (95% confidence interval, 0.56-1.11).

However, when they looked specifically at women without a history of psychiatric illness, the association became significant, at an OR of 0.73 for attempted suicide among hormonal contraceptive users (95% CI, 0.58-0.91), while the relationship remained nonsignificant in women with a history of psychiatric disorders.

Further analysis suggested the significant association was confined to women taking combined hormonal contraceptives, at an OR of 0.57 for suicide attempt versus nonusers (95% CI, 0.44-0.75), and those use EE-containing preparations (OR, 0.54; 95% CI, 0.40-0.73).

There was a suggestion in the data that hormonal contraceptives containing desogestrel or drospirenone alongside EE may offer the greatest reduction in attempted suicide risk, but that did not survive multivariate analysis.

Dr. Toffol also noted that they were not able to capture data on use of intrauterine devices in their analysis.

“There is a growing number of municipalities in Finland that are providing free-of-charge contraception to young women” that is often an intrauterine device, she said. The researchers hope to include these women in a future analysis.
 

‘Age matters’

Commenting on the findings, Alexis C. Edwards, PhD, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, said the current study’s findings “made a lot of sense.” Dr. Edwards wasn’t involved with this study but conducted a previous study of 216,702 Swedish women aged 15-22 years that showed use of combination or progestin-only oral contraceptives was associated with an increased risk for suicidal behavior.

She agreed with Dr. Toffol that the “much larger age range” in the new study may have played a role in showing the opposite result.

“The trajectory that we saw if we had been able to continue following the women for longer – which we couldn’t, due to limitations of the registries – [was that] using hormonal contraceptives was going to end up being protective, so I do think that it matters what age you’re looking at,” she said.

Dr. Edwards noted the takeaway from both studies “is that, even if there is a slight increase in risk from using hormonal contraceptives, it’s short lived and it’s probably specific to young women, which is important.”

She suggested the hormonal benefit from extended contraceptive use could come from the regulation of mood, as it offers a “more stable hormonal course than what their body might be putting them through in the absence of using the pill.”

Overall, it is “really lovely to see very well-executed studies on this, providing more empirical evidence on this question, because it is something that’s relevant to anyone who’s potentially going to be using hormonal contraception,” Dr. Edwards said.
 

Clinical implications?

Andrea Fiorillo, MD, PhD, department of psychiatry, University of Campania “Luigi Vanvitelli,” Naples, Italy, said in a press release that the “striking” findings of the current study need “careful evaluation.”

They also need to be replicated in “different cohorts of women and controlled for the impact of several psychosocial stressors, such as economic upheavals, social insecurity, and uncertainty due to the COVID pandemic,” said Dr. Fiorillo, who was not involved with the research.

Nevertheless, she believes the “clinical implications of the study are obvious and may help to destigmatize the use of hormonal contraceptives.”

The study was funded by the Jane and Aatos Erkko Foundation, the Avohoidon Tsukimis äätiö (Foundation for Primary Care Research), the Yrj ö Jahnsson Foundation, and the Finnish Cultural Foundation. No relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

Contrary to previous analyses, women without a history of psychiatric illness who take combined hormonal contraceptives do not have an increased risk for attempted suicide but may have a reduced risk with extended use, new research suggests.

In a study of more than 800 women younger than age 50 who attempted suicide and more than 3,000 age-matched peers, results showed those who took hormonal contraceptives had a 27% reduced risk for attempted suicide.

areeya_ann/Thinkstock

Further analysis showed this was confined to women without a history of psychiatric illness and the reduction in risk rose to 43% among those who took combined hormonal contraceptives rather than progestin-only versions.

The protective effect against attempted suicide increased further to 46% if ethinyl estradiol (EE)–containing preparations were used. Moreover, the beneficial effect of contraceptive use increased over time.

The main message is the “current use of hormonal contraceptives is not associated with an increased risk of attempted suicide in our population,” study presenter Elena Toffol, MD, PhD, department of public health, University of Helsinki, told meeting attendees at the European Psychiatric Association 2022 Congress.
 

Age range differences

Dr. Toffol said there could be “several reasons” why the results are different from those in previous studies, including that the researchers included a “larger age range.” She noted it is known that “older women have a lower rate of attempted suicide and use different types of contraceptives.”

Dr. Toffol said in an interview that, although it’s “hard to estimate any causality” because this is an observational study, it is “tempting to speculate, and it is plausible, that hormones partly play a role with some, but not all, women being more sensitive to hormonal influences.”

However, the results “may also reflect life choices or a protective life status; for example, more stable relationships or more conscious and health-focused behaviors,” she said.

“It may also be that the underlying characteristics of women who are prescribed or opt for certain types of contraceptives are somehow related to their suicidal risk,” she added.

In 2019, the global age-standardized suicide rate was 9.0 per 100,000, which translates into more than 700,000 deaths every year, Dr. Toffol noted.

However, she emphasized the World Health Organization has calculated that, for every adult who dies by suicide, more than 20 people attempt suicide. In addition, data from the U.S. Centers for Disease Control and Prevention indicate that attempted suicides are three times more common among young women than in men.

“What are the reasons for this gender gap?” Dr. Toffol asked during her presentation.

“It is known that the major risk factor for suicidal behavior is a psychiatric disorder, and in particular depression and mood disorders. And depression and mood disorders are more common in women than in men,” she said.

However, there is also “growing interest into the role of biological factors” in the risk for suicide, including hormones and hormonal contraception. Some studies have also suggested that there is an increased risk for depression and “both completed and attempted suicide” after starting hormonal contraception.

Dr. Toffol added that about 70% of European women use some form of contraception and, among Finnish women, 40% choose a hormonal contraceptive.
 

Nested analysis

The researchers conducted a nested case-control analysis combining 2017 national prescription data on 587,823 women aged 15-49 years with information from general and primary healthcare registers for the years 2018 to 2019.

They were able to identify 818 cases of attempted suicide among the women. These were matched 4:1 with 3,272 age-matched healthy women who acted as the control group. Use of hormonal contraceptives in the previous 180 days was determined for the whole cohort.

Among users of hormonal contraceptives, there were 344 attempted suicides in 2017, at an incidence rate of 0.59 per 1,000 person-years. This compared with 474 attempted suicides among nonusers, at an incidence rate of 0.81 per 1000 person-years.

Kaplan-Meier analysis showed there was a significant difference in rates for attempted suicide among hormonal contraceptive users versus nonusers, at an incidence rate ratio of 0.73 (P < .0001) – and the difference increased over time.

In addition, the incidence of attempted suicide decreased with increasing age, with the highest incidence rate in women aged 15-19 years (1.62 per 1,000 person-years).

Conditional logistic regression analysis that controlled for education, marital status, chronic disease, recent psychiatric hospitalization, and current use of psychotropic medication showed hormonal contraceptive use was not linked to an increased risk of attempted suicide overall, at an odds ratio of 0.79 (95% confidence interval, 0.56-1.11).

However, when they looked specifically at women without a history of psychiatric illness, the association became significant, at an OR of 0.73 for attempted suicide among hormonal contraceptive users (95% CI, 0.58-0.91), while the relationship remained nonsignificant in women with a history of psychiatric disorders.

Further analysis suggested the significant association was confined to women taking combined hormonal contraceptives, at an OR of 0.57 for suicide attempt versus nonusers (95% CI, 0.44-0.75), and those use EE-containing preparations (OR, 0.54; 95% CI, 0.40-0.73).

There was a suggestion in the data that hormonal contraceptives containing desogestrel or drospirenone alongside EE may offer the greatest reduction in attempted suicide risk, but that did not survive multivariate analysis.

Dr. Toffol also noted that they were not able to capture data on use of intrauterine devices in their analysis.

“There is a growing number of municipalities in Finland that are providing free-of-charge contraception to young women” that is often an intrauterine device, she said. The researchers hope to include these women in a future analysis.
 

‘Age matters’

Commenting on the findings, Alexis C. Edwards, PhD, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, said the current study’s findings “made a lot of sense.” Dr. Edwards wasn’t involved with this study but conducted a previous study of 216,702 Swedish women aged 15-22 years that showed use of combination or progestin-only oral contraceptives was associated with an increased risk for suicidal behavior.

She agreed with Dr. Toffol that the “much larger age range” in the new study may have played a role in showing the opposite result.

“The trajectory that we saw if we had been able to continue following the women for longer – which we couldn’t, due to limitations of the registries – [was that] using hormonal contraceptives was going to end up being protective, so I do think that it matters what age you’re looking at,” she said.

Dr. Edwards noted the takeaway from both studies “is that, even if there is a slight increase in risk from using hormonal contraceptives, it’s short lived and it’s probably specific to young women, which is important.”

She suggested the hormonal benefit from extended contraceptive use could come from the regulation of mood, as it offers a “more stable hormonal course than what their body might be putting them through in the absence of using the pill.”

Overall, it is “really lovely to see very well-executed studies on this, providing more empirical evidence on this question, because it is something that’s relevant to anyone who’s potentially going to be using hormonal contraception,” Dr. Edwards said.
 

Clinical implications?

Andrea Fiorillo, MD, PhD, department of psychiatry, University of Campania “Luigi Vanvitelli,” Naples, Italy, said in a press release that the “striking” findings of the current study need “careful evaluation.”

They also need to be replicated in “different cohorts of women and controlled for the impact of several psychosocial stressors, such as economic upheavals, social insecurity, and uncertainty due to the COVID pandemic,” said Dr. Fiorillo, who was not involved with the research.

Nevertheless, she believes the “clinical implications of the study are obvious and may help to destigmatize the use of hormonal contraceptives.”

The study was funded by the Jane and Aatos Erkko Foundation, the Avohoidon Tsukimis äätiö (Foundation for Primary Care Research), the Yrj ö Jahnsson Foundation, and the Finnish Cultural Foundation. No relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

ATLANTA – Potential once-daily male oral contraceptives have passed a first clinical hurdle, showing a degree of testosterone suppression that should be sufficient for a contraceptive effect without causing symptomatic hypogonadism, according to phase 1 study results to be presented at the annual meeting of the Endocrine Society.

Credit: Flickr/Marco Verch Professional Photographer/CC by 2.0

There are two pills in development and the studies so far suggest that both or a combination might be able to provide an acceptable balance of efficacy and tolerability, according to Tamar Jacobsohn, a researcher in the Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.

The two drugs evaluated in this study are dimethandrolone undecanoate (DMAU) and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-MNTDC). Both are bifunctional prodrugs with androgenic and progestogenic effects. The prodrugs are designed to be cleaved after ingestion so that the active hormones are released over 24 hours, permitting once-daily dosing.

“As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production,” explained Ms. Jacobsohn in an interview.

However, she noted that there is still a long way to go on this research path. While the phase 1 studies have shown tolerability, the biology involved in suppressing sperm production suggests that men would need to take these pills daily for about 3 months at the very beginning of contraceptive treatment, until adequate sperm suppression is achieved to prevent pregnancy.

“We are working toward a phase 2 trial that will include a contraceptive efficacy endpoint, but there are lots of steps to get there, including more early phase studies,” she noted.

“There is a huge unmet need in terms of male contraceptive methods,” said Arthi Thirumalai, MBBS, an endocrinologist and assistant professor of medicine at the University of Washington School of Medicine in Seattle.

Senior author of a 2020 review article on male contraception, Dr. Thirumalai said in an interview that prodrugs and other hormonal methods to lower testosterone and suppress sperm production are attractive because of convenience, efficacy, and reversibility,

“We hope that oral formulations can be used to address this need,” said Dr. Thirumalai, who has participated in several experimental and clinical studies of male contraception methods. She is, in fact, one of the many coauthors of the data presented by Ms. Jacobsohn.

Ms. Jacobsohn emphasized: “Development of an effective, reversible male contraceptive method will improve reproductive options for men and women, have a major impact on public health by decreasing unintended pregnancy, and allow men to have an increasingly active role in family planning.”

Phase 1 results with DMAU and MNTDC

The work that led to phase 1 studies suggested that each of the drugs — DMAU and MNTDC — might provide adequate hormone suppression to reduce sperm counts without inducing unacceptable symptoms of hypogonadism. To test this potential, dose-ranging phase 1 studies with an endpoint of testosterone suppression were conducted with each one.

In the two placebo-controlled phase 1a studies, which are to be presented in a poster on June 13, healthy male subjects were randomly assigned to two pills of active therapy, four pills of active therapy, or placebo. In the two studies combined, 39 subjects received DMAU, 30 received 11b-MNTDC, and 28 received placebo.

Efficacy was evaluated by measuring testosterone levels. Tolerability was largely based on patient questionnaires.

At the end of 7 days, testosterone levels remained at reference levels (400 to 600 ng/dL) in those who received placebo. The levels fell to less than 100 ng/dL in all subjects assigned to an active agent regardless of which agent or dose was used.

From day 7 to 28, there was less median suppression of testosterone on 200 mg than 400 mg daily (92.7 ng/dL vs. 49.6 ng/dL; P < .001), but both remained below the target of 100 ng/dL, Ms. Jacobsohn reported.

The difference in degree of testosterone suppression did not appear to influence tolerability.

Subjects on four vs. two daily pills “did not report a significant difference in general satisfaction or their willingness to use the pills in the future or recommend them to other men,” said Ms. Jacobson, presenting P values for these outcomes among subjects on active therapy relative to placebo that were not significant, ranging from 0.48 to 0.85.

Overall, there were no serious adverse events. Mild side effects associated with hypogonadism did occur, but “all resolved by the end of the study,” she said.

Zero sperm production is not the goal. Lowering it sufficiently is

Dr. Thirumalai said the need for a male contraceptive is strong. While condoms have a substantial failure rate, vasectomy is not reliably reversible even though the majority of men agree that the responsibility for preventing pregnancy should be shared, she said.

Dr. Thirumalai’s earlier review article found that clinical trials of hormonal suppression to provide male contraception have been conducted for at least 30 years. The challenge has been finding an effective therapy that is well tolerated.

Drugs that combine both androgenic and progestogenic activity might be the answer. By manipulating hormones that lower testosterone, sperm production is reduced without eliminating a man’s ability to ejaculate. Zero sperm production is not the goal, according to data in Dr. Thirumalai’s review article.

Rather, studies suggest that when ejaculate contains less than 1 million sperm per mL (levels typically range from 15 to 200 million sperm/mL), the antipregnancy efficacy is similar to that achieved with female oral contraceptives.

However, clinical trials to demonstrate that this can be achieved safely have yet to be conducted.

Ms. Jacobsohn said that sperm half-life is about 3 months. This means that patients would need to be on hormonal therapy for a period of about this duration before reliable contraception is achieved.

In other words, the efficacy endpoint used in this current study [of 28 days duration] does not ensure effective contraception, but Ms. Jacobsohn suggested this is nevertheless an important step forward in clinical development.

Ms. Jacobsohn and Dr. Thirumalai report no relevant financial relationships.

A version of this article first appeared on Medscape.com .

ATLANTA – Potential once-daily male oral contraceptives have passed a first clinical hurdle, showing a degree of testosterone suppression that should be sufficient for a contraceptive effect without causing symptomatic hypogonadism, according to phase 1 study results to be presented at the annual meeting of the Endocrine Society.

Credit: Flickr/Marco Verch Professional Photographer/CC by 2.0

There are two pills in development and the studies so far suggest that both or a combination might be able to provide an acceptable balance of efficacy and tolerability, according to Tamar Jacobsohn, a researcher in the Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.

The two drugs evaluated in this study are dimethandrolone undecanoate (DMAU) and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-MNTDC). Both are bifunctional prodrugs with androgenic and progestogenic effects. The prodrugs are designed to be cleaved after ingestion so that the active hormones are released over 24 hours, permitting once-daily dosing.

“As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production,” explained Ms. Jacobsohn in an interview.

However, she noted that there is still a long way to go on this research path. While the phase 1 studies have shown tolerability, the biology involved in suppressing sperm production suggests that men would need to take these pills daily for about 3 months at the very beginning of contraceptive treatment, until adequate sperm suppression is achieved to prevent pregnancy.

“We are working toward a phase 2 trial that will include a contraceptive efficacy endpoint, but there are lots of steps to get there, including more early phase studies,” she noted.

“There is a huge unmet need in terms of male contraceptive methods,” said Arthi Thirumalai, MBBS, an endocrinologist and assistant professor of medicine at the University of Washington School of Medicine in Seattle.

Senior author of a 2020 review article on male contraception, Dr. Thirumalai said in an interview that prodrugs and other hormonal methods to lower testosterone and suppress sperm production are attractive because of convenience, efficacy, and reversibility,

“We hope that oral formulations can be used to address this need,” said Dr. Thirumalai, who has participated in several experimental and clinical studies of male contraception methods. She is, in fact, one of the many coauthors of the data presented by Ms. Jacobsohn.

Ms. Jacobsohn emphasized: “Development of an effective, reversible male contraceptive method will improve reproductive options for men and women, have a major impact on public health by decreasing unintended pregnancy, and allow men to have an increasingly active role in family planning.”

Phase 1 results with DMAU and MNTDC

The work that led to phase 1 studies suggested that each of the drugs — DMAU and MNTDC — might provide adequate hormone suppression to reduce sperm counts without inducing unacceptable symptoms of hypogonadism. To test this potential, dose-ranging phase 1 studies with an endpoint of testosterone suppression were conducted with each one.

In the two placebo-controlled phase 1a studies, which are to be presented in a poster on June 13, healthy male subjects were randomly assigned to two pills of active therapy, four pills of active therapy, or placebo. In the two studies combined, 39 subjects received DMAU, 30 received 11b-MNTDC, and 28 received placebo.

Efficacy was evaluated by measuring testosterone levels. Tolerability was largely based on patient questionnaires.

At the end of 7 days, testosterone levels remained at reference levels (400 to 600 ng/dL) in those who received placebo. The levels fell to less than 100 ng/dL in all subjects assigned to an active agent regardless of which agent or dose was used.

From day 7 to 28, there was less median suppression of testosterone on 200 mg than 400 mg daily (92.7 ng/dL vs. 49.6 ng/dL; P < .001), but both remained below the target of 100 ng/dL, Ms. Jacobsohn reported.

The difference in degree of testosterone suppression did not appear to influence tolerability.

Subjects on four vs. two daily pills “did not report a significant difference in general satisfaction or their willingness to use the pills in the future or recommend them to other men,” said Ms. Jacobson, presenting P values for these outcomes among subjects on active therapy relative to placebo that were not significant, ranging from 0.48 to 0.85.

Overall, there were no serious adverse events. Mild side effects associated with hypogonadism did occur, but “all resolved by the end of the study,” she said.

Zero sperm production is not the goal. Lowering it sufficiently is

Dr. Thirumalai said the need for a male contraceptive is strong. While condoms have a substantial failure rate, vasectomy is not reliably reversible even though the majority of men agree that the responsibility for preventing pregnancy should be shared, she said.

Dr. Thirumalai’s earlier review article found that clinical trials of hormonal suppression to provide male contraception have been conducted for at least 30 years. The challenge has been finding an effective therapy that is well tolerated.

Drugs that combine both androgenic and progestogenic activity might be the answer. By manipulating hormones that lower testosterone, sperm production is reduced without eliminating a man’s ability to ejaculate. Zero sperm production is not the goal, according to data in Dr. Thirumalai’s review article.

Rather, studies suggest that when ejaculate contains less than 1 million sperm per mL (levels typically range from 15 to 200 million sperm/mL), the antipregnancy efficacy is similar to that achieved with female oral contraceptives.

However, clinical trials to demonstrate that this can be achieved safely have yet to be conducted.

Ms. Jacobsohn said that sperm half-life is about 3 months. This means that patients would need to be on hormonal therapy for a period of about this duration before reliable contraception is achieved.

In other words, the efficacy endpoint used in this current study [of 28 days duration] does not ensure effective contraception, but Ms. Jacobsohn suggested this is nevertheless an important step forward in clinical development.

Ms. Jacobsohn and Dr. Thirumalai report no relevant financial relationships.

A version of this article first appeared on Medscape.com .

ATLANTA – Potential once-daily male oral contraceptives have passed a first clinical hurdle, showing a degree of testosterone suppression that should be sufficient for a contraceptive effect without causing symptomatic hypogonadism, according to phase 1 study results to be presented at the annual meeting of the Endocrine Society.

Credit: Flickr/Marco Verch Professional Photographer/CC by 2.0

There are two pills in development and the studies so far suggest that both or a combination might be able to provide an acceptable balance of efficacy and tolerability, according to Tamar Jacobsohn, a researcher in the Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.

The two drugs evaluated in this study are dimethandrolone undecanoate (DMAU) and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-MNTDC). Both are bifunctional prodrugs with androgenic and progestogenic effects. The prodrugs are designed to be cleaved after ingestion so that the active hormones are released over 24 hours, permitting once-daily dosing.

“As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production,” explained Ms. Jacobsohn in an interview.

However, she noted that there is still a long way to go on this research path. While the phase 1 studies have shown tolerability, the biology involved in suppressing sperm production suggests that men would need to take these pills daily for about 3 months at the very beginning of contraceptive treatment, until adequate sperm suppression is achieved to prevent pregnancy.

“We are working toward a phase 2 trial that will include a contraceptive efficacy endpoint, but there are lots of steps to get there, including more early phase studies,” she noted.

“There is a huge unmet need in terms of male contraceptive methods,” said Arthi Thirumalai, MBBS, an endocrinologist and assistant professor of medicine at the University of Washington School of Medicine in Seattle.

Senior author of a 2020 review article on male contraception, Dr. Thirumalai said in an interview that prodrugs and other hormonal methods to lower testosterone and suppress sperm production are attractive because of convenience, efficacy, and reversibility,

“We hope that oral formulations can be used to address this need,” said Dr. Thirumalai, who has participated in several experimental and clinical studies of male contraception methods. She is, in fact, one of the many coauthors of the data presented by Ms. Jacobsohn.

Ms. Jacobsohn emphasized: “Development of an effective, reversible male contraceptive method will improve reproductive options for men and women, have a major impact on public health by decreasing unintended pregnancy, and allow men to have an increasingly active role in family planning.”

Phase 1 results with DMAU and MNTDC

The work that led to phase 1 studies suggested that each of the drugs — DMAU and MNTDC — might provide adequate hormone suppression to reduce sperm counts without inducing unacceptable symptoms of hypogonadism. To test this potential, dose-ranging phase 1 studies with an endpoint of testosterone suppression were conducted with each one.

In the two placebo-controlled phase 1a studies, which are to be presented in a poster on June 13, healthy male subjects were randomly assigned to two pills of active therapy, four pills of active therapy, or placebo. In the two studies combined, 39 subjects received DMAU, 30 received 11b-MNTDC, and 28 received placebo.

Efficacy was evaluated by measuring testosterone levels. Tolerability was largely based on patient questionnaires.

At the end of 7 days, testosterone levels remained at reference levels (400 to 600 ng/dL) in those who received placebo. The levels fell to less than 100 ng/dL in all subjects assigned to an active agent regardless of which agent or dose was used.

From day 7 to 28, there was less median suppression of testosterone on 200 mg than 400 mg daily (92.7 ng/dL vs. 49.6 ng/dL; P < .001), but both remained below the target of 100 ng/dL, Ms. Jacobsohn reported.

The difference in degree of testosterone suppression did not appear to influence tolerability.

Subjects on four vs. two daily pills “did not report a significant difference in general satisfaction or their willingness to use the pills in the future or recommend them to other men,” said Ms. Jacobson, presenting P values for these outcomes among subjects on active therapy relative to placebo that were not significant, ranging from 0.48 to 0.85.

Overall, there were no serious adverse events. Mild side effects associated with hypogonadism did occur, but “all resolved by the end of the study,” she said.

Zero sperm production is not the goal. Lowering it sufficiently is

Dr. Thirumalai said the need for a male contraceptive is strong. While condoms have a substantial failure rate, vasectomy is not reliably reversible even though the majority of men agree that the responsibility for preventing pregnancy should be shared, she said.

Dr. Thirumalai’s earlier review article found that clinical trials of hormonal suppression to provide male contraception have been conducted for at least 30 years. The challenge has been finding an effective therapy that is well tolerated.

Drugs that combine both androgenic and progestogenic activity might be the answer. By manipulating hormones that lower testosterone, sperm production is reduced without eliminating a man’s ability to ejaculate. Zero sperm production is not the goal, according to data in Dr. Thirumalai’s review article.

Rather, studies suggest that when ejaculate contains less than 1 million sperm per mL (levels typically range from 15 to 200 million sperm/mL), the antipregnancy efficacy is similar to that achieved with female oral contraceptives.

However, clinical trials to demonstrate that this can be achieved safely have yet to be conducted.

Ms. Jacobsohn said that sperm half-life is about 3 months. This means that patients would need to be on hormonal therapy for a period of about this duration before reliable contraception is achieved.

In other words, the efficacy endpoint used in this current study [of 28 days duration] does not ensure effective contraception, but Ms. Jacobsohn suggested this is nevertheless an important step forward in clinical development.

Ms. Jacobsohn and Dr. Thirumalai report no relevant financial relationships.

A version of this article first appeared on Medscape.com .

Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.

A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.

The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.

In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.

To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.

They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.

During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.  

This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.

However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”

Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”

‘Trial is not definitive’

Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.

Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.

While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.

“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.

Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.

“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.

On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”

“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
 

Earlier data inconclusive

Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.

Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.

But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.

Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.  

A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
 

Meta-analysis results

Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.

The men were a mean age of 65, had a mean body mass index of 30 kg/m², and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes. 

Cardiovascular and cerebrovascular outcomes were not primary outcomes.

During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).

In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.

The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.

Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.

The only detected adverse effects were edema and a modest lowering of HDL cholesterol.

“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.

However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”

“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.  

The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
 

A version of this article first appeared on Medscape.com.

Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.

A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.

The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.

In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.

To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.

They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.

During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.  

This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.

However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”

Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”

‘Trial is not definitive’

Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.

Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.

While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.

“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.

Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.

“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.

On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”

“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
 

Earlier data inconclusive

Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.

Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.

But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.

Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.  

A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
 

Meta-analysis results

Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.

The men were a mean age of 65, had a mean body mass index of 30 kg/m², and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes. 

Cardiovascular and cerebrovascular outcomes were not primary outcomes.

During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).

In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.

The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.

Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.

The only detected adverse effects were edema and a modest lowering of HDL cholesterol.

“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.

However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”

“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.  

The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
 

A version of this article first appeared on Medscape.com.

Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.

A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.

The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.

In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.

To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.

They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.

During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.  

This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.

However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”

Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”

‘Trial is not definitive’

Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.

Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.

While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.

“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.

Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.

“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.

On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”

“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
 

Earlier data inconclusive

Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.

Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.

But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.

Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.  

A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
 

Meta-analysis results

Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.

The men were a mean age of 65, had a mean body mass index of 30 kg/m², and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes. 

Cardiovascular and cerebrovascular outcomes were not primary outcomes.

During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).

In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.

The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.

Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.

The only detected adverse effects were edema and a modest lowering of HDL cholesterol.

“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.

However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”

“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.  

The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
 

A version of this article first appeared on Medscape.com.