Reproductive Endocrinology

A genomic study has revealed new insights into the function of anti-Müllerian hormone (AMH) in the context of reproductive biology and fertility.

Insights into the physiological, and potentially therapeutic, function were identified based on data from single-cell RNA sequencing, derived from transcriptomic analysis and immunolabeling of antral follicles.

“The specific contribution of elevated AMH to the molecular pathology of polycystic ovary syndrome (PCOS) and its defining clinical features is unclear, as no study, to date, has examined the effect of chronically elevated AMH in an experimentally controlled in vivo model,” study author Limor Man, MD, of Weill Cornell Medicine, New York, and colleagues wrote. The group’s findings were published in Science Advances.

The researchers used ovarian cortical xenografts with cotransplantation of engineered endothelial cells to examine the effect of chronic paracrine AMH stimulus on human folliculogenesis.

They cotransplanted human ovarian cortex with control or AMH-expressing endothelial cells in immunocompromised mice and recovered antral follicles for purification and subsequent analysis. Overall, 38 antral follicles were observed (19 control and 19 AMH) at long-term intervals, defined as intervals greater than 10 weeks.

The researchers found that long-term xenografts showed an accelerated growth rate in the setting of chronically elevated AMH and exhibited a molecular signature indicative of more advanced stages of follicle maturation, including that of luteinization.

In mice, exogenous AMH follicles showed a decreased ratio of primordial to growing follicles and antral follicles of increased diameter.

In addition, transcriptomic and immunolabeling analyses revealed that chronic high AMH had a marked influence on the growth and transcriptomic signature of antral-stage follicles, with a universal increase in factors related to the synthesis and/or metabolism of cholesterol and sex steroid hormones, as well as early expression of factors often seen at later stages of folliculogenesis.

“These data decouple elevated AMH from the metabolic and hyperandrogenic conditions that define PCOS and suggest that chronically elevated AMH induces a molecular cascade that contributes, at least in part, to the anovulatory phenotype in these patients,” the researchers wrote.

Furthermore, they found evidence to suggest that chronic high AMH can induce expression of the luteinizing hormone receptor at earlier stages of folliculogenesis, thereby worsening the disruptive effect of elevated luteinizing hormone from the pituitary.

“[These] findings underscore the broad influence of AMH on transcriptional activity and maturation state of follicles and support an independent role for dysregulation of AMH signaling in driving anovulation in women with PCOS,” they wrote.

While these findings are intriguing, the researchers cautioned against drawing conclusions from the study since elevated AMH is almost always seen in combination with one or more symptomatic hallmarks in PCOS.

“Despite [some] limitations, [our] analysis provides a deep and high-resolution examination of AMH action on human folliculogenesis and suggests a prominent effect on antral follicle maturation,” they explained.
 

Expert perspective

“From age 25, AMH levels begin their decline until reaching undetectable levels at menopause,” Mark P. Trolice, MD, director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando, said in an interview. “Women with PCOS experience a chronic and frustrating pathophysiologic problem whose origins and mechanism have evaded researchers for decades.

“As AMH elevations in utero may contribute to fetal susceptibility to PCOS, this study provides another potential link by suggesting that chronically elevated AMH induces anovulation,” he added. “We await, with great anticipation, future clinical studies to potentially further illustrate the apparent and intriguing role of AMH in the development of PCOS.”

This study was supported by the Queenie Victorina Neri Scholarship and a Research Grant from the American Society for Reproductive Medicine. One author reported financial relationships with Oviva Therapeutics; no other conflicts of interest were reported.

A genomic study has revealed new insights into the function of anti-Müllerian hormone (AMH) in the context of reproductive biology and fertility.

Insights into the physiological, and potentially therapeutic, function were identified based on data from single-cell RNA sequencing, derived from transcriptomic analysis and immunolabeling of antral follicles.

“The specific contribution of elevated AMH to the molecular pathology of polycystic ovary syndrome (PCOS) and its defining clinical features is unclear, as no study, to date, has examined the effect of chronically elevated AMH in an experimentally controlled in vivo model,” study author Limor Man, MD, of Weill Cornell Medicine, New York, and colleagues wrote. The group’s findings were published in Science Advances.

The researchers used ovarian cortical xenografts with cotransplantation of engineered endothelial cells to examine the effect of chronic paracrine AMH stimulus on human folliculogenesis.

They cotransplanted human ovarian cortex with control or AMH-expressing endothelial cells in immunocompromised mice and recovered antral follicles for purification and subsequent analysis. Overall, 38 antral follicles were observed (19 control and 19 AMH) at long-term intervals, defined as intervals greater than 10 weeks.

The researchers found that long-term xenografts showed an accelerated growth rate in the setting of chronically elevated AMH and exhibited a molecular signature indicative of more advanced stages of follicle maturation, including that of luteinization.

In mice, exogenous AMH follicles showed a decreased ratio of primordial to growing follicles and antral follicles of increased diameter.

In addition, transcriptomic and immunolabeling analyses revealed that chronic high AMH had a marked influence on the growth and transcriptomic signature of antral-stage follicles, with a universal increase in factors related to the synthesis and/or metabolism of cholesterol and sex steroid hormones, as well as early expression of factors often seen at later stages of folliculogenesis.

“These data decouple elevated AMH from the metabolic and hyperandrogenic conditions that define PCOS and suggest that chronically elevated AMH induces a molecular cascade that contributes, at least in part, to the anovulatory phenotype in these patients,” the researchers wrote.

Furthermore, they found evidence to suggest that chronic high AMH can induce expression of the luteinizing hormone receptor at earlier stages of folliculogenesis, thereby worsening the disruptive effect of elevated luteinizing hormone from the pituitary.

“[These] findings underscore the broad influence of AMH on transcriptional activity and maturation state of follicles and support an independent role for dysregulation of AMH signaling in driving anovulation in women with PCOS,” they wrote.

While these findings are intriguing, the researchers cautioned against drawing conclusions from the study since elevated AMH is almost always seen in combination with one or more symptomatic hallmarks in PCOS.

“Despite [some] limitations, [our] analysis provides a deep and high-resolution examination of AMH action on human folliculogenesis and suggests a prominent effect on antral follicle maturation,” they explained.
 

Expert perspective

“From age 25, AMH levels begin their decline until reaching undetectable levels at menopause,” Mark P. Trolice, MD, director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando, said in an interview. “Women with PCOS experience a chronic and frustrating pathophysiologic problem whose origins and mechanism have evaded researchers for decades.

“As AMH elevations in utero may contribute to fetal susceptibility to PCOS, this study provides another potential link by suggesting that chronically elevated AMH induces anovulation,” he added. “We await, with great anticipation, future clinical studies to potentially further illustrate the apparent and intriguing role of AMH in the development of PCOS.”

This study was supported by the Queenie Victorina Neri Scholarship and a Research Grant from the American Society for Reproductive Medicine. One author reported financial relationships with Oviva Therapeutics; no other conflicts of interest were reported.

A genomic study has revealed new insights into the function of anti-Müllerian hormone (AMH) in the context of reproductive biology and fertility.

Insights into the physiological, and potentially therapeutic, function were identified based on data from single-cell RNA sequencing, derived from transcriptomic analysis and immunolabeling of antral follicles.

“The specific contribution of elevated AMH to the molecular pathology of polycystic ovary syndrome (PCOS) and its defining clinical features is unclear, as no study, to date, has examined the effect of chronically elevated AMH in an experimentally controlled in vivo model,” study author Limor Man, MD, of Weill Cornell Medicine, New York, and colleagues wrote. The group’s findings were published in Science Advances.

The researchers used ovarian cortical xenografts with cotransplantation of engineered endothelial cells to examine the effect of chronic paracrine AMH stimulus on human folliculogenesis.

They cotransplanted human ovarian cortex with control or AMH-expressing endothelial cells in immunocompromised mice and recovered antral follicles for purification and subsequent analysis. Overall, 38 antral follicles were observed (19 control and 19 AMH) at long-term intervals, defined as intervals greater than 10 weeks.

The researchers found that long-term xenografts showed an accelerated growth rate in the setting of chronically elevated AMH and exhibited a molecular signature indicative of more advanced stages of follicle maturation, including that of luteinization.

In mice, exogenous AMH follicles showed a decreased ratio of primordial to growing follicles and antral follicles of increased diameter.

In addition, transcriptomic and immunolabeling analyses revealed that chronic high AMH had a marked influence on the growth and transcriptomic signature of antral-stage follicles, with a universal increase in factors related to the synthesis and/or metabolism of cholesterol and sex steroid hormones, as well as early expression of factors often seen at later stages of folliculogenesis.

“These data decouple elevated AMH from the metabolic and hyperandrogenic conditions that define PCOS and suggest that chronically elevated AMH induces a molecular cascade that contributes, at least in part, to the anovulatory phenotype in these patients,” the researchers wrote.

Furthermore, they found evidence to suggest that chronic high AMH can induce expression of the luteinizing hormone receptor at earlier stages of folliculogenesis, thereby worsening the disruptive effect of elevated luteinizing hormone from the pituitary.

“[These] findings underscore the broad influence of AMH on transcriptional activity and maturation state of follicles and support an independent role for dysregulation of AMH signaling in driving anovulation in women with PCOS,” they wrote.

While these findings are intriguing, the researchers cautioned against drawing conclusions from the study since elevated AMH is almost always seen in combination with one or more symptomatic hallmarks in PCOS.

“Despite [some] limitations, [our] analysis provides a deep and high-resolution examination of AMH action on human folliculogenesis and suggests a prominent effect on antral follicle maturation,” they explained.
 

Expert perspective

“From age 25, AMH levels begin their decline until reaching undetectable levels at menopause,” Mark P. Trolice, MD, director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando, said in an interview. “Women with PCOS experience a chronic and frustrating pathophysiologic problem whose origins and mechanism have evaded researchers for decades.

“As AMH elevations in utero may contribute to fetal susceptibility to PCOS, this study provides another potential link by suggesting that chronically elevated AMH induces anovulation,” he added. “We await, with great anticipation, future clinical studies to potentially further illustrate the apparent and intriguing role of AMH in the development of PCOS.”

This study was supported by the Queenie Victorina Neri Scholarship and a Research Grant from the American Society for Reproductive Medicine. One author reported financial relationships with Oviva Therapeutics; no other conflicts of interest were reported.

Female-pattern hair loss (FPHL) was identified in 52% of postmenopausal women, and 4% of these cases involved extensive baldness, based on data from 178 individuals.

FPHL can develop at any time from teenage years through and beyond menopause, wrote Sukanya Chaikittisilpa, MD, of Chulalongkorn University, Bangkok, and colleagues.

The cause of FPHL remains uncertain, but the presence of estrogen receptors in hair follicles suggests that the hormone changes of menopause may affect hair growth, the researchers said.

In a study published in Menopause, the researchers evaluated 178 postmenopausal women aged 50-65 years for FPHL. FPLH was determined based on photographs and on measures of hormone levels, hair density, and hair diameter.

The overall prevalence of FPHL was 52.2%. The hair loss was divided into three categories indicating mild, moderate, and severe (Ludwig grades I, II, and III) with prevalence of 73.2%, 22.6%, and 4.3%, respectively. The prevalence of FPHL also increased with age and time since menopause. In a simple logistic regression analysis, age 56 years and older and more than 6 years since menopause were significantly associated with FPHL (odds ratios, 3.41 and 1.98, respectively).

However, after adjustment for multiple variables, only a body mass index of 25 kg/m² or higher also was associated with increased prevalence of FPHL (adjusted OR, 2.65).

A total of 60% of the study participants met criteria for low self-esteem, including all the women in the severe hair loss category.

“The postmenopausal women with FPHL in our cohort had lower total hair density, terminal hair density, hair thickness, hair unit density, and average hair per unit than those with normal hair patterns,” although vellus hair density was higher in women with FPHL, the researchers wrote in their discussion of the findings. This distinction may be caused in part by the shortened hair cycle and reduced anagen phase of velluslike follicles, they said.

The study findings were limited by several factors, including the cross-sectional design and the inclusion of only women from a single menopause clinic, which may not reflect FPHL in the general population, as well as the reliance on patients’ recall, the researchers noted. Another limitation was the inability to assess postmenopausal hormone levels, they added.

However, “This study may be the first FPHL study conducted in a menopause clinic that targeted only healthy postmenopausal women,” they wrote. More research is needed to determine the potential role of estrogen and testosterone on FPHL in postmenopausal women, and whether a history of polycystic ovarian syndrome has an effect, they said. Meanwhile, current study results may help clinicians and patients determine the most appropriate menopausal hormone therapies for postmenopausal women with FPHL, they concluded.
 

Consider lifestyle and self-esteem issues

The current study is important at this time because a larger proportion of women are either reaching menopause or are menopausal, said Constance Bohon, MD, a gynecologist in private practice in Washington, in an interview.

“Whatever we in the medical community can do to help women transition into the menopausal years with the least anxiety is important,” including helping women feel comfortable about their appearance, she said.

“For women in the peri- and postmenopausal years, hair loss is a relatively common concern,” Dr. Bohon said. However, in the current study, “I was surprised that it was associated with low self-esteem and obesity,” she noted. “For these women, it would be interesting to know whether they also had concerns about the appearance of their bodies, or just their hair loss,” she said. The question is whether the hair loss in and of itself caused low self-esteem in the study population, or whether it exacerbated their already poor self-assessment, Dr. Bohon said. “Another consideration is that perhaps these women were already feeling the effects of aging and were trying to change their appearance by using hair dyes, and now they find themselves losing hair as well,” she noted.

The takeaway message for clinicians is that discussions with perimenopausal and postmenopausal women should include the topic of hair loss along with hot flashes and night sweats, said Dr. Bohon.

Women who are experiencing hair loss or concerned about the possibility of hair loss should ask their doctors about possible interventions that may mitigate or prevent further hair loss, she said.

As for additional research, “the most important issue is to determine the factors that are associated with hair loss in the perimenopausal and postmenopausal years,” Dr. Bohon said. Research questions should include impact of dyeing or straightening hair on the likelihood of hair loss, and whether women with more severe hot flashes/night sweats and/or sleeplessness have more hair loss than women who do not experience any of the symptoms as they go through menopause, she emphasized.

Other considerations are whether certain diets or foods are more common among women who have more hair loss, and whether weight loss into a normal range or weight gain into a body mass index greater than 25 kg/m² affects hair loss, said Dr. Bohon. Also, don’t discount the impact of stress, and whether women who have lost hair identify certain stressful times that preceded their hair loss, as well as what medications could be associated with hair loss, and whether hormone therapy might prevent hair loss, she said.

The study was supported by the Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University. The researchers had no financial conflicts to disclose. Dr. Bohon had no financial conflicts to disclose and serves on the Editorial Advisory Board of Ob.Gyn. News.

Female-pattern hair loss (FPHL) was identified in 52% of postmenopausal women, and 4% of these cases involved extensive baldness, based on data from 178 individuals.

FPHL can develop at any time from teenage years through and beyond menopause, wrote Sukanya Chaikittisilpa, MD, of Chulalongkorn University, Bangkok, and colleagues.

The cause of FPHL remains uncertain, but the presence of estrogen receptors in hair follicles suggests that the hormone changes of menopause may affect hair growth, the researchers said.

In a study published in Menopause, the researchers evaluated 178 postmenopausal women aged 50-65 years for FPHL. FPLH was determined based on photographs and on measures of hormone levels, hair density, and hair diameter.

The overall prevalence of FPHL was 52.2%. The hair loss was divided into three categories indicating mild, moderate, and severe (Ludwig grades I, II, and III) with prevalence of 73.2%, 22.6%, and 4.3%, respectively. The prevalence of FPHL also increased with age and time since menopause. In a simple logistic regression analysis, age 56 years and older and more than 6 years since menopause were significantly associated with FPHL (odds ratios, 3.41 and 1.98, respectively).

However, after adjustment for multiple variables, only a body mass index of 25 kg/m² or higher also was associated with increased prevalence of FPHL (adjusted OR, 2.65).

A total of 60% of the study participants met criteria for low self-esteem, including all the women in the severe hair loss category.

“The postmenopausal women with FPHL in our cohort had lower total hair density, terminal hair density, hair thickness, hair unit density, and average hair per unit than those with normal hair patterns,” although vellus hair density was higher in women with FPHL, the researchers wrote in their discussion of the findings. This distinction may be caused in part by the shortened hair cycle and reduced anagen phase of velluslike follicles, they said.

The study findings were limited by several factors, including the cross-sectional design and the inclusion of only women from a single menopause clinic, which may not reflect FPHL in the general population, as well as the reliance on patients’ recall, the researchers noted. Another limitation was the inability to assess postmenopausal hormone levels, they added.

However, “This study may be the first FPHL study conducted in a menopause clinic that targeted only healthy postmenopausal women,” they wrote. More research is needed to determine the potential role of estrogen and testosterone on FPHL in postmenopausal women, and whether a history of polycystic ovarian syndrome has an effect, they said. Meanwhile, current study results may help clinicians and patients determine the most appropriate menopausal hormone therapies for postmenopausal women with FPHL, they concluded.
 

Consider lifestyle and self-esteem issues

The current study is important at this time because a larger proportion of women are either reaching menopause or are menopausal, said Constance Bohon, MD, a gynecologist in private practice in Washington, in an interview.

“Whatever we in the medical community can do to help women transition into the menopausal years with the least anxiety is important,” including helping women feel comfortable about their appearance, she said.

“For women in the peri- and postmenopausal years, hair loss is a relatively common concern,” Dr. Bohon said. However, in the current study, “I was surprised that it was associated with low self-esteem and obesity,” she noted. “For these women, it would be interesting to know whether they also had concerns about the appearance of their bodies, or just their hair loss,” she said. The question is whether the hair loss in and of itself caused low self-esteem in the study population, or whether it exacerbated their already poor self-assessment, Dr. Bohon said. “Another consideration is that perhaps these women were already feeling the effects of aging and were trying to change their appearance by using hair dyes, and now they find themselves losing hair as well,” she noted.

The takeaway message for clinicians is that discussions with perimenopausal and postmenopausal women should include the topic of hair loss along with hot flashes and night sweats, said Dr. Bohon.

Women who are experiencing hair loss or concerned about the possibility of hair loss should ask their doctors about possible interventions that may mitigate or prevent further hair loss, she said.

As for additional research, “the most important issue is to determine the factors that are associated with hair loss in the perimenopausal and postmenopausal years,” Dr. Bohon said. Research questions should include impact of dyeing or straightening hair on the likelihood of hair loss, and whether women with more severe hot flashes/night sweats and/or sleeplessness have more hair loss than women who do not experience any of the symptoms as they go through menopause, she emphasized.

Other considerations are whether certain diets or foods are more common among women who have more hair loss, and whether weight loss into a normal range or weight gain into a body mass index greater than 25 kg/m² affects hair loss, said Dr. Bohon. Also, don’t discount the impact of stress, and whether women who have lost hair identify certain stressful times that preceded their hair loss, as well as what medications could be associated with hair loss, and whether hormone therapy might prevent hair loss, she said.

The study was supported by the Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University. The researchers had no financial conflicts to disclose. Dr. Bohon had no financial conflicts to disclose and serves on the Editorial Advisory Board of Ob.Gyn. News.

Female-pattern hair loss (FPHL) was identified in 52% of postmenopausal women, and 4% of these cases involved extensive baldness, based on data from 178 individuals.

FPHL can develop at any time from teenage years through and beyond menopause, wrote Sukanya Chaikittisilpa, MD, of Chulalongkorn University, Bangkok, and colleagues.

The cause of FPHL remains uncertain, but the presence of estrogen receptors in hair follicles suggests that the hormone changes of menopause may affect hair growth, the researchers said.

In a study published in Menopause, the researchers evaluated 178 postmenopausal women aged 50-65 years for FPHL. FPLH was determined based on photographs and on measures of hormone levels, hair density, and hair diameter.

The overall prevalence of FPHL was 52.2%. The hair loss was divided into three categories indicating mild, moderate, and severe (Ludwig grades I, II, and III) with prevalence of 73.2%, 22.6%, and 4.3%, respectively. The prevalence of FPHL also increased with age and time since menopause. In a simple logistic regression analysis, age 56 years and older and more than 6 years since menopause were significantly associated with FPHL (odds ratios, 3.41 and 1.98, respectively).

However, after adjustment for multiple variables, only a body mass index of 25 kg/m² or higher also was associated with increased prevalence of FPHL (adjusted OR, 2.65).

A total of 60% of the study participants met criteria for low self-esteem, including all the women in the severe hair loss category.

“The postmenopausal women with FPHL in our cohort had lower total hair density, terminal hair density, hair thickness, hair unit density, and average hair per unit than those with normal hair patterns,” although vellus hair density was higher in women with FPHL, the researchers wrote in their discussion of the findings. This distinction may be caused in part by the shortened hair cycle and reduced anagen phase of velluslike follicles, they said.

The study findings were limited by several factors, including the cross-sectional design and the inclusion of only women from a single menopause clinic, which may not reflect FPHL in the general population, as well as the reliance on patients’ recall, the researchers noted. Another limitation was the inability to assess postmenopausal hormone levels, they added.

However, “This study may be the first FPHL study conducted in a menopause clinic that targeted only healthy postmenopausal women,” they wrote. More research is needed to determine the potential role of estrogen and testosterone on FPHL in postmenopausal women, and whether a history of polycystic ovarian syndrome has an effect, they said. Meanwhile, current study results may help clinicians and patients determine the most appropriate menopausal hormone therapies for postmenopausal women with FPHL, they concluded.
 

Consider lifestyle and self-esteem issues

The current study is important at this time because a larger proportion of women are either reaching menopause or are menopausal, said Constance Bohon, MD, a gynecologist in private practice in Washington, in an interview.

“Whatever we in the medical community can do to help women transition into the menopausal years with the least anxiety is important,” including helping women feel comfortable about their appearance, she said.

“For women in the peri- and postmenopausal years, hair loss is a relatively common concern,” Dr. Bohon said. However, in the current study, “I was surprised that it was associated with low self-esteem and obesity,” she noted. “For these women, it would be interesting to know whether they also had concerns about the appearance of their bodies, or just their hair loss,” she said. The question is whether the hair loss in and of itself caused low self-esteem in the study population, or whether it exacerbated their already poor self-assessment, Dr. Bohon said. “Another consideration is that perhaps these women were already feeling the effects of aging and were trying to change their appearance by using hair dyes, and now they find themselves losing hair as well,” she noted.

The takeaway message for clinicians is that discussions with perimenopausal and postmenopausal women should include the topic of hair loss along with hot flashes and night sweats, said Dr. Bohon.

Women who are experiencing hair loss or concerned about the possibility of hair loss should ask their doctors about possible interventions that may mitigate or prevent further hair loss, she said.

As for additional research, “the most important issue is to determine the factors that are associated with hair loss in the perimenopausal and postmenopausal years,” Dr. Bohon said. Research questions should include impact of dyeing or straightening hair on the likelihood of hair loss, and whether women with more severe hot flashes/night sweats and/or sleeplessness have more hair loss than women who do not experience any of the symptoms as they go through menopause, she emphasized.

Other considerations are whether certain diets or foods are more common among women who have more hair loss, and whether weight loss into a normal range or weight gain into a body mass index greater than 25 kg/m² affects hair loss, said Dr. Bohon. Also, don’t discount the impact of stress, and whether women who have lost hair identify certain stressful times that preceded their hair loss, as well as what medications could be associated with hair loss, and whether hormone therapy might prevent hair loss, she said.

The study was supported by the Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University. The researchers had no financial conflicts to disclose. Dr. Bohon had no financial conflicts to disclose and serves on the Editorial Advisory Board of Ob.Gyn. News.

Pregnant women with a history of spontaneous abortion had a significantly increased risk of gestational diabetes in subsequent pregnancies, based on data from more than 100,000 women.

Gestational diabetes is associated not only with adverse perinatal outcomes, but also with an increased risk of long-term cardiovascular and metabolic health issues in mothers and children, wrote Yan Zhao, PhD, of Tongji University, Shanghai, and colleagues.

Previous studies also have shown that spontaneous abortion (SAB) is associated with later maternal risk of cardiovascular disease and venous thromboembolism, the researchers said. The same mechanisms might contribute to the development of gestational diabetes, but the association between abortion history and gestational diabetes risk in subsequent pregnancies remains unclear, they added.

In a study published in JAMA Network Open, the researchers identified 102,259 pregnant women seen for routine prenatal care at a single hospital in Shanghai between January 2014 and December 2019. The mean age of the women was 29.8 years.

During the study period, 14,579 women experienced SAB (14.3%), 17,935 experienced induced abortion (17.5%), and 4,017 experienced both (11.9%).

In all, 12,153 cases of gestational diabetes were identified, for a prevalence of 11.9%. The relative risk of gestational diabetes was 1.25 for women who experienced SAB and 1.15 for those who experienced both SAB and induced abortion, and the association between SAB and gestational diabetes increased in a number-dependent manner, the researchers said. The increase in relative risk for gestational diabetes in pregnant women with one SAB, two SABs, and three or more SABs was 18%, 41%, and 43%, compared to pregnant women with no SAB history.

However, no association appeared between a history of induced abortion and gestational diabetes, the researchers said. “To date, no study has reported the association of prior induced abortion with gestational diabetes,” they wrote.

The study findings were limited by several factors including the reliance on self-reports for history of SAB and therefore possible underreporting, the researchers noted. Other limitations included the lack of data on the timing of SABs; therefore, the time between SAB and gestational diabetes diagnosis could not be included in the analysis, they said. Unknown variables and the inclusion only of women from a single city in China might limit the generalizability of the results, they added.

More research is needed to understand the biological mechanisms behind the association between SAB and gestational diabetes, an association that has potential public health implications, they noted. However, the results suggest that “pregnant women with a history of SAB, especially those with a history of recurrent SAB, should attend more antenatal visits to monitor their blood glucose and implement early prevention and intervention,” such as healthful eating and regular exercise, they wrote.
 

Findings confirm, not surprise

The diagnosis of gestational diabetes in the current study “was made with a slightly different test than we typically use in the United States – a 1-hour nonfasting glucola followed by a confirmatory 3-hour fasting glucola,” Sarah W. Prager, MD, of the University of Washington, Seattle, said in an interview. The current study of both SAB and gestational diabetes is important because both conditions are very common and have been the focus of increased attention in the popular media and in scientific study, she said.

Dr. Prager said she was not surprised by the findings of a link between a history of gestational diabetes and a history of SAB, “but the association is likely that people at risk for gestational diabetes or who have undiagnosed diabetes/glucose intolerance are more likely to experience SAB,” she noted. “I would be surprised if the direction of the association is that SAB puts people at risk for gestational diabetes; more likely undiagnosed diabetes is a risk factor for SAB,” she added. “Perhaps we should be screening for glucose intolerance and other metabolic disorders more frequently in people who have especially recurrent SAB, as the more miscarriages someone had, the more likely they were in this study to be diagnosed with gestational diabetes;” or perhaps those with a history of SAB/recurrent SAB should be screened closer to 24 weeks’ than 28 weeks’ gestation to enable earlier intervention in those more likely to have gestational diabetes, Dr. Prager said.

The study was supported by the Key Program of the National Natural Science Foundation of China, the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Shanghai Municipal Medical and Health Discipline Construction Projects, and the Shanghai Rising-Star Program. The researchers and Dr. Prager had no financial conflicts to disclose. Dr. Prager serves on the editorial advisory board of Ob.Gyn. News.

Pregnant women with a history of spontaneous abortion had a significantly increased risk of gestational diabetes in subsequent pregnancies, based on data from more than 100,000 women.

Gestational diabetes is associated not only with adverse perinatal outcomes, but also with an increased risk of long-term cardiovascular and metabolic health issues in mothers and children, wrote Yan Zhao, PhD, of Tongji University, Shanghai, and colleagues.

Previous studies also have shown that spontaneous abortion (SAB) is associated with later maternal risk of cardiovascular disease and venous thromboembolism, the researchers said. The same mechanisms might contribute to the development of gestational diabetes, but the association between abortion history and gestational diabetes risk in subsequent pregnancies remains unclear, they added.

In a study published in JAMA Network Open, the researchers identified 102,259 pregnant women seen for routine prenatal care at a single hospital in Shanghai between January 2014 and December 2019. The mean age of the women was 29.8 years.

During the study period, 14,579 women experienced SAB (14.3%), 17,935 experienced induced abortion (17.5%), and 4,017 experienced both (11.9%).

In all, 12,153 cases of gestational diabetes were identified, for a prevalence of 11.9%. The relative risk of gestational diabetes was 1.25 for women who experienced SAB and 1.15 for those who experienced both SAB and induced abortion, and the association between SAB and gestational diabetes increased in a number-dependent manner, the researchers said. The increase in relative risk for gestational diabetes in pregnant women with one SAB, two SABs, and three or more SABs was 18%, 41%, and 43%, compared to pregnant women with no SAB history.

However, no association appeared between a history of induced abortion and gestational diabetes, the researchers said. “To date, no study has reported the association of prior induced abortion with gestational diabetes,” they wrote.

The study findings were limited by several factors including the reliance on self-reports for history of SAB and therefore possible underreporting, the researchers noted. Other limitations included the lack of data on the timing of SABs; therefore, the time between SAB and gestational diabetes diagnosis could not be included in the analysis, they said. Unknown variables and the inclusion only of women from a single city in China might limit the generalizability of the results, they added.

More research is needed to understand the biological mechanisms behind the association between SAB and gestational diabetes, an association that has potential public health implications, they noted. However, the results suggest that “pregnant women with a history of SAB, especially those with a history of recurrent SAB, should attend more antenatal visits to monitor their blood glucose and implement early prevention and intervention,” such as healthful eating and regular exercise, they wrote.
 

Findings confirm, not surprise

The diagnosis of gestational diabetes in the current study “was made with a slightly different test than we typically use in the United States – a 1-hour nonfasting glucola followed by a confirmatory 3-hour fasting glucola,” Sarah W. Prager, MD, of the University of Washington, Seattle, said in an interview. The current study of both SAB and gestational diabetes is important because both conditions are very common and have been the focus of increased attention in the popular media and in scientific study, she said.

Dr. Prager said she was not surprised by the findings of a link between a history of gestational diabetes and a history of SAB, “but the association is likely that people at risk for gestational diabetes or who have undiagnosed diabetes/glucose intolerance are more likely to experience SAB,” she noted. “I would be surprised if the direction of the association is that SAB puts people at risk for gestational diabetes; more likely undiagnosed diabetes is a risk factor for SAB,” she added. “Perhaps we should be screening for glucose intolerance and other metabolic disorders more frequently in people who have especially recurrent SAB, as the more miscarriages someone had, the more likely they were in this study to be diagnosed with gestational diabetes;” or perhaps those with a history of SAB/recurrent SAB should be screened closer to 24 weeks’ than 28 weeks’ gestation to enable earlier intervention in those more likely to have gestational diabetes, Dr. Prager said.

The study was supported by the Key Program of the National Natural Science Foundation of China, the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Shanghai Municipal Medical and Health Discipline Construction Projects, and the Shanghai Rising-Star Program. The researchers and Dr. Prager had no financial conflicts to disclose. Dr. Prager serves on the editorial advisory board of Ob.Gyn. News.

Pregnant women with a history of spontaneous abortion had a significantly increased risk of gestational diabetes in subsequent pregnancies, based on data from more than 100,000 women.

Gestational diabetes is associated not only with adverse perinatal outcomes, but also with an increased risk of long-term cardiovascular and metabolic health issues in mothers and children, wrote Yan Zhao, PhD, of Tongji University, Shanghai, and colleagues.

Previous studies also have shown that spontaneous abortion (SAB) is associated with later maternal risk of cardiovascular disease and venous thromboembolism, the researchers said. The same mechanisms might contribute to the development of gestational diabetes, but the association between abortion history and gestational diabetes risk in subsequent pregnancies remains unclear, they added.

In a study published in JAMA Network Open, the researchers identified 102,259 pregnant women seen for routine prenatal care at a single hospital in Shanghai between January 2014 and December 2019. The mean age of the women was 29.8 years.

During the study period, 14,579 women experienced SAB (14.3%), 17,935 experienced induced abortion (17.5%), and 4,017 experienced both (11.9%).

In all, 12,153 cases of gestational diabetes were identified, for a prevalence of 11.9%. The relative risk of gestational diabetes was 1.25 for women who experienced SAB and 1.15 for those who experienced both SAB and induced abortion, and the association between SAB and gestational diabetes increased in a number-dependent manner, the researchers said. The increase in relative risk for gestational diabetes in pregnant women with one SAB, two SABs, and three or more SABs was 18%, 41%, and 43%, compared to pregnant women with no SAB history.

However, no association appeared between a history of induced abortion and gestational diabetes, the researchers said. “To date, no study has reported the association of prior induced abortion with gestational diabetes,” they wrote.

The study findings were limited by several factors including the reliance on self-reports for history of SAB and therefore possible underreporting, the researchers noted. Other limitations included the lack of data on the timing of SABs; therefore, the time between SAB and gestational diabetes diagnosis could not be included in the analysis, they said. Unknown variables and the inclusion only of women from a single city in China might limit the generalizability of the results, they added.

More research is needed to understand the biological mechanisms behind the association between SAB and gestational diabetes, an association that has potential public health implications, they noted. However, the results suggest that “pregnant women with a history of SAB, especially those with a history of recurrent SAB, should attend more antenatal visits to monitor their blood glucose and implement early prevention and intervention,” such as healthful eating and regular exercise, they wrote.
 

Findings confirm, not surprise

The diagnosis of gestational diabetes in the current study “was made with a slightly different test than we typically use in the United States – a 1-hour nonfasting glucola followed by a confirmatory 3-hour fasting glucola,” Sarah W. Prager, MD, of the University of Washington, Seattle, said in an interview. The current study of both SAB and gestational diabetes is important because both conditions are very common and have been the focus of increased attention in the popular media and in scientific study, she said.

Dr. Prager said she was not surprised by the findings of a link between a history of gestational diabetes and a history of SAB, “but the association is likely that people at risk for gestational diabetes or who have undiagnosed diabetes/glucose intolerance are more likely to experience SAB,” she noted. “I would be surprised if the direction of the association is that SAB puts people at risk for gestational diabetes; more likely undiagnosed diabetes is a risk factor for SAB,” she added. “Perhaps we should be screening for glucose intolerance and other metabolic disorders more frequently in people who have especially recurrent SAB, as the more miscarriages someone had, the more likely they were in this study to be diagnosed with gestational diabetes;” or perhaps those with a history of SAB/recurrent SAB should be screened closer to 24 weeks’ than 28 weeks’ gestation to enable earlier intervention in those more likely to have gestational diabetes, Dr. Prager said.

The study was supported by the Key Program of the National Natural Science Foundation of China, the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Shanghai Municipal Medical and Health Discipline Construction Projects, and the Shanghai Rising-Star Program. The researchers and Dr. Prager had no financial conflicts to disclose. Dr. Prager serves on the editorial advisory board of Ob.Gyn. News.

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Getting a COVID-19 mRNA vaccine did not affect pregnancy rates for women trying to conceive with in vitro fertilization or ovarian response to treatment, findings of a new study indicate.

The study was led by Sarit Avraham, MD, with the IVF unit, department of obstetrics and gynecology, Shamir Medical Center in Tzrifi, Israel. The findings were published online in Fertility and Sterility in a preproof version.

“Women should be vaccinated for COVID-19 prior to attempting to conceive via IVF treatments, given the higher risk of severe illness in pregnant women,” the authors wrote.

Doubts arose from “the theoretical concept of the supposed similarity between the SARS-CoV-2 spike protein and the syncytin protein that is speculated to take part in the fertilization process and the formation of the placenta,” the authors wrote.

Some then assumed that the COVID vaccine might kick off an immune response that could affect implantation and pregnancy. But this study and others before it found otherwise.

Researchers included 200 vaccinated women trying to conceive with IVF treatments in the retrospective study, and compared them with 200 unvaccinated patients of similar age (average age in both groups, 36 years) who were not previously infected with COVID-19. All the women were undergoing IVF from January to April 2021 and all the vaccinated women completed two doses of the BNT162b2 (Pfizer/BioNTech) vaccine at least 2 weeks before ovarian stimulation.

Researchers compared the average number of oocytes retrieved and clinical pregnancy rates between the two groups.
 

No difference between groups

Two hundred patients underwent oocyte retrieval 14-68 days after receiving a COVID shot; there was no significant difference by vaccination status in the number retrieved per cycle (10.63 in the vaccinated group vs. 10.72 in the unvaccinated group; P = .93).

There was also no difference in the clinical pregnancy rates after fresh embryo transfers. The rate among 128 vaccinated patients was 32.8% versus 33.1% in the 133 unvaccinated patients (P = .96), with 42 and 44 clinical pregnancies, respectively.

A total of 113 patients (66 in the study group and 47 in the controls) underwent freeze-all cycles to preserve fertility and fertilization rates were similar between vaccinated and unvaccinated (55.43% vaccinated vs. 54.29% unvaccinated; P = .73). The average number of cryopreserved embryos was 3.59 (vaccinated) versus 3.28 (unvaccinated) (P = .80).

In a subanalysis of outcomes by age, researchers found vaccination status had no effect on number of oocytes or pregnancy rates in the 39-and-older group. That’s important because it shows the vaccine did not affect outcomes even in a population with reduced ovarian reserves, the authors wrote.

The authors noted one of the study’s limitations is that it didn’t include information about vaccination or past infection status of the male partners.
 

Question should be put to rest

Sarah Cross, MD, a maternal-fetal medicine specialist at the University of Minnesota, Minneapolis, said the study is the biggest she’s seen that concludes COVID vaccinations are safe and highly encouraged for women before trying to conceive, but other smaller studies have come to the same conclusion.

She pointed to research including a study from 2021 with similar findings that concluded: “Physicians and public health personnel can counsel women of reproductive age that neither previous illness with COVID-19 nor antibodies produced from vaccination to COVID-19 will cause sterility.”

She said she thinks the question of whether COVID shots are safe with IVF has been answered and the results of the latest study add proof to counter misinformation around the issue.

“The COVID-19 vaccine does not affect fertility,” she said. “I don’t know how many more [studies] we need.”

The harm is in not getting vaccinated, she said. Pregnancy significantly increases a woman’s chance of getting severe COVID, the need for hospitalization, mechanical ventilation, and risk of death.

“I personally have never had a hospitalized patient who’s been vaccinated,” Dr. Cross said. “The worst thing for the fetus is to have a critically ill mother.”

Dr. Cross, whose high-risk patients include those seeking counseling before IVF, added: “I would counsel all of them that they should absolutely get vaccinated prior to pregnancy, when they’re pregnant, whenever it is, as soon as they possibly can.”

The study authors and Dr. Cross report no relevant financial relationships.

Getting a COVID-19 mRNA vaccine did not affect pregnancy rates for women trying to conceive with in vitro fertilization or ovarian response to treatment, findings of a new study indicate.

The study was led by Sarit Avraham, MD, with the IVF unit, department of obstetrics and gynecology, Shamir Medical Center in Tzrifi, Israel. The findings were published online in Fertility and Sterility in a preproof version.

“Women should be vaccinated for COVID-19 prior to attempting to conceive via IVF treatments, given the higher risk of severe illness in pregnant women,” the authors wrote.

Doubts arose from “the theoretical concept of the supposed similarity between the SARS-CoV-2 spike protein and the syncytin protein that is speculated to take part in the fertilization process and the formation of the placenta,” the authors wrote.

Some then assumed that the COVID vaccine might kick off an immune response that could affect implantation and pregnancy. But this study and others before it found otherwise.

Researchers included 200 vaccinated women trying to conceive with IVF treatments in the retrospective study, and compared them with 200 unvaccinated patients of similar age (average age in both groups, 36 years) who were not previously infected with COVID-19. All the women were undergoing IVF from January to April 2021 and all the vaccinated women completed two doses of the BNT162b2 (Pfizer/BioNTech) vaccine at least 2 weeks before ovarian stimulation.

Researchers compared the average number of oocytes retrieved and clinical pregnancy rates between the two groups.
 

No difference between groups

Two hundred patients underwent oocyte retrieval 14-68 days after receiving a COVID shot; there was no significant difference by vaccination status in the number retrieved per cycle (10.63 in the vaccinated group vs. 10.72 in the unvaccinated group; P = .93).

There was also no difference in the clinical pregnancy rates after fresh embryo transfers. The rate among 128 vaccinated patients was 32.8% versus 33.1% in the 133 unvaccinated patients (P = .96), with 42 and 44 clinical pregnancies, respectively.

A total of 113 patients (66 in the study group and 47 in the controls) underwent freeze-all cycles to preserve fertility and fertilization rates were similar between vaccinated and unvaccinated (55.43% vaccinated vs. 54.29% unvaccinated; P = .73). The average number of cryopreserved embryos was 3.59 (vaccinated) versus 3.28 (unvaccinated) (P = .80).

In a subanalysis of outcomes by age, researchers found vaccination status had no effect on number of oocytes or pregnancy rates in the 39-and-older group. That’s important because it shows the vaccine did not affect outcomes even in a population with reduced ovarian reserves, the authors wrote.

The authors noted one of the study’s limitations is that it didn’t include information about vaccination or past infection status of the male partners.
 

Question should be put to rest

Sarah Cross, MD, a maternal-fetal medicine specialist at the University of Minnesota, Minneapolis, said the study is the biggest she’s seen that concludes COVID vaccinations are safe and highly encouraged for women before trying to conceive, but other smaller studies have come to the same conclusion.

She pointed to research including a study from 2021 with similar findings that concluded: “Physicians and public health personnel can counsel women of reproductive age that neither previous illness with COVID-19 nor antibodies produced from vaccination to COVID-19 will cause sterility.”

She said she thinks the question of whether COVID shots are safe with IVF has been answered and the results of the latest study add proof to counter misinformation around the issue.

“The COVID-19 vaccine does not affect fertility,” she said. “I don’t know how many more [studies] we need.”

The harm is in not getting vaccinated, she said. Pregnancy significantly increases a woman’s chance of getting severe COVID, the need for hospitalization, mechanical ventilation, and risk of death.

“I personally have never had a hospitalized patient who’s been vaccinated,” Dr. Cross said. “The worst thing for the fetus is to have a critically ill mother.”

Dr. Cross, whose high-risk patients include those seeking counseling before IVF, added: “I would counsel all of them that they should absolutely get vaccinated prior to pregnancy, when they’re pregnant, whenever it is, as soon as they possibly can.”

The study authors and Dr. Cross report no relevant financial relationships.

Getting a COVID-19 mRNA vaccine did not affect pregnancy rates for women trying to conceive with in vitro fertilization or ovarian response to treatment, findings of a new study indicate.

The study was led by Sarit Avraham, MD, with the IVF unit, department of obstetrics and gynecology, Shamir Medical Center in Tzrifi, Israel. The findings were published online in Fertility and Sterility in a preproof version.

“Women should be vaccinated for COVID-19 prior to attempting to conceive via IVF treatments, given the higher risk of severe illness in pregnant women,” the authors wrote.

Doubts arose from “the theoretical concept of the supposed similarity between the SARS-CoV-2 spike protein and the syncytin protein that is speculated to take part in the fertilization process and the formation of the placenta,” the authors wrote.

Some then assumed that the COVID vaccine might kick off an immune response that could affect implantation and pregnancy. But this study and others before it found otherwise.

Researchers included 200 vaccinated women trying to conceive with IVF treatments in the retrospective study, and compared them with 200 unvaccinated patients of similar age (average age in both groups, 36 years) who were not previously infected with COVID-19. All the women were undergoing IVF from January to April 2021 and all the vaccinated women completed two doses of the BNT162b2 (Pfizer/BioNTech) vaccine at least 2 weeks before ovarian stimulation.

Researchers compared the average number of oocytes retrieved and clinical pregnancy rates between the two groups.
 

No difference between groups

Two hundred patients underwent oocyte retrieval 14-68 days after receiving a COVID shot; there was no significant difference by vaccination status in the number retrieved per cycle (10.63 in the vaccinated group vs. 10.72 in the unvaccinated group; P = .93).

There was also no difference in the clinical pregnancy rates after fresh embryo transfers. The rate among 128 vaccinated patients was 32.8% versus 33.1% in the 133 unvaccinated patients (P = .96), with 42 and 44 clinical pregnancies, respectively.

A total of 113 patients (66 in the study group and 47 in the controls) underwent freeze-all cycles to preserve fertility and fertilization rates were similar between vaccinated and unvaccinated (55.43% vaccinated vs. 54.29% unvaccinated; P = .73). The average number of cryopreserved embryos was 3.59 (vaccinated) versus 3.28 (unvaccinated) (P = .80).

In a subanalysis of outcomes by age, researchers found vaccination status had no effect on number of oocytes or pregnancy rates in the 39-and-older group. That’s important because it shows the vaccine did not affect outcomes even in a population with reduced ovarian reserves, the authors wrote.

The authors noted one of the study’s limitations is that it didn’t include information about vaccination or past infection status of the male partners.
 

Question should be put to rest

Sarah Cross, MD, a maternal-fetal medicine specialist at the University of Minnesota, Minneapolis, said the study is the biggest she’s seen that concludes COVID vaccinations are safe and highly encouraged for women before trying to conceive, but other smaller studies have come to the same conclusion.

She pointed to research including a study from 2021 with similar findings that concluded: “Physicians and public health personnel can counsel women of reproductive age that neither previous illness with COVID-19 nor antibodies produced from vaccination to COVID-19 will cause sterility.”

She said she thinks the question of whether COVID shots are safe with IVF has been answered and the results of the latest study add proof to counter misinformation around the issue.

“The COVID-19 vaccine does not affect fertility,” she said. “I don’t know how many more [studies] we need.”

The harm is in not getting vaccinated, she said. Pregnancy significantly increases a woman’s chance of getting severe COVID, the need for hospitalization, mechanical ventilation, and risk of death.

“I personally have never had a hospitalized patient who’s been vaccinated,” Dr. Cross said. “The worst thing for the fetus is to have a critically ill mother.”

Dr. Cross, whose high-risk patients include those seeking counseling before IVF, added: “I would counsel all of them that they should absolutely get vaccinated prior to pregnancy, when they’re pregnant, whenever it is, as soon as they possibly can.”

The study authors and Dr. Cross report no relevant financial relationships.

Long or irregular menstrual cycles in relatively young women are linked an increased risk of both prevalent and incident nonalcoholic fatty liver disease (NAFLD), according to a cross-sectional study that included data on more than 70,000 women.

“Our results indicate that menstrual irregularity, which is easier to diagnose and usually presented earlier than PCOS [polycystic ovary syndrome] highlights the possibility of identifying premenopausal women at risk of developing NAFLD,” reported a team of authors primarily from Sungkyunkwan University, Seoul, South Korea.

The study evaluated women aged younger than 40 years who were participating in the Kangbuk Samsung Health Study, which involves a comprehensive biennial health examination at health centers in South Korea. Of the 135,090 women enrolled over a 6-year period who had at least one follow-up examination, 72,092 were available for analysis after excluding for a sizable list of confounding factors such as liver disease and infections; exposure to steatogenic medications, such as corticosteroids; hysterectomy; and pregnancy.
 

NAFLD prevalence climbs with longer menses

Of these women, 36.378 (27.7%) had menstrual cycles of 26-30 days and were identified as the index group. The prevalence of NAFLD in this group was 5.8%. For those with a menstrual cycle of 31-39 days, the prevalence rate climbed to 7.2%. For those with a menstrual cycle of at least 40 days or too irregular to estimate, the prevalence was 9.7%. The prevalence was 7.1% for those with a menstrual cycle less than 21 days.

The results of this study were published in the Journal of Clinical Endocrinology & Metabolism.

In those without NAFLD at baseline who were then followed for a mean of 4.4 years, there were 4,524 incident cases of NAFLD. Incidence density was calculated per 103 patient-years. In the index group, the rate was 18.4. It climbed to 20.2 for those with a menstrual cycle of 31-39 days and then to 22.9 for those with a menstrual cycle of at least 40 days. For those with a cycle of fewer than 21 days, the rate was 26.8.

After adjusting for age, body mass index, insulin resistance, and other confounders, the hazard ratio for incident NAFLD for those with long or irregular menstrual cycles compared with the incident group corresponded with a 22% increased risk (HR, 1.22; 95% confidence interval, 1.14-1.31). When calculated in a time-dependent analysis, the risk of NAFLD was increased by almost 50% (HR, 1.49; 95% CI, 1.38-1.60).


 

Risk persists with PCOS exclusion

PCOS has previously been associated with increased risk of NAFLD, but the association between long or irregular menstrual cycles and NAFLD persisted after women with PCOS were excluded.

The mechanism that links menstrual irregularity with NAFLD is unclear, but the investigators said that estrogen exposure is implicated. In addition to a previously reported associated between low estradiol levels and antiestrogens such as tamoxifen with increased risk of NAFLD, they cited studies associating estrogen replacement therapy with a reduced risk of NAFLD. The role of estrogen in suppressing inflammation, oxidative stress, and insulin resistance are all activities that might link more regular menses with a reduced risk of NAFLD, the authors contended.

Women older than 40 years were excluded from this analysis to reduce the possibility of perimenopausal changes as a confounding factor.

Of study limitations acknowledged by the investigators, the presence of NAFLD was diagnosed on ultrasonography rather than histology. Information on sex hormone or prolactin levels was not captured in relation to NAFLD incidence, and the lack of exposure to estrogen replacement therapy and oral contraceptives was based on self-reports from the participants.

Still, the large study size and the consistency of results after adjustment for multiple risk factors argue that long and irregular menstrual cycles do identify women at risk for NAFLD. One implication is that irregular menses can be a marker for NAFLD risk.

“Our findings do not prove a causal relationship, but they show that long or irregular menstrual cycles were significantly associated with an increased risk of developing NAFLD,” said Seungho Ryu, MD, PhD, a professor at the Sungkyunkwan University. Senior author of this study, Dr. Ryu emphasized in an interview that the association “was not explained by obesity or any other risk factor for NAFLD.”
 

Lifestyle changes may lower risk

The message is that “young women with long or irregular menstrual cycles may benefit from lifestyle changes to reduce the risk of NAFLD,” Dr. Ryu stated.

The Study of Women’s Health Across the Nation, which was started in 1994, has not evaluated NAFLD, but it did show a relationship between longer menstrual cycles and more cardiometabolic risk factors, according to Nanette Santoro MD, professor and chair, department of obstetrics & gynecology, University of Colorado at Denver, Aurora.

This suggests that others are “thinking along the same lines,” but in discussing this study with this news organization, she characterized some of the design elements as well as some of the findings in this study as “peculiar.”

In addition to a “very, very narrow definition of regular cycles,” she questioned the consistent hazard ratio for NAFLD for those with long cycles relative to other types of irregular menses. Presuming that the group with longer cycles would have included at least some patients with undiagnosed PCOS, she was would have expected that the risk would have been highest in this group. While conceding that differences in body composition of Korean women is a potential explanation for this apparent discrepancy, “I would like to see confirmed in other samples of women with more detailed metabolic assessments to understand who is at risk,” she said.

Not least problematic for the strength of the conclusions, the hazard ratio for NAFLD among women with long or irregular menstrual cycles was “pretty low.” She described this as a level at which the risk “is very susceptible to confounding and unlikely to influence clinical practice.”

Anuja Dokras, MD, PHD, a professor of obstetrics and gynecology and director of the PCOS Center at the University of Pennsylvania, Philadelphia, also questioned whether undiagnosed PCOS might have skewed the data.

“There is increasing data on the association between PCOS and NAFLD. Irregular menses is a key criterion for PCOS, and PCOS is the commonest reason for anovulation,” she said. Dr. Dokras therefore considered it possible that patients with unrecognized PCOS were included in the study, weakening the claim that risk of NAFLD and long menstrual cycles remains significant after controlling for PCOS.

Dr. Ryu and coinvestigators, Dr. Santoro, and Dr. Dokras reported no potential conflicts of interest.

Long or irregular menstrual cycles in relatively young women are linked an increased risk of both prevalent and incident nonalcoholic fatty liver disease (NAFLD), according to a cross-sectional study that included data on more than 70,000 women.

“Our results indicate that menstrual irregularity, which is easier to diagnose and usually presented earlier than PCOS [polycystic ovary syndrome] highlights the possibility of identifying premenopausal women at risk of developing NAFLD,” reported a team of authors primarily from Sungkyunkwan University, Seoul, South Korea.

The study evaluated women aged younger than 40 years who were participating in the Kangbuk Samsung Health Study, which involves a comprehensive biennial health examination at health centers in South Korea. Of the 135,090 women enrolled over a 6-year period who had at least one follow-up examination, 72,092 were available for analysis after excluding for a sizable list of confounding factors such as liver disease and infections; exposure to steatogenic medications, such as corticosteroids; hysterectomy; and pregnancy.
 

NAFLD prevalence climbs with longer menses

Of these women, 36.378 (27.7%) had menstrual cycles of 26-30 days and were identified as the index group. The prevalence of NAFLD in this group was 5.8%. For those with a menstrual cycle of 31-39 days, the prevalence rate climbed to 7.2%. For those with a menstrual cycle of at least 40 days or too irregular to estimate, the prevalence was 9.7%. The prevalence was 7.1% for those with a menstrual cycle less than 21 days.

The results of this study were published in the Journal of Clinical Endocrinology & Metabolism.

In those without NAFLD at baseline who were then followed for a mean of 4.4 years, there were 4,524 incident cases of NAFLD. Incidence density was calculated per 103 patient-years. In the index group, the rate was 18.4. It climbed to 20.2 for those with a menstrual cycle of 31-39 days and then to 22.9 for those with a menstrual cycle of at least 40 days. For those with a cycle of fewer than 21 days, the rate was 26.8.

After adjusting for age, body mass index, insulin resistance, and other confounders, the hazard ratio for incident NAFLD for those with long or irregular menstrual cycles compared with the incident group corresponded with a 22% increased risk (HR, 1.22; 95% confidence interval, 1.14-1.31). When calculated in a time-dependent analysis, the risk of NAFLD was increased by almost 50% (HR, 1.49; 95% CI, 1.38-1.60).


 

Risk persists with PCOS exclusion

PCOS has previously been associated with increased risk of NAFLD, but the association between long or irregular menstrual cycles and NAFLD persisted after women with PCOS were excluded.

The mechanism that links menstrual irregularity with NAFLD is unclear, but the investigators said that estrogen exposure is implicated. In addition to a previously reported associated between low estradiol levels and antiestrogens such as tamoxifen with increased risk of NAFLD, they cited studies associating estrogen replacement therapy with a reduced risk of NAFLD. The role of estrogen in suppressing inflammation, oxidative stress, and insulin resistance are all activities that might link more regular menses with a reduced risk of NAFLD, the authors contended.

Women older than 40 years were excluded from this analysis to reduce the possibility of perimenopausal changes as a confounding factor.

Of study limitations acknowledged by the investigators, the presence of NAFLD was diagnosed on ultrasonography rather than histology. Information on sex hormone or prolactin levels was not captured in relation to NAFLD incidence, and the lack of exposure to estrogen replacement therapy and oral contraceptives was based on self-reports from the participants.

Still, the large study size and the consistency of results after adjustment for multiple risk factors argue that long and irregular menstrual cycles do identify women at risk for NAFLD. One implication is that irregular menses can be a marker for NAFLD risk.

“Our findings do not prove a causal relationship, but they show that long or irregular menstrual cycles were significantly associated with an increased risk of developing NAFLD,” said Seungho Ryu, MD, PhD, a professor at the Sungkyunkwan University. Senior author of this study, Dr. Ryu emphasized in an interview that the association “was not explained by obesity or any other risk factor for NAFLD.”
 

Lifestyle changes may lower risk

The message is that “young women with long or irregular menstrual cycles may benefit from lifestyle changes to reduce the risk of NAFLD,” Dr. Ryu stated.

The Study of Women’s Health Across the Nation, which was started in 1994, has not evaluated NAFLD, but it did show a relationship between longer menstrual cycles and more cardiometabolic risk factors, according to Nanette Santoro MD, professor and chair, department of obstetrics & gynecology, University of Colorado at Denver, Aurora.

This suggests that others are “thinking along the same lines,” but in discussing this study with this news organization, she characterized some of the design elements as well as some of the findings in this study as “peculiar.”

In addition to a “very, very narrow definition of regular cycles,” she questioned the consistent hazard ratio for NAFLD for those with long cycles relative to other types of irregular menses. Presuming that the group with longer cycles would have included at least some patients with undiagnosed PCOS, she was would have expected that the risk would have been highest in this group. While conceding that differences in body composition of Korean women is a potential explanation for this apparent discrepancy, “I would like to see confirmed in other samples of women with more detailed metabolic assessments to understand who is at risk,” she said.

Not least problematic for the strength of the conclusions, the hazard ratio for NAFLD among women with long or irregular menstrual cycles was “pretty low.” She described this as a level at which the risk “is very susceptible to confounding and unlikely to influence clinical practice.”

Anuja Dokras, MD, PHD, a professor of obstetrics and gynecology and director of the PCOS Center at the University of Pennsylvania, Philadelphia, also questioned whether undiagnosed PCOS might have skewed the data.

“There is increasing data on the association between PCOS and NAFLD. Irregular menses is a key criterion for PCOS, and PCOS is the commonest reason for anovulation,” she said. Dr. Dokras therefore considered it possible that patients with unrecognized PCOS were included in the study, weakening the claim that risk of NAFLD and long menstrual cycles remains significant after controlling for PCOS.

Dr. Ryu and coinvestigators, Dr. Santoro, and Dr. Dokras reported no potential conflicts of interest.

Long or irregular menstrual cycles in relatively young women are linked an increased risk of both prevalent and incident nonalcoholic fatty liver disease (NAFLD), according to a cross-sectional study that included data on more than 70,000 women.

“Our results indicate that menstrual irregularity, which is easier to diagnose and usually presented earlier than PCOS [polycystic ovary syndrome] highlights the possibility of identifying premenopausal women at risk of developing NAFLD,” reported a team of authors primarily from Sungkyunkwan University, Seoul, South Korea.

The study evaluated women aged younger than 40 years who were participating in the Kangbuk Samsung Health Study, which involves a comprehensive biennial health examination at health centers in South Korea. Of the 135,090 women enrolled over a 6-year period who had at least one follow-up examination, 72,092 were available for analysis after excluding for a sizable list of confounding factors such as liver disease and infections; exposure to steatogenic medications, such as corticosteroids; hysterectomy; and pregnancy.
 

NAFLD prevalence climbs with longer menses

Of these women, 36.378 (27.7%) had menstrual cycles of 26-30 days and were identified as the index group. The prevalence of NAFLD in this group was 5.8%. For those with a menstrual cycle of 31-39 days, the prevalence rate climbed to 7.2%. For those with a menstrual cycle of at least 40 days or too irregular to estimate, the prevalence was 9.7%. The prevalence was 7.1% for those with a menstrual cycle less than 21 days.

The results of this study were published in the Journal of Clinical Endocrinology & Metabolism.

In those without NAFLD at baseline who were then followed for a mean of 4.4 years, there were 4,524 incident cases of NAFLD. Incidence density was calculated per 103 patient-years. In the index group, the rate was 18.4. It climbed to 20.2 for those with a menstrual cycle of 31-39 days and then to 22.9 for those with a menstrual cycle of at least 40 days. For those with a cycle of fewer than 21 days, the rate was 26.8.

After adjusting for age, body mass index, insulin resistance, and other confounders, the hazard ratio for incident NAFLD for those with long or irregular menstrual cycles compared with the incident group corresponded with a 22% increased risk (HR, 1.22; 95% confidence interval, 1.14-1.31). When calculated in a time-dependent analysis, the risk of NAFLD was increased by almost 50% (HR, 1.49; 95% CI, 1.38-1.60).


 

Risk persists with PCOS exclusion

PCOS has previously been associated with increased risk of NAFLD, but the association between long or irregular menstrual cycles and NAFLD persisted after women with PCOS were excluded.

The mechanism that links menstrual irregularity with NAFLD is unclear, but the investigators said that estrogen exposure is implicated. In addition to a previously reported associated between low estradiol levels and antiestrogens such as tamoxifen with increased risk of NAFLD, they cited studies associating estrogen replacement therapy with a reduced risk of NAFLD. The role of estrogen in suppressing inflammation, oxidative stress, and insulin resistance are all activities that might link more regular menses with a reduced risk of NAFLD, the authors contended.

Women older than 40 years were excluded from this analysis to reduce the possibility of perimenopausal changes as a confounding factor.

Of study limitations acknowledged by the investigators, the presence of NAFLD was diagnosed on ultrasonography rather than histology. Information on sex hormone or prolactin levels was not captured in relation to NAFLD incidence, and the lack of exposure to estrogen replacement therapy and oral contraceptives was based on self-reports from the participants.

Still, the large study size and the consistency of results after adjustment for multiple risk factors argue that long and irregular menstrual cycles do identify women at risk for NAFLD. One implication is that irregular menses can be a marker for NAFLD risk.

“Our findings do not prove a causal relationship, but they show that long or irregular menstrual cycles were significantly associated with an increased risk of developing NAFLD,” said Seungho Ryu, MD, PhD, a professor at the Sungkyunkwan University. Senior author of this study, Dr. Ryu emphasized in an interview that the association “was not explained by obesity or any other risk factor for NAFLD.”
 

Lifestyle changes may lower risk

The message is that “young women with long or irregular menstrual cycles may benefit from lifestyle changes to reduce the risk of NAFLD,” Dr. Ryu stated.

The Study of Women’s Health Across the Nation, which was started in 1994, has not evaluated NAFLD, but it did show a relationship between longer menstrual cycles and more cardiometabolic risk factors, according to Nanette Santoro MD, professor and chair, department of obstetrics & gynecology, University of Colorado at Denver, Aurora.

This suggests that others are “thinking along the same lines,” but in discussing this study with this news organization, she characterized some of the design elements as well as some of the findings in this study as “peculiar.”

In addition to a “very, very narrow definition of regular cycles,” she questioned the consistent hazard ratio for NAFLD for those with long cycles relative to other types of irregular menses. Presuming that the group with longer cycles would have included at least some patients with undiagnosed PCOS, she was would have expected that the risk would have been highest in this group. While conceding that differences in body composition of Korean women is a potential explanation for this apparent discrepancy, “I would like to see confirmed in other samples of women with more detailed metabolic assessments to understand who is at risk,” she said.

Not least problematic for the strength of the conclusions, the hazard ratio for NAFLD among women with long or irregular menstrual cycles was “pretty low.” She described this as a level at which the risk “is very susceptible to confounding and unlikely to influence clinical practice.”

Anuja Dokras, MD, PHD, a professor of obstetrics and gynecology and director of the PCOS Center at the University of Pennsylvania, Philadelphia, also questioned whether undiagnosed PCOS might have skewed the data.

“There is increasing data on the association between PCOS and NAFLD. Irregular menses is a key criterion for PCOS, and PCOS is the commonest reason for anovulation,” she said. Dr. Dokras therefore considered it possible that patients with unrecognized PCOS were included in the study, weakening the claim that risk of NAFLD and long menstrual cycles remains significant after controlling for PCOS.

Dr. Ryu and coinvestigators, Dr. Santoro, and Dr. Dokras reported no potential conflicts of interest.

Exposure to phthalates through maternal blood and cord blood affected outcomes including head circumference and anogenital index for male and female infants, according to data from 65 mother-infant pairs.

Phthalates are recognized endocrine disruptors that have been associated with adverse birth outcomes, but the specific relationship between maternal phthalate exposure and birth outcomes has not been well studied, wrote Hsiao-Lin Hwa, MD, of National Taiwan University, Taipei, and colleagues.

Previous research suggests that trace exposure to hazardous chemicals during the fetal period “may cause fetal metabolic dysfunction and adversely change the morphology of body systems,” they said. In 2011, “the Taiwan Food and Drug Administration found that di‐2‐ethylhexyl phthalate (DEHP) and DiNP [di‐isononyl phthalate] had been illegally added as emulsifiers to replace palm oil in beverages and food,” they added. The researchers sought to examine the association between infant birth outcomes and phthalate exposure levels in the Taiwanese population after 2011. In a study published in Environmental Toxicology and Chemistry, the researchers recruited 65 pregnant women in Taiwan between 2016 and 2017. Birth length, birth weight, head circumference, anogenital distance (AGD), anoscrotal distance (ASD), and anofourchette distance (AFD) were measured for each newborn at the time of delivery. The average age of the women was 33.6 years, and the rate of low birth weight was 13.7%. The mean measures of birth length, birth weight, head circumference, and chest circumference were 47.6 cm, 3022 g, 32.9 cm, and 30.8 mm, respectively. The mean AFD and ASD were 14.2 mm and 22.3 mm, respectively.

The researchers tested for 12 phthalates in maternal blood and cord blood samples. Of these, the six most frequently detected phthalate metabolites were mono‐ethyl phthalate (MEP), mono‐isobutyl phthalate (MiBP), mono‐n‐butyl phthalate (MnBP), mono‐(2‐ethyl‐5‐oxohexyl)‐phthalate (MEOHP), mono‐(2‐ethyl‐5‐hydroxyhexyl) phthalate (MEHHP), and mono‐n‐octyl phthalate (MOP); these six were present in 80%–100% of the maternal blood samples.

Overall, the mean levels of MEP, MiBP, MnBP, and MEHP were relatively higher in both maternal and infant blood than other phthalates, the researchers noted. The mean concentrations of metabolites in maternal blood and infant cord blood were 0.03-2.27 ng/mL and 0.01-3.74 ng/mL, respectively.

Among male infants, levels of MMP, MiBP, and MEHP in maternal blood were inversely related to anogenital index (AGI), with P values for regression coefficients ranging from .011 to .033. In addition, the total concentration of MEHP, MEOHP, and MEHHP (designated as Σdi‐2‐ethylhexyl phthalate, ΣDEHP) was inversely related to AGI in males.

Among female infants, however, phthalates in cord blood, rather than maternal blood, were positively related to AGI, including MMP, MibP, MnBP, and MOP, with P values for regression coefficients ranging from .001 to .034.

Cord blood levels of MnBP, MEOHP, MEHP, and ΣDEHP were inversely associated with gestational age-adjusted head circumference in all infants, with beta coefficients of –0.15, –0.12, –0.01, and –0.01, respectively (P < .05 for all).

“The detection rates of MEHHP, MEOHP, and MEHP in the cord blood were lower than those in the maternal blood, particularly those of MEHHP and MEOHP, which were approximately 25% lower,” which may be caused by slow placental transfer, the researchers wrote in their discussion section. “The high detection rate of phthalate metabolites indicated that our subjects may continue to be exposed to these phthalates even after the 2011 Taiwan DEHP incident,” they noted.

The study findings were limited by several factors including the possibility for contamination of samples and other environmental confounders, the researchers noted. However, the results support the role of phthalates as endocrine disruptors, and the distinction in effects between males and females “may suggest that phthalate monoesters are potentially estrogenic and antiandrogenic chemicals,” they added.

“Further investigations involving multiple phthalate analyses during pregnancy and measurements throughout childhood are necessary to confirm our findings,” they concluded.
 

Direct clinical implications remain uncertain

“Phthalates are a group of chemicals that are used to make plastic more durable; they are found in multiple everyday materials, food products, and common household products,” Marissa Platner, MD, of Emory University, Atlanta, said in an interview. “It is known that we are exposed to phthalates on a routine basis but the long-term effects of this exposure are unclear,” she said.

The current study findings “were not entirely surprising given data from prior animal studies because they do imply that there is some placental transfer of the phthalate metabolites that can cause adverse effects on the developing fetus,” said Dr. Platner. “However, they also demonstrate that the placenta acts as a filter for certain larger molecules to protect the fetus,” she said.

“This study was based on a small sample size, therefore the clinical implications are not clear,” Dr. Platner noted. “However it may be worthwhile after further research to encourage our pregnant patients to try to decrease their exposure to phthalates,” she said.

Dr. Platner identified two areas for additional research to explore the role of phthalate exposure.

“The first would be to assess the level of maternal phthalate exposure throughout the pregnancy instead of just at one point in time, and the second would be to assess how the reproductive system differences at birth translate to long-term outcomes in children, such as early puberty in females or decreased fertility in males,” she said.  

The study was funded by the Ministry of Science and Technology of Taiwan and the Far Eastern Memorial Hospital‐National Taiwan University Hospital. The researchers and Dr. Platner had no financial conflicts to disclose.

Exposure to phthalates through maternal blood and cord blood affected outcomes including head circumference and anogenital index for male and female infants, according to data from 65 mother-infant pairs.

Phthalates are recognized endocrine disruptors that have been associated with adverse birth outcomes, but the specific relationship between maternal phthalate exposure and birth outcomes has not been well studied, wrote Hsiao-Lin Hwa, MD, of National Taiwan University, Taipei, and colleagues.

Previous research suggests that trace exposure to hazardous chemicals during the fetal period “may cause fetal metabolic dysfunction and adversely change the morphology of body systems,” they said. In 2011, “the Taiwan Food and Drug Administration found that di‐2‐ethylhexyl phthalate (DEHP) and DiNP [di‐isononyl phthalate] had been illegally added as emulsifiers to replace palm oil in beverages and food,” they added. The researchers sought to examine the association between infant birth outcomes and phthalate exposure levels in the Taiwanese population after 2011. In a study published in Environmental Toxicology and Chemistry, the researchers recruited 65 pregnant women in Taiwan between 2016 and 2017. Birth length, birth weight, head circumference, anogenital distance (AGD), anoscrotal distance (ASD), and anofourchette distance (AFD) were measured for each newborn at the time of delivery. The average age of the women was 33.6 years, and the rate of low birth weight was 13.7%. The mean measures of birth length, birth weight, head circumference, and chest circumference were 47.6 cm, 3022 g, 32.9 cm, and 30.8 mm, respectively. The mean AFD and ASD were 14.2 mm and 22.3 mm, respectively.

The researchers tested for 12 phthalates in maternal blood and cord blood samples. Of these, the six most frequently detected phthalate metabolites were mono‐ethyl phthalate (MEP), mono‐isobutyl phthalate (MiBP), mono‐n‐butyl phthalate (MnBP), mono‐(2‐ethyl‐5‐oxohexyl)‐phthalate (MEOHP), mono‐(2‐ethyl‐5‐hydroxyhexyl) phthalate (MEHHP), and mono‐n‐octyl phthalate (MOP); these six were present in 80%–100% of the maternal blood samples.

Overall, the mean levels of MEP, MiBP, MnBP, and MEHP were relatively higher in both maternal and infant blood than other phthalates, the researchers noted. The mean concentrations of metabolites in maternal blood and infant cord blood were 0.03-2.27 ng/mL and 0.01-3.74 ng/mL, respectively.

Among male infants, levels of MMP, MiBP, and MEHP in maternal blood were inversely related to anogenital index (AGI), with P values for regression coefficients ranging from .011 to .033. In addition, the total concentration of MEHP, MEOHP, and MEHHP (designated as Σdi‐2‐ethylhexyl phthalate, ΣDEHP) was inversely related to AGI in males.

Among female infants, however, phthalates in cord blood, rather than maternal blood, were positively related to AGI, including MMP, MibP, MnBP, and MOP, with P values for regression coefficients ranging from .001 to .034.

Cord blood levels of MnBP, MEOHP, MEHP, and ΣDEHP were inversely associated with gestational age-adjusted head circumference in all infants, with beta coefficients of –0.15, –0.12, –0.01, and –0.01, respectively (P < .05 for all).

“The detection rates of MEHHP, MEOHP, and MEHP in the cord blood were lower than those in the maternal blood, particularly those of MEHHP and MEOHP, which were approximately 25% lower,” which may be caused by slow placental transfer, the researchers wrote in their discussion section. “The high detection rate of phthalate metabolites indicated that our subjects may continue to be exposed to these phthalates even after the 2011 Taiwan DEHP incident,” they noted.

The study findings were limited by several factors including the possibility for contamination of samples and other environmental confounders, the researchers noted. However, the results support the role of phthalates as endocrine disruptors, and the distinction in effects between males and females “may suggest that phthalate monoesters are potentially estrogenic and antiandrogenic chemicals,” they added.

“Further investigations involving multiple phthalate analyses during pregnancy and measurements throughout childhood are necessary to confirm our findings,” they concluded.
 

Direct clinical implications remain uncertain

“Phthalates are a group of chemicals that are used to make plastic more durable; they are found in multiple everyday materials, food products, and common household products,” Marissa Platner, MD, of Emory University, Atlanta, said in an interview. “It is known that we are exposed to phthalates on a routine basis but the long-term effects of this exposure are unclear,” she said.

The current study findings “were not entirely surprising given data from prior animal studies because they do imply that there is some placental transfer of the phthalate metabolites that can cause adverse effects on the developing fetus,” said Dr. Platner. “However, they also demonstrate that the placenta acts as a filter for certain larger molecules to protect the fetus,” she said.

“This study was based on a small sample size, therefore the clinical implications are not clear,” Dr. Platner noted. “However it may be worthwhile after further research to encourage our pregnant patients to try to decrease their exposure to phthalates,” she said.

Dr. Platner identified two areas for additional research to explore the role of phthalate exposure.

“The first would be to assess the level of maternal phthalate exposure throughout the pregnancy instead of just at one point in time, and the second would be to assess how the reproductive system differences at birth translate to long-term outcomes in children, such as early puberty in females or decreased fertility in males,” she said.  

The study was funded by the Ministry of Science and Technology of Taiwan and the Far Eastern Memorial Hospital‐National Taiwan University Hospital. The researchers and Dr. Platner had no financial conflicts to disclose.

Exposure to phthalates through maternal blood and cord blood affected outcomes including head circumference and anogenital index for male and female infants, according to data from 65 mother-infant pairs.

Phthalates are recognized endocrine disruptors that have been associated with adverse birth outcomes, but the specific relationship between maternal phthalate exposure and birth outcomes has not been well studied, wrote Hsiao-Lin Hwa, MD, of National Taiwan University, Taipei, and colleagues.

Previous research suggests that trace exposure to hazardous chemicals during the fetal period “may cause fetal metabolic dysfunction and adversely change the morphology of body systems,” they said. In 2011, “the Taiwan Food and Drug Administration found that di‐2‐ethylhexyl phthalate (DEHP) and DiNP [di‐isononyl phthalate] had been illegally added as emulsifiers to replace palm oil in beverages and food,” they added. The researchers sought to examine the association between infant birth outcomes and phthalate exposure levels in the Taiwanese population after 2011. In a study published in Environmental Toxicology and Chemistry, the researchers recruited 65 pregnant women in Taiwan between 2016 and 2017. Birth length, birth weight, head circumference, anogenital distance (AGD), anoscrotal distance (ASD), and anofourchette distance (AFD) were measured for each newborn at the time of delivery. The average age of the women was 33.6 years, and the rate of low birth weight was 13.7%. The mean measures of birth length, birth weight, head circumference, and chest circumference were 47.6 cm, 3022 g, 32.9 cm, and 30.8 mm, respectively. The mean AFD and ASD were 14.2 mm and 22.3 mm, respectively.

The researchers tested for 12 phthalates in maternal blood and cord blood samples. Of these, the six most frequently detected phthalate metabolites were mono‐ethyl phthalate (MEP), mono‐isobutyl phthalate (MiBP), mono‐n‐butyl phthalate (MnBP), mono‐(2‐ethyl‐5‐oxohexyl)‐phthalate (MEOHP), mono‐(2‐ethyl‐5‐hydroxyhexyl) phthalate (MEHHP), and mono‐n‐octyl phthalate (MOP); these six were present in 80%–100% of the maternal blood samples.

Overall, the mean levels of MEP, MiBP, MnBP, and MEHP were relatively higher in both maternal and infant blood than other phthalates, the researchers noted. The mean concentrations of metabolites in maternal blood and infant cord blood were 0.03-2.27 ng/mL and 0.01-3.74 ng/mL, respectively.

Among male infants, levels of MMP, MiBP, and MEHP in maternal blood were inversely related to anogenital index (AGI), with P values for regression coefficients ranging from .011 to .033. In addition, the total concentration of MEHP, MEOHP, and MEHHP (designated as Σdi‐2‐ethylhexyl phthalate, ΣDEHP) was inversely related to AGI in males.

Among female infants, however, phthalates in cord blood, rather than maternal blood, were positively related to AGI, including MMP, MibP, MnBP, and MOP, with P values for regression coefficients ranging from .001 to .034.

Cord blood levels of MnBP, MEOHP, MEHP, and ΣDEHP were inversely associated with gestational age-adjusted head circumference in all infants, with beta coefficients of –0.15, –0.12, –0.01, and –0.01, respectively (P < .05 for all).

“The detection rates of MEHHP, MEOHP, and MEHP in the cord blood were lower than those in the maternal blood, particularly those of MEHHP and MEOHP, which were approximately 25% lower,” which may be caused by slow placental transfer, the researchers wrote in their discussion section. “The high detection rate of phthalate metabolites indicated that our subjects may continue to be exposed to these phthalates even after the 2011 Taiwan DEHP incident,” they noted.

The study findings were limited by several factors including the possibility for contamination of samples and other environmental confounders, the researchers noted. However, the results support the role of phthalates as endocrine disruptors, and the distinction in effects between males and females “may suggest that phthalate monoesters are potentially estrogenic and antiandrogenic chemicals,” they added.

“Further investigations involving multiple phthalate analyses during pregnancy and measurements throughout childhood are necessary to confirm our findings,” they concluded.
 

Direct clinical implications remain uncertain

“Phthalates are a group of chemicals that are used to make plastic more durable; they are found in multiple everyday materials, food products, and common household products,” Marissa Platner, MD, of Emory University, Atlanta, said in an interview. “It is known that we are exposed to phthalates on a routine basis but the long-term effects of this exposure are unclear,” she said.

The current study findings “were not entirely surprising given data from prior animal studies because they do imply that there is some placental transfer of the phthalate metabolites that can cause adverse effects on the developing fetus,” said Dr. Platner. “However, they also demonstrate that the placenta acts as a filter for certain larger molecules to protect the fetus,” she said.

“This study was based on a small sample size, therefore the clinical implications are not clear,” Dr. Platner noted. “However it may be worthwhile after further research to encourage our pregnant patients to try to decrease their exposure to phthalates,” she said.

Dr. Platner identified two areas for additional research to explore the role of phthalate exposure.

“The first would be to assess the level of maternal phthalate exposure throughout the pregnancy instead of just at one point in time, and the second would be to assess how the reproductive system differences at birth translate to long-term outcomes in children, such as early puberty in females or decreased fertility in males,” she said.  

The study was funded by the Ministry of Science and Technology of Taiwan and the Far Eastern Memorial Hospital‐National Taiwan University Hospital. The researchers and Dr. Platner had no financial conflicts to disclose.

“Just relax, stop thinking about it and, more than likely, it will happen.” If ever there was a controversial subject in medicine, especially in reproduction, the relationship between stress and infertility would be high on the list. Who among us has not overheard or even personally shared with an infertility patient that they should try and reduce their stress to improve fertility? The theory is certainly not new. Hippocrates, back in the 5th century B.C., was one of the first to associate a woman’s psychological state with her reproductive potential. His contention was that a physical sign of psychological stress in women (which scholars later dubbed “hysteria”) could result in sterility. In medieval times, a German abbess and mystic named Hildegard of Bingen posited women suffering from melancholy – a condition that we today might call depression – were infertile as a result.

The deeper meaning behind the flippant advice to relax is implicit blame; that is, a woman interprets the link of stress and infertility as a declaration that she is sabotaging reproduction. Not only is this assumption flawed, but it does further damage to a woman’s emotional fragility. To provide the presumption of stress affecting reproduction, a recent survey of over 5,000 infertility patients found, remarkably, 98% considered emotional stress as either a cause or a contributor to infertility, and 31% believed stress was a cause of miscarriage, although racial differences existed (J Assist Reprod Genet. 2021 Apr;38[4]:877-87). This relationship was mostly seen in women who used complementary and alternative medicine, Black women, and those who frequented Internet search engines. Whereas women who had a professional degree, had more infertility insurance coverage, and were nonreligious were less likely to attribute stress to infertility. Intriguingly, the more engaged the physicians, the less patients linked stress with infertility, while the contrary also applied.

The power of stress can be exemplified by the pathophysiology of amenorrhea. Functional hypothalamic amenorrhea is the most common cause of the female athlete triad of secondary amenorrhea in women of childbearing age. It is a reversible disorder caused by stress related to weight loss, excessive exercise and/or traumatic mental experiences (Endocrines. 2021;2:203-11). Stress of infertility has also been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities (J Psychosom Obstet Gynaecol. 1993;14[Suppl]:45-52).

A definitive link between stress and infertility is evasive because of the lack of controlled, prospective longitudinal studies and the challenge of reducing variables in the analysis. The question remains which developed initially – the stress or the infertility? Infertility treatment is a physical, emotional, and financial investment. Stress and the duration of infertility are correlative. The additive factor is that poor insurance coverage for costly fertility treatment can not only heighten stress but, concurrently, subject the patient to the risk of exploitation driven by desperation whereby they accept unproven “add-ons” offered with assisted reproductive technologies (ART).

Both acute and chronic stress affect the number of oocytes retrieved and fertilized with ART as well as live birth delivery and birth weights (Fertil Steril. 2001;76:675-87). Men are also affected by stress, which is manifested by decreased libido and impaired semen, further compromised as the duration of infertility continues. The gut-derived hormone ghrelin appears to play a role with stress and reproduction (Endocr Rev. 2017;38:432-67).

As the relationship between stress and infertility is far from proven, there are conflicting study results. Two meta-analyses failed to show any association between stress and the outcomes of ART cycles (Hum Reprod. 2011;26:2763-76; BMJ. 2011;342:d223). In contrast, a recent study suggested stress during infertility treatment was contributed by the variables of low spousal support, financial constraints, and social coercion in the early years of marriage (J Hum Reprod Sci. 2018;11:172-9). Emotional distress was found to be three times greater in women whose families had unrealistic expectations from treatments.

Fortunately, psychotherapy during the ART cycle has demonstrated a benefit in outcomes. Domar revealed psychological support and cognitive behavior therapy resulted in higher pregnancy rates than in the control group (Fertil Steril. 2000;73:805-12). Another recent study appears to support stress reduction improving reproductive potential (Dialogues Clin Neurosci. 2018;20[1]:41-7).

Given the evidence provided in this article, it behooves infertility clinics to address baseline (chronic) stress and acute stress (because of infertility) prior to initiating treatment (see Figure). While the definitive answer addressing the impact of stress on reproduction remains unknown, we may share with our patients a definition in which they may find enlightenment, “Stress is trying to control an event in which one is incapable.”

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

“Just relax, stop thinking about it and, more than likely, it will happen.” If ever there was a controversial subject in medicine, especially in reproduction, the relationship between stress and infertility would be high on the list. Who among us has not overheard or even personally shared with an infertility patient that they should try and reduce their stress to improve fertility? The theory is certainly not new. Hippocrates, back in the 5th century B.C., was one of the first to associate a woman’s psychological state with her reproductive potential. His contention was that a physical sign of psychological stress in women (which scholars later dubbed “hysteria”) could result in sterility. In medieval times, a German abbess and mystic named Hildegard of Bingen posited women suffering from melancholy – a condition that we today might call depression – were infertile as a result.

The deeper meaning behind the flippant advice to relax is implicit blame; that is, a woman interprets the link of stress and infertility as a declaration that she is sabotaging reproduction. Not only is this assumption flawed, but it does further damage to a woman’s emotional fragility. To provide the presumption of stress affecting reproduction, a recent survey of over 5,000 infertility patients found, remarkably, 98% considered emotional stress as either a cause or a contributor to infertility, and 31% believed stress was a cause of miscarriage, although racial differences existed (J Assist Reprod Genet. 2021 Apr;38[4]:877-87). This relationship was mostly seen in women who used complementary and alternative medicine, Black women, and those who frequented Internet search engines. Whereas women who had a professional degree, had more infertility insurance coverage, and were nonreligious were less likely to attribute stress to infertility. Intriguingly, the more engaged the physicians, the less patients linked stress with infertility, while the contrary also applied.

The power of stress can be exemplified by the pathophysiology of amenorrhea. Functional hypothalamic amenorrhea is the most common cause of the female athlete triad of secondary amenorrhea in women of childbearing age. It is a reversible disorder caused by stress related to weight loss, excessive exercise and/or traumatic mental experiences (Endocrines. 2021;2:203-11). Stress of infertility has also been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities (J Psychosom Obstet Gynaecol. 1993;14[Suppl]:45-52).

A definitive link between stress and infertility is evasive because of the lack of controlled, prospective longitudinal studies and the challenge of reducing variables in the analysis. The question remains which developed initially – the stress or the infertility? Infertility treatment is a physical, emotional, and financial investment. Stress and the duration of infertility are correlative. The additive factor is that poor insurance coverage for costly fertility treatment can not only heighten stress but, concurrently, subject the patient to the risk of exploitation driven by desperation whereby they accept unproven “add-ons” offered with assisted reproductive technologies (ART).

Both acute and chronic stress affect the number of oocytes retrieved and fertilized with ART as well as live birth delivery and birth weights (Fertil Steril. 2001;76:675-87). Men are also affected by stress, which is manifested by decreased libido and impaired semen, further compromised as the duration of infertility continues. The gut-derived hormone ghrelin appears to play a role with stress and reproduction (Endocr Rev. 2017;38:432-67).

As the relationship between stress and infertility is far from proven, there are conflicting study results. Two meta-analyses failed to show any association between stress and the outcomes of ART cycles (Hum Reprod. 2011;26:2763-76; BMJ. 2011;342:d223). In contrast, a recent study suggested stress during infertility treatment was contributed by the variables of low spousal support, financial constraints, and social coercion in the early years of marriage (J Hum Reprod Sci. 2018;11:172-9). Emotional distress was found to be three times greater in women whose families had unrealistic expectations from treatments.

Fortunately, psychotherapy during the ART cycle has demonstrated a benefit in outcomes. Domar revealed psychological support and cognitive behavior therapy resulted in higher pregnancy rates than in the control group (Fertil Steril. 2000;73:805-12). Another recent study appears to support stress reduction improving reproductive potential (Dialogues Clin Neurosci. 2018;20[1]:41-7).

Given the evidence provided in this article, it behooves infertility clinics to address baseline (chronic) stress and acute stress (because of infertility) prior to initiating treatment (see Figure). While the definitive answer addressing the impact of stress on reproduction remains unknown, we may share with our patients a definition in which they may find enlightenment, “Stress is trying to control an event in which one is incapable.”

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

“Just relax, stop thinking about it and, more than likely, it will happen.” If ever there was a controversial subject in medicine, especially in reproduction, the relationship between stress and infertility would be high on the list. Who among us has not overheard or even personally shared with an infertility patient that they should try and reduce their stress to improve fertility? The theory is certainly not new. Hippocrates, back in the 5th century B.C., was one of the first to associate a woman’s psychological state with her reproductive potential. His contention was that a physical sign of psychological stress in women (which scholars later dubbed “hysteria”) could result in sterility. In medieval times, a German abbess and mystic named Hildegard of Bingen posited women suffering from melancholy – a condition that we today might call depression – were infertile as a result.

The deeper meaning behind the flippant advice to relax is implicit blame; that is, a woman interprets the link of stress and infertility as a declaration that she is sabotaging reproduction. Not only is this assumption flawed, but it does further damage to a woman’s emotional fragility. To provide the presumption of stress affecting reproduction, a recent survey of over 5,000 infertility patients found, remarkably, 98% considered emotional stress as either a cause or a contributor to infertility, and 31% believed stress was a cause of miscarriage, although racial differences existed (J Assist Reprod Genet. 2021 Apr;38[4]:877-87). This relationship was mostly seen in women who used complementary and alternative medicine, Black women, and those who frequented Internet search engines. Whereas women who had a professional degree, had more infertility insurance coverage, and were nonreligious were less likely to attribute stress to infertility. Intriguingly, the more engaged the physicians, the less patients linked stress with infertility, while the contrary also applied.

The power of stress can be exemplified by the pathophysiology of amenorrhea. Functional hypothalamic amenorrhea is the most common cause of the female athlete triad of secondary amenorrhea in women of childbearing age. It is a reversible disorder caused by stress related to weight loss, excessive exercise and/or traumatic mental experiences (Endocrines. 2021;2:203-11). Stress of infertility has also been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities (J Psychosom Obstet Gynaecol. 1993;14[Suppl]:45-52).

A definitive link between stress and infertility is evasive because of the lack of controlled, prospective longitudinal studies and the challenge of reducing variables in the analysis. The question remains which developed initially – the stress or the infertility? Infertility treatment is a physical, emotional, and financial investment. Stress and the duration of infertility are correlative. The additive factor is that poor insurance coverage for costly fertility treatment can not only heighten stress but, concurrently, subject the patient to the risk of exploitation driven by desperation whereby they accept unproven “add-ons” offered with assisted reproductive technologies (ART).

Both acute and chronic stress affect the number of oocytes retrieved and fertilized with ART as well as live birth delivery and birth weights (Fertil Steril. 2001;76:675-87). Men are also affected by stress, which is manifested by decreased libido and impaired semen, further compromised as the duration of infertility continues. The gut-derived hormone ghrelin appears to play a role with stress and reproduction (Endocr Rev. 2017;38:432-67).

As the relationship between stress and infertility is far from proven, there are conflicting study results. Two meta-analyses failed to show any association between stress and the outcomes of ART cycles (Hum Reprod. 2011;26:2763-76; BMJ. 2011;342:d223). In contrast, a recent study suggested stress during infertility treatment was contributed by the variables of low spousal support, financial constraints, and social coercion in the early years of marriage (J Hum Reprod Sci. 2018;11:172-9). Emotional distress was found to be three times greater in women whose families had unrealistic expectations from treatments.

Fortunately, psychotherapy during the ART cycle has demonstrated a benefit in outcomes. Domar revealed psychological support and cognitive behavior therapy resulted in higher pregnancy rates than in the control group (Fertil Steril. 2000;73:805-12). Another recent study appears to support stress reduction improving reproductive potential (Dialogues Clin Neurosci. 2018;20[1]:41-7).

Given the evidence provided in this article, it behooves infertility clinics to address baseline (chronic) stress and acute stress (because of infertility) prior to initiating treatment (see Figure). While the definitive answer addressing the impact of stress on reproduction remains unknown, we may share with our patients a definition in which they may find enlightenment, “Stress is trying to control an event in which one is incapable.”

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

Polycystic ovary syndrome is common in girls with type 2 diabetes, findings of a new study suggest, and authors say screening for PCOS is critical in this group.

In a systematic review and meta-analysis involving 470 girls (average age 12.9-16.1 years) with type 2 diabetes in six studies, the prevalence of PCOS was nearly 1 in 5 (19.58%; 95% confidence interval, 12.02%-27.14%; P = .002), substantially higher than that of PCOS in the general adolescent population.

PCOS, a complex endocrine disorder, occurs in 1.14%-11.04% of adolescent girls globally, according to the paper published online in JAMA Network Open.

The secondary outcome studied links to prevalence of PCOS with race and obesity.

Insulin resistance and compensatory hyperinsulinemia are present in 44%-70% of women with PCOS, suggesting that they are more likely to develop type 2 diabetes, according to the researchers led by Milena Cioana, BHSc, with the department of pediatrics, McMaster University, Hamilton, Ont.

Kelly A. Curran, MD, an assistant professor of pediatrics at the University of Oklahoma Health Sciences Center in Oklahoma City, where she practices adolescent medicine, said in an interview that it has been known that women with PCOS have higher rates of diabetes and many in the field have suspected the relationship is bidirectional.

“In my clinical practice, I’ve seen a high percentage of women with type 2 diabetes present with irregular menses, some of whom have gone on to be diagnosed with PCOS,” said Dr. Curran, who was not involved with the study.

However, she said, she was surprised the prevalence of PCOS reported in this paper – nearly one in five – was so high. Early diagnosis is important for PCOS to prevent complications such as hypertension, hyperglycemia, and dyslipidemia.

Psychiatric conditions are also prevalent in patients with PCOS, including anxiety (18%), depression (16%), and ADHD (9%).

Dr. Curran agreed there is a need to screen for PCOS and to evaluate for other causes of irregular periods in patients with type 2 diabetes.

“Menstrual irregularities are often overlooked in young women without further work-up, especially in patients who have chronic illnesses,” she noted.
 

Results come with a caveat

However, the authors said, results should be viewed with caution because “studies including the larger numbers of girls did not report the criteria used to diagnose PCOS, which is a challenge during adolescence.”

Diagnostic criteria for PCOS during adolescence include the combination of menstrual irregularities according to time since their first period and clinical or biochemical hyperandrogenism after excluding other potential causes.

Dr. Curran explained that PCOS symptoms include irregular periods and acne which can overlap with normal changes in puberty. In her experience, PCOS is often diagnosed without patients meeting full criteria. She agreed further research with standardized criteria is urgently needed.

The European Society of Human Reproduction and Embryology/American Society of Reproductive Medicine, the Pediatric Endocrine Society, and the International Consortium of Paediatric Endocrinology guidelines suggest that using ultrasound to check the size of ovaries could help diagnose PCOS, but other guidelines are more conservative, the authors noted.

They added that “there is a need for a consensus to establish the pediatric criteria for diagnosing PCOS in adolescents to ensure accurate diagnosis and lower the misclassification rates.”
 

Assessing links to obesity and race

Still unclear, the authors wrote, is whether and how obesity and race affect prevalence of PCOS among girls with type 2 diabetes.

The authors wrote: “Although earlier studies suggested that obesity-related insulin resistance and hyperinsulinemia can contribute to PCOS pathogenesis, insulin resistance in patients with PCOS may be present independently of [body mass index]. Obesity seems to increase the risk of PCOS only slightly and might represent a referral bias for PCOS.”

Few studies included in the meta-analysis had race-specific data, so the authors were limited in assessing associations between race and PCOS prevalence.

“However,” they wrote, “our data demonstrate that Indian girls had the highest prevalence, followed by White girls, and then Indigenous girls in Canada.”

Further studies are needed to help define at-risk subgroups and evaluate treatment strategies, the authors noted.

They reported having no relevant financial relationships. Dr. Curran had no conflicts of interest.

Polycystic ovary syndrome is common in girls with type 2 diabetes, findings of a new study suggest, and authors say screening for PCOS is critical in this group.

In a systematic review and meta-analysis involving 470 girls (average age 12.9-16.1 years) with type 2 diabetes in six studies, the prevalence of PCOS was nearly 1 in 5 (19.58%; 95% confidence interval, 12.02%-27.14%; P = .002), substantially higher than that of PCOS in the general adolescent population.

PCOS, a complex endocrine disorder, occurs in 1.14%-11.04% of adolescent girls globally, according to the paper published online in JAMA Network Open.

The secondary outcome studied links to prevalence of PCOS with race and obesity.

Insulin resistance and compensatory hyperinsulinemia are present in 44%-70% of women with PCOS, suggesting that they are more likely to develop type 2 diabetes, according to the researchers led by Milena Cioana, BHSc, with the department of pediatrics, McMaster University, Hamilton, Ont.

Kelly A. Curran, MD, an assistant professor of pediatrics at the University of Oklahoma Health Sciences Center in Oklahoma City, where she practices adolescent medicine, said in an interview that it has been known that women with PCOS have higher rates of diabetes and many in the field have suspected the relationship is bidirectional.

“In my clinical practice, I’ve seen a high percentage of women with type 2 diabetes present with irregular menses, some of whom have gone on to be diagnosed with PCOS,” said Dr. Curran, who was not involved with the study.

However, she said, she was surprised the prevalence of PCOS reported in this paper – nearly one in five – was so high. Early diagnosis is important for PCOS to prevent complications such as hypertension, hyperglycemia, and dyslipidemia.

Psychiatric conditions are also prevalent in patients with PCOS, including anxiety (18%), depression (16%), and ADHD (9%).

Dr. Curran agreed there is a need to screen for PCOS and to evaluate for other causes of irregular periods in patients with type 2 diabetes.

“Menstrual irregularities are often overlooked in young women without further work-up, especially in patients who have chronic illnesses,” she noted.
 

Results come with a caveat

However, the authors said, results should be viewed with caution because “studies including the larger numbers of girls did not report the criteria used to diagnose PCOS, which is a challenge during adolescence.”

Diagnostic criteria for PCOS during adolescence include the combination of menstrual irregularities according to time since their first period and clinical or biochemical hyperandrogenism after excluding other potential causes.

Dr. Curran explained that PCOS symptoms include irregular periods and acne which can overlap with normal changes in puberty. In her experience, PCOS is often diagnosed without patients meeting full criteria. She agreed further research with standardized criteria is urgently needed.

The European Society of Human Reproduction and Embryology/American Society of Reproductive Medicine, the Pediatric Endocrine Society, and the International Consortium of Paediatric Endocrinology guidelines suggest that using ultrasound to check the size of ovaries could help diagnose PCOS, but other guidelines are more conservative, the authors noted.

They added that “there is a need for a consensus to establish the pediatric criteria for diagnosing PCOS in adolescents to ensure accurate diagnosis and lower the misclassification rates.”
 

Assessing links to obesity and race

Still unclear, the authors wrote, is whether and how obesity and race affect prevalence of PCOS among girls with type 2 diabetes.

The authors wrote: “Although earlier studies suggested that obesity-related insulin resistance and hyperinsulinemia can contribute to PCOS pathogenesis, insulin resistance in patients with PCOS may be present independently of [body mass index]. Obesity seems to increase the risk of PCOS only slightly and might represent a referral bias for PCOS.”

Few studies included in the meta-analysis had race-specific data, so the authors were limited in assessing associations between race and PCOS prevalence.

“However,” they wrote, “our data demonstrate that Indian girls had the highest prevalence, followed by White girls, and then Indigenous girls in Canada.”

Further studies are needed to help define at-risk subgroups and evaluate treatment strategies, the authors noted.

They reported having no relevant financial relationships. Dr. Curran had no conflicts of interest.

Polycystic ovary syndrome is common in girls with type 2 diabetes, findings of a new study suggest, and authors say screening for PCOS is critical in this group.

In a systematic review and meta-analysis involving 470 girls (average age 12.9-16.1 years) with type 2 diabetes in six studies, the prevalence of PCOS was nearly 1 in 5 (19.58%; 95% confidence interval, 12.02%-27.14%; P = .002), substantially higher than that of PCOS in the general adolescent population.

PCOS, a complex endocrine disorder, occurs in 1.14%-11.04% of adolescent girls globally, according to the paper published online in JAMA Network Open.

The secondary outcome studied links to prevalence of PCOS with race and obesity.

Insulin resistance and compensatory hyperinsulinemia are present in 44%-70% of women with PCOS, suggesting that they are more likely to develop type 2 diabetes, according to the researchers led by Milena Cioana, BHSc, with the department of pediatrics, McMaster University, Hamilton, Ont.

Kelly A. Curran, MD, an assistant professor of pediatrics at the University of Oklahoma Health Sciences Center in Oklahoma City, where she practices adolescent medicine, said in an interview that it has been known that women with PCOS have higher rates of diabetes and many in the field have suspected the relationship is bidirectional.

“In my clinical practice, I’ve seen a high percentage of women with type 2 diabetes present with irregular menses, some of whom have gone on to be diagnosed with PCOS,” said Dr. Curran, who was not involved with the study.

However, she said, she was surprised the prevalence of PCOS reported in this paper – nearly one in five – was so high. Early diagnosis is important for PCOS to prevent complications such as hypertension, hyperglycemia, and dyslipidemia.

Psychiatric conditions are also prevalent in patients with PCOS, including anxiety (18%), depression (16%), and ADHD (9%).

Dr. Curran agreed there is a need to screen for PCOS and to evaluate for other causes of irregular periods in patients with type 2 diabetes.

“Menstrual irregularities are often overlooked in young women without further work-up, especially in patients who have chronic illnesses,” she noted.
 

Results come with a caveat

However, the authors said, results should be viewed with caution because “studies including the larger numbers of girls did not report the criteria used to diagnose PCOS, which is a challenge during adolescence.”

Diagnostic criteria for PCOS during adolescence include the combination of menstrual irregularities according to time since their first period and clinical or biochemical hyperandrogenism after excluding other potential causes.

Dr. Curran explained that PCOS symptoms include irregular periods and acne which can overlap with normal changes in puberty. In her experience, PCOS is often diagnosed without patients meeting full criteria. She agreed further research with standardized criteria is urgently needed.

The European Society of Human Reproduction and Embryology/American Society of Reproductive Medicine, the Pediatric Endocrine Society, and the International Consortium of Paediatric Endocrinology guidelines suggest that using ultrasound to check the size of ovaries could help diagnose PCOS, but other guidelines are more conservative, the authors noted.

They added that “there is a need for a consensus to establish the pediatric criteria for diagnosing PCOS in adolescents to ensure accurate diagnosis and lower the misclassification rates.”
 

Assessing links to obesity and race

Still unclear, the authors wrote, is whether and how obesity and race affect prevalence of PCOS among girls with type 2 diabetes.

The authors wrote: “Although earlier studies suggested that obesity-related insulin resistance and hyperinsulinemia can contribute to PCOS pathogenesis, insulin resistance in patients with PCOS may be present independently of [body mass index]. Obesity seems to increase the risk of PCOS only slightly and might represent a referral bias for PCOS.”

Few studies included in the meta-analysis had race-specific data, so the authors were limited in assessing associations between race and PCOS prevalence.

“However,” they wrote, “our data demonstrate that Indian girls had the highest prevalence, followed by White girls, and then Indigenous girls in Canada.”

Further studies are needed to help define at-risk subgroups and evaluate treatment strategies, the authors noted.

They reported having no relevant financial relationships. Dr. Curran had no conflicts of interest.

A small study of deceased nonvaccinated men who died of COVID-19 complications suggests the testes may be a sanctuary for the SARS-CoV-2 virus, raising questions about potential consequences for reproductive health among those infected.

The study, published online Feb. 8 on the preprint server MedRxiv, found that “patients who become critically ill exhibit severe damages and may harbor the active virus in testes,” which can “serve as a viral sanctuary.”

Guilherme M.J. Costa, PhD, a professor at Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, led the study, which has not yet been peer-reviewed.

“A critical point of this article is that the virus was active in the patient’s testis after a long period of infection, indicating that the testis is able to maintain the viable virus for extended periods. It happens for many kinds of viruses in this genital organ,” Dr. Costa said in an interview.

Brian Keith McNeil, MD, vice-chair, department of urology at SUNY Downstate Health Sciences University in New York, told this news organization that the topic of COVID-19 and fertility has been discussed but data are sparse on the subject.

“The question this raises is whether or not COVID can live in the testes, and based on this it seems it can,” he said, adding that it also raises the question of whether COVID-19 could be transmitted through semen. “It leads one to wonder whether this could have a long-term impact on fertility in men and women.”

The authors wrote that deep testicular evaluation of patients who have been infected with COVID-19 is critical because the testes have one of the highest expressions of angiotensin converting enzyme 2 (ACE2) receptors, which play a large role in entrance of the virus into cells.

“A direct influence of SARS-CoV-2 in testicular cells might deregulate ACE2, elevating the levels of angiotensin II, a potent pro-inflammatory and angiogenic peptide,” the authors wrote.
 

Sperm-producing cells infected

In 2021, the researchers enrolled 11 male patients deceased from COVID-19 complications; none had received a vaccine. Infection was confirmed by SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) performed during their hospital stay. All 11 patients were admitted to the intensive care unit with severe pulmonary symptoms.

All but one of the patients had children and none had scrotal symptoms or complaints during their time in the hospital. Their clinical histories revealed no testicular disorders.

Dr. Costa said they found that detecting SARS-CoV-2 mRNA in testes is difficult in a conventional RT-PCR test.

Therefore, “We modified the protocol of the RT-PCR and used nanosensors. We observed that SARS-CoV-2 has a huge tropism for the testes in this context,” he said.

He said the team performed stainings and “discovered that macrophages and germ cells are highly infected.”

That’s important, he said, because an immune cell, which is supposed to fight the virus, is infected in the tissue. Also, the germ cell, responsible for sperm production, is infected.

“This reopens the worries about the presence of SARS-CoV-2 in semen, as other authors mentioned,” he said.
 

New findings

The team also found that the testes are a good place for viral replication.

The authors say they are the first to show:

• The longer the severe condition, the lower the number of surviving germ cells.
• There was fluctuation in several essential testicular genes.
• The intratesticular testosterone levels are 30 times reduced in the testes of COVID-19 patients.

The control group was composed of six patients who had undergone testicle removal after prostate cancer was suspected. Collection of both testicles from the test group was performed within 3 hours of death after a family member signed an informed consent document.

Recent research on semen demonstrates that patients who recovered from COVID-19 reestablish their sperm quality after 3 months of infection.

That study, in Fertility and Sterility, found that sperm quality was initially reduced for months in some men after recovery from COVID-19.

The team studied semen samples from 120 Belgian men (mean age, 35 years) at an average 52 days after their last COVID-19 symptoms. The semen was not found to be infectious.

But among 35 men who provided samples within a month after infection, reductions in sperm motility were evident in 60% and sperm counts were reduced in 37%, according to the report.
 

Testicular damage

The results [of the Costa et al. paper] emphasize the importance of testicular damage in severe COVID-19,” Rafael Kroon Campos, PhD, a postdoctoral fellow in the department of microbiology & immunology at the University of Texas Medical Branch at Galveston, said in an interview.

He noted that other viruses have also been shown to infect or otherwise cause testicular damage or orchitis, such as Zika, Ebola, and the closely related SARS-CoV-1. Sexual transmission has been documented for Zika and Ebola viruses.

Dr. Campos said with SARS-CoV-2, it is unclear whether sexual transmission plays a role.

“Some reports found evidence of viral RNA in semen, but these were rare occurrences. The study by Costa and colleagues used a combination of sensitive techniques and they were able to detect a small amount of viral RNA and viral protein in the testicular tissue of the deceased patients, as well as show viral factories indicating replication of the virus by electron microscopy,” he said.

Dr. Campos said the findings are particularly important and concerning because of the large number of severe cases of COVID-19.

“It is critical to continue to investigate the impact of the disease in testes, including the impact of different variants of concern on testicular damage,” he said.

Dr. McNeil and Dr. Campos have disclosed no relevant financial relationships.

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

A small study of deceased nonvaccinated men who died of COVID-19 complications suggests the testes may be a sanctuary for the SARS-CoV-2 virus, raising questions about potential consequences for reproductive health among those infected.

The study, published online Feb. 8 on the preprint server MedRxiv, found that “patients who become critically ill exhibit severe damages and may harbor the active virus in testes,” which can “serve as a viral sanctuary.”

Guilherme M.J. Costa, PhD, a professor at Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, led the study, which has not yet been peer-reviewed.

“A critical point of this article is that the virus was active in the patient’s testis after a long period of infection, indicating that the testis is able to maintain the viable virus for extended periods. It happens for many kinds of viruses in this genital organ,” Dr. Costa said in an interview.

Brian Keith McNeil, MD, vice-chair, department of urology at SUNY Downstate Health Sciences University in New York, told this news organization that the topic of COVID-19 and fertility has been discussed but data are sparse on the subject.

“The question this raises is whether or not COVID can live in the testes, and based on this it seems it can,” he said, adding that it also raises the question of whether COVID-19 could be transmitted through semen. “It leads one to wonder whether this could have a long-term impact on fertility in men and women.”

The authors wrote that deep testicular evaluation of patients who have been infected with COVID-19 is critical because the testes have one of the highest expressions of angiotensin converting enzyme 2 (ACE2) receptors, which play a large role in entrance of the virus into cells.

“A direct influence of SARS-CoV-2 in testicular cells might deregulate ACE2, elevating the levels of angiotensin II, a potent pro-inflammatory and angiogenic peptide,” the authors wrote.
 

Sperm-producing cells infected

In 2021, the researchers enrolled 11 male patients deceased from COVID-19 complications; none had received a vaccine. Infection was confirmed by SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) performed during their hospital stay. All 11 patients were admitted to the intensive care unit with severe pulmonary symptoms.

All but one of the patients had children and none had scrotal symptoms or complaints during their time in the hospital. Their clinical histories revealed no testicular disorders.

Dr. Costa said they found that detecting SARS-CoV-2 mRNA in testes is difficult in a conventional RT-PCR test.

Therefore, “We modified the protocol of the RT-PCR and used nanosensors. We observed that SARS-CoV-2 has a huge tropism for the testes in this context,” he said.

He said the team performed stainings and “discovered that macrophages and germ cells are highly infected.”

That’s important, he said, because an immune cell, which is supposed to fight the virus, is infected in the tissue. Also, the germ cell, responsible for sperm production, is infected.

“This reopens the worries about the presence of SARS-CoV-2 in semen, as other authors mentioned,” he said.
 

New findings

The team also found that the testes are a good place for viral replication.

The authors say they are the first to show:

• The longer the severe condition, the lower the number of surviving germ cells.
• There was fluctuation in several essential testicular genes.
• The intratesticular testosterone levels are 30 times reduced in the testes of COVID-19 patients.

The control group was composed of six patients who had undergone testicle removal after prostate cancer was suspected. Collection of both testicles from the test group was performed within 3 hours of death after a family member signed an informed consent document.

Recent research on semen demonstrates that patients who recovered from COVID-19 reestablish their sperm quality after 3 months of infection.

That study, in Fertility and Sterility, found that sperm quality was initially reduced for months in some men after recovery from COVID-19.

The team studied semen samples from 120 Belgian men (mean age, 35 years) at an average 52 days after their last COVID-19 symptoms. The semen was not found to be infectious.

But among 35 men who provided samples within a month after infection, reductions in sperm motility were evident in 60% and sperm counts were reduced in 37%, according to the report.
 

Testicular damage

The results [of the Costa et al. paper] emphasize the importance of testicular damage in severe COVID-19,” Rafael Kroon Campos, PhD, a postdoctoral fellow in the department of microbiology & immunology at the University of Texas Medical Branch at Galveston, said in an interview.

He noted that other viruses have also been shown to infect or otherwise cause testicular damage or orchitis, such as Zika, Ebola, and the closely related SARS-CoV-1. Sexual transmission has been documented for Zika and Ebola viruses.

Dr. Campos said with SARS-CoV-2, it is unclear whether sexual transmission plays a role.

“Some reports found evidence of viral RNA in semen, but these were rare occurrences. The study by Costa and colleagues used a combination of sensitive techniques and they were able to detect a small amount of viral RNA and viral protein in the testicular tissue of the deceased patients, as well as show viral factories indicating replication of the virus by electron microscopy,” he said.

Dr. Campos said the findings are particularly important and concerning because of the large number of severe cases of COVID-19.

“It is critical to continue to investigate the impact of the disease in testes, including the impact of different variants of concern on testicular damage,” he said.

Dr. McNeil and Dr. Campos have disclosed no relevant financial relationships.

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

A small study of deceased nonvaccinated men who died of COVID-19 complications suggests the testes may be a sanctuary for the SARS-CoV-2 virus, raising questions about potential consequences for reproductive health among those infected.

The study, published online Feb. 8 on the preprint server MedRxiv, found that “patients who become critically ill exhibit severe damages and may harbor the active virus in testes,” which can “serve as a viral sanctuary.”

Guilherme M.J. Costa, PhD, a professor at Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, led the study, which has not yet been peer-reviewed.

“A critical point of this article is that the virus was active in the patient’s testis after a long period of infection, indicating that the testis is able to maintain the viable virus for extended periods. It happens for many kinds of viruses in this genital organ,” Dr. Costa said in an interview.

Brian Keith McNeil, MD, vice-chair, department of urology at SUNY Downstate Health Sciences University in New York, told this news organization that the topic of COVID-19 and fertility has been discussed but data are sparse on the subject.

“The question this raises is whether or not COVID can live in the testes, and based on this it seems it can,” he said, adding that it also raises the question of whether COVID-19 could be transmitted through semen. “It leads one to wonder whether this could have a long-term impact on fertility in men and women.”

The authors wrote that deep testicular evaluation of patients who have been infected with COVID-19 is critical because the testes have one of the highest expressions of angiotensin converting enzyme 2 (ACE2) receptors, which play a large role in entrance of the virus into cells.

“A direct influence of SARS-CoV-2 in testicular cells might deregulate ACE2, elevating the levels of angiotensin II, a potent pro-inflammatory and angiogenic peptide,” the authors wrote.
 

Sperm-producing cells infected

In 2021, the researchers enrolled 11 male patients deceased from COVID-19 complications; none had received a vaccine. Infection was confirmed by SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) performed during their hospital stay. All 11 patients were admitted to the intensive care unit with severe pulmonary symptoms.

All but one of the patients had children and none had scrotal symptoms or complaints during their time in the hospital. Their clinical histories revealed no testicular disorders.

Dr. Costa said they found that detecting SARS-CoV-2 mRNA in testes is difficult in a conventional RT-PCR test.

Therefore, “We modified the protocol of the RT-PCR and used nanosensors. We observed that SARS-CoV-2 has a huge tropism for the testes in this context,” he said.

He said the team performed stainings and “discovered that macrophages and germ cells are highly infected.”

That’s important, he said, because an immune cell, which is supposed to fight the virus, is infected in the tissue. Also, the germ cell, responsible for sperm production, is infected.

“This reopens the worries about the presence of SARS-CoV-2 in semen, as other authors mentioned,” he said.
 

New findings

The team also found that the testes are a good place for viral replication.

The authors say they are the first to show:

• The longer the severe condition, the lower the number of surviving germ cells.
• There was fluctuation in several essential testicular genes.
• The intratesticular testosterone levels are 30 times reduced in the testes of COVID-19 patients.

The control group was composed of six patients who had undergone testicle removal after prostate cancer was suspected. Collection of both testicles from the test group was performed within 3 hours of death after a family member signed an informed consent document.

Recent research on semen demonstrates that patients who recovered from COVID-19 reestablish their sperm quality after 3 months of infection.

That study, in Fertility and Sterility, found that sperm quality was initially reduced for months in some men after recovery from COVID-19.

The team studied semen samples from 120 Belgian men (mean age, 35 years) at an average 52 days after their last COVID-19 symptoms. The semen was not found to be infectious.

But among 35 men who provided samples within a month after infection, reductions in sperm motility were evident in 60% and sperm counts were reduced in 37%, according to the report.
 

Testicular damage

The results [of the Costa et al. paper] emphasize the importance of testicular damage in severe COVID-19,” Rafael Kroon Campos, PhD, a postdoctoral fellow in the department of microbiology & immunology at the University of Texas Medical Branch at Galveston, said in an interview.

He noted that other viruses have also been shown to infect or otherwise cause testicular damage or orchitis, such as Zika, Ebola, and the closely related SARS-CoV-1. Sexual transmission has been documented for Zika and Ebola viruses.

Dr. Campos said with SARS-CoV-2, it is unclear whether sexual transmission plays a role.

“Some reports found evidence of viral RNA in semen, but these were rare occurrences. The study by Costa and colleagues used a combination of sensitive techniques and they were able to detect a small amount of viral RNA and viral protein in the testicular tissue of the deceased patients, as well as show viral factories indicating replication of the virus by electron microscopy,” he said.

Dr. Campos said the findings are particularly important and concerning because of the large number of severe cases of COVID-19.

“It is critical to continue to investigate the impact of the disease in testes, including the impact of different variants of concern on testicular damage,” he said.

Dr. McNeil and Dr. Campos have disclosed no relevant financial relationships.

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