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Metformin Gets a Reproductive Reprieve — For Diabetic Moms and Dads Alike
For decades it’s been thought that preconception use of the oral antidiabetic metformin by mothers and fathers might result in adverse fetal outcomes, including congenital malformations and stillbirths.
Women with type 2 diabetes (T2D) are often advised to switch to insulin before or during early pregnancy out of concern for fetal safety. But two studies from the Harvard T.H. Chan School of Public Health in Boston, Massachusetts — one in mothers, the other in fathers — report that metformin, a common and cost-effective antidiabetic agent, is not associated with a significant increased risk of teratogenicity and negative perinatal outcomes. The studies appear in Annals of Internal Medicine.
The studies may make it easier for physicians to reassure diabetic parents-to-be about the safety of metformin use before conception and in early pregnancy,
In the context of sparse existing safety data, the maternal analysis looked at Medicaid data on 12,489 mothers (mean age, about 30) receiving metformin for pregestational T2D during the period 2000-2018. “Many women become pregnant while still taking noninsulin oral antidiabetics, mostly metformin, and one safety concern is whether metformin could cause birth defects,” lead author Yu-Han Chiu, MD, ScD, an epidemiologist, said in an interview, commenting on the impetus for the study.
“On the one hand, metformin can cross the placenta and might directly affect the fetus. On the other hand, poor blood sugar control is a risk factor for birth defects,” she continued. “Insulin in combination with metformin might control blood sugar better than using insulin alone, which may lower the risk of birth defects.”
Switched to insulin monotherapy or prescribed additional insulin within 90 days of their last menstrual period, mothers were assessed for nonchromosomal fetal malformations and nonlive births, spontaneous abortion, and termination. Continuing metformin or adding insulin to metformin in early pregnancy resulted in little to no increased risk for major malformations in infants.
The estimated risk for nonlive birth was 32.7% with insulin monotherapy and 34.3% with insulin plus metformin polytherapy, for a risk ratio (RR) of 1.02 (95% confidence interval (CI), 1.01-1.04).
In addition, the estimated risk for live birth with congenital malformations was 8.0% (5.70-10.2) under insulin monotherapy and 5.7% under insulin plus metformin (95% CI, 4.5-7.3), amounting to a risk ratio of 0.72 (0.51-1.09).
While the results may involve residual confounding by participants’ glycemic control and body mass index, Dr. Chiu said, “Our findings suggest that the current clinical recommendations to switch from metformin to insulin before pregnancy, due to concerns about birth defects, may require reconsideration.”
She noted that previous trials showed adding metformin to insulin in mid-late pregnancy also improved blood sugar control with no increase in risk of birth defects. “However, most of these studies started treatment too late — between 10 and 34 weeks of pregnancy — to determine if metformin could cause birth defects.”
Observational studies found that women with pregestational diabetes who used noninsulin antidiabetics (mainly metformin) in the first trimester had a lower risk of birth defects, compared with those who used insulin, Dr. Chiu added. “However, comparing metformin with insulin may have some biases because women who used metformin generally have less severe diabetes than those who used insulin.”
Aligning with these reassuring findings, a randomized, placebo-controlled trial reported that adding metformin to insulin did not lead to a higher incidence of neonatal morbidity and mortality and was associated with better maternal glycemic control and reduced maternal weight gain. Metformin-exposed offspring, however, had lower birth weights and a higher incidence of being small for gestational age.
Similarly, a recent Nordic register study of more than 3.7 million infants also found no evidence of an increased risk of major defects with the use of metformin vs insulin in the first trimester.
Despite such reassuring findings, however, Dr. Chiu stressed the need to study other pregnancy and infant outcomes as well as the safety of other oral antidiabetics during pregnancy.
Metformin in Fathers
Turning to fathers, a much larger cohort study by Harvard T.H. Chan investigators looked at the effect of paternal metformin use and also found it to be safe.
The Harvard investigators analyzed diabetic men in 383,851 live births from 1999 to 2020 in an Israeli health fund cohort, excluding those with diabetic spouses. Across different T2D medication groups, paternal age ranged from about 35 to about 43 years. The data revealed that paternal use of metformin monotherapy in the preconception sperm production period was, after adjustment of crude numbers, not associated with major congenital malformations (MCMs) in newborns.
“While metformin has an overall good safety profile, it can lower androgen levels, and there had been some concerns that its use in fathers could alter the sperm, causing adverse effects to the fetus,” lead author and neuroepidemiologist Ran S. Rotem, MD, ScD, of the Harvard School of Public Health, Boston, Massachusetts, said in interview. “Given the increasing prevalence of diabetes in young individuals, more fathers are conceiving a child while using the medication, which could lead to a substantial population effect even if the individual risk is low. But our study suggests that the medication is safe to use by fathers before conception.”
The prevalence of MCMs in the cohort was 4.7% in children of fathers unexposed to diabetes medications (n = 381,041), compared with 6.2% in children of fathers exposed during preconception spermatogenesis to metformin (n = 1730).
By these crude numbers, children with preconception paternal metformin exposure had a nearly 30% increased odds of MCMs. But whereas the crude odds ratio (OR) for MCMs with paternal metformin exposure in all formulations was 1.28 (95% CI, 1.01-1.64), the adjusted OR was 1.00 (95% CI, 0.76 -1.31). Within specific regimens, the adjusted OR was 0.86 (95% CI, 0.60-1.23) for metformin in monotherapy and 1.36 (95% CI, 1.00-1.85) for metformin in polytherapy.
At the outset, Dr. Rotem’s group hypothesized that any crude associations between metformin in polytherapy and birth defects could potentially be explained by poorer underlying parental cardiometabolic risk profiles in those taking multiple diabetes medications. Compared with that of unexposed fathers, the prevalence of cardiometabolic morbidity was indeed substantially higher among both fathers who used metformin during spermatogenesis and their spouses.
In addition, these fathers were more likely to be older, to be smokers, and to have fertility problems. Similarly, mothers were more likely to have cardiovascular comorbidity and to have had fertility problems when the father used metformin.
Moreover, children born to men who used diabetes medications before conception were much more likely to have mothers who also had diabetes and other metabolic conditions, Dr. Rotem noted. “This makes sense since we know that many of these conditions are affected by diet and lifestyle factors that are probably shared across individuals living in the same household.”
Recent research has shown that paternal health and behavior before conception can affect offspring development and long-term health. Characteristics including obesity, diabetes, and metabolic syndrome are seen to affect offspring via complex indirect and direct mechanisms, both genetic and nongenetic.
Doing little to dispel safety concerns, a recent Danish national study reported a link between preconception paternal metformin and major birth defects, particularly genital birth defects in boys. That study, however, lacked data on medication adherence and glycemic control.
“These are well-conducted studies, but it would be useful to see them replicated in different populations, as the sample sizes eligible for analysis are relatively small and some of the confidence intervals are wide,” said Robert W. Platt, PhD, a professor in the departments of Pediatrics and of Epidemiology, Biostatistics, and Occupational Health at McGill University in Montreal, Canada. “However, the results suggest that type 2 diabetics can focus on the most effective treatment pathway for their condition. Metformin does not appear to confer an increased risk of congenital malformations.”
According to an accompanying editorial by Sarah Martins da Silva. MBChB, MD, a reproductive medicine specialist at the University of Dundee in Scotland, the Israeli findings highlight the importance of factoring the sometimes overlooked issue of paternal health into reproductive planning and prenatal care. She stressed that individual risks and benefits should always be carefully considered and results interpreted with caution since such studies lack information on glycemic control. “Nonetheless, these recent analyses suggest that metformin is a safe and effective treatment option for T2D for men and women trying to conceive as well as for managing hyperglycemia in pregnant women in the first trimester,” she wrote and agreed that it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.
The studies by Dr. Chiu and Dr. Rotem were funded by the National Institutes of Health. Dr. Chiu and Dr. Rotem had no competing interests to declare. Dr. Hernandez Diaz, a coauthor on both studies, reported funding from Takeda and consulting for Moderna, Johnson & Johnson, and UCB. Several authors reported support from government and not-for-profit research funding agencies. Dr. Platt disclosed no competing interests. Editorial commentator Dr. Martins da Silva disclosed consulting, speaking, travel, and advisory fees from, variously, Dyneval, Ferring Pharmaceutical, Merck, IBSA, and Gedeon Richer.
For decades it’s been thought that preconception use of the oral antidiabetic metformin by mothers and fathers might result in adverse fetal outcomes, including congenital malformations and stillbirths.
Women with type 2 diabetes (T2D) are often advised to switch to insulin before or during early pregnancy out of concern for fetal safety. But two studies from the Harvard T.H. Chan School of Public Health in Boston, Massachusetts — one in mothers, the other in fathers — report that metformin, a common and cost-effective antidiabetic agent, is not associated with a significant increased risk of teratogenicity and negative perinatal outcomes. The studies appear in Annals of Internal Medicine.
The studies may make it easier for physicians to reassure diabetic parents-to-be about the safety of metformin use before conception and in early pregnancy,
In the context of sparse existing safety data, the maternal analysis looked at Medicaid data on 12,489 mothers (mean age, about 30) receiving metformin for pregestational T2D during the period 2000-2018. “Many women become pregnant while still taking noninsulin oral antidiabetics, mostly metformin, and one safety concern is whether metformin could cause birth defects,” lead author Yu-Han Chiu, MD, ScD, an epidemiologist, said in an interview, commenting on the impetus for the study.
“On the one hand, metformin can cross the placenta and might directly affect the fetus. On the other hand, poor blood sugar control is a risk factor for birth defects,” she continued. “Insulin in combination with metformin might control blood sugar better than using insulin alone, which may lower the risk of birth defects.”
Switched to insulin monotherapy or prescribed additional insulin within 90 days of their last menstrual period, mothers were assessed for nonchromosomal fetal malformations and nonlive births, spontaneous abortion, and termination. Continuing metformin or adding insulin to metformin in early pregnancy resulted in little to no increased risk for major malformations in infants.
The estimated risk for nonlive birth was 32.7% with insulin monotherapy and 34.3% with insulin plus metformin polytherapy, for a risk ratio (RR) of 1.02 (95% confidence interval (CI), 1.01-1.04).
In addition, the estimated risk for live birth with congenital malformations was 8.0% (5.70-10.2) under insulin monotherapy and 5.7% under insulin plus metformin (95% CI, 4.5-7.3), amounting to a risk ratio of 0.72 (0.51-1.09).
While the results may involve residual confounding by participants’ glycemic control and body mass index, Dr. Chiu said, “Our findings suggest that the current clinical recommendations to switch from metformin to insulin before pregnancy, due to concerns about birth defects, may require reconsideration.”
She noted that previous trials showed adding metformin to insulin in mid-late pregnancy also improved blood sugar control with no increase in risk of birth defects. “However, most of these studies started treatment too late — between 10 and 34 weeks of pregnancy — to determine if metformin could cause birth defects.”
Observational studies found that women with pregestational diabetes who used noninsulin antidiabetics (mainly metformin) in the first trimester had a lower risk of birth defects, compared with those who used insulin, Dr. Chiu added. “However, comparing metformin with insulin may have some biases because women who used metformin generally have less severe diabetes than those who used insulin.”
Aligning with these reassuring findings, a randomized, placebo-controlled trial reported that adding metformin to insulin did not lead to a higher incidence of neonatal morbidity and mortality and was associated with better maternal glycemic control and reduced maternal weight gain. Metformin-exposed offspring, however, had lower birth weights and a higher incidence of being small for gestational age.
Similarly, a recent Nordic register study of more than 3.7 million infants also found no evidence of an increased risk of major defects with the use of metformin vs insulin in the first trimester.
Despite such reassuring findings, however, Dr. Chiu stressed the need to study other pregnancy and infant outcomes as well as the safety of other oral antidiabetics during pregnancy.
Metformin in Fathers
Turning to fathers, a much larger cohort study by Harvard T.H. Chan investigators looked at the effect of paternal metformin use and also found it to be safe.
The Harvard investigators analyzed diabetic men in 383,851 live births from 1999 to 2020 in an Israeli health fund cohort, excluding those with diabetic spouses. Across different T2D medication groups, paternal age ranged from about 35 to about 43 years. The data revealed that paternal use of metformin monotherapy in the preconception sperm production period was, after adjustment of crude numbers, not associated with major congenital malformations (MCMs) in newborns.
“While metformin has an overall good safety profile, it can lower androgen levels, and there had been some concerns that its use in fathers could alter the sperm, causing adverse effects to the fetus,” lead author and neuroepidemiologist Ran S. Rotem, MD, ScD, of the Harvard School of Public Health, Boston, Massachusetts, said in interview. “Given the increasing prevalence of diabetes in young individuals, more fathers are conceiving a child while using the medication, which could lead to a substantial population effect even if the individual risk is low. But our study suggests that the medication is safe to use by fathers before conception.”
The prevalence of MCMs in the cohort was 4.7% in children of fathers unexposed to diabetes medications (n = 381,041), compared with 6.2% in children of fathers exposed during preconception spermatogenesis to metformin (n = 1730).
By these crude numbers, children with preconception paternal metformin exposure had a nearly 30% increased odds of MCMs. But whereas the crude odds ratio (OR) for MCMs with paternal metformin exposure in all formulations was 1.28 (95% CI, 1.01-1.64), the adjusted OR was 1.00 (95% CI, 0.76 -1.31). Within specific regimens, the adjusted OR was 0.86 (95% CI, 0.60-1.23) for metformin in monotherapy and 1.36 (95% CI, 1.00-1.85) for metformin in polytherapy.
At the outset, Dr. Rotem’s group hypothesized that any crude associations between metformin in polytherapy and birth defects could potentially be explained by poorer underlying parental cardiometabolic risk profiles in those taking multiple diabetes medications. Compared with that of unexposed fathers, the prevalence of cardiometabolic morbidity was indeed substantially higher among both fathers who used metformin during spermatogenesis and their spouses.
In addition, these fathers were more likely to be older, to be smokers, and to have fertility problems. Similarly, mothers were more likely to have cardiovascular comorbidity and to have had fertility problems when the father used metformin.
Moreover, children born to men who used diabetes medications before conception were much more likely to have mothers who also had diabetes and other metabolic conditions, Dr. Rotem noted. “This makes sense since we know that many of these conditions are affected by diet and lifestyle factors that are probably shared across individuals living in the same household.”
Recent research has shown that paternal health and behavior before conception can affect offspring development and long-term health. Characteristics including obesity, diabetes, and metabolic syndrome are seen to affect offspring via complex indirect and direct mechanisms, both genetic and nongenetic.
Doing little to dispel safety concerns, a recent Danish national study reported a link between preconception paternal metformin and major birth defects, particularly genital birth defects in boys. That study, however, lacked data on medication adherence and glycemic control.
“These are well-conducted studies, but it would be useful to see them replicated in different populations, as the sample sizes eligible for analysis are relatively small and some of the confidence intervals are wide,” said Robert W. Platt, PhD, a professor in the departments of Pediatrics and of Epidemiology, Biostatistics, and Occupational Health at McGill University in Montreal, Canada. “However, the results suggest that type 2 diabetics can focus on the most effective treatment pathway for their condition. Metformin does not appear to confer an increased risk of congenital malformations.”
According to an accompanying editorial by Sarah Martins da Silva. MBChB, MD, a reproductive medicine specialist at the University of Dundee in Scotland, the Israeli findings highlight the importance of factoring the sometimes overlooked issue of paternal health into reproductive planning and prenatal care. She stressed that individual risks and benefits should always be carefully considered and results interpreted with caution since such studies lack information on glycemic control. “Nonetheless, these recent analyses suggest that metformin is a safe and effective treatment option for T2D for men and women trying to conceive as well as for managing hyperglycemia in pregnant women in the first trimester,” she wrote and agreed that it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.
The studies by Dr. Chiu and Dr. Rotem were funded by the National Institutes of Health. Dr. Chiu and Dr. Rotem had no competing interests to declare. Dr. Hernandez Diaz, a coauthor on both studies, reported funding from Takeda and consulting for Moderna, Johnson & Johnson, and UCB. Several authors reported support from government and not-for-profit research funding agencies. Dr. Platt disclosed no competing interests. Editorial commentator Dr. Martins da Silva disclosed consulting, speaking, travel, and advisory fees from, variously, Dyneval, Ferring Pharmaceutical, Merck, IBSA, and Gedeon Richer.
For decades it’s been thought that preconception use of the oral antidiabetic metformin by mothers and fathers might result in adverse fetal outcomes, including congenital malformations and stillbirths.
Women with type 2 diabetes (T2D) are often advised to switch to insulin before or during early pregnancy out of concern for fetal safety. But two studies from the Harvard T.H. Chan School of Public Health in Boston, Massachusetts — one in mothers, the other in fathers — report that metformin, a common and cost-effective antidiabetic agent, is not associated with a significant increased risk of teratogenicity and negative perinatal outcomes. The studies appear in Annals of Internal Medicine.
The studies may make it easier for physicians to reassure diabetic parents-to-be about the safety of metformin use before conception and in early pregnancy,
In the context of sparse existing safety data, the maternal analysis looked at Medicaid data on 12,489 mothers (mean age, about 30) receiving metformin for pregestational T2D during the period 2000-2018. “Many women become pregnant while still taking noninsulin oral antidiabetics, mostly metformin, and one safety concern is whether metformin could cause birth defects,” lead author Yu-Han Chiu, MD, ScD, an epidemiologist, said in an interview, commenting on the impetus for the study.
“On the one hand, metformin can cross the placenta and might directly affect the fetus. On the other hand, poor blood sugar control is a risk factor for birth defects,” she continued. “Insulin in combination with metformin might control blood sugar better than using insulin alone, which may lower the risk of birth defects.”
Switched to insulin monotherapy or prescribed additional insulin within 90 days of their last menstrual period, mothers were assessed for nonchromosomal fetal malformations and nonlive births, spontaneous abortion, and termination. Continuing metformin or adding insulin to metformin in early pregnancy resulted in little to no increased risk for major malformations in infants.
The estimated risk for nonlive birth was 32.7% with insulin monotherapy and 34.3% with insulin plus metformin polytherapy, for a risk ratio (RR) of 1.02 (95% confidence interval (CI), 1.01-1.04).
In addition, the estimated risk for live birth with congenital malformations was 8.0% (5.70-10.2) under insulin monotherapy and 5.7% under insulin plus metformin (95% CI, 4.5-7.3), amounting to a risk ratio of 0.72 (0.51-1.09).
While the results may involve residual confounding by participants’ glycemic control and body mass index, Dr. Chiu said, “Our findings suggest that the current clinical recommendations to switch from metformin to insulin before pregnancy, due to concerns about birth defects, may require reconsideration.”
She noted that previous trials showed adding metformin to insulin in mid-late pregnancy also improved blood sugar control with no increase in risk of birth defects. “However, most of these studies started treatment too late — between 10 and 34 weeks of pregnancy — to determine if metformin could cause birth defects.”
Observational studies found that women with pregestational diabetes who used noninsulin antidiabetics (mainly metformin) in the first trimester had a lower risk of birth defects, compared with those who used insulin, Dr. Chiu added. “However, comparing metformin with insulin may have some biases because women who used metformin generally have less severe diabetes than those who used insulin.”
Aligning with these reassuring findings, a randomized, placebo-controlled trial reported that adding metformin to insulin did not lead to a higher incidence of neonatal morbidity and mortality and was associated with better maternal glycemic control and reduced maternal weight gain. Metformin-exposed offspring, however, had lower birth weights and a higher incidence of being small for gestational age.
Similarly, a recent Nordic register study of more than 3.7 million infants also found no evidence of an increased risk of major defects with the use of metformin vs insulin in the first trimester.
Despite such reassuring findings, however, Dr. Chiu stressed the need to study other pregnancy and infant outcomes as well as the safety of other oral antidiabetics during pregnancy.
Metformin in Fathers
Turning to fathers, a much larger cohort study by Harvard T.H. Chan investigators looked at the effect of paternal metformin use and also found it to be safe.
The Harvard investigators analyzed diabetic men in 383,851 live births from 1999 to 2020 in an Israeli health fund cohort, excluding those with diabetic spouses. Across different T2D medication groups, paternal age ranged from about 35 to about 43 years. The data revealed that paternal use of metformin monotherapy in the preconception sperm production period was, after adjustment of crude numbers, not associated with major congenital malformations (MCMs) in newborns.
“While metformin has an overall good safety profile, it can lower androgen levels, and there had been some concerns that its use in fathers could alter the sperm, causing adverse effects to the fetus,” lead author and neuroepidemiologist Ran S. Rotem, MD, ScD, of the Harvard School of Public Health, Boston, Massachusetts, said in interview. “Given the increasing prevalence of diabetes in young individuals, more fathers are conceiving a child while using the medication, which could lead to a substantial population effect even if the individual risk is low. But our study suggests that the medication is safe to use by fathers before conception.”
The prevalence of MCMs in the cohort was 4.7% in children of fathers unexposed to diabetes medications (n = 381,041), compared with 6.2% in children of fathers exposed during preconception spermatogenesis to metformin (n = 1730).
By these crude numbers, children with preconception paternal metformin exposure had a nearly 30% increased odds of MCMs. But whereas the crude odds ratio (OR) for MCMs with paternal metformin exposure in all formulations was 1.28 (95% CI, 1.01-1.64), the adjusted OR was 1.00 (95% CI, 0.76 -1.31). Within specific regimens, the adjusted OR was 0.86 (95% CI, 0.60-1.23) for metformin in monotherapy and 1.36 (95% CI, 1.00-1.85) for metformin in polytherapy.
At the outset, Dr. Rotem’s group hypothesized that any crude associations between metformin in polytherapy and birth defects could potentially be explained by poorer underlying parental cardiometabolic risk profiles in those taking multiple diabetes medications. Compared with that of unexposed fathers, the prevalence of cardiometabolic morbidity was indeed substantially higher among both fathers who used metformin during spermatogenesis and their spouses.
In addition, these fathers were more likely to be older, to be smokers, and to have fertility problems. Similarly, mothers were more likely to have cardiovascular comorbidity and to have had fertility problems when the father used metformin.
Moreover, children born to men who used diabetes medications before conception were much more likely to have mothers who also had diabetes and other metabolic conditions, Dr. Rotem noted. “This makes sense since we know that many of these conditions are affected by diet and lifestyle factors that are probably shared across individuals living in the same household.”
Recent research has shown that paternal health and behavior before conception can affect offspring development and long-term health. Characteristics including obesity, diabetes, and metabolic syndrome are seen to affect offspring via complex indirect and direct mechanisms, both genetic and nongenetic.
Doing little to dispel safety concerns, a recent Danish national study reported a link between preconception paternal metformin and major birth defects, particularly genital birth defects in boys. That study, however, lacked data on medication adherence and glycemic control.
“These are well-conducted studies, but it would be useful to see them replicated in different populations, as the sample sizes eligible for analysis are relatively small and some of the confidence intervals are wide,” said Robert W. Platt, PhD, a professor in the departments of Pediatrics and of Epidemiology, Biostatistics, and Occupational Health at McGill University in Montreal, Canada. “However, the results suggest that type 2 diabetics can focus on the most effective treatment pathway for their condition. Metformin does not appear to confer an increased risk of congenital malformations.”
According to an accompanying editorial by Sarah Martins da Silva. MBChB, MD, a reproductive medicine specialist at the University of Dundee in Scotland, the Israeli findings highlight the importance of factoring the sometimes overlooked issue of paternal health into reproductive planning and prenatal care. She stressed that individual risks and benefits should always be carefully considered and results interpreted with caution since such studies lack information on glycemic control. “Nonetheless, these recent analyses suggest that metformin is a safe and effective treatment option for T2D for men and women trying to conceive as well as for managing hyperglycemia in pregnant women in the first trimester,” she wrote and agreed that it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.
The studies by Dr. Chiu and Dr. Rotem were funded by the National Institutes of Health. Dr. Chiu and Dr. Rotem had no competing interests to declare. Dr. Hernandez Diaz, a coauthor on both studies, reported funding from Takeda and consulting for Moderna, Johnson & Johnson, and UCB. Several authors reported support from government and not-for-profit research funding agencies. Dr. Platt disclosed no competing interests. Editorial commentator Dr. Martins da Silva disclosed consulting, speaking, travel, and advisory fees from, variously, Dyneval, Ferring Pharmaceutical, Merck, IBSA, and Gedeon Richer.
Polycystic Ovarian Syndrome: New Science Offers Old Remedy
An ancient Chinese remedy for malaria could offer new hope to the 10% of reproductive-age women living with polycystic ovarian syndrome (PCOS), a poorly understood endocrine disorder that can cause hormonal imbalances, irregular periods, and cysts in the ovaries.
“PCOS is among the most common disorders of reproductive-age women,” said endocrinologist Andrea Dunaif, MD, a professor at the Icahn School of Medicine at Mount Sinai, New York City, who studies diabetes and women’s health. “It is a major risk factor for obesity, type 2 diabetes, and heart disease.” It’s also a leading cause of infertility.
Yet despite how common it is, PCOS has no Food and Drug Administration–approved treatments, though a few early-stage clinical trials are underway. Many women end up taking off-label medications such as oral contraceptives, insulin-sensitizing agents, and antiandrogens to help manage symptoms. Surgery can also be used to treat fertility problems associated with PCOS, though it may not work for everyone.
In a new study, a derivative of artemisinin — a molecule that comes from Artemisia plants, which have been used as far back as 1596 to treat malaria in China — helped relieve PCOS symptoms in rats and a small group of women.
Previously, the study’s lead researcher Qi-qun Tang, MD, PhD, had found that this derivative, called artemether, can increase thermogenesis, boosting metabolism. Dr. Tang and his team at Fudan University, Shanghai, China, wanted to see if it would help with PCOS, which is associated with metabolic problems such as insulin resistance.
What the Researchers Did
To simulate PCOS in rats, the team treated the rodents with insulin and human chorionic gonadotropin. Then, they tested artemether on the rats and found that it lowered androgen production in the ovaries.
“A common feature [of PCOS] is that the ovaries, and often the adrenal glands, make increased male hormones, nowhere near what a man makes but slightly above what a normal woman makes,” said Dr. Dunaif, who was not involved in the study.
Artemether “inhibits one of the steroidogenic enzymes, CYP11A1, which is important in the production of male hormones,” Dr. Tang said. It does this by increasing the enzyme’s interaction with a protein called LONP1, triggering the enzyme’s breakdown. Increased levels of LONP1 also appeared to suppress androgen production in the ovaries.
In a pilot clinical study of 19 women with PCOS, taking dihydroartemisinin — an approved drug used to treat malaria that contains active artemisinin derivatives — for 12 weeks substantially reduced serum testosterone and anti-Müllerian hormone levels (which are higher in women with PCOS). Using ultrasound, the researchers found that the antral follicle count (also higher than normal with PCOS) had been reduced. All participants had regular menstrual cycles during treatment. And no one reported significant side effects.
“Regular menstrual cycles suggest that there is ovulation, which can result in conception,” Dr. Dunaif said. Still, testing would be needed to confirm that cycles are ovulatory.
Lowering androgen levels “could improve a substantial portion of the symptoms of PCOS,” said Dr. Dunaif. But the research didn’t see an improvement in insulin sensitivity among the women, suggesting that targeting androgens may not help the metabolic symptoms.
What’s Next?
A larger, placebo-controlled trial would still be needed to assess the drug’s efficacy, said Dr. Dunaif, pointing out that the human study did not have a placebo arm.
And unanswered questions remain. Are there any adrenal effects of the compound? “The enzymes that produce androgens are shared between the ovary and the adrenal [gland],” Dr. Dunaif said, but she pointed out that the study doesn’t address whether there is an adrenal benefit. It’s something to look at in future research.
Still, because artemisinin is an established drug, it may come to market faster than a new molecule would, she said. However, a pharmaceutical company would need to be willing to take on the drug. (Dr. Tang said several companies have already expressed interest.)
And while you can buy artemisinin on the Internet, Dr. Dunaif warned not to start taking it if you have PCOS. “I don’t think we’re at that point,” Dr. Dunaif said.
A version of this article first appeared on Medscape.com.
An ancient Chinese remedy for malaria could offer new hope to the 10% of reproductive-age women living with polycystic ovarian syndrome (PCOS), a poorly understood endocrine disorder that can cause hormonal imbalances, irregular periods, and cysts in the ovaries.
“PCOS is among the most common disorders of reproductive-age women,” said endocrinologist Andrea Dunaif, MD, a professor at the Icahn School of Medicine at Mount Sinai, New York City, who studies diabetes and women’s health. “It is a major risk factor for obesity, type 2 diabetes, and heart disease.” It’s also a leading cause of infertility.
Yet despite how common it is, PCOS has no Food and Drug Administration–approved treatments, though a few early-stage clinical trials are underway. Many women end up taking off-label medications such as oral contraceptives, insulin-sensitizing agents, and antiandrogens to help manage symptoms. Surgery can also be used to treat fertility problems associated with PCOS, though it may not work for everyone.
In a new study, a derivative of artemisinin — a molecule that comes from Artemisia plants, which have been used as far back as 1596 to treat malaria in China — helped relieve PCOS symptoms in rats and a small group of women.
Previously, the study’s lead researcher Qi-qun Tang, MD, PhD, had found that this derivative, called artemether, can increase thermogenesis, boosting metabolism. Dr. Tang and his team at Fudan University, Shanghai, China, wanted to see if it would help with PCOS, which is associated with metabolic problems such as insulin resistance.
What the Researchers Did
To simulate PCOS in rats, the team treated the rodents with insulin and human chorionic gonadotropin. Then, they tested artemether on the rats and found that it lowered androgen production in the ovaries.
“A common feature [of PCOS] is that the ovaries, and often the adrenal glands, make increased male hormones, nowhere near what a man makes but slightly above what a normal woman makes,” said Dr. Dunaif, who was not involved in the study.
Artemether “inhibits one of the steroidogenic enzymes, CYP11A1, which is important in the production of male hormones,” Dr. Tang said. It does this by increasing the enzyme’s interaction with a protein called LONP1, triggering the enzyme’s breakdown. Increased levels of LONP1 also appeared to suppress androgen production in the ovaries.
In a pilot clinical study of 19 women with PCOS, taking dihydroartemisinin — an approved drug used to treat malaria that contains active artemisinin derivatives — for 12 weeks substantially reduced serum testosterone and anti-Müllerian hormone levels (which are higher in women with PCOS). Using ultrasound, the researchers found that the antral follicle count (also higher than normal with PCOS) had been reduced. All participants had regular menstrual cycles during treatment. And no one reported significant side effects.
“Regular menstrual cycles suggest that there is ovulation, which can result in conception,” Dr. Dunaif said. Still, testing would be needed to confirm that cycles are ovulatory.
Lowering androgen levels “could improve a substantial portion of the symptoms of PCOS,” said Dr. Dunaif. But the research didn’t see an improvement in insulin sensitivity among the women, suggesting that targeting androgens may not help the metabolic symptoms.
What’s Next?
A larger, placebo-controlled trial would still be needed to assess the drug’s efficacy, said Dr. Dunaif, pointing out that the human study did not have a placebo arm.
And unanswered questions remain. Are there any adrenal effects of the compound? “The enzymes that produce androgens are shared between the ovary and the adrenal [gland],” Dr. Dunaif said, but she pointed out that the study doesn’t address whether there is an adrenal benefit. It’s something to look at in future research.
Still, because artemisinin is an established drug, it may come to market faster than a new molecule would, she said. However, a pharmaceutical company would need to be willing to take on the drug. (Dr. Tang said several companies have already expressed interest.)
And while you can buy artemisinin on the Internet, Dr. Dunaif warned not to start taking it if you have PCOS. “I don’t think we’re at that point,” Dr. Dunaif said.
A version of this article first appeared on Medscape.com.
An ancient Chinese remedy for malaria could offer new hope to the 10% of reproductive-age women living with polycystic ovarian syndrome (PCOS), a poorly understood endocrine disorder that can cause hormonal imbalances, irregular periods, and cysts in the ovaries.
“PCOS is among the most common disorders of reproductive-age women,” said endocrinologist Andrea Dunaif, MD, a professor at the Icahn School of Medicine at Mount Sinai, New York City, who studies diabetes and women’s health. “It is a major risk factor for obesity, type 2 diabetes, and heart disease.” It’s also a leading cause of infertility.
Yet despite how common it is, PCOS has no Food and Drug Administration–approved treatments, though a few early-stage clinical trials are underway. Many women end up taking off-label medications such as oral contraceptives, insulin-sensitizing agents, and antiandrogens to help manage symptoms. Surgery can also be used to treat fertility problems associated with PCOS, though it may not work for everyone.
In a new study, a derivative of artemisinin — a molecule that comes from Artemisia plants, which have been used as far back as 1596 to treat malaria in China — helped relieve PCOS symptoms in rats and a small group of women.
Previously, the study’s lead researcher Qi-qun Tang, MD, PhD, had found that this derivative, called artemether, can increase thermogenesis, boosting metabolism. Dr. Tang and his team at Fudan University, Shanghai, China, wanted to see if it would help with PCOS, which is associated with metabolic problems such as insulin resistance.
What the Researchers Did
To simulate PCOS in rats, the team treated the rodents with insulin and human chorionic gonadotropin. Then, they tested artemether on the rats and found that it lowered androgen production in the ovaries.
“A common feature [of PCOS] is that the ovaries, and often the adrenal glands, make increased male hormones, nowhere near what a man makes but slightly above what a normal woman makes,” said Dr. Dunaif, who was not involved in the study.
Artemether “inhibits one of the steroidogenic enzymes, CYP11A1, which is important in the production of male hormones,” Dr. Tang said. It does this by increasing the enzyme’s interaction with a protein called LONP1, triggering the enzyme’s breakdown. Increased levels of LONP1 also appeared to suppress androgen production in the ovaries.
In a pilot clinical study of 19 women with PCOS, taking dihydroartemisinin — an approved drug used to treat malaria that contains active artemisinin derivatives — for 12 weeks substantially reduced serum testosterone and anti-Müllerian hormone levels (which are higher in women with PCOS). Using ultrasound, the researchers found that the antral follicle count (also higher than normal with PCOS) had been reduced. All participants had regular menstrual cycles during treatment. And no one reported significant side effects.
“Regular menstrual cycles suggest that there is ovulation, which can result in conception,” Dr. Dunaif said. Still, testing would be needed to confirm that cycles are ovulatory.
Lowering androgen levels “could improve a substantial portion of the symptoms of PCOS,” said Dr. Dunaif. But the research didn’t see an improvement in insulin sensitivity among the women, suggesting that targeting androgens may not help the metabolic symptoms.
What’s Next?
A larger, placebo-controlled trial would still be needed to assess the drug’s efficacy, said Dr. Dunaif, pointing out that the human study did not have a placebo arm.
And unanswered questions remain. Are there any adrenal effects of the compound? “The enzymes that produce androgens are shared between the ovary and the adrenal [gland],” Dr. Dunaif said, but she pointed out that the study doesn’t address whether there is an adrenal benefit. It’s something to look at in future research.
Still, because artemisinin is an established drug, it may come to market faster than a new molecule would, she said. However, a pharmaceutical company would need to be willing to take on the drug. (Dr. Tang said several companies have already expressed interest.)
And while you can buy artemisinin on the Internet, Dr. Dunaif warned not to start taking it if you have PCOS. “I don’t think we’re at that point,” Dr. Dunaif said.
A version of this article first appeared on Medscape.com.
FROM SCIENCE
Investigational Male Contraceptive Suppresses Sperm Rapidly
BOSTON — An investigational male contraceptive gel suppresses sperm more rapidly than previous products in development, new data suggested.
The product, 8 mg segesterone acetate (Nestorone) combined with 74 mg testosterone (“NesT”) is a gel that a man applies daily to both shoulders. The progesterone blocks spermatogenesis, and the testosterone restores blood levels to maintain sexual function. It is under development by the National Institute of Child Health and Human Development (NICHD) in collaboration with the Population Council, the Los Angeles Biomedical Research Institute, and the University of Washington School of Medicine.
Currently, the only available male contraceptives are vasectomy, which isn’t easily reversible, and condoms, which have a high failure rate. Previous attempts to develop a “male pill” have been unsuccessful for a variety of reasons, but so far, this product appears effective and safe, Diana Blithe, PhD, chief of the Contraceptive Development Program at NICHD, said at a press briefing held on June 2, 2024, during the annual meeting of the Endocrine Society.
“It’s been a long time coming. … Men need and want more contraceptive options such as an effective reversible method,” she told this news organization.
New phase 2b data show that among 222 couples in which the man initially had normal (> 15 million/mL) sperm counts, the median time to suppression (< 1 million/mL) was less than 8 weeks with NesT compared with 9-15 weeks seen in previous trials of injected male hormonal contraceptives. Nearly all (86%) had achieved suppression by 15 weeks.
After two consecutive counts of < 1 million/mL, the couples entered the trial’s ongoing 2-year efficacy phase. There have been no major safety concerns thus far, but “we need more data,” Dr. Blithe noted.
Asked to comment, session moderator Frances Hayes, MBBCh, associate clinical chief of the Division of Reproductive Endocrinology at Massachusetts General Hospital, Boston, said, “certainly, I think it’s a big advance on what we have so far. … I think it’s showing great promise.”
Dr. Hayes did caution, though, that “with real-world use, daily application of a gel might be a bit more challenging than taking an injection…an injection is more consistent. With a gel, patients might forget or shower it off. But I don’t think 1 day of interruption would be a significant thing.”
Transference of the topical to a partner or a child is another potential concern, Dr. Hayes noted, although this is true of current testosterone gel products as well. During the briefing, Dr. Blithe said that this issue is why the product is recommended to be placed on the upper arms rather than the abdomen or another spot more likely to come into contact with another person. Also, in the trial, men were instructed to wear shirts during intercourse.
Regarding the rapidity of sperm suppression, Dr. Hayes said, “It’s surprising. It looks great as a reversible contraceptive. … Normally, you think of the life cycle of the sperm being about 72 days. So to see 50% suppression by 8 weeks, and then 85%-90% by 15 weeks, that’s very rapid. It may be that the progesterone that they’re using is very potent. Progestins can have some negative effects on lipids and mood. We didn’t really see the safety data in this presentation. So that will be interesting to see.”
During the briefing, Dr. Blithe said that the phase 2b trial is expected to finish by the end of this year, and in the meantime, the researchers are communicating with the US Food and Drug Administration about the design of a phase 3 trial because this is an unprecedented area. “They don’t have guidelines yet. They’ll need to develop them first.”
Dr. Blithe has been the NICHD principal investigator on cooperative research and development agreements with HRA Pharma and Daré Bioscience. Dr. Hayes had no disclosures.
A version of this article appeared on Medscape.com .
BOSTON — An investigational male contraceptive gel suppresses sperm more rapidly than previous products in development, new data suggested.
The product, 8 mg segesterone acetate (Nestorone) combined with 74 mg testosterone (“NesT”) is a gel that a man applies daily to both shoulders. The progesterone blocks spermatogenesis, and the testosterone restores blood levels to maintain sexual function. It is under development by the National Institute of Child Health and Human Development (NICHD) in collaboration with the Population Council, the Los Angeles Biomedical Research Institute, and the University of Washington School of Medicine.
Currently, the only available male contraceptives are vasectomy, which isn’t easily reversible, and condoms, which have a high failure rate. Previous attempts to develop a “male pill” have been unsuccessful for a variety of reasons, but so far, this product appears effective and safe, Diana Blithe, PhD, chief of the Contraceptive Development Program at NICHD, said at a press briefing held on June 2, 2024, during the annual meeting of the Endocrine Society.
“It’s been a long time coming. … Men need and want more contraceptive options such as an effective reversible method,” she told this news organization.
New phase 2b data show that among 222 couples in which the man initially had normal (> 15 million/mL) sperm counts, the median time to suppression (< 1 million/mL) was less than 8 weeks with NesT compared with 9-15 weeks seen in previous trials of injected male hormonal contraceptives. Nearly all (86%) had achieved suppression by 15 weeks.
After two consecutive counts of < 1 million/mL, the couples entered the trial’s ongoing 2-year efficacy phase. There have been no major safety concerns thus far, but “we need more data,” Dr. Blithe noted.
Asked to comment, session moderator Frances Hayes, MBBCh, associate clinical chief of the Division of Reproductive Endocrinology at Massachusetts General Hospital, Boston, said, “certainly, I think it’s a big advance on what we have so far. … I think it’s showing great promise.”
Dr. Hayes did caution, though, that “with real-world use, daily application of a gel might be a bit more challenging than taking an injection…an injection is more consistent. With a gel, patients might forget or shower it off. But I don’t think 1 day of interruption would be a significant thing.”
Transference of the topical to a partner or a child is another potential concern, Dr. Hayes noted, although this is true of current testosterone gel products as well. During the briefing, Dr. Blithe said that this issue is why the product is recommended to be placed on the upper arms rather than the abdomen or another spot more likely to come into contact with another person. Also, in the trial, men were instructed to wear shirts during intercourse.
Regarding the rapidity of sperm suppression, Dr. Hayes said, “It’s surprising. It looks great as a reversible contraceptive. … Normally, you think of the life cycle of the sperm being about 72 days. So to see 50% suppression by 8 weeks, and then 85%-90% by 15 weeks, that’s very rapid. It may be that the progesterone that they’re using is very potent. Progestins can have some negative effects on lipids and mood. We didn’t really see the safety data in this presentation. So that will be interesting to see.”
During the briefing, Dr. Blithe said that the phase 2b trial is expected to finish by the end of this year, and in the meantime, the researchers are communicating with the US Food and Drug Administration about the design of a phase 3 trial because this is an unprecedented area. “They don’t have guidelines yet. They’ll need to develop them first.”
Dr. Blithe has been the NICHD principal investigator on cooperative research and development agreements with HRA Pharma and Daré Bioscience. Dr. Hayes had no disclosures.
A version of this article appeared on Medscape.com .
BOSTON — An investigational male contraceptive gel suppresses sperm more rapidly than previous products in development, new data suggested.
The product, 8 mg segesterone acetate (Nestorone) combined with 74 mg testosterone (“NesT”) is a gel that a man applies daily to both shoulders. The progesterone blocks spermatogenesis, and the testosterone restores blood levels to maintain sexual function. It is under development by the National Institute of Child Health and Human Development (NICHD) in collaboration with the Population Council, the Los Angeles Biomedical Research Institute, and the University of Washington School of Medicine.
Currently, the only available male contraceptives are vasectomy, which isn’t easily reversible, and condoms, which have a high failure rate. Previous attempts to develop a “male pill” have been unsuccessful for a variety of reasons, but so far, this product appears effective and safe, Diana Blithe, PhD, chief of the Contraceptive Development Program at NICHD, said at a press briefing held on June 2, 2024, during the annual meeting of the Endocrine Society.
“It’s been a long time coming. … Men need and want more contraceptive options such as an effective reversible method,” she told this news organization.
New phase 2b data show that among 222 couples in which the man initially had normal (> 15 million/mL) sperm counts, the median time to suppression (< 1 million/mL) was less than 8 weeks with NesT compared with 9-15 weeks seen in previous trials of injected male hormonal contraceptives. Nearly all (86%) had achieved suppression by 15 weeks.
After two consecutive counts of < 1 million/mL, the couples entered the trial’s ongoing 2-year efficacy phase. There have been no major safety concerns thus far, but “we need more data,” Dr. Blithe noted.
Asked to comment, session moderator Frances Hayes, MBBCh, associate clinical chief of the Division of Reproductive Endocrinology at Massachusetts General Hospital, Boston, said, “certainly, I think it’s a big advance on what we have so far. … I think it’s showing great promise.”
Dr. Hayes did caution, though, that “with real-world use, daily application of a gel might be a bit more challenging than taking an injection…an injection is more consistent. With a gel, patients might forget or shower it off. But I don’t think 1 day of interruption would be a significant thing.”
Transference of the topical to a partner or a child is another potential concern, Dr. Hayes noted, although this is true of current testosterone gel products as well. During the briefing, Dr. Blithe said that this issue is why the product is recommended to be placed on the upper arms rather than the abdomen or another spot more likely to come into contact with another person. Also, in the trial, men were instructed to wear shirts during intercourse.
Regarding the rapidity of sperm suppression, Dr. Hayes said, “It’s surprising. It looks great as a reversible contraceptive. … Normally, you think of the life cycle of the sperm being about 72 days. So to see 50% suppression by 8 weeks, and then 85%-90% by 15 weeks, that’s very rapid. It may be that the progesterone that they’re using is very potent. Progestins can have some negative effects on lipids and mood. We didn’t really see the safety data in this presentation. So that will be interesting to see.”
During the briefing, Dr. Blithe said that the phase 2b trial is expected to finish by the end of this year, and in the meantime, the researchers are communicating with the US Food and Drug Administration about the design of a phase 3 trial because this is an unprecedented area. “They don’t have guidelines yet. They’ll need to develop them first.”
Dr. Blithe has been the NICHD principal investigator on cooperative research and development agreements with HRA Pharma and Daré Bioscience. Dr. Hayes had no disclosures.
A version of this article appeared on Medscape.com .
FROM ENDO 2024
Frontal Fibrosing Alopecia: Study Finds Oral Contraceptive Use Modulates Risk In Women with Genetic Variant
TOPLINE:
Investigators found that .
METHODOLOGY:
- OC use has been considered a possible factor behind the increased incidence of FFA because it was first documented in 1994, and a recent genome-wide association study of FFA identified a signal for an association with a variant in CYP1B1.
- The same researchers conducted a gene-environment interaction study with a case-control design involving 489 White female patients (mean age, 65.8 years) with FFA and 34,254 controls, matched for age and genetic ancestry.
- Data were collected from July 2015 to September 2017 and analyzed from October 2022 to December 2023.
- The study aimed to investigate the modulatory effect of OC use on the CYP1B1 variant’s impact on FFA risk, using logistic regression models for analysis.
TAKEAWAY:
- The use of OCs was associated with a 1.9 times greater risk for FFA in individuals with the specific CYP1B1 genetic variant, but there was no association among those with no history of OC use.
- The study suggests a significant gene-environment interaction, indicating that OC use may influence FFA risk in genetically predisposed individuals.
IN PRACTICE:
“This gene-environment interaction analysis suggests that the protective effect of the CYPIB1 missense variant on FFA risk might be mediated by exposure” to OCs, the authors wrote. The study, they added, “underscores the importance of considering genetic predispositions and environmental factors, such as oral contraceptive use, in understanding and managing frontal fibrosing alopecia.”
SOURCE:
Tuntas Rayinda, MD, MSc, PhD, of St. John’s Institute of Dermatology, King’s College London, led the study, which was published online May 29, 2024, in JAMA Dermatology.
LIMITATIONS:
The study’s reliance on self-reported OC use may have introduced recall and differences in ascertainment of OC use between patient and control groups and could have affected the study’s findings. The study also did not collect information on the type of OC used, which could have influenced the observed interaction.
DISCLOSURES:
The study was supported by the British Skin Foundation Young Investigator Award. One investigator reported being a subinvestigator on an alopecia areata study funded by Pfizer. No other disclosures were reported.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
TOPLINE:
Investigators found that .
METHODOLOGY:
- OC use has been considered a possible factor behind the increased incidence of FFA because it was first documented in 1994, and a recent genome-wide association study of FFA identified a signal for an association with a variant in CYP1B1.
- The same researchers conducted a gene-environment interaction study with a case-control design involving 489 White female patients (mean age, 65.8 years) with FFA and 34,254 controls, matched for age and genetic ancestry.
- Data were collected from July 2015 to September 2017 and analyzed from October 2022 to December 2023.
- The study aimed to investigate the modulatory effect of OC use on the CYP1B1 variant’s impact on FFA risk, using logistic regression models for analysis.
TAKEAWAY:
- The use of OCs was associated with a 1.9 times greater risk for FFA in individuals with the specific CYP1B1 genetic variant, but there was no association among those with no history of OC use.
- The study suggests a significant gene-environment interaction, indicating that OC use may influence FFA risk in genetically predisposed individuals.
IN PRACTICE:
“This gene-environment interaction analysis suggests that the protective effect of the CYPIB1 missense variant on FFA risk might be mediated by exposure” to OCs, the authors wrote. The study, they added, “underscores the importance of considering genetic predispositions and environmental factors, such as oral contraceptive use, in understanding and managing frontal fibrosing alopecia.”
SOURCE:
Tuntas Rayinda, MD, MSc, PhD, of St. John’s Institute of Dermatology, King’s College London, led the study, which was published online May 29, 2024, in JAMA Dermatology.
LIMITATIONS:
The study’s reliance on self-reported OC use may have introduced recall and differences in ascertainment of OC use between patient and control groups and could have affected the study’s findings. The study also did not collect information on the type of OC used, which could have influenced the observed interaction.
DISCLOSURES:
The study was supported by the British Skin Foundation Young Investigator Award. One investigator reported being a subinvestigator on an alopecia areata study funded by Pfizer. No other disclosures were reported.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
TOPLINE:
Investigators found that .
METHODOLOGY:
- OC use has been considered a possible factor behind the increased incidence of FFA because it was first documented in 1994, and a recent genome-wide association study of FFA identified a signal for an association with a variant in CYP1B1.
- The same researchers conducted a gene-environment interaction study with a case-control design involving 489 White female patients (mean age, 65.8 years) with FFA and 34,254 controls, matched for age and genetic ancestry.
- Data were collected from July 2015 to September 2017 and analyzed from October 2022 to December 2023.
- The study aimed to investigate the modulatory effect of OC use on the CYP1B1 variant’s impact on FFA risk, using logistic regression models for analysis.
TAKEAWAY:
- The use of OCs was associated with a 1.9 times greater risk for FFA in individuals with the specific CYP1B1 genetic variant, but there was no association among those with no history of OC use.
- The study suggests a significant gene-environment interaction, indicating that OC use may influence FFA risk in genetically predisposed individuals.
IN PRACTICE:
“This gene-environment interaction analysis suggests that the protective effect of the CYPIB1 missense variant on FFA risk might be mediated by exposure” to OCs, the authors wrote. The study, they added, “underscores the importance of considering genetic predispositions and environmental factors, such as oral contraceptive use, in understanding and managing frontal fibrosing alopecia.”
SOURCE:
Tuntas Rayinda, MD, MSc, PhD, of St. John’s Institute of Dermatology, King’s College London, led the study, which was published online May 29, 2024, in JAMA Dermatology.
LIMITATIONS:
The study’s reliance on self-reported OC use may have introduced recall and differences in ascertainment of OC use between patient and control groups and could have affected the study’s findings. The study also did not collect information on the type of OC used, which could have influenced the observed interaction.
DISCLOSURES:
The study was supported by the British Skin Foundation Young Investigator Award. One investigator reported being a subinvestigator on an alopecia areata study funded by Pfizer. No other disclosures were reported.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
Most women can conceive after breast cancer treatment
The findings, presented May 23 in advance of the annual meeting of the American Society of Clinical Oncology (ASCO) represent the most comprehensive look to date at fertility outcomes following treatment for women diagnosed with breast cancer before age 40 (Abstract 1518).
Kimia Sorouri, MD, a research fellow at the Dana-Farber Cancer Center in Boston, Massachusetts, and her colleagues, looked at data from the Young Women’s Breast Cancer study, a multicenter longitudinal cohort study, for 1213 U.S. and Canadian women (74% non-Hispanic white) who were diagnosed with stages 0-III breast cancer between 2006 and 2016. None of the included patients had metastatic disease, prior hysterectomy, or prior oophorectomy at diagnosis.
During a median 11 years of follow up, 197 of the women reported attempting pregnancy. Of these, 73% reported becoming pregnant, and 65% delivered a live infant a median 4 years after cancer diagnosis. The median age at diagnosis was 32 years, and 28% opted for egg or embryo freezing to preserve fertility. Importantly, 68% received chemotherapy, which can impair fertility, with only a small percentage undergoing ovarian suppression during chemotherapy treatment.
Key predictors of pregnancy or live birth in this study were “financial comfort,” a self-reported measure defined as having money left over to spend after bills are paid (odds ratio [OR], 2.04; 95% CI 1.01-4.12; P = .047); younger age at the time of diagnosis; and undergoing fertility preservation interventions at diagnosis (OR, 2.78; 95% CI 1.29-6.00; P = .009). Chemotherapy and other treatment factors were not seen to be associated with pregnancy or birth outcomes.
“Current research that informs our understanding of the impact of breast cancer treatment on pregnancy and live birth rates is fairly limited,” Dr. Sorouri said during an online press conference announcing the findings. Quality data on fertility outcomes has been limited to studies in certain subgroups, such as women with estrogen receptor–positive breast cancers, she noted, while other studies “have short-term follow-up and critically lack prospective assessment of attempt at conception.”
The new findings show, Dr. Sorouri said, “that in this modern cohort with a heightened awareness of fertility, access to fertility preservation can help to mitigate a portion of the damage from chemotherapy and other agents. Importantly, this highlights the need for increased accessibility of fertility preservation services for women newly diagnosed with breast cancer who are interested in a future pregnancy.”
Commenting on Dr. Sorouri and colleagues’ findings, Julie Gralow, MD, a breast cancer researcher and ASCO’s chief medical officer, stressed that, while younger age at diagnosis and financial comfort were two factors outside the scope of clinical oncology practice, “we can impact fertility preservation prior to treatment.”
She called it “critical” that every patient be informed of the impact of a breast cancer diagnosis and treatment on future fertility, and that all young patients interested in future fertility be offered fertility preservation prior to beginning treatment.
Ann Partridge, MD, of Dana-Farber, said in an interview that the findings reflected a decades’ long change in approach. “Twenty years ago when we first started this cohort, people would tell women ‘you can’t get pregnant. It’s too dangerous. You won’t be able to.’ And some indeed aren’t able to, but the majority who are attempting are succeeding, especially if they preserve their eggs or embryos. So even if chemo puts you into menopause or made you subfertile, if you’ve preserved eggs or embryos, we now can mitigate that distressing effect that many cancer patients have suffered from historically. That’s the good news here.”
Nonetheless, Dr. Partridge, an oncologist and the last author of the study, noted, the results reflected success only for women actively attempting pregnancy. “Remember, we’re not including the people who didn’t attempt. There may be some who went into menopause who never banked eggs or embryos, and may never have tried because they went to a doctor who told them they’re not fertile.” Further, she said, not all insurances cover in vitro fertilization for women who have had breast cancer.
The fact that financial comfort was correlated with reproductive success, Dr. Partridge said, speaks to broader issues about access. “It may not be all about insurers. It may be to have the ability, to have the time, the education and the wherewithal to do this right — and about being with doctors who talk about it.”
Dr. Sorouri and colleagues’ study was sponsored by the Breast Cancer Research Foundation and Susan G. Komen. Several co-authors disclosed receiving speaking and/or consulting fees from pharmaceutical companies, and one reported being an employee of GlaxoSmithKline. Dr. Sorouri reported no industry funding, while Dr. Partridge reported research funding from Novartis.
The findings, presented May 23 in advance of the annual meeting of the American Society of Clinical Oncology (ASCO) represent the most comprehensive look to date at fertility outcomes following treatment for women diagnosed with breast cancer before age 40 (Abstract 1518).
Kimia Sorouri, MD, a research fellow at the Dana-Farber Cancer Center in Boston, Massachusetts, and her colleagues, looked at data from the Young Women’s Breast Cancer study, a multicenter longitudinal cohort study, for 1213 U.S. and Canadian women (74% non-Hispanic white) who were diagnosed with stages 0-III breast cancer between 2006 and 2016. None of the included patients had metastatic disease, prior hysterectomy, or prior oophorectomy at diagnosis.
During a median 11 years of follow up, 197 of the women reported attempting pregnancy. Of these, 73% reported becoming pregnant, and 65% delivered a live infant a median 4 years after cancer diagnosis. The median age at diagnosis was 32 years, and 28% opted for egg or embryo freezing to preserve fertility. Importantly, 68% received chemotherapy, which can impair fertility, with only a small percentage undergoing ovarian suppression during chemotherapy treatment.
Key predictors of pregnancy or live birth in this study were “financial comfort,” a self-reported measure defined as having money left over to spend after bills are paid (odds ratio [OR], 2.04; 95% CI 1.01-4.12; P = .047); younger age at the time of diagnosis; and undergoing fertility preservation interventions at diagnosis (OR, 2.78; 95% CI 1.29-6.00; P = .009). Chemotherapy and other treatment factors were not seen to be associated with pregnancy or birth outcomes.
“Current research that informs our understanding of the impact of breast cancer treatment on pregnancy and live birth rates is fairly limited,” Dr. Sorouri said during an online press conference announcing the findings. Quality data on fertility outcomes has been limited to studies in certain subgroups, such as women with estrogen receptor–positive breast cancers, she noted, while other studies “have short-term follow-up and critically lack prospective assessment of attempt at conception.”
The new findings show, Dr. Sorouri said, “that in this modern cohort with a heightened awareness of fertility, access to fertility preservation can help to mitigate a portion of the damage from chemotherapy and other agents. Importantly, this highlights the need for increased accessibility of fertility preservation services for women newly diagnosed with breast cancer who are interested in a future pregnancy.”
Commenting on Dr. Sorouri and colleagues’ findings, Julie Gralow, MD, a breast cancer researcher and ASCO’s chief medical officer, stressed that, while younger age at diagnosis and financial comfort were two factors outside the scope of clinical oncology practice, “we can impact fertility preservation prior to treatment.”
She called it “critical” that every patient be informed of the impact of a breast cancer diagnosis and treatment on future fertility, and that all young patients interested in future fertility be offered fertility preservation prior to beginning treatment.
Ann Partridge, MD, of Dana-Farber, said in an interview that the findings reflected a decades’ long change in approach. “Twenty years ago when we first started this cohort, people would tell women ‘you can’t get pregnant. It’s too dangerous. You won’t be able to.’ And some indeed aren’t able to, but the majority who are attempting are succeeding, especially if they preserve their eggs or embryos. So even if chemo puts you into menopause or made you subfertile, if you’ve preserved eggs or embryos, we now can mitigate that distressing effect that many cancer patients have suffered from historically. That’s the good news here.”
Nonetheless, Dr. Partridge, an oncologist and the last author of the study, noted, the results reflected success only for women actively attempting pregnancy. “Remember, we’re not including the people who didn’t attempt. There may be some who went into menopause who never banked eggs or embryos, and may never have tried because they went to a doctor who told them they’re not fertile.” Further, she said, not all insurances cover in vitro fertilization for women who have had breast cancer.
The fact that financial comfort was correlated with reproductive success, Dr. Partridge said, speaks to broader issues about access. “It may not be all about insurers. It may be to have the ability, to have the time, the education and the wherewithal to do this right — and about being with doctors who talk about it.”
Dr. Sorouri and colleagues’ study was sponsored by the Breast Cancer Research Foundation and Susan G. Komen. Several co-authors disclosed receiving speaking and/or consulting fees from pharmaceutical companies, and one reported being an employee of GlaxoSmithKline. Dr. Sorouri reported no industry funding, while Dr. Partridge reported research funding from Novartis.
The findings, presented May 23 in advance of the annual meeting of the American Society of Clinical Oncology (ASCO) represent the most comprehensive look to date at fertility outcomes following treatment for women diagnosed with breast cancer before age 40 (Abstract 1518).
Kimia Sorouri, MD, a research fellow at the Dana-Farber Cancer Center in Boston, Massachusetts, and her colleagues, looked at data from the Young Women’s Breast Cancer study, a multicenter longitudinal cohort study, for 1213 U.S. and Canadian women (74% non-Hispanic white) who were diagnosed with stages 0-III breast cancer between 2006 and 2016. None of the included patients had metastatic disease, prior hysterectomy, or prior oophorectomy at diagnosis.
During a median 11 years of follow up, 197 of the women reported attempting pregnancy. Of these, 73% reported becoming pregnant, and 65% delivered a live infant a median 4 years after cancer diagnosis. The median age at diagnosis was 32 years, and 28% opted for egg or embryo freezing to preserve fertility. Importantly, 68% received chemotherapy, which can impair fertility, with only a small percentage undergoing ovarian suppression during chemotherapy treatment.
Key predictors of pregnancy or live birth in this study were “financial comfort,” a self-reported measure defined as having money left over to spend after bills are paid (odds ratio [OR], 2.04; 95% CI 1.01-4.12; P = .047); younger age at the time of diagnosis; and undergoing fertility preservation interventions at diagnosis (OR, 2.78; 95% CI 1.29-6.00; P = .009). Chemotherapy and other treatment factors were not seen to be associated with pregnancy or birth outcomes.
“Current research that informs our understanding of the impact of breast cancer treatment on pregnancy and live birth rates is fairly limited,” Dr. Sorouri said during an online press conference announcing the findings. Quality data on fertility outcomes has been limited to studies in certain subgroups, such as women with estrogen receptor–positive breast cancers, she noted, while other studies “have short-term follow-up and critically lack prospective assessment of attempt at conception.”
The new findings show, Dr. Sorouri said, “that in this modern cohort with a heightened awareness of fertility, access to fertility preservation can help to mitigate a portion of the damage from chemotherapy and other agents. Importantly, this highlights the need for increased accessibility of fertility preservation services for women newly diagnosed with breast cancer who are interested in a future pregnancy.”
Commenting on Dr. Sorouri and colleagues’ findings, Julie Gralow, MD, a breast cancer researcher and ASCO’s chief medical officer, stressed that, while younger age at diagnosis and financial comfort were two factors outside the scope of clinical oncology practice, “we can impact fertility preservation prior to treatment.”
She called it “critical” that every patient be informed of the impact of a breast cancer diagnosis and treatment on future fertility, and that all young patients interested in future fertility be offered fertility preservation prior to beginning treatment.
Ann Partridge, MD, of Dana-Farber, said in an interview that the findings reflected a decades’ long change in approach. “Twenty years ago when we first started this cohort, people would tell women ‘you can’t get pregnant. It’s too dangerous. You won’t be able to.’ And some indeed aren’t able to, but the majority who are attempting are succeeding, especially if they preserve their eggs or embryos. So even if chemo puts you into menopause or made you subfertile, if you’ve preserved eggs or embryos, we now can mitigate that distressing effect that many cancer patients have suffered from historically. That’s the good news here.”
Nonetheless, Dr. Partridge, an oncologist and the last author of the study, noted, the results reflected success only for women actively attempting pregnancy. “Remember, we’re not including the people who didn’t attempt. There may be some who went into menopause who never banked eggs or embryos, and may never have tried because they went to a doctor who told them they’re not fertile.” Further, she said, not all insurances cover in vitro fertilization for women who have had breast cancer.
The fact that financial comfort was correlated with reproductive success, Dr. Partridge said, speaks to broader issues about access. “It may not be all about insurers. It may be to have the ability, to have the time, the education and the wherewithal to do this right — and about being with doctors who talk about it.”
Dr. Sorouri and colleagues’ study was sponsored by the Breast Cancer Research Foundation and Susan G. Komen. Several co-authors disclosed receiving speaking and/or consulting fees from pharmaceutical companies, and one reported being an employee of GlaxoSmithKline. Dr. Sorouri reported no industry funding, while Dr. Partridge reported research funding from Novartis.
FROM ASCO 2024
Research Highlights From ESMO Breast Cancer
Among the topics the speakers addressed were breast cancer prevention, early breast cancer, advanced breast cancer, and supportive care.
In recent years, the way clinicians look at carcinogenesis in breast cancer has changed, and many new targets for potential early detection and prevention have emerged, said Suzette Delaloge, MD, of Gustave Roussy, Paris, France, in her presentation at the meeting.
Instant risk assessment at different time points could potentially intercept cancer among high-risk individuals, she said.
A study by Mikael Eriksson, PhD, and colleagues focused on external validation of the Profound AI tool to identify breast cancer risk in the general population. The researchers showed an area under the curve of 0.72 in their AI risk model, which has the potential to be clinically meaningful, although it must be prospectively validated, Dr. Delaloge said in her presentation.
She also reviewed two studies on the use of genes to further refine breast cancer risk among carriers. One of these, a prospective study presented in a session by Kelly-Anne Phillips, MD, of Peter MacCallum Cancer Center, Melbourne, Australia, used the CANRISK online risk assessment tool and validated increased breast cancer risk in BRCA1 and BRCA2 carriers, with AUCs of 0.79 and 0.78, respectively. The other study, which was by Maria Rezqallah Aron, MD, and colleagues examined polygenic scores as a way to refine breast cancer risk stratification among carriers of the ALM and PALB2 genes as well. These genes might be useful in identifying individuals who could benefit from early intervention, including surgery, Dr. Delaloge said.
Translational Research
“Preparing my talk, I felt like a kid in a candy store,” because of the amount of new translational research presented, including several studies of endocrine treatment–based approaches to therapy, said Marleen Kok, MD, of the Netherlands Cancer Institute, Amsterdam.
In her presentation, Dr. Kok highlighted findings from an analysis of patients in the monarchE study (a trial of high-risk patients) showing a consistent improvement in invasive disease-free survival for the subset of patients with germline BRCA1 and BRCA2 mutations who received abemaciclib plus endocrine therapy.
The value of tumor-infiltrating lymphocytes (TILs) on patients who are not receiving chemotherapy is important because of the focus on prognosis, and prospective trials are underway, she said.
A poster on the impact of chemotherapy and stromal tumor-infiltrating lymphocytes (sTILs) in stage I triple-negative breast cancer showed no association between chemotherapy and better outcomes regardless of sTILs in patients who did and did not receive chemotherapy, which has implications for potential treatment sparing in this population, Dr. Kok noted.
Artificial Intelligence (AI) was the subject of several posters at the meeting, and Dr. Kok identified a multisite European study of an automated HER2 scoring system as notable for its size and accuracy. In the study, the accuracy among pathologists was much higher with the assistance of AI, she said. Using AI for more complex analysis has shown success, she said.
Dr. Kok ended her talk with a poster that surveyed breast cancer patients about their understanding of their disease. The results showed that less than half (44%) of patients reported that their healthcare providers had given them enough information to learn about their breast cancer type, and less than one third could recall terminology about biomarkers; the study is important because it shows that clinicians need to do better in explaining these terms to patients, Dr. Kok said.
Early Breast Cancer
Right-sizing therapy, meaning identifying the right treatment for every patient, is a key element of new research in early breast cancer, said Erika Hamilton, MD, of the Sarah Cannon Research Institute, Nashville, Tenn.
She highlighted safety and treatment duration updates from the NATALEE study, which compared adjuvant ribociclib plus nonsteroidal aromatase inhibitor (NSAI) to NSAI alone for ER+/HER2- breast cancer. The current analysis presented at the meeting showed significant benefits with the addition of ribociclib and no evidence of new safety signals or adverse event exacerbations at 3 years, she said. Dose modifications had no significant impact on efficacy, she added.
The findings of no impact of dose reduction on efficacy in both the NATALEE and monarchE studies provide important information on whether dosage can be reduced in patients, which will increase the odds that patients will tolerate extended therapy with good outcomes and stay on their prescribed therapies, Dr. Hamilton emphasized.
The CARABELA study, a phase 2 trial of neoadjuvant letrozole plus abemaciclib vs adriamycin and cyclophosphamide (AC), showed clinically similar response rates but did not meet its endpoint for residual cancer burden (RCB) scores. These data add to results from other studies and show that it is too soon to universally replace neoadjuvant chemotherapy as first-line treatment for highly proliferative ER+ breast cancer, Dr. Hamilton said in her presentation.
Advanced Breast Cancer
Take-home messages about advanced breast cancer include growing evidence for the potential benefits of antibody drug conjugates (ADCs), said Eva Ciruelos, MD, of University Hospital, Madrid, Spain. The TROPION-BREAST01 study, a phase 3 randomized trial, showed significant and clinically meaningful improvement in progression-free survival in patients with previously treated, inoperable, or metastatic HR+/HER2- breast cancer who received datopotamab deruxtecan (Dato-DXd) compared with those who received chemotherapy.
Data from an additional safety analysis were presented at the meeting; although Dato-DXd, a trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate, was well-tolerated, it is important to remain aware of toxicities, notably oral mucositis, which occurred in 55.6% of the patients in the study across all grades, and ocular surface toxicity, which occurred in 40% of patients across all grades, Dr. Ciruelos emphasized.
Key research in the area of advanced triple-negative breast cancer included data from the IMPASSION 132 study. This study is “specifically centered on early relapsers,” a population often excluded from other trials, Dr. Ciruelos said. In this study, patients with advanced triple-negative breast cancer were randomized to chemotherapy with or without atezolizumab, and the study showed no benefits with atezolizumab for overall survival, progression-free survival, or overall response rate, she said. “This is something to work with, because this is a very refractory population,” Dr. Ciruelos noted.
New immunotherapy combinations are needed to improve survival in advanced breast cancer patients, Dr. Ciruelos said. At the meeting, researchers presented interim data from a subset of patients in the MORPHEUS-pan breast cancer trial, a phase 1B/2 study involving multiple treatment combinations in locally advanced/metastatic breast cancer patients.
The interim analysis included 18-week data from triple-negative breast cancer patients and compared outcomes for patients randomized to atezolizumab with or without sacituzumab govitecan (SG).
The study was small, with only 31 patients in the combination arm and 11 controls, but the results were promising, with an overall response rate of 76.7% in the combination arm vs 66.7% in the control arm, Dr. Ciruelos said.
Supportive Care
Key supportive care takeaways included data on pregnancy in young breast cancer survivors and the safety of vaginal estrogen therapy in breast cancer patients with genitourinary symptoms, said Anne May, MD, of the University Medical Center Utrecht, Utrecht, Netherlands.
A study previously published in JAMA including nearly 5000 BRCA carriers who were diagnosed with invasive breast cancer at age 40 years or younger showed no association between pregnancy after breast cancer and adverse maternal or fetal outcomes, and pregnancy had no significant impact on overall survival. The authors presented new data on the safety of assisted reproductive techniques (ART) based on the 543 pregnancies in the original study, at the meeting. Of these, 436 conceived naturally, and 107 used ART. After a median of 9.1 years, ART had no effect on disease-free survival compared to natural conception (hazard ratio [HR], 0.64). Based on these findings, fertility preservation should be offered to all women who receive a breast cancer diagnosis and are interested in future fertility, Dr. May said.
Conceiving after breast cancer treatment and follow-up should not be contraindicated for young BRCA carriers, she added.No trial data are available for the effects of vaginal estrogen therapy (VET) on disease-free survival in breast cancer survivors with genitourinary symptoms caused by declining estrogen levels, Dr. May said. However, researchers in France and Switzerland conducted an emulation of a hypothetical target trial using data from the French National social security system for more than 130,000 individuals. Although VET therapy had no impact on disease-free survival in most breast cancer survivors overall, it did have a negative impact in a subset of patients with HR-positive and HR-negative tumors who were treated with aromatase inhibitors. The study was hypothetical, but important because the results suggest that clinicians can safely propose VTE to patients who report genitourinary symptoms after treatment for early-stage breast cancer with tamoxifen, but VTE should be avoided in patients treated with aromatase inhibitors, Dr. May said.
Dr. Delaloge disclosed research support to her institution from AstraZeneca, MSD, Bristol Myers Squibb, Sanofi, Taiho, Novartis, European Commission, INCa, Banque des Territoires, and Fondation Philanthropia. She also disclosed honoraria to her institution from AstraZeneca, Gilead, Novartis, Elsan, Besins, Sanofi, Exact Sciences, and Lilly, as well as travel support from Novartis.
Dr. Kok disclosed research funding from AstraZeneca, Bristol Myers Squibb, Daichi, and Roche, and advisory board membership/speaker’s fees from Alderaan Biotechnology, BIONTECH, Domain Therapeutics, AstraZeneca, Daichi, Bristol Myers Squibb, Gilead, Medscape, MSD, and Roche.
Dr. Hamilton disclosed a consulting advisory role (to her institution) for Accutar Biotechology, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Entos, Forsum Pharma, Gilead Sciences, Greenwich LifeSciences, Jazz Pharmaceuticals, Lilly, Medical Pharma Services, Mersana, Novartis, Olema Pharmaceuticals, Orum Therapeutics, Roche/Genentech, Stemline Therapeutics, ands others. She also disclosed contracted research/grant support to her institution only from Abbvie, Acerta Pharma, Accutar Biotechnology , ADC Therapeutics, AKESOBIO Australia , Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Diamond and others.
Dr. Ciruelos disclosed serving as an external advisor for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, and Lilly, as well as serving as a speaker for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, Lilly, and Pierre Fabre. She also disclosed travel grants from Roche, Pfizer, and AstraZeneca, and research grants from Seagen and Roche.
Dr. May had no financial conflicts to disclose.
Among the topics the speakers addressed were breast cancer prevention, early breast cancer, advanced breast cancer, and supportive care.
In recent years, the way clinicians look at carcinogenesis in breast cancer has changed, and many new targets for potential early detection and prevention have emerged, said Suzette Delaloge, MD, of Gustave Roussy, Paris, France, in her presentation at the meeting.
Instant risk assessment at different time points could potentially intercept cancer among high-risk individuals, she said.
A study by Mikael Eriksson, PhD, and colleagues focused on external validation of the Profound AI tool to identify breast cancer risk in the general population. The researchers showed an area under the curve of 0.72 in their AI risk model, which has the potential to be clinically meaningful, although it must be prospectively validated, Dr. Delaloge said in her presentation.
She also reviewed two studies on the use of genes to further refine breast cancer risk among carriers. One of these, a prospective study presented in a session by Kelly-Anne Phillips, MD, of Peter MacCallum Cancer Center, Melbourne, Australia, used the CANRISK online risk assessment tool and validated increased breast cancer risk in BRCA1 and BRCA2 carriers, with AUCs of 0.79 and 0.78, respectively. The other study, which was by Maria Rezqallah Aron, MD, and colleagues examined polygenic scores as a way to refine breast cancer risk stratification among carriers of the ALM and PALB2 genes as well. These genes might be useful in identifying individuals who could benefit from early intervention, including surgery, Dr. Delaloge said.
Translational Research
“Preparing my talk, I felt like a kid in a candy store,” because of the amount of new translational research presented, including several studies of endocrine treatment–based approaches to therapy, said Marleen Kok, MD, of the Netherlands Cancer Institute, Amsterdam.
In her presentation, Dr. Kok highlighted findings from an analysis of patients in the monarchE study (a trial of high-risk patients) showing a consistent improvement in invasive disease-free survival for the subset of patients with germline BRCA1 and BRCA2 mutations who received abemaciclib plus endocrine therapy.
The value of tumor-infiltrating lymphocytes (TILs) on patients who are not receiving chemotherapy is important because of the focus on prognosis, and prospective trials are underway, she said.
A poster on the impact of chemotherapy and stromal tumor-infiltrating lymphocytes (sTILs) in stage I triple-negative breast cancer showed no association between chemotherapy and better outcomes regardless of sTILs in patients who did and did not receive chemotherapy, which has implications for potential treatment sparing in this population, Dr. Kok noted.
Artificial Intelligence (AI) was the subject of several posters at the meeting, and Dr. Kok identified a multisite European study of an automated HER2 scoring system as notable for its size and accuracy. In the study, the accuracy among pathologists was much higher with the assistance of AI, she said. Using AI for more complex analysis has shown success, she said.
Dr. Kok ended her talk with a poster that surveyed breast cancer patients about their understanding of their disease. The results showed that less than half (44%) of patients reported that their healthcare providers had given them enough information to learn about their breast cancer type, and less than one third could recall terminology about biomarkers; the study is important because it shows that clinicians need to do better in explaining these terms to patients, Dr. Kok said.
Early Breast Cancer
Right-sizing therapy, meaning identifying the right treatment for every patient, is a key element of new research in early breast cancer, said Erika Hamilton, MD, of the Sarah Cannon Research Institute, Nashville, Tenn.
She highlighted safety and treatment duration updates from the NATALEE study, which compared adjuvant ribociclib plus nonsteroidal aromatase inhibitor (NSAI) to NSAI alone for ER+/HER2- breast cancer. The current analysis presented at the meeting showed significant benefits with the addition of ribociclib and no evidence of new safety signals or adverse event exacerbations at 3 years, she said. Dose modifications had no significant impact on efficacy, she added.
The findings of no impact of dose reduction on efficacy in both the NATALEE and monarchE studies provide important information on whether dosage can be reduced in patients, which will increase the odds that patients will tolerate extended therapy with good outcomes and stay on their prescribed therapies, Dr. Hamilton emphasized.
The CARABELA study, a phase 2 trial of neoadjuvant letrozole plus abemaciclib vs adriamycin and cyclophosphamide (AC), showed clinically similar response rates but did not meet its endpoint for residual cancer burden (RCB) scores. These data add to results from other studies and show that it is too soon to universally replace neoadjuvant chemotherapy as first-line treatment for highly proliferative ER+ breast cancer, Dr. Hamilton said in her presentation.
Advanced Breast Cancer
Take-home messages about advanced breast cancer include growing evidence for the potential benefits of antibody drug conjugates (ADCs), said Eva Ciruelos, MD, of University Hospital, Madrid, Spain. The TROPION-BREAST01 study, a phase 3 randomized trial, showed significant and clinically meaningful improvement in progression-free survival in patients with previously treated, inoperable, or metastatic HR+/HER2- breast cancer who received datopotamab deruxtecan (Dato-DXd) compared with those who received chemotherapy.
Data from an additional safety analysis were presented at the meeting; although Dato-DXd, a trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate, was well-tolerated, it is important to remain aware of toxicities, notably oral mucositis, which occurred in 55.6% of the patients in the study across all grades, and ocular surface toxicity, which occurred in 40% of patients across all grades, Dr. Ciruelos emphasized.
Key research in the area of advanced triple-negative breast cancer included data from the IMPASSION 132 study. This study is “specifically centered on early relapsers,” a population often excluded from other trials, Dr. Ciruelos said. In this study, patients with advanced triple-negative breast cancer were randomized to chemotherapy with or without atezolizumab, and the study showed no benefits with atezolizumab for overall survival, progression-free survival, or overall response rate, she said. “This is something to work with, because this is a very refractory population,” Dr. Ciruelos noted.
New immunotherapy combinations are needed to improve survival in advanced breast cancer patients, Dr. Ciruelos said. At the meeting, researchers presented interim data from a subset of patients in the MORPHEUS-pan breast cancer trial, a phase 1B/2 study involving multiple treatment combinations in locally advanced/metastatic breast cancer patients.
The interim analysis included 18-week data from triple-negative breast cancer patients and compared outcomes for patients randomized to atezolizumab with or without sacituzumab govitecan (SG).
The study was small, with only 31 patients in the combination arm and 11 controls, but the results were promising, with an overall response rate of 76.7% in the combination arm vs 66.7% in the control arm, Dr. Ciruelos said.
Supportive Care
Key supportive care takeaways included data on pregnancy in young breast cancer survivors and the safety of vaginal estrogen therapy in breast cancer patients with genitourinary symptoms, said Anne May, MD, of the University Medical Center Utrecht, Utrecht, Netherlands.
A study previously published in JAMA including nearly 5000 BRCA carriers who were diagnosed with invasive breast cancer at age 40 years or younger showed no association between pregnancy after breast cancer and adverse maternal or fetal outcomes, and pregnancy had no significant impact on overall survival. The authors presented new data on the safety of assisted reproductive techniques (ART) based on the 543 pregnancies in the original study, at the meeting. Of these, 436 conceived naturally, and 107 used ART. After a median of 9.1 years, ART had no effect on disease-free survival compared to natural conception (hazard ratio [HR], 0.64). Based on these findings, fertility preservation should be offered to all women who receive a breast cancer diagnosis and are interested in future fertility, Dr. May said.
Conceiving after breast cancer treatment and follow-up should not be contraindicated for young BRCA carriers, she added.No trial data are available for the effects of vaginal estrogen therapy (VET) on disease-free survival in breast cancer survivors with genitourinary symptoms caused by declining estrogen levels, Dr. May said. However, researchers in France and Switzerland conducted an emulation of a hypothetical target trial using data from the French National social security system for more than 130,000 individuals. Although VET therapy had no impact on disease-free survival in most breast cancer survivors overall, it did have a negative impact in a subset of patients with HR-positive and HR-negative tumors who were treated with aromatase inhibitors. The study was hypothetical, but important because the results suggest that clinicians can safely propose VTE to patients who report genitourinary symptoms after treatment for early-stage breast cancer with tamoxifen, but VTE should be avoided in patients treated with aromatase inhibitors, Dr. May said.
Dr. Delaloge disclosed research support to her institution from AstraZeneca, MSD, Bristol Myers Squibb, Sanofi, Taiho, Novartis, European Commission, INCa, Banque des Territoires, and Fondation Philanthropia. She also disclosed honoraria to her institution from AstraZeneca, Gilead, Novartis, Elsan, Besins, Sanofi, Exact Sciences, and Lilly, as well as travel support from Novartis.
Dr. Kok disclosed research funding from AstraZeneca, Bristol Myers Squibb, Daichi, and Roche, and advisory board membership/speaker’s fees from Alderaan Biotechnology, BIONTECH, Domain Therapeutics, AstraZeneca, Daichi, Bristol Myers Squibb, Gilead, Medscape, MSD, and Roche.
Dr. Hamilton disclosed a consulting advisory role (to her institution) for Accutar Biotechology, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Entos, Forsum Pharma, Gilead Sciences, Greenwich LifeSciences, Jazz Pharmaceuticals, Lilly, Medical Pharma Services, Mersana, Novartis, Olema Pharmaceuticals, Orum Therapeutics, Roche/Genentech, Stemline Therapeutics, ands others. She also disclosed contracted research/grant support to her institution only from Abbvie, Acerta Pharma, Accutar Biotechnology , ADC Therapeutics, AKESOBIO Australia , Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Diamond and others.
Dr. Ciruelos disclosed serving as an external advisor for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, and Lilly, as well as serving as a speaker for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, Lilly, and Pierre Fabre. She also disclosed travel grants from Roche, Pfizer, and AstraZeneca, and research grants from Seagen and Roche.
Dr. May had no financial conflicts to disclose.
Among the topics the speakers addressed were breast cancer prevention, early breast cancer, advanced breast cancer, and supportive care.
In recent years, the way clinicians look at carcinogenesis in breast cancer has changed, and many new targets for potential early detection and prevention have emerged, said Suzette Delaloge, MD, of Gustave Roussy, Paris, France, in her presentation at the meeting.
Instant risk assessment at different time points could potentially intercept cancer among high-risk individuals, she said.
A study by Mikael Eriksson, PhD, and colleagues focused on external validation of the Profound AI tool to identify breast cancer risk in the general population. The researchers showed an area under the curve of 0.72 in their AI risk model, which has the potential to be clinically meaningful, although it must be prospectively validated, Dr. Delaloge said in her presentation.
She also reviewed two studies on the use of genes to further refine breast cancer risk among carriers. One of these, a prospective study presented in a session by Kelly-Anne Phillips, MD, of Peter MacCallum Cancer Center, Melbourne, Australia, used the CANRISK online risk assessment tool and validated increased breast cancer risk in BRCA1 and BRCA2 carriers, with AUCs of 0.79 and 0.78, respectively. The other study, which was by Maria Rezqallah Aron, MD, and colleagues examined polygenic scores as a way to refine breast cancer risk stratification among carriers of the ALM and PALB2 genes as well. These genes might be useful in identifying individuals who could benefit from early intervention, including surgery, Dr. Delaloge said.
Translational Research
“Preparing my talk, I felt like a kid in a candy store,” because of the amount of new translational research presented, including several studies of endocrine treatment–based approaches to therapy, said Marleen Kok, MD, of the Netherlands Cancer Institute, Amsterdam.
In her presentation, Dr. Kok highlighted findings from an analysis of patients in the monarchE study (a trial of high-risk patients) showing a consistent improvement in invasive disease-free survival for the subset of patients with germline BRCA1 and BRCA2 mutations who received abemaciclib plus endocrine therapy.
The value of tumor-infiltrating lymphocytes (TILs) on patients who are not receiving chemotherapy is important because of the focus on prognosis, and prospective trials are underway, she said.
A poster on the impact of chemotherapy and stromal tumor-infiltrating lymphocytes (sTILs) in stage I triple-negative breast cancer showed no association between chemotherapy and better outcomes regardless of sTILs in patients who did and did not receive chemotherapy, which has implications for potential treatment sparing in this population, Dr. Kok noted.
Artificial Intelligence (AI) was the subject of several posters at the meeting, and Dr. Kok identified a multisite European study of an automated HER2 scoring system as notable for its size and accuracy. In the study, the accuracy among pathologists was much higher with the assistance of AI, she said. Using AI for more complex analysis has shown success, she said.
Dr. Kok ended her talk with a poster that surveyed breast cancer patients about their understanding of their disease. The results showed that less than half (44%) of patients reported that their healthcare providers had given them enough information to learn about their breast cancer type, and less than one third could recall terminology about biomarkers; the study is important because it shows that clinicians need to do better in explaining these terms to patients, Dr. Kok said.
Early Breast Cancer
Right-sizing therapy, meaning identifying the right treatment for every patient, is a key element of new research in early breast cancer, said Erika Hamilton, MD, of the Sarah Cannon Research Institute, Nashville, Tenn.
She highlighted safety and treatment duration updates from the NATALEE study, which compared adjuvant ribociclib plus nonsteroidal aromatase inhibitor (NSAI) to NSAI alone for ER+/HER2- breast cancer. The current analysis presented at the meeting showed significant benefits with the addition of ribociclib and no evidence of new safety signals or adverse event exacerbations at 3 years, she said. Dose modifications had no significant impact on efficacy, she added.
The findings of no impact of dose reduction on efficacy in both the NATALEE and monarchE studies provide important information on whether dosage can be reduced in patients, which will increase the odds that patients will tolerate extended therapy with good outcomes and stay on their prescribed therapies, Dr. Hamilton emphasized.
The CARABELA study, a phase 2 trial of neoadjuvant letrozole plus abemaciclib vs adriamycin and cyclophosphamide (AC), showed clinically similar response rates but did not meet its endpoint for residual cancer burden (RCB) scores. These data add to results from other studies and show that it is too soon to universally replace neoadjuvant chemotherapy as first-line treatment for highly proliferative ER+ breast cancer, Dr. Hamilton said in her presentation.
Advanced Breast Cancer
Take-home messages about advanced breast cancer include growing evidence for the potential benefits of antibody drug conjugates (ADCs), said Eva Ciruelos, MD, of University Hospital, Madrid, Spain. The TROPION-BREAST01 study, a phase 3 randomized trial, showed significant and clinically meaningful improvement in progression-free survival in patients with previously treated, inoperable, or metastatic HR+/HER2- breast cancer who received datopotamab deruxtecan (Dato-DXd) compared with those who received chemotherapy.
Data from an additional safety analysis were presented at the meeting; although Dato-DXd, a trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate, was well-tolerated, it is important to remain aware of toxicities, notably oral mucositis, which occurred in 55.6% of the patients in the study across all grades, and ocular surface toxicity, which occurred in 40% of patients across all grades, Dr. Ciruelos emphasized.
Key research in the area of advanced triple-negative breast cancer included data from the IMPASSION 132 study. This study is “specifically centered on early relapsers,” a population often excluded from other trials, Dr. Ciruelos said. In this study, patients with advanced triple-negative breast cancer were randomized to chemotherapy with or without atezolizumab, and the study showed no benefits with atezolizumab for overall survival, progression-free survival, or overall response rate, she said. “This is something to work with, because this is a very refractory population,” Dr. Ciruelos noted.
New immunotherapy combinations are needed to improve survival in advanced breast cancer patients, Dr. Ciruelos said. At the meeting, researchers presented interim data from a subset of patients in the MORPHEUS-pan breast cancer trial, a phase 1B/2 study involving multiple treatment combinations in locally advanced/metastatic breast cancer patients.
The interim analysis included 18-week data from triple-negative breast cancer patients and compared outcomes for patients randomized to atezolizumab with or without sacituzumab govitecan (SG).
The study was small, with only 31 patients in the combination arm and 11 controls, but the results were promising, with an overall response rate of 76.7% in the combination arm vs 66.7% in the control arm, Dr. Ciruelos said.
Supportive Care
Key supportive care takeaways included data on pregnancy in young breast cancer survivors and the safety of vaginal estrogen therapy in breast cancer patients with genitourinary symptoms, said Anne May, MD, of the University Medical Center Utrecht, Utrecht, Netherlands.
A study previously published in JAMA including nearly 5000 BRCA carriers who were diagnosed with invasive breast cancer at age 40 years or younger showed no association between pregnancy after breast cancer and adverse maternal or fetal outcomes, and pregnancy had no significant impact on overall survival. The authors presented new data on the safety of assisted reproductive techniques (ART) based on the 543 pregnancies in the original study, at the meeting. Of these, 436 conceived naturally, and 107 used ART. After a median of 9.1 years, ART had no effect on disease-free survival compared to natural conception (hazard ratio [HR], 0.64). Based on these findings, fertility preservation should be offered to all women who receive a breast cancer diagnosis and are interested in future fertility, Dr. May said.
Conceiving after breast cancer treatment and follow-up should not be contraindicated for young BRCA carriers, she added.No trial data are available for the effects of vaginal estrogen therapy (VET) on disease-free survival in breast cancer survivors with genitourinary symptoms caused by declining estrogen levels, Dr. May said. However, researchers in France and Switzerland conducted an emulation of a hypothetical target trial using data from the French National social security system for more than 130,000 individuals. Although VET therapy had no impact on disease-free survival in most breast cancer survivors overall, it did have a negative impact in a subset of patients with HR-positive and HR-negative tumors who were treated with aromatase inhibitors. The study was hypothetical, but important because the results suggest that clinicians can safely propose VTE to patients who report genitourinary symptoms after treatment for early-stage breast cancer with tamoxifen, but VTE should be avoided in patients treated with aromatase inhibitors, Dr. May said.
Dr. Delaloge disclosed research support to her institution from AstraZeneca, MSD, Bristol Myers Squibb, Sanofi, Taiho, Novartis, European Commission, INCa, Banque des Territoires, and Fondation Philanthropia. She also disclosed honoraria to her institution from AstraZeneca, Gilead, Novartis, Elsan, Besins, Sanofi, Exact Sciences, and Lilly, as well as travel support from Novartis.
Dr. Kok disclosed research funding from AstraZeneca, Bristol Myers Squibb, Daichi, and Roche, and advisory board membership/speaker’s fees from Alderaan Biotechnology, BIONTECH, Domain Therapeutics, AstraZeneca, Daichi, Bristol Myers Squibb, Gilead, Medscape, MSD, and Roche.
Dr. Hamilton disclosed a consulting advisory role (to her institution) for Accutar Biotechology, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Entos, Forsum Pharma, Gilead Sciences, Greenwich LifeSciences, Jazz Pharmaceuticals, Lilly, Medical Pharma Services, Mersana, Novartis, Olema Pharmaceuticals, Orum Therapeutics, Roche/Genentech, Stemline Therapeutics, ands others. She also disclosed contracted research/grant support to her institution only from Abbvie, Acerta Pharma, Accutar Biotechnology , ADC Therapeutics, AKESOBIO Australia , Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Diamond and others.
Dr. Ciruelos disclosed serving as an external advisor for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, and Lilly, as well as serving as a speaker for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, Lilly, and Pierre Fabre. She also disclosed travel grants from Roche, Pfizer, and AstraZeneca, and research grants from Seagen and Roche.
Dr. May had no financial conflicts to disclose.
FROM ESMO BREAST CANCER 2024
ART Safe for Breast Cancer Survivors with BRCA1/2 Mutations
For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However,
“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
Unmet Fertility Needs for Women With Breast Cancer
With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.
According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.
“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
Study Design and Patient Population
The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.
Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.
Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
No Increased Risks for Pregnancy and Fetal Outcomes
Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.
Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.
“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
No Adverse Effects on Breast Cancer Prognosis
At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).
“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.
Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.
“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
Clinical Implications and Future Work
According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.
“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”
During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.
“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.
She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”
Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”
Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).
For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However,
“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
Unmet Fertility Needs for Women With Breast Cancer
With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.
According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.
“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
Study Design and Patient Population
The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.
Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.
Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
No Increased Risks for Pregnancy and Fetal Outcomes
Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.
Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.
“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
No Adverse Effects on Breast Cancer Prognosis
At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).
“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.
Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.
“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
Clinical Implications and Future Work
According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.
“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”
During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.
“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.
She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”
Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”
Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).
For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However,
“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
Unmet Fertility Needs for Women With Breast Cancer
With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.
According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.
“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
Study Design and Patient Population
The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.
Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.
Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
No Increased Risks for Pregnancy and Fetal Outcomes
Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.
Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.
“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
No Adverse Effects on Breast Cancer Prognosis
At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).
“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.
Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.
“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
Clinical Implications and Future Work
According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.
“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”
During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.
“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.
She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”
Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”
Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).
FROM ESMO BREAST CANCER 2024
Scientists Create First Map of a Human Ovary: What to Know
For years, scientists have sought to create a human artificial ovary, restoring fertility in patients without other options. The first cellular map of a human ovary, recently developed at the University of Michigan, Ann Arbor, represents a big leap forward in that quest.
“You cannot build something if you don’t have the blueprint,” said biomedical engineer Ariella Shikanov, PhD, associate professor at University of Michigan, who helped create what she and colleagues call an atlas of the ovary. “By creating a map or an atlas, we can now follow what nature created and engineer the building blocks of an ovary — and build a nature-like structure.”
So far, the concept of an artificial ovary has been successful only in mice, with the development of a 3D-printed prosthetic ovary that enabled sterilized mice to have pups. Researchers hope that artificial human ovary technology could someday help women left infertile after cancer treatment, as well as patients who don›t respond to fertility treatments and those with premature ovarian failure.
But Dr. Shikanov believes this research will go even further, providing a valuable resource to scientists studying diseases and other conditions related to the ovary.
“Whenever people think about the ovary, if they think about it at all, they usually think about fertility,” said Dr. Shikanov. The ovary is so much more.
Besides producing and carrying a woman’s unfertilized eggs during her lifetime, the ovary is also responsible for endocrine function — the production of estrogen and progesterone, which in addition to supporting reproductive health, help maintain a woman’s cardiovascular, bone, and mental health.
“We don’t really understand everything that is happening in the ovary yet,” Dr. Shikanov said. “But we know it is an important organ.”
Mapping the Ovary
Because people don’t typically donate their ovaries, there are not many available for research, especially from younger reproductive age women, said Dr. Shikanov. So, the scientists set out to build a resource. They described their work in Science Advances.
To create their atlas, the researchers studied two premenopausal donor ovaries, profiling 18,000 genes in 257 regions. From three additional donor ovaries, they also generated single-cell RNA sequencing data for 21,198 cells.
“We identified four major cell types and four immune cell subtypes in the ovary,” said Dr. Shikanov. Taking samples from different areas of the ovary revealed distinct gene activities for oocytes, theca cells, and granulosa cells — expanding scientists’ understanding of the molecular programs driving ovarian follicle development.
What’s unique about their work is the focus on both single cell and spatial analysis, said study coauthor Jun Z. Li, PhD, associate chair of the University of Michigan’s department of computational medicine and bioinformatics. Specifically, they used a relatively new method called spatial transcriptomics, which allows them to see which genes are being activated and where.
“We are constructing the spatial arrangement of the cells in the ovary,” said Dr. Li. “This spatial analysis is like saying, ‘Let me look at where you are and who your neighbor is.’ ”
Their findings are built on other genetic and cellular research in the field, Dr. Li noted. Biomedical engineers in other areas of medicine are applying similar technologies to other organs including the heart, the breast, and bone — part of a larger project called the Human Cell Atlas.
Advancing Women’s Health Research
Historically, women’s health research has been underfunded and underrepresented, but the authors believe their atlas of the ovary is a significant step forward.
“There are a lot of biological questions that we don’t know the answers to about the ovary,” said Dr. Shikanov.
One of the biggest mysteries is why so many eggs never become fertilizable. Each human female is born with about one to two million ovarian follicles. Each follicle carries one immature egg. Around puberty, two thirds of these follicles die off. And most that are left never develop into fertilizable eggs.
“The majority of these follicles either just grow and secrete hormones or undergo atresia,” Dr. Shikanov said. “One question that we wanted to understand is, what determines an egg that can grow, ovulate, and become a fertilizable egg and potentially develop into a new human being from one that does not?”
Another big question researchers have is, what’s happening with other types of cells in the ovary — the supporting cells that produce endocrine hormones? Where are they located and what proteins and RNA are they making? Their research begins to unravel some of these questions and lays a foundation for future studies.
“We wanted to analyze the transcriptional signatures from specific regions and then do bioinformatical analysis and really combine structure, function, and transcriptional signatures,” Dr. Shikanov said.
Knowing the transcriptional signatures can help researchers understand disease mechanisms and then go on to develop treatments for these diseases.
Winifred Mak, MD, PhD, a reproductive endocrinologist and infertility specialist at Dell Medical School, University of Texas, Austin, studies cancer fertility preservation. “For me, it is interesting to see that there are so many different clusters of cells in the ovary that have been identified by this study that we were not necessarily aware of before,” said Dr. Mak, who is not involved in the new research. “Also, the identification of new genes not previously studied in the human ovary.”
What’s Next
Dozens of scientists who study reproductive health are already reaching out to the researchers about their work, Dr. Shikanov said.
“We get contacted almost every day from researchers all around the world asking for data sets or asking for details from this paper,” she said, “from people who study ovarian cancer, for example.”
Dr. Mak said having a map of a normal ovary could also help researchers who study premature ovarian insufficiency — why the ovary sometimes goes into premature menopause — and polycystic ovarian syndrome.
Another big area of research interest is ovarian aging. “Women live so much longer now, but we still reach menopause at the age of 50,” Dr. Shikanov said. “So, there are efforts going toward understanding ovarian aging and maybe preventing it to extend ovarian longevity.”
Dr. Mak said it will enable scientists to “look at different age women and see what genes change across the reproductive lifespan.”
The atlas may also eventually lead to treatments that help restore fertility in individuals who had and were treated for cancer as children, people who undergo sex transitions, and those whose reproductive organs have been impacted by trauma in conflict settings or accidents, Dr. Li said.
The applications are numerous and exciting, Dr. Shikanov said. “Our atlas is like a benchmark. Now researchers can collect ovaries from individuals with these diseases and conditions and try to compare what’s different.”
A version of this article appeared on Medscape.com.
For years, scientists have sought to create a human artificial ovary, restoring fertility in patients without other options. The first cellular map of a human ovary, recently developed at the University of Michigan, Ann Arbor, represents a big leap forward in that quest.
“You cannot build something if you don’t have the blueprint,” said biomedical engineer Ariella Shikanov, PhD, associate professor at University of Michigan, who helped create what she and colleagues call an atlas of the ovary. “By creating a map or an atlas, we can now follow what nature created and engineer the building blocks of an ovary — and build a nature-like structure.”
So far, the concept of an artificial ovary has been successful only in mice, with the development of a 3D-printed prosthetic ovary that enabled sterilized mice to have pups. Researchers hope that artificial human ovary technology could someday help women left infertile after cancer treatment, as well as patients who don›t respond to fertility treatments and those with premature ovarian failure.
But Dr. Shikanov believes this research will go even further, providing a valuable resource to scientists studying diseases and other conditions related to the ovary.
“Whenever people think about the ovary, if they think about it at all, they usually think about fertility,” said Dr. Shikanov. The ovary is so much more.
Besides producing and carrying a woman’s unfertilized eggs during her lifetime, the ovary is also responsible for endocrine function — the production of estrogen and progesterone, which in addition to supporting reproductive health, help maintain a woman’s cardiovascular, bone, and mental health.
“We don’t really understand everything that is happening in the ovary yet,” Dr. Shikanov said. “But we know it is an important organ.”
Mapping the Ovary
Because people don’t typically donate their ovaries, there are not many available for research, especially from younger reproductive age women, said Dr. Shikanov. So, the scientists set out to build a resource. They described their work in Science Advances.
To create their atlas, the researchers studied two premenopausal donor ovaries, profiling 18,000 genes in 257 regions. From three additional donor ovaries, they also generated single-cell RNA sequencing data for 21,198 cells.
“We identified four major cell types and four immune cell subtypes in the ovary,” said Dr. Shikanov. Taking samples from different areas of the ovary revealed distinct gene activities for oocytes, theca cells, and granulosa cells — expanding scientists’ understanding of the molecular programs driving ovarian follicle development.
What’s unique about their work is the focus on both single cell and spatial analysis, said study coauthor Jun Z. Li, PhD, associate chair of the University of Michigan’s department of computational medicine and bioinformatics. Specifically, they used a relatively new method called spatial transcriptomics, which allows them to see which genes are being activated and where.
“We are constructing the spatial arrangement of the cells in the ovary,” said Dr. Li. “This spatial analysis is like saying, ‘Let me look at where you are and who your neighbor is.’ ”
Their findings are built on other genetic and cellular research in the field, Dr. Li noted. Biomedical engineers in other areas of medicine are applying similar technologies to other organs including the heart, the breast, and bone — part of a larger project called the Human Cell Atlas.
Advancing Women’s Health Research
Historically, women’s health research has been underfunded and underrepresented, but the authors believe their atlas of the ovary is a significant step forward.
“There are a lot of biological questions that we don’t know the answers to about the ovary,” said Dr. Shikanov.
One of the biggest mysteries is why so many eggs never become fertilizable. Each human female is born with about one to two million ovarian follicles. Each follicle carries one immature egg. Around puberty, two thirds of these follicles die off. And most that are left never develop into fertilizable eggs.
“The majority of these follicles either just grow and secrete hormones or undergo atresia,” Dr. Shikanov said. “One question that we wanted to understand is, what determines an egg that can grow, ovulate, and become a fertilizable egg and potentially develop into a new human being from one that does not?”
Another big question researchers have is, what’s happening with other types of cells in the ovary — the supporting cells that produce endocrine hormones? Where are they located and what proteins and RNA are they making? Their research begins to unravel some of these questions and lays a foundation for future studies.
“We wanted to analyze the transcriptional signatures from specific regions and then do bioinformatical analysis and really combine structure, function, and transcriptional signatures,” Dr. Shikanov said.
Knowing the transcriptional signatures can help researchers understand disease mechanisms and then go on to develop treatments for these diseases.
Winifred Mak, MD, PhD, a reproductive endocrinologist and infertility specialist at Dell Medical School, University of Texas, Austin, studies cancer fertility preservation. “For me, it is interesting to see that there are so many different clusters of cells in the ovary that have been identified by this study that we were not necessarily aware of before,” said Dr. Mak, who is not involved in the new research. “Also, the identification of new genes not previously studied in the human ovary.”
What’s Next
Dozens of scientists who study reproductive health are already reaching out to the researchers about their work, Dr. Shikanov said.
“We get contacted almost every day from researchers all around the world asking for data sets or asking for details from this paper,” she said, “from people who study ovarian cancer, for example.”
Dr. Mak said having a map of a normal ovary could also help researchers who study premature ovarian insufficiency — why the ovary sometimes goes into premature menopause — and polycystic ovarian syndrome.
Another big area of research interest is ovarian aging. “Women live so much longer now, but we still reach menopause at the age of 50,” Dr. Shikanov said. “So, there are efforts going toward understanding ovarian aging and maybe preventing it to extend ovarian longevity.”
Dr. Mak said it will enable scientists to “look at different age women and see what genes change across the reproductive lifespan.”
The atlas may also eventually lead to treatments that help restore fertility in individuals who had and were treated for cancer as children, people who undergo sex transitions, and those whose reproductive organs have been impacted by trauma in conflict settings or accidents, Dr. Li said.
The applications are numerous and exciting, Dr. Shikanov said. “Our atlas is like a benchmark. Now researchers can collect ovaries from individuals with these diseases and conditions and try to compare what’s different.”
A version of this article appeared on Medscape.com.
For years, scientists have sought to create a human artificial ovary, restoring fertility in patients without other options. The first cellular map of a human ovary, recently developed at the University of Michigan, Ann Arbor, represents a big leap forward in that quest.
“You cannot build something if you don’t have the blueprint,” said biomedical engineer Ariella Shikanov, PhD, associate professor at University of Michigan, who helped create what she and colleagues call an atlas of the ovary. “By creating a map or an atlas, we can now follow what nature created and engineer the building blocks of an ovary — and build a nature-like structure.”
So far, the concept of an artificial ovary has been successful only in mice, with the development of a 3D-printed prosthetic ovary that enabled sterilized mice to have pups. Researchers hope that artificial human ovary technology could someday help women left infertile after cancer treatment, as well as patients who don›t respond to fertility treatments and those with premature ovarian failure.
But Dr. Shikanov believes this research will go even further, providing a valuable resource to scientists studying diseases and other conditions related to the ovary.
“Whenever people think about the ovary, if they think about it at all, they usually think about fertility,” said Dr. Shikanov. The ovary is so much more.
Besides producing and carrying a woman’s unfertilized eggs during her lifetime, the ovary is also responsible for endocrine function — the production of estrogen and progesterone, which in addition to supporting reproductive health, help maintain a woman’s cardiovascular, bone, and mental health.
“We don’t really understand everything that is happening in the ovary yet,” Dr. Shikanov said. “But we know it is an important organ.”
Mapping the Ovary
Because people don’t typically donate their ovaries, there are not many available for research, especially from younger reproductive age women, said Dr. Shikanov. So, the scientists set out to build a resource. They described their work in Science Advances.
To create their atlas, the researchers studied two premenopausal donor ovaries, profiling 18,000 genes in 257 regions. From three additional donor ovaries, they also generated single-cell RNA sequencing data for 21,198 cells.
“We identified four major cell types and four immune cell subtypes in the ovary,” said Dr. Shikanov. Taking samples from different areas of the ovary revealed distinct gene activities for oocytes, theca cells, and granulosa cells — expanding scientists’ understanding of the molecular programs driving ovarian follicle development.
What’s unique about their work is the focus on both single cell and spatial analysis, said study coauthor Jun Z. Li, PhD, associate chair of the University of Michigan’s department of computational medicine and bioinformatics. Specifically, they used a relatively new method called spatial transcriptomics, which allows them to see which genes are being activated and where.
“We are constructing the spatial arrangement of the cells in the ovary,” said Dr. Li. “This spatial analysis is like saying, ‘Let me look at where you are and who your neighbor is.’ ”
Their findings are built on other genetic and cellular research in the field, Dr. Li noted. Biomedical engineers in other areas of medicine are applying similar technologies to other organs including the heart, the breast, and bone — part of a larger project called the Human Cell Atlas.
Advancing Women’s Health Research
Historically, women’s health research has been underfunded and underrepresented, but the authors believe their atlas of the ovary is a significant step forward.
“There are a lot of biological questions that we don’t know the answers to about the ovary,” said Dr. Shikanov.
One of the biggest mysteries is why so many eggs never become fertilizable. Each human female is born with about one to two million ovarian follicles. Each follicle carries one immature egg. Around puberty, two thirds of these follicles die off. And most that are left never develop into fertilizable eggs.
“The majority of these follicles either just grow and secrete hormones or undergo atresia,” Dr. Shikanov said. “One question that we wanted to understand is, what determines an egg that can grow, ovulate, and become a fertilizable egg and potentially develop into a new human being from one that does not?”
Another big question researchers have is, what’s happening with other types of cells in the ovary — the supporting cells that produce endocrine hormones? Where are they located and what proteins and RNA are they making? Their research begins to unravel some of these questions and lays a foundation for future studies.
“We wanted to analyze the transcriptional signatures from specific regions and then do bioinformatical analysis and really combine structure, function, and transcriptional signatures,” Dr. Shikanov said.
Knowing the transcriptional signatures can help researchers understand disease mechanisms and then go on to develop treatments for these diseases.
Winifred Mak, MD, PhD, a reproductive endocrinologist and infertility specialist at Dell Medical School, University of Texas, Austin, studies cancer fertility preservation. “For me, it is interesting to see that there are so many different clusters of cells in the ovary that have been identified by this study that we were not necessarily aware of before,” said Dr. Mak, who is not involved in the new research. “Also, the identification of new genes not previously studied in the human ovary.”
What’s Next
Dozens of scientists who study reproductive health are already reaching out to the researchers about their work, Dr. Shikanov said.
“We get contacted almost every day from researchers all around the world asking for data sets or asking for details from this paper,” she said, “from people who study ovarian cancer, for example.”
Dr. Mak said having a map of a normal ovary could also help researchers who study premature ovarian insufficiency — why the ovary sometimes goes into premature menopause — and polycystic ovarian syndrome.
Another big area of research interest is ovarian aging. “Women live so much longer now, but we still reach menopause at the age of 50,” Dr. Shikanov said. “So, there are efforts going toward understanding ovarian aging and maybe preventing it to extend ovarian longevity.”
Dr. Mak said it will enable scientists to “look at different age women and see what genes change across the reproductive lifespan.”
The atlas may also eventually lead to treatments that help restore fertility in individuals who had and were treated for cancer as children, people who undergo sex transitions, and those whose reproductive organs have been impacted by trauma in conflict settings or accidents, Dr. Li said.
The applications are numerous and exciting, Dr. Shikanov said. “Our atlas is like a benchmark. Now researchers can collect ovaries from individuals with these diseases and conditions and try to compare what’s different.”
A version of this article appeared on Medscape.com.
Unplanned Pregnancy With Weight Loss Drugs: Fact or Fiction?
Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.
At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue.
About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.
She had three pressing questions for me:
Q: How had this happened while she had taken the birth control pills faithfully?
A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold:
- Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
- The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
- Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.
Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?
A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.
Q: What would happen to her weight loss efforts?
A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy.
After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful.
*Patient’s name changed.
A version of this article appeared on Medscape.com.
Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.
At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue.
About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.
She had three pressing questions for me:
Q: How had this happened while she had taken the birth control pills faithfully?
A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold:
- Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
- The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
- Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.
Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?
A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.
Q: What would happen to her weight loss efforts?
A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy.
After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful.
*Patient’s name changed.
A version of this article appeared on Medscape.com.
Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.
At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue.
About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.
She had three pressing questions for me:
Q: How had this happened while she had taken the birth control pills faithfully?
A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold:
- Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
- The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
- Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.
Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?
A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.
Q: What would happen to her weight loss efforts?
A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy.
After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful.
*Patient’s name changed.
A version of this article appeared on Medscape.com.
High-Dose Prednisone Can Reduce Rate of Pregnancy Post-Vasectomy
In the first randomized controlled trial of prednisone for postvasectomy reversals, fertility researchers found that a high dose of the steroid reduced the rate of subsequent pregnancy.
“This is the first time it’s been shown that high doses [of prednisone] can make someone infertile,” said Landon Trost, MD, director of the Male Fertility and Peyronie’s Clinic in Orem, Utah, and a faculty member at Mayo Clinic, in Rochester, Minnesota, who presented the study (Abstract MP42-19) on May 4 at the 2024 annual meeting of the American Urological Association (AUA) in San Antonio, Texas.
Dr. Trost called the findings “a real shock. I almost didn’t believe the data when I saw it. It opens up a whole new set of areas for research and exploration.”
Dr. Trost’s clinic performs 1200 reversals per year out of the estimated 20,000 performed annually in the United States, he said. He said his practice has stopped using high-dose prednisone as a result of the study, which he performed at his own expense to examine the varying protocols for vasectomy reversal.
William Berg, MD, director of the Stony Brook Urology Men’s Health Program, in Stony Brook, New York, said that the expected patency rate for modern postvasectomy reversals, if performed properly, can be as high as 98%. However, in some men, patency occurs initially, but the accumulation of scar tissue at the site of reversal causes sperm counts in ejaculate to drop to zero.
Since the 1970s, urologists — with limited research to back — the practice prescribed prednisone to patients with the goal of preventing scarring and blockages associated with vasectomy reversals. Dr. Berg called this practice “unsubstantiated” and noted that Dr. Trost’s study is the first prospective randomized controlled trial of this approach.
The study enrolled 75 men, with a mean age of roughly 38 years. The mean time since vasectomy was 6.6 years.
The low-dose arm (25 patients) received 5 mg of prednisone per week alternating with no treatment per week over 6 months. The high-dose arm (n = 14) received 20 mg of prednisone, tapered to 10 mg, 5 mg, and then off over 1 month, followed by every other month for 6 months. A prednisone-as-needed group (n = 11) received a tapered course of prednisone on the basis of whether they had decreasing or zero sperm counts. They received 20 mg for 5 days, 10 mg for 5 days, and 5 mg for 20 days.
A control arm (n = 25) received no prednisone.
Urologists typically use patency rates to measure success of vasectomy reversals. The patency rates at 12 months in Dr. Trost’s study were 100% in the control participants, prednisone-as-needed, and low-dose groups and 92% (13/14) in the high-dose group.
Dr. Trost said that the story was told in the pregnancy rates. At the 1-year mark, pregnancy rates were 67% in the low-risk group and 65% in the control group but 38% and 17% in the prednisone-as-needed and high-dose group, respectively (P = .02).
The mean maximum sperm concentration was 40 million per mL, ranging from 29.7 million per mL for men in the control group to 54.3 million per mL in the low-dose group.
Dr. Trost said that he immediately stopped using high doses of prednisone in his practice and predicted that other clinics would follow suit.
Dr. Berg said the drop in pregnancies with higher doses of prednisone is a first-time finding and suggests that a high dose may “be detrimental to sperm function in some way. I don’t think this ever has been described before.”
Dr. Trost financed the study himself. Dr. Berg reported no conflicts.
A version of this article first appeared on Medscape.com.
In the first randomized controlled trial of prednisone for postvasectomy reversals, fertility researchers found that a high dose of the steroid reduced the rate of subsequent pregnancy.
“This is the first time it’s been shown that high doses [of prednisone] can make someone infertile,” said Landon Trost, MD, director of the Male Fertility and Peyronie’s Clinic in Orem, Utah, and a faculty member at Mayo Clinic, in Rochester, Minnesota, who presented the study (Abstract MP42-19) on May 4 at the 2024 annual meeting of the American Urological Association (AUA) in San Antonio, Texas.
Dr. Trost called the findings “a real shock. I almost didn’t believe the data when I saw it. It opens up a whole new set of areas for research and exploration.”
Dr. Trost’s clinic performs 1200 reversals per year out of the estimated 20,000 performed annually in the United States, he said. He said his practice has stopped using high-dose prednisone as a result of the study, which he performed at his own expense to examine the varying protocols for vasectomy reversal.
William Berg, MD, director of the Stony Brook Urology Men’s Health Program, in Stony Brook, New York, said that the expected patency rate for modern postvasectomy reversals, if performed properly, can be as high as 98%. However, in some men, patency occurs initially, but the accumulation of scar tissue at the site of reversal causes sperm counts in ejaculate to drop to zero.
Since the 1970s, urologists — with limited research to back — the practice prescribed prednisone to patients with the goal of preventing scarring and blockages associated with vasectomy reversals. Dr. Berg called this practice “unsubstantiated” and noted that Dr. Trost’s study is the first prospective randomized controlled trial of this approach.
The study enrolled 75 men, with a mean age of roughly 38 years. The mean time since vasectomy was 6.6 years.
The low-dose arm (25 patients) received 5 mg of prednisone per week alternating with no treatment per week over 6 months. The high-dose arm (n = 14) received 20 mg of prednisone, tapered to 10 mg, 5 mg, and then off over 1 month, followed by every other month for 6 months. A prednisone-as-needed group (n = 11) received a tapered course of prednisone on the basis of whether they had decreasing or zero sperm counts. They received 20 mg for 5 days, 10 mg for 5 days, and 5 mg for 20 days.
A control arm (n = 25) received no prednisone.
Urologists typically use patency rates to measure success of vasectomy reversals. The patency rates at 12 months in Dr. Trost’s study were 100% in the control participants, prednisone-as-needed, and low-dose groups and 92% (13/14) in the high-dose group.
Dr. Trost said that the story was told in the pregnancy rates. At the 1-year mark, pregnancy rates were 67% in the low-risk group and 65% in the control group but 38% and 17% in the prednisone-as-needed and high-dose group, respectively (P = .02).
The mean maximum sperm concentration was 40 million per mL, ranging from 29.7 million per mL for men in the control group to 54.3 million per mL in the low-dose group.
Dr. Trost said that he immediately stopped using high doses of prednisone in his practice and predicted that other clinics would follow suit.
Dr. Berg said the drop in pregnancies with higher doses of prednisone is a first-time finding and suggests that a high dose may “be detrimental to sperm function in some way. I don’t think this ever has been described before.”
Dr. Trost financed the study himself. Dr. Berg reported no conflicts.
A version of this article first appeared on Medscape.com.
In the first randomized controlled trial of prednisone for postvasectomy reversals, fertility researchers found that a high dose of the steroid reduced the rate of subsequent pregnancy.
“This is the first time it’s been shown that high doses [of prednisone] can make someone infertile,” said Landon Trost, MD, director of the Male Fertility and Peyronie’s Clinic in Orem, Utah, and a faculty member at Mayo Clinic, in Rochester, Minnesota, who presented the study (Abstract MP42-19) on May 4 at the 2024 annual meeting of the American Urological Association (AUA) in San Antonio, Texas.
Dr. Trost called the findings “a real shock. I almost didn’t believe the data when I saw it. It opens up a whole new set of areas for research and exploration.”
Dr. Trost’s clinic performs 1200 reversals per year out of the estimated 20,000 performed annually in the United States, he said. He said his practice has stopped using high-dose prednisone as a result of the study, which he performed at his own expense to examine the varying protocols for vasectomy reversal.
William Berg, MD, director of the Stony Brook Urology Men’s Health Program, in Stony Brook, New York, said that the expected patency rate for modern postvasectomy reversals, if performed properly, can be as high as 98%. However, in some men, patency occurs initially, but the accumulation of scar tissue at the site of reversal causes sperm counts in ejaculate to drop to zero.
Since the 1970s, urologists — with limited research to back — the practice prescribed prednisone to patients with the goal of preventing scarring and blockages associated with vasectomy reversals. Dr. Berg called this practice “unsubstantiated” and noted that Dr. Trost’s study is the first prospective randomized controlled trial of this approach.
The study enrolled 75 men, with a mean age of roughly 38 years. The mean time since vasectomy was 6.6 years.
The low-dose arm (25 patients) received 5 mg of prednisone per week alternating with no treatment per week over 6 months. The high-dose arm (n = 14) received 20 mg of prednisone, tapered to 10 mg, 5 mg, and then off over 1 month, followed by every other month for 6 months. A prednisone-as-needed group (n = 11) received a tapered course of prednisone on the basis of whether they had decreasing or zero sperm counts. They received 20 mg for 5 days, 10 mg for 5 days, and 5 mg for 20 days.
A control arm (n = 25) received no prednisone.
Urologists typically use patency rates to measure success of vasectomy reversals. The patency rates at 12 months in Dr. Trost’s study were 100% in the control participants, prednisone-as-needed, and low-dose groups and 92% (13/14) in the high-dose group.
Dr. Trost said that the story was told in the pregnancy rates. At the 1-year mark, pregnancy rates were 67% in the low-risk group and 65% in the control group but 38% and 17% in the prednisone-as-needed and high-dose group, respectively (P = .02).
The mean maximum sperm concentration was 40 million per mL, ranging from 29.7 million per mL for men in the control group to 54.3 million per mL in the low-dose group.
Dr. Trost said that he immediately stopped using high doses of prednisone in his practice and predicted that other clinics would follow suit.
Dr. Berg said the drop in pregnancies with higher doses of prednisone is a first-time finding and suggests that a high dose may “be detrimental to sperm function in some way. I don’t think this ever has been described before.”
Dr. Trost financed the study himself. Dr. Berg reported no conflicts.
A version of this article first appeared on Medscape.com.
FROM AUA 2024