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Testosterone replacement shows CV benefit in hypogonadal men
Data from a long-term study suggest that testosterone replacement therapy (TRT) for men with hypogonadism may reduce the risk for major adverse cardiovascular events. Previous studies have yielded conflicting results on whether there is a benefit.
The latest results come from a study of 805 men with hypogonadism from Germany and Qatar who were followed for nearly a decade. For those who received parenteral testosterone 1,000 mg every 12 weeks, there were improvements in classical cardiovascular risk factors, such as obesity, lipid level, and inflammatory markers, whereas among those who chose not to take testosterone (control patients), all of these factors worsened.
In addition, there were only 16 deaths among patients in the TRT group, and none of the deaths were from myocardial infarction or stroke. In contrast, there were 74 deaths among the control patients, as well as 70 cases of MI and 59 strokes.
The men in the study were all at relatively high risk for cardiovascular adverse events. In the TRT group, the mean Framingham Risk score was 15.5; in the control group, it was 15.8. This translates into mean 10-year risks of 22.7% and 23.5%, respectively.
“Given that all these men would normally have been expected to suffer a heart attack or stroke in the next 5-10 years with no other intervention, it was a real surprise to see no cardiovascular events at all in the group on testosterone therapy. It’s clear that this treatment can significantly reduce the risks in this particular group,” commented lead investigator Omar Aboumarzouk, MD, from Hamad Medical in Doha, Qatar.
He presented the new data at the 2021 annual congress of the European Association of Urology.
Dr. Aboumarzouk emphasized, however, that, “while men need testosterone for certain psychological and biological functions, only those with low levels who display other symptoms are likely to benefit from testosterone therapy.”
Maarten Albersen, MD, a urologist at the University of Leuven (Belgium), who was not involved in the study, noted that, although the study showed a reduction in major adverse cardiovascular events and mortality among the men who received TRT, the risk scores were in the intermediate range, and the men in the TRT group were slightly younger and were at slightly lower risk at baseline.
“The study was long enough to see differences in the rate of cardiovascular events. However, the numbers involved and the fact that the trial was not randomized mean it’s still difficult to draw any hard conclusions,” he said.
Registry study
The data came from a cumulative registry study begun in 2004 to assess the long-term efficacy and safety of TRT every 3 months in men with hypogonadism. The study, conducted in Bremen, Dresden, and Muenster in Germany, as well as in Doha, Qatar, is ongoing.
At total of 805 men were enrolled; 412 received TRT, and 393 declined testosterone replacement and served as control patients.
The investigators reported 10-year data. Statistical models controlled for age, body mass index, smoking, alcohol, total and HDL cholesterol level, systolic blood pressure, and type 2 diabetes.
The median age at baseline was lower among those in the TRT arm, at 57.7 years versus 63.7 years for control patients (P < .001).
All classical cardiovascular risk factors, including obesity, glycemic control, lipid pattern, and C-reactive protein, improved in the TRT group and worsened in the control group.
Dr. Albersen noted that “a new trial is now underway, aiming to recruit 6,000 participants, and this should provide definitive answers on the cardiovascular risks or even benefits of hormone therapy in men with low testosterone.”
No funding source for the study was reported. Dr. Aboumarzouk and Dr. Albersen have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Data from a long-term study suggest that testosterone replacement therapy (TRT) for men with hypogonadism may reduce the risk for major adverse cardiovascular events. Previous studies have yielded conflicting results on whether there is a benefit.
The latest results come from a study of 805 men with hypogonadism from Germany and Qatar who were followed for nearly a decade. For those who received parenteral testosterone 1,000 mg every 12 weeks, there were improvements in classical cardiovascular risk factors, such as obesity, lipid level, and inflammatory markers, whereas among those who chose not to take testosterone (control patients), all of these factors worsened.
In addition, there were only 16 deaths among patients in the TRT group, and none of the deaths were from myocardial infarction or stroke. In contrast, there were 74 deaths among the control patients, as well as 70 cases of MI and 59 strokes.
The men in the study were all at relatively high risk for cardiovascular adverse events. In the TRT group, the mean Framingham Risk score was 15.5; in the control group, it was 15.8. This translates into mean 10-year risks of 22.7% and 23.5%, respectively.
“Given that all these men would normally have been expected to suffer a heart attack or stroke in the next 5-10 years with no other intervention, it was a real surprise to see no cardiovascular events at all in the group on testosterone therapy. It’s clear that this treatment can significantly reduce the risks in this particular group,” commented lead investigator Omar Aboumarzouk, MD, from Hamad Medical in Doha, Qatar.
He presented the new data at the 2021 annual congress of the European Association of Urology.
Dr. Aboumarzouk emphasized, however, that, “while men need testosterone for certain psychological and biological functions, only those with low levels who display other symptoms are likely to benefit from testosterone therapy.”
Maarten Albersen, MD, a urologist at the University of Leuven (Belgium), who was not involved in the study, noted that, although the study showed a reduction in major adverse cardiovascular events and mortality among the men who received TRT, the risk scores were in the intermediate range, and the men in the TRT group were slightly younger and were at slightly lower risk at baseline.
“The study was long enough to see differences in the rate of cardiovascular events. However, the numbers involved and the fact that the trial was not randomized mean it’s still difficult to draw any hard conclusions,” he said.
Registry study
The data came from a cumulative registry study begun in 2004 to assess the long-term efficacy and safety of TRT every 3 months in men with hypogonadism. The study, conducted in Bremen, Dresden, and Muenster in Germany, as well as in Doha, Qatar, is ongoing.
At total of 805 men were enrolled; 412 received TRT, and 393 declined testosterone replacement and served as control patients.
The investigators reported 10-year data. Statistical models controlled for age, body mass index, smoking, alcohol, total and HDL cholesterol level, systolic blood pressure, and type 2 diabetes.
The median age at baseline was lower among those in the TRT arm, at 57.7 years versus 63.7 years for control patients (P < .001).
All classical cardiovascular risk factors, including obesity, glycemic control, lipid pattern, and C-reactive protein, improved in the TRT group and worsened in the control group.
Dr. Albersen noted that “a new trial is now underway, aiming to recruit 6,000 participants, and this should provide definitive answers on the cardiovascular risks or even benefits of hormone therapy in men with low testosterone.”
No funding source for the study was reported. Dr. Aboumarzouk and Dr. Albersen have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Data from a long-term study suggest that testosterone replacement therapy (TRT) for men with hypogonadism may reduce the risk for major adverse cardiovascular events. Previous studies have yielded conflicting results on whether there is a benefit.
The latest results come from a study of 805 men with hypogonadism from Germany and Qatar who were followed for nearly a decade. For those who received parenteral testosterone 1,000 mg every 12 weeks, there were improvements in classical cardiovascular risk factors, such as obesity, lipid level, and inflammatory markers, whereas among those who chose not to take testosterone (control patients), all of these factors worsened.
In addition, there were only 16 deaths among patients in the TRT group, and none of the deaths were from myocardial infarction or stroke. In contrast, there were 74 deaths among the control patients, as well as 70 cases of MI and 59 strokes.
The men in the study were all at relatively high risk for cardiovascular adverse events. In the TRT group, the mean Framingham Risk score was 15.5; in the control group, it was 15.8. This translates into mean 10-year risks of 22.7% and 23.5%, respectively.
“Given that all these men would normally have been expected to suffer a heart attack or stroke in the next 5-10 years with no other intervention, it was a real surprise to see no cardiovascular events at all in the group on testosterone therapy. It’s clear that this treatment can significantly reduce the risks in this particular group,” commented lead investigator Omar Aboumarzouk, MD, from Hamad Medical in Doha, Qatar.
He presented the new data at the 2021 annual congress of the European Association of Urology.
Dr. Aboumarzouk emphasized, however, that, “while men need testosterone for certain psychological and biological functions, only those with low levels who display other symptoms are likely to benefit from testosterone therapy.”
Maarten Albersen, MD, a urologist at the University of Leuven (Belgium), who was not involved in the study, noted that, although the study showed a reduction in major adverse cardiovascular events and mortality among the men who received TRT, the risk scores were in the intermediate range, and the men in the TRT group were slightly younger and were at slightly lower risk at baseline.
“The study was long enough to see differences in the rate of cardiovascular events. However, the numbers involved and the fact that the trial was not randomized mean it’s still difficult to draw any hard conclusions,” he said.
Registry study
The data came from a cumulative registry study begun in 2004 to assess the long-term efficacy and safety of TRT every 3 months in men with hypogonadism. The study, conducted in Bremen, Dresden, and Muenster in Germany, as well as in Doha, Qatar, is ongoing.
At total of 805 men were enrolled; 412 received TRT, and 393 declined testosterone replacement and served as control patients.
The investigators reported 10-year data. Statistical models controlled for age, body mass index, smoking, alcohol, total and HDL cholesterol level, systolic blood pressure, and type 2 diabetes.
The median age at baseline was lower among those in the TRT arm, at 57.7 years versus 63.7 years for control patients (P < .001).
All classical cardiovascular risk factors, including obesity, glycemic control, lipid pattern, and C-reactive protein, improved in the TRT group and worsened in the control group.
Dr. Albersen noted that “a new trial is now underway, aiming to recruit 6,000 participants, and this should provide definitive answers on the cardiovascular risks or even benefits of hormone therapy in men with low testosterone.”
No funding source for the study was reported. Dr. Aboumarzouk and Dr. Albersen have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Reassuring rates of ADHD after assisted reproductive techniques
according to a study published in Pediatrics.
The findings, based on an analysis of data from more than 1.5 million children in Sweden, provide “additional reassurance concerning offspring neurodevelopment after use of ART,” study author Chen Wang, MPH, and colleagues said. The results show the importance of accounting for underlying infertility when studying ART safety, they added. Mr. Wang is a researcher in the department of medical epidemiology and biostatistics at Karolinska Institutet in Stockholm.
Prior research has not shown major differences during early childhood between children conceived with ART and those conceived spontaneously. To examine long-term neurodevelopmental outcomes, including ADHD and school performance, the investigators analyzed data in Swedish population registers from children born between 1986 and 2012.
Infertility and the use of ART became increasingly common during the study period, the researchers noted. Between 1986 and 2001, 7% of births were to couples with known infertility, and 13% of these births were achieved with ART. Between 1996 and 2012, 11% of births were to couples with infertility, and 26% of these births were achieved with ART.
“Couples with infertility were more likely older and married or cohabiting, compared with couples with no known infertility,” Mr. Wang and colleagues reported. “Among infertile couples, those that conceived with ART had, on average, higher age and education, and the women were less likely to smoke.”
The investigators estimated that the cumulative incidence of ADHD by age 15 years was 6.2% in children conceived with ART, 7.3% among children of couples with infertility who did not use ART, and 7.1% in children born to couples with no known infertility.
Overall, children conceived with ART were at lower risk of ADHD (hazard ratio, 0.83). But after adjusting for parental characteristics and health factors, the researchers found a “slightly elevated risk of ADHD with ART,” with adjusted HRs of 1.05-1.07.
When the researchers focused on children born to couples with infertility, ART was associated with a lower risk of ADHD (adjusted HR, 0.80), compared with spontaneous conception. Accounting for parental characteristics and health history, however, “attenuated the association toward the null,” the researchers reported.
The researchers also compared ART methods, including intracytoplasmic sperm injection versus standard in vitro fertilization (IVF), and fresh embryo transfer versus frozen embryo transfer. The various procedures were not associated with substantially different risks.
Patterns for school performance were generally similar to those for ADHD.
“In this large follow-up of nationwide birth cohorts, we observed lower risk of ADHD and slightly better overall school performance in children conceived with ART, compared with all other children. Differences in parental characteristics appeared to completely explain and even slightly reverse the associations,” the study authors said. “When the comparison was restricted to children of couples with known infertility, no differences were seen.”
The study was well designed and “spans more than 25 years of ART during which treatments have changed dramatically,” commented Barbara Luke, ScD, MPH, professor of obstetrics, gynecology, and reproductive biology at Michigan State University, East Lansing.
Dr. Luke and colleagues have studied academic achievement in children conceived with IVF in Texas. The results of the Swedish study “are in line with U.S. studies, and are generally reassuring,” Dr. Luke said.
The U.S. studies also showed that parental factors may play a role in understanding academic performance.
“In our studies of third-grade and sixth-grade academic outcomes, we found differences by racial/Hispanic origin groups, gender, and maternal age,” she said.
The study by Mr. Wang and coauthors was funded by grants from a Swedish government agency and the National Institutes of Health. The researchers and Dr. Luke had no relevant financial disclosures.
according to a study published in Pediatrics.
The findings, based on an analysis of data from more than 1.5 million children in Sweden, provide “additional reassurance concerning offspring neurodevelopment after use of ART,” study author Chen Wang, MPH, and colleagues said. The results show the importance of accounting for underlying infertility when studying ART safety, they added. Mr. Wang is a researcher in the department of medical epidemiology and biostatistics at Karolinska Institutet in Stockholm.
Prior research has not shown major differences during early childhood between children conceived with ART and those conceived spontaneously. To examine long-term neurodevelopmental outcomes, including ADHD and school performance, the investigators analyzed data in Swedish population registers from children born between 1986 and 2012.
Infertility and the use of ART became increasingly common during the study period, the researchers noted. Between 1986 and 2001, 7% of births were to couples with known infertility, and 13% of these births were achieved with ART. Between 1996 and 2012, 11% of births were to couples with infertility, and 26% of these births were achieved with ART.
“Couples with infertility were more likely older and married or cohabiting, compared with couples with no known infertility,” Mr. Wang and colleagues reported. “Among infertile couples, those that conceived with ART had, on average, higher age and education, and the women were less likely to smoke.”
The investigators estimated that the cumulative incidence of ADHD by age 15 years was 6.2% in children conceived with ART, 7.3% among children of couples with infertility who did not use ART, and 7.1% in children born to couples with no known infertility.
Overall, children conceived with ART were at lower risk of ADHD (hazard ratio, 0.83). But after adjusting for parental characteristics and health factors, the researchers found a “slightly elevated risk of ADHD with ART,” with adjusted HRs of 1.05-1.07.
When the researchers focused on children born to couples with infertility, ART was associated with a lower risk of ADHD (adjusted HR, 0.80), compared with spontaneous conception. Accounting for parental characteristics and health history, however, “attenuated the association toward the null,” the researchers reported.
The researchers also compared ART methods, including intracytoplasmic sperm injection versus standard in vitro fertilization (IVF), and fresh embryo transfer versus frozen embryo transfer. The various procedures were not associated with substantially different risks.
Patterns for school performance were generally similar to those for ADHD.
“In this large follow-up of nationwide birth cohorts, we observed lower risk of ADHD and slightly better overall school performance in children conceived with ART, compared with all other children. Differences in parental characteristics appeared to completely explain and even slightly reverse the associations,” the study authors said. “When the comparison was restricted to children of couples with known infertility, no differences were seen.”
The study was well designed and “spans more than 25 years of ART during which treatments have changed dramatically,” commented Barbara Luke, ScD, MPH, professor of obstetrics, gynecology, and reproductive biology at Michigan State University, East Lansing.
Dr. Luke and colleagues have studied academic achievement in children conceived with IVF in Texas. The results of the Swedish study “are in line with U.S. studies, and are generally reassuring,” Dr. Luke said.
The U.S. studies also showed that parental factors may play a role in understanding academic performance.
“In our studies of third-grade and sixth-grade academic outcomes, we found differences by racial/Hispanic origin groups, gender, and maternal age,” she said.
The study by Mr. Wang and coauthors was funded by grants from a Swedish government agency and the National Institutes of Health. The researchers and Dr. Luke had no relevant financial disclosures.
according to a study published in Pediatrics.
The findings, based on an analysis of data from more than 1.5 million children in Sweden, provide “additional reassurance concerning offspring neurodevelopment after use of ART,” study author Chen Wang, MPH, and colleagues said. The results show the importance of accounting for underlying infertility when studying ART safety, they added. Mr. Wang is a researcher in the department of medical epidemiology and biostatistics at Karolinska Institutet in Stockholm.
Prior research has not shown major differences during early childhood between children conceived with ART and those conceived spontaneously. To examine long-term neurodevelopmental outcomes, including ADHD and school performance, the investigators analyzed data in Swedish population registers from children born between 1986 and 2012.
Infertility and the use of ART became increasingly common during the study period, the researchers noted. Between 1986 and 2001, 7% of births were to couples with known infertility, and 13% of these births were achieved with ART. Between 1996 and 2012, 11% of births were to couples with infertility, and 26% of these births were achieved with ART.
“Couples with infertility were more likely older and married or cohabiting, compared with couples with no known infertility,” Mr. Wang and colleagues reported. “Among infertile couples, those that conceived with ART had, on average, higher age and education, and the women were less likely to smoke.”
The investigators estimated that the cumulative incidence of ADHD by age 15 years was 6.2% in children conceived with ART, 7.3% among children of couples with infertility who did not use ART, and 7.1% in children born to couples with no known infertility.
Overall, children conceived with ART were at lower risk of ADHD (hazard ratio, 0.83). But after adjusting for parental characteristics and health factors, the researchers found a “slightly elevated risk of ADHD with ART,” with adjusted HRs of 1.05-1.07.
When the researchers focused on children born to couples with infertility, ART was associated with a lower risk of ADHD (adjusted HR, 0.80), compared with spontaneous conception. Accounting for parental characteristics and health history, however, “attenuated the association toward the null,” the researchers reported.
The researchers also compared ART methods, including intracytoplasmic sperm injection versus standard in vitro fertilization (IVF), and fresh embryo transfer versus frozen embryo transfer. The various procedures were not associated with substantially different risks.
Patterns for school performance were generally similar to those for ADHD.
“In this large follow-up of nationwide birth cohorts, we observed lower risk of ADHD and slightly better overall school performance in children conceived with ART, compared with all other children. Differences in parental characteristics appeared to completely explain and even slightly reverse the associations,” the study authors said. “When the comparison was restricted to children of couples with known infertility, no differences were seen.”
The study was well designed and “spans more than 25 years of ART during which treatments have changed dramatically,” commented Barbara Luke, ScD, MPH, professor of obstetrics, gynecology, and reproductive biology at Michigan State University, East Lansing.
Dr. Luke and colleagues have studied academic achievement in children conceived with IVF in Texas. The results of the Swedish study “are in line with U.S. studies, and are generally reassuring,” Dr. Luke said.
The U.S. studies also showed that parental factors may play a role in understanding academic performance.
“In our studies of third-grade and sixth-grade academic outcomes, we found differences by racial/Hispanic origin groups, gender, and maternal age,” she said.
The study by Mr. Wang and coauthors was funded by grants from a Swedish government agency and the National Institutes of Health. The researchers and Dr. Luke had no relevant financial disclosures.
FROM PEDIATRICS
Placental allograft, cytology processor, cell-free RNA testing, and male infertility
Human placental allograft
For case reports involving Revita and for more information, visit https://www.stimlabs.com/revita.
FDA approval for cytology processor
For more information, visit: https://www.hologic.com/.
Cell-free RNA testing for pregnancy complications
Currently, Mirvie is recruiting for their Miracle of Life study, which requests that single gestation pregnant mothers who are not scheduled for cesarean delivery provide a blood sample during their second trimester. Women can see if they are eligible for study participation by visiting https://www.curebase.com/study/miracle/home.
For more information, visit: https://mirvie.com/.
Male fertility platform
For more information, visit: https://posterityhealth.com/.
Human placental allograft
For case reports involving Revita and for more information, visit https://www.stimlabs.com/revita.
FDA approval for cytology processor
For more information, visit: https://www.hologic.com/.
Cell-free RNA testing for pregnancy complications
Currently, Mirvie is recruiting for their Miracle of Life study, which requests that single gestation pregnant mothers who are not scheduled for cesarean delivery provide a blood sample during their second trimester. Women can see if they are eligible for study participation by visiting https://www.curebase.com/study/miracle/home.
For more information, visit: https://mirvie.com/.
Male fertility platform
For more information, visit: https://posterityhealth.com/.
Human placental allograft
For case reports involving Revita and for more information, visit https://www.stimlabs.com/revita.
FDA approval for cytology processor
For more information, visit: https://www.hologic.com/.
Cell-free RNA testing for pregnancy complications
Currently, Mirvie is recruiting for their Miracle of Life study, which requests that single gestation pregnant mothers who are not scheduled for cesarean delivery provide a blood sample during their second trimester. Women can see if they are eligible for study participation by visiting https://www.curebase.com/study/miracle/home.
For more information, visit: https://mirvie.com/.
Male fertility platform
For more information, visit: https://posterityhealth.com/.
No increase in breast cancer risk with fertility treatments
No link between fertility treatment and an increase in the risk for breast cancer was found in the largest study of the issue to date.
This study “provides the evidence needed to reassure women and couples seeking fertility treatments,” commented senior author Sesh Sunkara, MD, a reproductive medicine specialist at King’s College London in a press release.
With an increasing number of women seeking help to become mothers, the question “is a matter of great importance” and a source of considerable concern among patients, the study authors comment.
This is the largest meta-analysis to date, involving 1.8 million women who were followed for an average of 27 years. The investigators found no link with the use of gonadotropins or clomiphene citrate to increase egg production in fertility cycles.
There has been concern over the years that fertility treatment could stimulate estrogen-sensitive precursor breast cancer cells.
More than 4,000 studies of this issue have been conducted since 1990, and results have been conflicting. The investigators analyzed results from the 20 strongest ones.
The new meta-analysis included nine retrospective studies, five case-control studies, five prospective studies, and one comparative study
The team cautioned that the quality of evidence in even these top 20 studies was “very low” but that such an approach is perhaps the best possible on this issue because a randomized trial among women seeking help to have children would be “ethically challenging.”
In the study, the team compared breast cancer incidence among women who underwent ovarian stimulation with the incidence in both age-matched unexposed women in the general population and unexposed infertile women.
There was no significant increase in the risk for breast cancer among women treated with any ovarian stimulation drug (pooled odds ratio, 1.03; 95% confidence interval, 0.86-1.23, but with substantial heterogeneity between study outcomes).
There was also no increased risk when the analysis was limited to the eight studies in which women were treated with both gonadotropins and clomiphene citrate (pooled OR, 0.92; 95% CI, 0.52-1.60, with substantial heterogeneity).
The authors noted that, among the many study limitations, no distinction was made between physiological dosing for anovulation and supraphysiological dosing for in vitro fertilization cycles. In addition, because the treated women were generally young, the follow-up period fell short of the age at which they’d be most at risk for breast cancer.
Individual patient data were also not available, but 14 studies did adjust for confounders, including weight, race, parity, age at first birth, age at menarche, and family history of breast cancer.
Although the findings are reassuring, “further long-term and detailed studies are now needed to confirm” them, Kotryna Temcinaite, PhD, senior research communications manager at the U.K. charity Breast Cancer Now, said in the press release.
A version of this article first appeared on Medscape.com.
No link between fertility treatment and an increase in the risk for breast cancer was found in the largest study of the issue to date.
This study “provides the evidence needed to reassure women and couples seeking fertility treatments,” commented senior author Sesh Sunkara, MD, a reproductive medicine specialist at King’s College London in a press release.
With an increasing number of women seeking help to become mothers, the question “is a matter of great importance” and a source of considerable concern among patients, the study authors comment.
This is the largest meta-analysis to date, involving 1.8 million women who were followed for an average of 27 years. The investigators found no link with the use of gonadotropins or clomiphene citrate to increase egg production in fertility cycles.
There has been concern over the years that fertility treatment could stimulate estrogen-sensitive precursor breast cancer cells.
More than 4,000 studies of this issue have been conducted since 1990, and results have been conflicting. The investigators analyzed results from the 20 strongest ones.
The new meta-analysis included nine retrospective studies, five case-control studies, five prospective studies, and one comparative study
The team cautioned that the quality of evidence in even these top 20 studies was “very low” but that such an approach is perhaps the best possible on this issue because a randomized trial among women seeking help to have children would be “ethically challenging.”
In the study, the team compared breast cancer incidence among women who underwent ovarian stimulation with the incidence in both age-matched unexposed women in the general population and unexposed infertile women.
There was no significant increase in the risk for breast cancer among women treated with any ovarian stimulation drug (pooled odds ratio, 1.03; 95% confidence interval, 0.86-1.23, but with substantial heterogeneity between study outcomes).
There was also no increased risk when the analysis was limited to the eight studies in which women were treated with both gonadotropins and clomiphene citrate (pooled OR, 0.92; 95% CI, 0.52-1.60, with substantial heterogeneity).
The authors noted that, among the many study limitations, no distinction was made between physiological dosing for anovulation and supraphysiological dosing for in vitro fertilization cycles. In addition, because the treated women were generally young, the follow-up period fell short of the age at which they’d be most at risk for breast cancer.
Individual patient data were also not available, but 14 studies did adjust for confounders, including weight, race, parity, age at first birth, age at menarche, and family history of breast cancer.
Although the findings are reassuring, “further long-term and detailed studies are now needed to confirm” them, Kotryna Temcinaite, PhD, senior research communications manager at the U.K. charity Breast Cancer Now, said in the press release.
A version of this article first appeared on Medscape.com.
No link between fertility treatment and an increase in the risk for breast cancer was found in the largest study of the issue to date.
This study “provides the evidence needed to reassure women and couples seeking fertility treatments,” commented senior author Sesh Sunkara, MD, a reproductive medicine specialist at King’s College London in a press release.
With an increasing number of women seeking help to become mothers, the question “is a matter of great importance” and a source of considerable concern among patients, the study authors comment.
This is the largest meta-analysis to date, involving 1.8 million women who were followed for an average of 27 years. The investigators found no link with the use of gonadotropins or clomiphene citrate to increase egg production in fertility cycles.
There has been concern over the years that fertility treatment could stimulate estrogen-sensitive precursor breast cancer cells.
More than 4,000 studies of this issue have been conducted since 1990, and results have been conflicting. The investigators analyzed results from the 20 strongest ones.
The new meta-analysis included nine retrospective studies, five case-control studies, five prospective studies, and one comparative study
The team cautioned that the quality of evidence in even these top 20 studies was “very low” but that such an approach is perhaps the best possible on this issue because a randomized trial among women seeking help to have children would be “ethically challenging.”
In the study, the team compared breast cancer incidence among women who underwent ovarian stimulation with the incidence in both age-matched unexposed women in the general population and unexposed infertile women.
There was no significant increase in the risk for breast cancer among women treated with any ovarian stimulation drug (pooled odds ratio, 1.03; 95% confidence interval, 0.86-1.23, but with substantial heterogeneity between study outcomes).
There was also no increased risk when the analysis was limited to the eight studies in which women were treated with both gonadotropins and clomiphene citrate (pooled OR, 0.92; 95% CI, 0.52-1.60, with substantial heterogeneity).
The authors noted that, among the many study limitations, no distinction was made between physiological dosing for anovulation and supraphysiological dosing for in vitro fertilization cycles. In addition, because the treated women were generally young, the follow-up period fell short of the age at which they’d be most at risk for breast cancer.
Individual patient data were also not available, but 14 studies did adjust for confounders, including weight, race, parity, age at first birth, age at menarche, and family history of breast cancer.
Although the findings are reassuring, “further long-term and detailed studies are now needed to confirm” them, Kotryna Temcinaite, PhD, senior research communications manager at the U.K. charity Breast Cancer Now, said in the press release.
A version of this article first appeared on Medscape.com.
Polycystic ovary syndrome: It’s not just about fertility
Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.
To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
Diagnosis in adults and adolescence
Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.
For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.
Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
The metabolic connection
A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.
Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.
The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
A genetic link
Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).
Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
Reproductive and gynecologic management
Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.
PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.
The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m2. (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.
Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.
Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
Metabolic/gynecologic management
Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.
The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).
Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.
No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
Conclusion
PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at obnews@mdedge.com.
Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.
To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
Diagnosis in adults and adolescence
Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.
For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.
Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
The metabolic connection
A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.
Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.
The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
A genetic link
Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).
Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
Reproductive and gynecologic management
Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.
PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.
The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m2. (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.
Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.
Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
Metabolic/gynecologic management
Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.
The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).
Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.
No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
Conclusion
PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at obnews@mdedge.com.
Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.
To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
Diagnosis in adults and adolescence
Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.
For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.
Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
The metabolic connection
A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.
Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.
The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
A genetic link
Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).
Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
Reproductive and gynecologic management
Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.
PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.
The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m2. (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.
Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.
Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
Metabolic/gynecologic management
Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.
The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).
Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.
No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
Conclusion
PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at obnews@mdedge.com.
55 new chemicals found in pregnant women, their newborns
Fifty-five chemicals never before reported in humans were found in pregnant women, according to a study from the University of California, San Francisco. The chemicals likely come from consumer products or industrial sources, researchers say.
Findings were published online in Environmental Science and Technology.
Co-first authors Aolin Wang, PhD, and Dimitri Panagopoulos Abrahamsson, PhD, postdoctoral fellows in UCSF’s obstetrics and gynecology department, and colleagues found 109 chemicals in the blood of pregnant women, including 42 “mystery chemicals” whose sources and uses are not known.
The chemicals were also found in their newborns, tests from umbilical cord blood show, suggesting the chemicals cross through the placenta.
Among the chemicals, 40 are used as plasticizers, 28 are used in cosmetics, another 25 are used in consumer products, 29 as pharmaceuticals, 23 as pesticides, three as flame retardants, and seven are PFAS [per- and polyfluoroalkyl substances] compounds used in multiple applications including carpeting and upholstery, the authors report.
Senior author Tracey Woodruff, PhD, MPH, characterized their discoveries as “disturbing.”
She told this news organization that it’s not only frustrating to know the chemicals are present but to know so little about them.
“We know it’s a chemical registered to be manufactured, and it’s used in commerce, but we don’t know where,” she explained. “That’s very disturbing, that we can’t trace them, and that shows a failure in public policy and government.”
“Exposures are occurring without our consent,” said Ms. Woodruff, a former U.S. Environmental Protection Agency scientist, who directs the Program on Reproductive Health and the Environment (PRHE) and the Environmental Research and Translation for Health (EaRTH) Center, both at UCSF.
She said researchers know from previous studies that when the U.S. government acts to remove harmful chemicals from the marketplace, the levels of those chemicals measured in people drop.
“Examples include lead, certain PFAS, flame retardant chemicals, and certain phthalates,” she said. “So public policies can be effective in preventing exposures that can be harmful.”
Technological advances led to the discoveries
The team used high-resolution mass spectrometry (HRMS) to identify human-made chemicals in people.
Dr. Abrahamsson said in an interview that the technology is relatively new in research and had not previously been used to scan for chemicals in pregnant women and their infants.
Because scientists often study what other scientists have studied, he said, the same chemicals tend to get attention. The wider scope made possible by the new technology helps illumine where to focus future research, he said.
A benefit of the technology is that now researchers don’t have to know which chemicals they are looking for when they scan blood samples, but they can observe whatever appears, he said.
Ms. Woodruff said, “We hope this is further data and evidence that support government policies that require industries to tell us where they are using their chemicals and how we might be exposed to them.”
She said this research will also help identify which chemicals to prioritize for monitoring in the environment.
Average age of the women in the study was 32 years. Nearly half were Hispanic; 37% were non-Hispanic Whites; and 17% were non-Hispanic Asians, Pacific Islanders, and African Americans. Half of the participants were born outside the United States and had lived in the U.S. for an average 22 years.
Sean Palfrey, MD, a professor of clinical pediatrics and public health at Boston University, said more chemical discoveries like these will come as technology continues to evolve.
Dr. Palfrey, who was not involved in the study, agrees with the authors that there is a lack of oversight as to what substances are used in products.
“Our industrial regulations are very poor and therefore our industries get away with using new and untested substances in their products,” he told this news organization.
“This lack of regulation is really important when it results in us not recognizing that known and serious toxins are being put into foods or other products, or when a new class of toxin has been invented which is a serious poison. Most of the toxins, though, are discovered in products in very low levels,” he said.
Dr. Palfrey said, however, that focus should stay on the known and serious toxins that seep into the environment from common products.
“It has taken us decades to ban certain flame retardants from home products,” he said. “TOSCA [the Toxic Substances Control Act passed by Congress in 1976] was too limited when it was passed decades ago and is now fearfully out of date. Unless we discover a COVID among the toxins discovered in studies like this, we should focus on the big stuff.”
The authors and Dr. Palfrey have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Fifty-five chemicals never before reported in humans were found in pregnant women, according to a study from the University of California, San Francisco. The chemicals likely come from consumer products or industrial sources, researchers say.
Findings were published online in Environmental Science and Technology.
Co-first authors Aolin Wang, PhD, and Dimitri Panagopoulos Abrahamsson, PhD, postdoctoral fellows in UCSF’s obstetrics and gynecology department, and colleagues found 109 chemicals in the blood of pregnant women, including 42 “mystery chemicals” whose sources and uses are not known.
The chemicals were also found in their newborns, tests from umbilical cord blood show, suggesting the chemicals cross through the placenta.
Among the chemicals, 40 are used as plasticizers, 28 are used in cosmetics, another 25 are used in consumer products, 29 as pharmaceuticals, 23 as pesticides, three as flame retardants, and seven are PFAS [per- and polyfluoroalkyl substances] compounds used in multiple applications including carpeting and upholstery, the authors report.
Senior author Tracey Woodruff, PhD, MPH, characterized their discoveries as “disturbing.”
She told this news organization that it’s not only frustrating to know the chemicals are present but to know so little about them.
“We know it’s a chemical registered to be manufactured, and it’s used in commerce, but we don’t know where,” she explained. “That’s very disturbing, that we can’t trace them, and that shows a failure in public policy and government.”
“Exposures are occurring without our consent,” said Ms. Woodruff, a former U.S. Environmental Protection Agency scientist, who directs the Program on Reproductive Health and the Environment (PRHE) and the Environmental Research and Translation for Health (EaRTH) Center, both at UCSF.
She said researchers know from previous studies that when the U.S. government acts to remove harmful chemicals from the marketplace, the levels of those chemicals measured in people drop.
“Examples include lead, certain PFAS, flame retardant chemicals, and certain phthalates,” she said. “So public policies can be effective in preventing exposures that can be harmful.”
Technological advances led to the discoveries
The team used high-resolution mass spectrometry (HRMS) to identify human-made chemicals in people.
Dr. Abrahamsson said in an interview that the technology is relatively new in research and had not previously been used to scan for chemicals in pregnant women and their infants.
Because scientists often study what other scientists have studied, he said, the same chemicals tend to get attention. The wider scope made possible by the new technology helps illumine where to focus future research, he said.
A benefit of the technology is that now researchers don’t have to know which chemicals they are looking for when they scan blood samples, but they can observe whatever appears, he said.
Ms. Woodruff said, “We hope this is further data and evidence that support government policies that require industries to tell us where they are using their chemicals and how we might be exposed to them.”
She said this research will also help identify which chemicals to prioritize for monitoring in the environment.
Average age of the women in the study was 32 years. Nearly half were Hispanic; 37% were non-Hispanic Whites; and 17% were non-Hispanic Asians, Pacific Islanders, and African Americans. Half of the participants were born outside the United States and had lived in the U.S. for an average 22 years.
Sean Palfrey, MD, a professor of clinical pediatrics and public health at Boston University, said more chemical discoveries like these will come as technology continues to evolve.
Dr. Palfrey, who was not involved in the study, agrees with the authors that there is a lack of oversight as to what substances are used in products.
“Our industrial regulations are very poor and therefore our industries get away with using new and untested substances in their products,” he told this news organization.
“This lack of regulation is really important when it results in us not recognizing that known and serious toxins are being put into foods or other products, or when a new class of toxin has been invented which is a serious poison. Most of the toxins, though, are discovered in products in very low levels,” he said.
Dr. Palfrey said, however, that focus should stay on the known and serious toxins that seep into the environment from common products.
“It has taken us decades to ban certain flame retardants from home products,” he said. “TOSCA [the Toxic Substances Control Act passed by Congress in 1976] was too limited when it was passed decades ago and is now fearfully out of date. Unless we discover a COVID among the toxins discovered in studies like this, we should focus on the big stuff.”
The authors and Dr. Palfrey have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Fifty-five chemicals never before reported in humans were found in pregnant women, according to a study from the University of California, San Francisco. The chemicals likely come from consumer products or industrial sources, researchers say.
Findings were published online in Environmental Science and Technology.
Co-first authors Aolin Wang, PhD, and Dimitri Panagopoulos Abrahamsson, PhD, postdoctoral fellows in UCSF’s obstetrics and gynecology department, and colleagues found 109 chemicals in the blood of pregnant women, including 42 “mystery chemicals” whose sources and uses are not known.
The chemicals were also found in their newborns, tests from umbilical cord blood show, suggesting the chemicals cross through the placenta.
Among the chemicals, 40 are used as plasticizers, 28 are used in cosmetics, another 25 are used in consumer products, 29 as pharmaceuticals, 23 as pesticides, three as flame retardants, and seven are PFAS [per- and polyfluoroalkyl substances] compounds used in multiple applications including carpeting and upholstery, the authors report.
Senior author Tracey Woodruff, PhD, MPH, characterized their discoveries as “disturbing.”
She told this news organization that it’s not only frustrating to know the chemicals are present but to know so little about them.
“We know it’s a chemical registered to be manufactured, and it’s used in commerce, but we don’t know where,” she explained. “That’s very disturbing, that we can’t trace them, and that shows a failure in public policy and government.”
“Exposures are occurring without our consent,” said Ms. Woodruff, a former U.S. Environmental Protection Agency scientist, who directs the Program on Reproductive Health and the Environment (PRHE) and the Environmental Research and Translation for Health (EaRTH) Center, both at UCSF.
She said researchers know from previous studies that when the U.S. government acts to remove harmful chemicals from the marketplace, the levels of those chemicals measured in people drop.
“Examples include lead, certain PFAS, flame retardant chemicals, and certain phthalates,” she said. “So public policies can be effective in preventing exposures that can be harmful.”
Technological advances led to the discoveries
The team used high-resolution mass spectrometry (HRMS) to identify human-made chemicals in people.
Dr. Abrahamsson said in an interview that the technology is relatively new in research and had not previously been used to scan for chemicals in pregnant women and their infants.
Because scientists often study what other scientists have studied, he said, the same chemicals tend to get attention. The wider scope made possible by the new technology helps illumine where to focus future research, he said.
A benefit of the technology is that now researchers don’t have to know which chemicals they are looking for when they scan blood samples, but they can observe whatever appears, he said.
Ms. Woodruff said, “We hope this is further data and evidence that support government policies that require industries to tell us where they are using their chemicals and how we might be exposed to them.”
She said this research will also help identify which chemicals to prioritize for monitoring in the environment.
Average age of the women in the study was 32 years. Nearly half were Hispanic; 37% were non-Hispanic Whites; and 17% were non-Hispanic Asians, Pacific Islanders, and African Americans. Half of the participants were born outside the United States and had lived in the U.S. for an average 22 years.
Sean Palfrey, MD, a professor of clinical pediatrics and public health at Boston University, said more chemical discoveries like these will come as technology continues to evolve.
Dr. Palfrey, who was not involved in the study, agrees with the authors that there is a lack of oversight as to what substances are used in products.
“Our industrial regulations are very poor and therefore our industries get away with using new and untested substances in their products,” he told this news organization.
“This lack of regulation is really important when it results in us not recognizing that known and serious toxins are being put into foods or other products, or when a new class of toxin has been invented which is a serious poison. Most of the toxins, though, are discovered in products in very low levels,” he said.
Dr. Palfrey said, however, that focus should stay on the known and serious toxins that seep into the environment from common products.
“It has taken us decades to ban certain flame retardants from home products,” he said. “TOSCA [the Toxic Substances Control Act passed by Congress in 1976] was too limited when it was passed decades ago and is now fearfully out of date. Unless we discover a COVID among the toxins discovered in studies like this, we should focus on the big stuff.”
The authors and Dr. Palfrey have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
High body fat tied to slowed breast maturation in girls with obesity
Girls in late stages of puberty who had elevated levels of body fat showed unusually high levels of several hormones that could contribute to an earlier age of menarche and also slow breast development, according to data from 90 girls who spanned a wide range of body fat in the first longitudinal study to examine links between fat volume, levels of reproductive hormones, and clinical manifestations of hormone action during puberty.
The results showed that girls with greater body fat had higher levels of follicle stimulating hormone, inhibin B, estrone, and certain male-like reproductive hormones, and that this pattern “is specifically tied to body fat,” said Natalie D. Shaw, MD, senior investigator for the study, reported at the annual meeting of the Endocrine Society.
“We found that total body fat is associated with the timing of menarche, as others have reported for body weight,” she noted. The new findings showed that every 1% rise in percent total body fat linked with a significant 3% rise in the likelihood of menarche, menstrual onset. In the new study the average age of menarche was 11.7 years among the overweight or obese girls and 12.8 years among those with normal weights.
But the study’s unique use of an average of about three serial ultrasound breast examinations of each subject during an average 4 years of follow-up also showed that higher levels of body fat linked with slowed breast development in later stages, specifically maturation from stage D to stages D/E and E.
For example, girls with 33% body fat spent an average of 8.2 months in stage D, which stretched to an average of 11.2 months among girls with 38% body fat, reported Madison T. Ortega, a researcher with the Pediatric Endocrinology Group of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., who presented the report at the meeting.
Ultrasound shows what inspection can’t
Results from “several studies have shown earlier breast development in overweight and obese girls by inspection and palpation,” but the new findings from ultrasound examination provide more nuance about the structural breast changes actually occurring in these adolescents, said Dr. Shaw, who heads the Pediatric Endocrinology Group. The current study “was not designed to capture the onset of breast development,” and “it is possible that increased androgens or insulin resistance in girls with higher body fat interferes with normal breast development,” she explained in an interview.
“The authors showed that the timing and progress of early stages of puberty were not earlier in overweight or obese girls. Luteinizing hormone, the indicator of neuroendocrine pubertal onset, and timing of early stages of breast development were the same in all weight groups. The authors also discovered falsely advanced Turner breast stage designations with ultrasonography in some girls with obesity. This might suggest that prior findings in epidemiologic studies of an earlier start to puberty based mostly on breast development stages identified by self-reported inspection and, rarely, palpation, may have been biased by breast adipose tissue,” said Christine M. Burt Solorzano, MD, a pediatric endocrinologist at the University of Virginia in Charlottesville, who was not involved in the study.
“Development of increased follicle-stimulating hormone in late puberty suggests that pubertal tempo, not onset, may be increased in girls with obesity, and goes along with earlier menarche. Their finding of increased androgen levels during mid to late puberty with obesity are consistent with prior findings,” including work published Dr. Burt Solorzano and her associates, she noted. “Delayed timing of advanced breast morphology was unexpected and may reflect relatively lower levels of progesterone in girls with obesity,” a hormone necessary for later stages of breast maturation.
The findings “reinforce that early breast development in the setting of obesity may in fact reflect adipose tissue and not be a true representation of neuroendocrine precocious puberty,” Dr. Burt Solorzano said in an interview. The findings “also suggest that pubertal initiation may not happen earlier in girls with obesity, as has been thought, but rather the tempo of puberty may be more rapid, leading to earlier menarche.”
A possible step toward PCOS
The long-term clinical consequences of the hormonal state linked with overweight and obesity “are unknown,” said Dr. Shaw. However, she and her coworkers followed a few of their subjects with elevated testosterone levels during midpuberty, and several developed signs of early polycystic ovarian syndrome (PCOS) such as irregular menstrual cycles, acne, and hirsutism. “It may be possible to identify girls at high risk for PCOS before menarche,” she suggested.
Dr. Burt Solorzano agreed that delayed breast development in girls with high levels of body fat may reflect inadequate progesterone production, which when coupled with an obesity-related excess level of androgens could put girls at risk for chronic anovulation and later PCOS.
“Weight management during childhood and early puberty may mitigate the adverse effects of obesity on pubertal progression and avoid some of the lifetime complications related to early menarche,” Dr. Burt Solorzano said.
The Body Weight and Puberty Study enrolled 36 girls who were overweight or obese and 54 girls with normal weight. They averaged 11 years of age, with a range of 8.2-14.7 years. Average percent body fat was 41% among the overweight or obese girls and 27% among those with normal weight. The results reported by Ms. Ortega also appeared in a report published Feb 22, 2021 (J Clin Endocrinol Metab. doi: 10.1210/clinem/dgab092).
Dr. Shaw, Ms. Ortega, and Dr. Burt Solorzano had no disclosures.
Girls in late stages of puberty who had elevated levels of body fat showed unusually high levels of several hormones that could contribute to an earlier age of menarche and also slow breast development, according to data from 90 girls who spanned a wide range of body fat in the first longitudinal study to examine links between fat volume, levels of reproductive hormones, and clinical manifestations of hormone action during puberty.
The results showed that girls with greater body fat had higher levels of follicle stimulating hormone, inhibin B, estrone, and certain male-like reproductive hormones, and that this pattern “is specifically tied to body fat,” said Natalie D. Shaw, MD, senior investigator for the study, reported at the annual meeting of the Endocrine Society.
“We found that total body fat is associated with the timing of menarche, as others have reported for body weight,” she noted. The new findings showed that every 1% rise in percent total body fat linked with a significant 3% rise in the likelihood of menarche, menstrual onset. In the new study the average age of menarche was 11.7 years among the overweight or obese girls and 12.8 years among those with normal weights.
But the study’s unique use of an average of about three serial ultrasound breast examinations of each subject during an average 4 years of follow-up also showed that higher levels of body fat linked with slowed breast development in later stages, specifically maturation from stage D to stages D/E and E.
For example, girls with 33% body fat spent an average of 8.2 months in stage D, which stretched to an average of 11.2 months among girls with 38% body fat, reported Madison T. Ortega, a researcher with the Pediatric Endocrinology Group of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., who presented the report at the meeting.
Ultrasound shows what inspection can’t
Results from “several studies have shown earlier breast development in overweight and obese girls by inspection and palpation,” but the new findings from ultrasound examination provide more nuance about the structural breast changes actually occurring in these adolescents, said Dr. Shaw, who heads the Pediatric Endocrinology Group. The current study “was not designed to capture the onset of breast development,” and “it is possible that increased androgens or insulin resistance in girls with higher body fat interferes with normal breast development,” she explained in an interview.
“The authors showed that the timing and progress of early stages of puberty were not earlier in overweight or obese girls. Luteinizing hormone, the indicator of neuroendocrine pubertal onset, and timing of early stages of breast development were the same in all weight groups. The authors also discovered falsely advanced Turner breast stage designations with ultrasonography in some girls with obesity. This might suggest that prior findings in epidemiologic studies of an earlier start to puberty based mostly on breast development stages identified by self-reported inspection and, rarely, palpation, may have been biased by breast adipose tissue,” said Christine M. Burt Solorzano, MD, a pediatric endocrinologist at the University of Virginia in Charlottesville, who was not involved in the study.
“Development of increased follicle-stimulating hormone in late puberty suggests that pubertal tempo, not onset, may be increased in girls with obesity, and goes along with earlier menarche. Their finding of increased androgen levels during mid to late puberty with obesity are consistent with prior findings,” including work published Dr. Burt Solorzano and her associates, she noted. “Delayed timing of advanced breast morphology was unexpected and may reflect relatively lower levels of progesterone in girls with obesity,” a hormone necessary for later stages of breast maturation.
The findings “reinforce that early breast development in the setting of obesity may in fact reflect adipose tissue and not be a true representation of neuroendocrine precocious puberty,” Dr. Burt Solorzano said in an interview. The findings “also suggest that pubertal initiation may not happen earlier in girls with obesity, as has been thought, but rather the tempo of puberty may be more rapid, leading to earlier menarche.”
A possible step toward PCOS
The long-term clinical consequences of the hormonal state linked with overweight and obesity “are unknown,” said Dr. Shaw. However, she and her coworkers followed a few of their subjects with elevated testosterone levels during midpuberty, and several developed signs of early polycystic ovarian syndrome (PCOS) such as irregular menstrual cycles, acne, and hirsutism. “It may be possible to identify girls at high risk for PCOS before menarche,” she suggested.
Dr. Burt Solorzano agreed that delayed breast development in girls with high levels of body fat may reflect inadequate progesterone production, which when coupled with an obesity-related excess level of androgens could put girls at risk for chronic anovulation and later PCOS.
“Weight management during childhood and early puberty may mitigate the adverse effects of obesity on pubertal progression and avoid some of the lifetime complications related to early menarche,” Dr. Burt Solorzano said.
The Body Weight and Puberty Study enrolled 36 girls who were overweight or obese and 54 girls with normal weight. They averaged 11 years of age, with a range of 8.2-14.7 years. Average percent body fat was 41% among the overweight or obese girls and 27% among those with normal weight. The results reported by Ms. Ortega also appeared in a report published Feb 22, 2021 (J Clin Endocrinol Metab. doi: 10.1210/clinem/dgab092).
Dr. Shaw, Ms. Ortega, and Dr. Burt Solorzano had no disclosures.
Girls in late stages of puberty who had elevated levels of body fat showed unusually high levels of several hormones that could contribute to an earlier age of menarche and also slow breast development, according to data from 90 girls who spanned a wide range of body fat in the first longitudinal study to examine links between fat volume, levels of reproductive hormones, and clinical manifestations of hormone action during puberty.
The results showed that girls with greater body fat had higher levels of follicle stimulating hormone, inhibin B, estrone, and certain male-like reproductive hormones, and that this pattern “is specifically tied to body fat,” said Natalie D. Shaw, MD, senior investigator for the study, reported at the annual meeting of the Endocrine Society.
“We found that total body fat is associated with the timing of menarche, as others have reported for body weight,” she noted. The new findings showed that every 1% rise in percent total body fat linked with a significant 3% rise in the likelihood of menarche, menstrual onset. In the new study the average age of menarche was 11.7 years among the overweight or obese girls and 12.8 years among those with normal weights.
But the study’s unique use of an average of about three serial ultrasound breast examinations of each subject during an average 4 years of follow-up also showed that higher levels of body fat linked with slowed breast development in later stages, specifically maturation from stage D to stages D/E and E.
For example, girls with 33% body fat spent an average of 8.2 months in stage D, which stretched to an average of 11.2 months among girls with 38% body fat, reported Madison T. Ortega, a researcher with the Pediatric Endocrinology Group of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., who presented the report at the meeting.
Ultrasound shows what inspection can’t
Results from “several studies have shown earlier breast development in overweight and obese girls by inspection and palpation,” but the new findings from ultrasound examination provide more nuance about the structural breast changes actually occurring in these adolescents, said Dr. Shaw, who heads the Pediatric Endocrinology Group. The current study “was not designed to capture the onset of breast development,” and “it is possible that increased androgens or insulin resistance in girls with higher body fat interferes with normal breast development,” she explained in an interview.
“The authors showed that the timing and progress of early stages of puberty were not earlier in overweight or obese girls. Luteinizing hormone, the indicator of neuroendocrine pubertal onset, and timing of early stages of breast development were the same in all weight groups. The authors also discovered falsely advanced Turner breast stage designations with ultrasonography in some girls with obesity. This might suggest that prior findings in epidemiologic studies of an earlier start to puberty based mostly on breast development stages identified by self-reported inspection and, rarely, palpation, may have been biased by breast adipose tissue,” said Christine M. Burt Solorzano, MD, a pediatric endocrinologist at the University of Virginia in Charlottesville, who was not involved in the study.
“Development of increased follicle-stimulating hormone in late puberty suggests that pubertal tempo, not onset, may be increased in girls with obesity, and goes along with earlier menarche. Their finding of increased androgen levels during mid to late puberty with obesity are consistent with prior findings,” including work published Dr. Burt Solorzano and her associates, she noted. “Delayed timing of advanced breast morphology was unexpected and may reflect relatively lower levels of progesterone in girls with obesity,” a hormone necessary for later stages of breast maturation.
The findings “reinforce that early breast development in the setting of obesity may in fact reflect adipose tissue and not be a true representation of neuroendocrine precocious puberty,” Dr. Burt Solorzano said in an interview. The findings “also suggest that pubertal initiation may not happen earlier in girls with obesity, as has been thought, but rather the tempo of puberty may be more rapid, leading to earlier menarche.”
A possible step toward PCOS
The long-term clinical consequences of the hormonal state linked with overweight and obesity “are unknown,” said Dr. Shaw. However, she and her coworkers followed a few of their subjects with elevated testosterone levels during midpuberty, and several developed signs of early polycystic ovarian syndrome (PCOS) such as irregular menstrual cycles, acne, and hirsutism. “It may be possible to identify girls at high risk for PCOS before menarche,” she suggested.
Dr. Burt Solorzano agreed that delayed breast development in girls with high levels of body fat may reflect inadequate progesterone production, which when coupled with an obesity-related excess level of androgens could put girls at risk for chronic anovulation and later PCOS.
“Weight management during childhood and early puberty may mitigate the adverse effects of obesity on pubertal progression and avoid some of the lifetime complications related to early menarche,” Dr. Burt Solorzano said.
The Body Weight and Puberty Study enrolled 36 girls who were overweight or obese and 54 girls with normal weight. They averaged 11 years of age, with a range of 8.2-14.7 years. Average percent body fat was 41% among the overweight or obese girls and 27% among those with normal weight. The results reported by Ms. Ortega also appeared in a report published Feb 22, 2021 (J Clin Endocrinol Metab. doi: 10.1210/clinem/dgab092).
Dr. Shaw, Ms. Ortega, and Dr. Burt Solorzano had no disclosures.
FROM ENDO 2021
Preimplantation genetic testing for aneuploidy
Why does the debate linger after 30 years?
The holy grail of assisted reproductive technology (ART) is the delivery of a healthy child. From the world’s first successful ART cycle of in vitro fertilization in 1978 (3 years later in the United States), the goal of every cycle is to provide the woman with an embryo that has the highest potential for implantation and, ultimately, a single live birth.
Embryo aneuploidy is a major factor in the success of human reproduction. As women age, aneuploidy is reported in less than 30% of women aged younger than 35 years but rises to 90% for those in their mid-40s. Intuitively and through randomized, controlled trials, chromosome testing of embryos is a reasonable approach toward improved cycle outcomes and allows for the transfer of a single euploid embryo.
Recently, the phrase “add-ons” has entered the vernacular of editorials on IVF. These additional procedures are offered to patients with the expectation of improving results, yet many have not been supported by rigorous scientifically controlled research trials, e.g., endometrial scratch, embryo glue, and time-lapse imaging of embryos. Where does preimplantation genetic testing (PGT) belong in the IVF armamentarium and why, after 30 years, are there two diametrically opposed views on its benefit? (We will not address testing for single gene defects or chromosome structural rearrangements.)
How did we get here?
The first iteration of PGT used fluorescence in situ hybridization to not only identify X-linked recessive diseases (Hum Genet. 1992;89:18-22) but also the most common chromosome disorders (13, 18, 21, X, Y) by removing one to two blastomere cells from a day 3 embryo (six- to eight-cell stage). Despite wide enthusiasm, the technique was eventually determined to reduce implantation by nearly 40% and was abandoned; presumably impairing the embryo by removing up to one-third of its make-up.
Because of extended embryo culture to the blastocyst stage along with the improved cryopreservation process of vitrification, the next generation of embryo analysis surfaced, what we now refer to as PGT 2.0. Currently, approximately five to six cells from the outer embryo trophectoderm are removed and sent to a specialized laboratory for 24-chromosome screening while the biopsied embryos are cryopreserved. Outcome data (aneuploidy rates, mosaicism) have been influenced by the evolution of genetic platforms – from array comparative genome hybridization to single-nucleotide polymorphism array, to quantitative polymerase chain reaction, to next-generation sequencing (NGS). The newest platform, NGS with high resolution, provides the most extensive degree of analysis by detecting unbalanced translocations and a low cut-off percentage for mosaicism (20%). The clinical error rate is approximately 1%-2%, improved from the 2%-4% of earlier techniques.
The phenomenon of mosaicism describes two distinct cell lines in one embryo (typically one normal and one abnormal) and is defined based on the percentage of mosaicism – currently, the lower limit is 20%. Embryos with less than 20%-30% mosaicism are considered euploid and those greater than 70%-80% are aneuploid. Of note, clinics that do not request the reporting of mosaicism can result in the potential discarding of embryos labeled as aneuploid that would otherwise have potentially resulted in a live birth. The higher the cut-off value for designating mosaicism, the lower the false-positive rate (declaring an embryo aneuploid when euploid). While there is no safe degree of mosaicism, most transfers have resulted in chromosomally normal infants despite a lower implantation rate and higher miscarriage rate.
Current status
The greatest advantage of PGT for aneuploidy (PGT-A) is its increase in promoting a single embryo transfer. Medical evidence supports pregnancy outcomes equivalent from a single euploid embryo transfer versus a double “untested” embryo transfer.
Only a handful of randomized, controlled trials have evaluated the efficacy of PGT-A. Outcomes have favored improved live birth rates; however, criticism exists for enrolling only good prognosis patients given their high likelihood of developing blastocyst embryos to biopsy. The only trial that used an “intention to treat” protocol (rather than randomization at the time of biopsy) did not demonstrate any difference in live birth or miscarriage comparing embryo selection by PGT-A versus embryo morphology alone. However, post hoc analysis did show a benefit with PGT-A in the 35- to 40-year-old age group, not in the less than 35-year-old group. All other trials demonstrated a reduction in miscarriage with PGT-A but only as a secondary outcome.
The medical literature does not support PGT-A to manage patients with recurrent pregnancy loss and there is no evidence for improvement in women aged less than 35 years or egg donors (F&S Reports. 2021;2:36-42). PGT-A has been effective in patients wishing family balancing.
Controversy
Enthusiasm for PGT-A is countered by lingering concerns. Trophectoderm cells are not in 100% concordance with the inner cell mass, which presumably explains the reports of chromosomally normal live births from the transfer of aneuploid embryos. Biopsy techniques among embryologists are not standardized. As a result, damage to the embryo has been raised as a possible explanation for equivalent pregnancy rates in studies showing no superiority of PGT-A in pregnancy outcome, although this point has recently been refuted.
PGT-A also embraces the “blast-or-bust” credo whereby no embryo transfer occurs unless a blastocyst embryo develops. This continues to beg the unanswerable question – would a woman who did not develop a blastocyst embryo for potential biopsy still conceive if she underwent a day 3 cleavage stage embryo transfer?
Future
Exciting iterations are encroaching for PGT 3.0. One method is blastocyst fluid aspiration to obtain DNA suitable for analysis by molecular genetic methods. Another is noninvasive PGT whereby spent media from the embryo is analyzed using cell-free DNA. Concordance with inner cell mass is reasonably good (approximately 85%) but needs to improve. A major advantage is the biopsy skill set among embryologists is eliminated. A criticism of noninvasive PGT is the risk of false-positive results from contamination of aneuploid cell secretion by physiologic apoptotic cells. Confined placental mosaicism can also increase aneuploidy in cell-free DNA thereby contributing to false positives.
Conclusion
PGT-A is robust technology that appears to benefit women aged above 35 years but not the general infertile population. Error rates must be consistent among laboratories and be lowered. Regarding mosaic embryos, the American Society for Reproductive Medicine guidelines recommend offering another egg retrieval if only mosaic embryos are available and to only consider mosaic embryo transfer following extensive genetic counseling. Long-term effects of PGT-A on children are lacking. The Cochrane Database concluded there was insufficient evidence to make PGT-A routine.
So, the debate is clear and ongoing – universal versus discretionary use of PGT-A? As in all things of life, one size does not fit all, and PGT-A is no exception.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Contact him at obnews@mdedge.com.
Why does the debate linger after 30 years?
Why does the debate linger after 30 years?
The holy grail of assisted reproductive technology (ART) is the delivery of a healthy child. From the world’s first successful ART cycle of in vitro fertilization in 1978 (3 years later in the United States), the goal of every cycle is to provide the woman with an embryo that has the highest potential for implantation and, ultimately, a single live birth.
Embryo aneuploidy is a major factor in the success of human reproduction. As women age, aneuploidy is reported in less than 30% of women aged younger than 35 years but rises to 90% for those in their mid-40s. Intuitively and through randomized, controlled trials, chromosome testing of embryos is a reasonable approach toward improved cycle outcomes and allows for the transfer of a single euploid embryo.
Recently, the phrase “add-ons” has entered the vernacular of editorials on IVF. These additional procedures are offered to patients with the expectation of improving results, yet many have not been supported by rigorous scientifically controlled research trials, e.g., endometrial scratch, embryo glue, and time-lapse imaging of embryos. Where does preimplantation genetic testing (PGT) belong in the IVF armamentarium and why, after 30 years, are there two diametrically opposed views on its benefit? (We will not address testing for single gene defects or chromosome structural rearrangements.)
How did we get here?
The first iteration of PGT used fluorescence in situ hybridization to not only identify X-linked recessive diseases (Hum Genet. 1992;89:18-22) but also the most common chromosome disorders (13, 18, 21, X, Y) by removing one to two blastomere cells from a day 3 embryo (six- to eight-cell stage). Despite wide enthusiasm, the technique was eventually determined to reduce implantation by nearly 40% and was abandoned; presumably impairing the embryo by removing up to one-third of its make-up.
Because of extended embryo culture to the blastocyst stage along with the improved cryopreservation process of vitrification, the next generation of embryo analysis surfaced, what we now refer to as PGT 2.0. Currently, approximately five to six cells from the outer embryo trophectoderm are removed and sent to a specialized laboratory for 24-chromosome screening while the biopsied embryos are cryopreserved. Outcome data (aneuploidy rates, mosaicism) have been influenced by the evolution of genetic platforms – from array comparative genome hybridization to single-nucleotide polymorphism array, to quantitative polymerase chain reaction, to next-generation sequencing (NGS). The newest platform, NGS with high resolution, provides the most extensive degree of analysis by detecting unbalanced translocations and a low cut-off percentage for mosaicism (20%). The clinical error rate is approximately 1%-2%, improved from the 2%-4% of earlier techniques.
The phenomenon of mosaicism describes two distinct cell lines in one embryo (typically one normal and one abnormal) and is defined based on the percentage of mosaicism – currently, the lower limit is 20%. Embryos with less than 20%-30% mosaicism are considered euploid and those greater than 70%-80% are aneuploid. Of note, clinics that do not request the reporting of mosaicism can result in the potential discarding of embryos labeled as aneuploid that would otherwise have potentially resulted in a live birth. The higher the cut-off value for designating mosaicism, the lower the false-positive rate (declaring an embryo aneuploid when euploid). While there is no safe degree of mosaicism, most transfers have resulted in chromosomally normal infants despite a lower implantation rate and higher miscarriage rate.
Current status
The greatest advantage of PGT for aneuploidy (PGT-A) is its increase in promoting a single embryo transfer. Medical evidence supports pregnancy outcomes equivalent from a single euploid embryo transfer versus a double “untested” embryo transfer.
Only a handful of randomized, controlled trials have evaluated the efficacy of PGT-A. Outcomes have favored improved live birth rates; however, criticism exists for enrolling only good prognosis patients given their high likelihood of developing blastocyst embryos to biopsy. The only trial that used an “intention to treat” protocol (rather than randomization at the time of biopsy) did not demonstrate any difference in live birth or miscarriage comparing embryo selection by PGT-A versus embryo morphology alone. However, post hoc analysis did show a benefit with PGT-A in the 35- to 40-year-old age group, not in the less than 35-year-old group. All other trials demonstrated a reduction in miscarriage with PGT-A but only as a secondary outcome.
The medical literature does not support PGT-A to manage patients with recurrent pregnancy loss and there is no evidence for improvement in women aged less than 35 years or egg donors (F&S Reports. 2021;2:36-42). PGT-A has been effective in patients wishing family balancing.
Controversy
Enthusiasm for PGT-A is countered by lingering concerns. Trophectoderm cells are not in 100% concordance with the inner cell mass, which presumably explains the reports of chromosomally normal live births from the transfer of aneuploid embryos. Biopsy techniques among embryologists are not standardized. As a result, damage to the embryo has been raised as a possible explanation for equivalent pregnancy rates in studies showing no superiority of PGT-A in pregnancy outcome, although this point has recently been refuted.
PGT-A also embraces the “blast-or-bust” credo whereby no embryo transfer occurs unless a blastocyst embryo develops. This continues to beg the unanswerable question – would a woman who did not develop a blastocyst embryo for potential biopsy still conceive if she underwent a day 3 cleavage stage embryo transfer?
Future
Exciting iterations are encroaching for PGT 3.0. One method is blastocyst fluid aspiration to obtain DNA suitable for analysis by molecular genetic methods. Another is noninvasive PGT whereby spent media from the embryo is analyzed using cell-free DNA. Concordance with inner cell mass is reasonably good (approximately 85%) but needs to improve. A major advantage is the biopsy skill set among embryologists is eliminated. A criticism of noninvasive PGT is the risk of false-positive results from contamination of aneuploid cell secretion by physiologic apoptotic cells. Confined placental mosaicism can also increase aneuploidy in cell-free DNA thereby contributing to false positives.
Conclusion
PGT-A is robust technology that appears to benefit women aged above 35 years but not the general infertile population. Error rates must be consistent among laboratories and be lowered. Regarding mosaic embryos, the American Society for Reproductive Medicine guidelines recommend offering another egg retrieval if only mosaic embryos are available and to only consider mosaic embryo transfer following extensive genetic counseling. Long-term effects of PGT-A on children are lacking. The Cochrane Database concluded there was insufficient evidence to make PGT-A routine.
So, the debate is clear and ongoing – universal versus discretionary use of PGT-A? As in all things of life, one size does not fit all, and PGT-A is no exception.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Contact him at obnews@mdedge.com.
The holy grail of assisted reproductive technology (ART) is the delivery of a healthy child. From the world’s first successful ART cycle of in vitro fertilization in 1978 (3 years later in the United States), the goal of every cycle is to provide the woman with an embryo that has the highest potential for implantation and, ultimately, a single live birth.
Embryo aneuploidy is a major factor in the success of human reproduction. As women age, aneuploidy is reported in less than 30% of women aged younger than 35 years but rises to 90% for those in their mid-40s. Intuitively and through randomized, controlled trials, chromosome testing of embryos is a reasonable approach toward improved cycle outcomes and allows for the transfer of a single euploid embryo.
Recently, the phrase “add-ons” has entered the vernacular of editorials on IVF. These additional procedures are offered to patients with the expectation of improving results, yet many have not been supported by rigorous scientifically controlled research trials, e.g., endometrial scratch, embryo glue, and time-lapse imaging of embryos. Where does preimplantation genetic testing (PGT) belong in the IVF armamentarium and why, after 30 years, are there two diametrically opposed views on its benefit? (We will not address testing for single gene defects or chromosome structural rearrangements.)
How did we get here?
The first iteration of PGT used fluorescence in situ hybridization to not only identify X-linked recessive diseases (Hum Genet. 1992;89:18-22) but also the most common chromosome disorders (13, 18, 21, X, Y) by removing one to two blastomere cells from a day 3 embryo (six- to eight-cell stage). Despite wide enthusiasm, the technique was eventually determined to reduce implantation by nearly 40% and was abandoned; presumably impairing the embryo by removing up to one-third of its make-up.
Because of extended embryo culture to the blastocyst stage along with the improved cryopreservation process of vitrification, the next generation of embryo analysis surfaced, what we now refer to as PGT 2.0. Currently, approximately five to six cells from the outer embryo trophectoderm are removed and sent to a specialized laboratory for 24-chromosome screening while the biopsied embryos are cryopreserved. Outcome data (aneuploidy rates, mosaicism) have been influenced by the evolution of genetic platforms – from array comparative genome hybridization to single-nucleotide polymorphism array, to quantitative polymerase chain reaction, to next-generation sequencing (NGS). The newest platform, NGS with high resolution, provides the most extensive degree of analysis by detecting unbalanced translocations and a low cut-off percentage for mosaicism (20%). The clinical error rate is approximately 1%-2%, improved from the 2%-4% of earlier techniques.
The phenomenon of mosaicism describes two distinct cell lines in one embryo (typically one normal and one abnormal) and is defined based on the percentage of mosaicism – currently, the lower limit is 20%. Embryos with less than 20%-30% mosaicism are considered euploid and those greater than 70%-80% are aneuploid. Of note, clinics that do not request the reporting of mosaicism can result in the potential discarding of embryos labeled as aneuploid that would otherwise have potentially resulted in a live birth. The higher the cut-off value for designating mosaicism, the lower the false-positive rate (declaring an embryo aneuploid when euploid). While there is no safe degree of mosaicism, most transfers have resulted in chromosomally normal infants despite a lower implantation rate and higher miscarriage rate.
Current status
The greatest advantage of PGT for aneuploidy (PGT-A) is its increase in promoting a single embryo transfer. Medical evidence supports pregnancy outcomes equivalent from a single euploid embryo transfer versus a double “untested” embryo transfer.
Only a handful of randomized, controlled trials have evaluated the efficacy of PGT-A. Outcomes have favored improved live birth rates; however, criticism exists for enrolling only good prognosis patients given their high likelihood of developing blastocyst embryos to biopsy. The only trial that used an “intention to treat” protocol (rather than randomization at the time of biopsy) did not demonstrate any difference in live birth or miscarriage comparing embryo selection by PGT-A versus embryo morphology alone. However, post hoc analysis did show a benefit with PGT-A in the 35- to 40-year-old age group, not in the less than 35-year-old group. All other trials demonstrated a reduction in miscarriage with PGT-A but only as a secondary outcome.
The medical literature does not support PGT-A to manage patients with recurrent pregnancy loss and there is no evidence for improvement in women aged less than 35 years or egg donors (F&S Reports. 2021;2:36-42). PGT-A has been effective in patients wishing family balancing.
Controversy
Enthusiasm for PGT-A is countered by lingering concerns. Trophectoderm cells are not in 100% concordance with the inner cell mass, which presumably explains the reports of chromosomally normal live births from the transfer of aneuploid embryos. Biopsy techniques among embryologists are not standardized. As a result, damage to the embryo has been raised as a possible explanation for equivalent pregnancy rates in studies showing no superiority of PGT-A in pregnancy outcome, although this point has recently been refuted.
PGT-A also embraces the “blast-or-bust” credo whereby no embryo transfer occurs unless a blastocyst embryo develops. This continues to beg the unanswerable question – would a woman who did not develop a blastocyst embryo for potential biopsy still conceive if she underwent a day 3 cleavage stage embryo transfer?
Future
Exciting iterations are encroaching for PGT 3.0. One method is blastocyst fluid aspiration to obtain DNA suitable for analysis by molecular genetic methods. Another is noninvasive PGT whereby spent media from the embryo is analyzed using cell-free DNA. Concordance with inner cell mass is reasonably good (approximately 85%) but needs to improve. A major advantage is the biopsy skill set among embryologists is eliminated. A criticism of noninvasive PGT is the risk of false-positive results from contamination of aneuploid cell secretion by physiologic apoptotic cells. Confined placental mosaicism can also increase aneuploidy in cell-free DNA thereby contributing to false positives.
Conclusion
PGT-A is robust technology that appears to benefit women aged above 35 years but not the general infertile population. Error rates must be consistent among laboratories and be lowered. Regarding mosaic embryos, the American Society for Reproductive Medicine guidelines recommend offering another egg retrieval if only mosaic embryos are available and to only consider mosaic embryo transfer following extensive genetic counseling. Long-term effects of PGT-A on children are lacking. The Cochrane Database concluded there was insufficient evidence to make PGT-A routine.
So, the debate is clear and ongoing – universal versus discretionary use of PGT-A? As in all things of life, one size does not fit all, and PGT-A is no exception.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Contact him at obnews@mdedge.com.
Oral contraceptive with new estrogen earns approval
The Food and Drug Administration has approved a new estrogen for the first time in more than 50 years.
The novel combined oral contraceptive, marketed as Nextstellis, contains 3 mg drospirenone (DRSP) and 14.2 mg of estetrol (E4) in tablet form. Estetrol is an estrogen that is naturally produced during pregnancy, but will now be produced from a plant source; it has not previously been used in oral contraceptives.
Approval of the unique estetrol/drospirenone combination was based on data from a pair of phase 3 clinical trials including 3,725 women. Overall, Nextstellis was safe and effective while meeting its primary endpoint of pregnancy prevention, according to a company press release. Participants also reported favorable results on secondary endpoints including cycle control, bleeding profile, safety, and tolerability.
Although many women take short-acting contraceptives containing estrogen and progestin, concerns persist about side effects, said Mitchell Creinin, MD, of the University of California, in the press release. In addition to providing effective contraception, the drug showed minimal impact on specific markers of concern, including triglycerides, cholesterol, and glucose, as well as weight and endocrine markers, Dr. Creinin said.
Nextstellis was developed by the Belgian biotech company Mithra Pharmaceuticals, and the drug is licensed for distribution in Australia and the United States by Mayne Pharma, with an expected launch at the end of June 2021.
The Food and Drug Administration has approved a new estrogen for the first time in more than 50 years.
The novel combined oral contraceptive, marketed as Nextstellis, contains 3 mg drospirenone (DRSP) and 14.2 mg of estetrol (E4) in tablet form. Estetrol is an estrogen that is naturally produced during pregnancy, but will now be produced from a plant source; it has not previously been used in oral contraceptives.
Approval of the unique estetrol/drospirenone combination was based on data from a pair of phase 3 clinical trials including 3,725 women. Overall, Nextstellis was safe and effective while meeting its primary endpoint of pregnancy prevention, according to a company press release. Participants also reported favorable results on secondary endpoints including cycle control, bleeding profile, safety, and tolerability.
Although many women take short-acting contraceptives containing estrogen and progestin, concerns persist about side effects, said Mitchell Creinin, MD, of the University of California, in the press release. In addition to providing effective contraception, the drug showed minimal impact on specific markers of concern, including triglycerides, cholesterol, and glucose, as well as weight and endocrine markers, Dr. Creinin said.
Nextstellis was developed by the Belgian biotech company Mithra Pharmaceuticals, and the drug is licensed for distribution in Australia and the United States by Mayne Pharma, with an expected launch at the end of June 2021.
The Food and Drug Administration has approved a new estrogen for the first time in more than 50 years.
The novel combined oral contraceptive, marketed as Nextstellis, contains 3 mg drospirenone (DRSP) and 14.2 mg of estetrol (E4) in tablet form. Estetrol is an estrogen that is naturally produced during pregnancy, but will now be produced from a plant source; it has not previously been used in oral contraceptives.
Approval of the unique estetrol/drospirenone combination was based on data from a pair of phase 3 clinical trials including 3,725 women. Overall, Nextstellis was safe and effective while meeting its primary endpoint of pregnancy prevention, according to a company press release. Participants also reported favorable results on secondary endpoints including cycle control, bleeding profile, safety, and tolerability.
Although many women take short-acting contraceptives containing estrogen and progestin, concerns persist about side effects, said Mitchell Creinin, MD, of the University of California, in the press release. In addition to providing effective contraception, the drug showed minimal impact on specific markers of concern, including triglycerides, cholesterol, and glucose, as well as weight and endocrine markers, Dr. Creinin said.
Nextstellis was developed by the Belgian biotech company Mithra Pharmaceuticals, and the drug is licensed for distribution in Australia and the United States by Mayne Pharma, with an expected launch at the end of June 2021.
Pregnancy after pioneering treatment for early menopause
A novel therapy combining platelet-rich plasma (PRP) with follicle-stimulating hormone that is injected directly into the ovaries has the potential to restore ovarian function for women who experience early menopause, possibly allowing for pregnancy without the need for donor eggs.
“The resumption of ovarian function in our participants means women with early menopause could have the opportunity to pursue pregnancy through IVF [in vitro fertilization] using their own eggs,” the authors of the groundbreaking pilot study report.
In the small study, published online March 29 in Menopause, menstruation resumed within a mean of about 5 weeks for 11 of 12 patients with early menopause who were treated with the technique. One patient achieved a clinical pregnancy.
In commenting on the study, Stephanie S. Faubion, MD, medical director of the North American Menopause Society, was cautious in her interpretation, noting the need for more research in larger samples.
“Any pregnancy that results from a regenerative therapy is novel,” she told this news organization. “Still, we are a long way away from this being a standard therapy for women with premature ovarian insufficiency.”
Pilot study: Platelet-rich plasma combination with FSH
Early menopause is the cessation of ovarian function at or before the age of 45 years. It is estimated that 12.2% of women experience early menopause. For these women, currently, the only chance of becoming pregnant is with donor eggs.
PRP, an autologous plasma preparation containing more than 10 times the concentration of growth factors and active metabolites than normal plasma, has recently been shown to have the potential to restore the menstrual cycles in perimenopausal women, allowing IVF. It has also been shown to benefit women with premature ovarian insufficiency (POI). However, there have been few reports of pregnancies or live births.
Chao Chin Hsu, MD, PhD, of the National Taiwan University Hospital, Taipei, and colleagues investigated whether the combination of the activated PRP treatment with gondatrophins such as FSH could provide a more robust effect so as to sufficiently stimulate follicles. They used the intraovarian injection of the combination to treat a 38-year-old woman with POI.
The effort was successful, and the woman gave birth to healthy twins.
To further evaluate the approach, the authors conducted a pilot study involving 12 women with early menopause (mean age, 44.4 years) between November 2018 and November 2019.
The women received intraovarian injection with PRP prepared from 40 mL of autologous peripheral blood combined with recombinant FSH.
Following the treatment, 11 of the 12 women experienced resumption of menstruation within a mean of 37 days. For seven patients, menstruation resumed within a month; for three, it resumed within about 2 months; and for one, it resumed after approximately 3 months.
Of note, the menstrual cycles were mostly irregular, with an interval of about 45.6 days.
The women’s average serum FSH level dropped significantly from 70.5 IU/L at baseline to 26.2 IU/L within days of treatment, as did the average luteinizing hormone level (34.8 before and 14.3 IU/L after treatment), indicative of improved ovary function.
For six participants, 10 oocyte retrieval procedures were performed after a mean of about 2 months. Thirteen mature eggs were retrieved, and fertilization via intracytoplasmic sperm injection was attempted, resulting in 10 fertilized oocytes.
Cleavage-stage embryos were transferred into two of the participants. One achieved a clinical pregnancy, defined as a pregnancy that was confirmed by ultrasound and by the presence of a fetal heartbeat. The pregnancy ended in miscarriage at 7 weeks’ gestation.
The length of controlled ovarian stimulation necessary for follicle growth ranged from 8 to 14 days, which the authors note is similar to that seen with women of normal reproductive age.
“Although the use of PRP in reproductive medicine is considered experimental, we demonstrated the restoration of ovarian function in early menopausal women who adopted whole dimension subcortical ovarian injection of PRP/gonadotropin,” the authors write.
“Most remarkably, an early menopausal woman achieved pregnancy after the treatment followed by IVF with her mature ovulating follicle,” they report.
Mechanisms, caveats
The mechanisms thought to underlie the success of the approach include increases in ovarian vascularization and stromal cell proliferation and reductions in oxidative stress and cell death in ovaries, the authors explain.
Key caveats with the treatment include the fact that anesthesia and laparoscopy are required, and precise administration is required at 15 injection sites in 1-2 mm of the ovarian subcortical area, which can be difficult to achieve, Dr. Hsu said in an interview.
“If a new instrument could be developed in which physicians can carry out this treatment through a vaginal approach, like the transvaginal retrieval of eggs in IVF treatments,” the approach could become more acceptable, Dr. Hsu added.
The authors call for studies with larger sample sizes and say it will also be interesting to determine effects in different groups: For example, women with cancer who have undergone chemotherapy.
Dr. Faubion, who is director of the Mayo Clinic Women’s Health, Rochester, Minn., says the causes of early menopause could be important in determining the treatment’s efficacy.
“[The therapy’s] success may depend on the reason the woman experienced early menopause: For instance, due to chemotherapy, radiation, virus, autoimmune disease, genetic mutation, or other cause,” she said.
She also noted that cost could be an important factor.
“I don’t see a cost estimate, but it will be substantial,” she said. “So, even if the success rate improves as this technique is further studied, cost and the invasive nature of the treatment may prove to be substantial barriers to this therapy becoming mainstream,” she said.
The authors and Dr. Faubion have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A novel therapy combining platelet-rich plasma (PRP) with follicle-stimulating hormone that is injected directly into the ovaries has the potential to restore ovarian function for women who experience early menopause, possibly allowing for pregnancy without the need for donor eggs.
“The resumption of ovarian function in our participants means women with early menopause could have the opportunity to pursue pregnancy through IVF [in vitro fertilization] using their own eggs,” the authors of the groundbreaking pilot study report.
In the small study, published online March 29 in Menopause, menstruation resumed within a mean of about 5 weeks for 11 of 12 patients with early menopause who were treated with the technique. One patient achieved a clinical pregnancy.
In commenting on the study, Stephanie S. Faubion, MD, medical director of the North American Menopause Society, was cautious in her interpretation, noting the need for more research in larger samples.
“Any pregnancy that results from a regenerative therapy is novel,” she told this news organization. “Still, we are a long way away from this being a standard therapy for women with premature ovarian insufficiency.”
Pilot study: Platelet-rich plasma combination with FSH
Early menopause is the cessation of ovarian function at or before the age of 45 years. It is estimated that 12.2% of women experience early menopause. For these women, currently, the only chance of becoming pregnant is with donor eggs.
PRP, an autologous plasma preparation containing more than 10 times the concentration of growth factors and active metabolites than normal plasma, has recently been shown to have the potential to restore the menstrual cycles in perimenopausal women, allowing IVF. It has also been shown to benefit women with premature ovarian insufficiency (POI). However, there have been few reports of pregnancies or live births.
Chao Chin Hsu, MD, PhD, of the National Taiwan University Hospital, Taipei, and colleagues investigated whether the combination of the activated PRP treatment with gondatrophins such as FSH could provide a more robust effect so as to sufficiently stimulate follicles. They used the intraovarian injection of the combination to treat a 38-year-old woman with POI.
The effort was successful, and the woman gave birth to healthy twins.
To further evaluate the approach, the authors conducted a pilot study involving 12 women with early menopause (mean age, 44.4 years) between November 2018 and November 2019.
The women received intraovarian injection with PRP prepared from 40 mL of autologous peripheral blood combined with recombinant FSH.
Following the treatment, 11 of the 12 women experienced resumption of menstruation within a mean of 37 days. For seven patients, menstruation resumed within a month; for three, it resumed within about 2 months; and for one, it resumed after approximately 3 months.
Of note, the menstrual cycles were mostly irregular, with an interval of about 45.6 days.
The women’s average serum FSH level dropped significantly from 70.5 IU/L at baseline to 26.2 IU/L within days of treatment, as did the average luteinizing hormone level (34.8 before and 14.3 IU/L after treatment), indicative of improved ovary function.
For six participants, 10 oocyte retrieval procedures were performed after a mean of about 2 months. Thirteen mature eggs were retrieved, and fertilization via intracytoplasmic sperm injection was attempted, resulting in 10 fertilized oocytes.
Cleavage-stage embryos were transferred into two of the participants. One achieved a clinical pregnancy, defined as a pregnancy that was confirmed by ultrasound and by the presence of a fetal heartbeat. The pregnancy ended in miscarriage at 7 weeks’ gestation.
The length of controlled ovarian stimulation necessary for follicle growth ranged from 8 to 14 days, which the authors note is similar to that seen with women of normal reproductive age.
“Although the use of PRP in reproductive medicine is considered experimental, we demonstrated the restoration of ovarian function in early menopausal women who adopted whole dimension subcortical ovarian injection of PRP/gonadotropin,” the authors write.
“Most remarkably, an early menopausal woman achieved pregnancy after the treatment followed by IVF with her mature ovulating follicle,” they report.
Mechanisms, caveats
The mechanisms thought to underlie the success of the approach include increases in ovarian vascularization and stromal cell proliferation and reductions in oxidative stress and cell death in ovaries, the authors explain.
Key caveats with the treatment include the fact that anesthesia and laparoscopy are required, and precise administration is required at 15 injection sites in 1-2 mm of the ovarian subcortical area, which can be difficult to achieve, Dr. Hsu said in an interview.
“If a new instrument could be developed in which physicians can carry out this treatment through a vaginal approach, like the transvaginal retrieval of eggs in IVF treatments,” the approach could become more acceptable, Dr. Hsu added.
The authors call for studies with larger sample sizes and say it will also be interesting to determine effects in different groups: For example, women with cancer who have undergone chemotherapy.
Dr. Faubion, who is director of the Mayo Clinic Women’s Health, Rochester, Minn., says the causes of early menopause could be important in determining the treatment’s efficacy.
“[The therapy’s] success may depend on the reason the woman experienced early menopause: For instance, due to chemotherapy, radiation, virus, autoimmune disease, genetic mutation, or other cause,” she said.
She also noted that cost could be an important factor.
“I don’t see a cost estimate, but it will be substantial,” she said. “So, even if the success rate improves as this technique is further studied, cost and the invasive nature of the treatment may prove to be substantial barriers to this therapy becoming mainstream,” she said.
The authors and Dr. Faubion have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A novel therapy combining platelet-rich plasma (PRP) with follicle-stimulating hormone that is injected directly into the ovaries has the potential to restore ovarian function for women who experience early menopause, possibly allowing for pregnancy without the need for donor eggs.
“The resumption of ovarian function in our participants means women with early menopause could have the opportunity to pursue pregnancy through IVF [in vitro fertilization] using their own eggs,” the authors of the groundbreaking pilot study report.
In the small study, published online March 29 in Menopause, menstruation resumed within a mean of about 5 weeks for 11 of 12 patients with early menopause who were treated with the technique. One patient achieved a clinical pregnancy.
In commenting on the study, Stephanie S. Faubion, MD, medical director of the North American Menopause Society, was cautious in her interpretation, noting the need for more research in larger samples.
“Any pregnancy that results from a regenerative therapy is novel,” she told this news organization. “Still, we are a long way away from this being a standard therapy for women with premature ovarian insufficiency.”
Pilot study: Platelet-rich plasma combination with FSH
Early menopause is the cessation of ovarian function at or before the age of 45 years. It is estimated that 12.2% of women experience early menopause. For these women, currently, the only chance of becoming pregnant is with donor eggs.
PRP, an autologous plasma preparation containing more than 10 times the concentration of growth factors and active metabolites than normal plasma, has recently been shown to have the potential to restore the menstrual cycles in perimenopausal women, allowing IVF. It has also been shown to benefit women with premature ovarian insufficiency (POI). However, there have been few reports of pregnancies or live births.
Chao Chin Hsu, MD, PhD, of the National Taiwan University Hospital, Taipei, and colleagues investigated whether the combination of the activated PRP treatment with gondatrophins such as FSH could provide a more robust effect so as to sufficiently stimulate follicles. They used the intraovarian injection of the combination to treat a 38-year-old woman with POI.
The effort was successful, and the woman gave birth to healthy twins.
To further evaluate the approach, the authors conducted a pilot study involving 12 women with early menopause (mean age, 44.4 years) between November 2018 and November 2019.
The women received intraovarian injection with PRP prepared from 40 mL of autologous peripheral blood combined with recombinant FSH.
Following the treatment, 11 of the 12 women experienced resumption of menstruation within a mean of 37 days. For seven patients, menstruation resumed within a month; for three, it resumed within about 2 months; and for one, it resumed after approximately 3 months.
Of note, the menstrual cycles were mostly irregular, with an interval of about 45.6 days.
The women’s average serum FSH level dropped significantly from 70.5 IU/L at baseline to 26.2 IU/L within days of treatment, as did the average luteinizing hormone level (34.8 before and 14.3 IU/L after treatment), indicative of improved ovary function.
For six participants, 10 oocyte retrieval procedures were performed after a mean of about 2 months. Thirteen mature eggs were retrieved, and fertilization via intracytoplasmic sperm injection was attempted, resulting in 10 fertilized oocytes.
Cleavage-stage embryos were transferred into two of the participants. One achieved a clinical pregnancy, defined as a pregnancy that was confirmed by ultrasound and by the presence of a fetal heartbeat. The pregnancy ended in miscarriage at 7 weeks’ gestation.
The length of controlled ovarian stimulation necessary for follicle growth ranged from 8 to 14 days, which the authors note is similar to that seen with women of normal reproductive age.
“Although the use of PRP in reproductive medicine is considered experimental, we demonstrated the restoration of ovarian function in early menopausal women who adopted whole dimension subcortical ovarian injection of PRP/gonadotropin,” the authors write.
“Most remarkably, an early menopausal woman achieved pregnancy after the treatment followed by IVF with her mature ovulating follicle,” they report.
Mechanisms, caveats
The mechanisms thought to underlie the success of the approach include increases in ovarian vascularization and stromal cell proliferation and reductions in oxidative stress and cell death in ovaries, the authors explain.
Key caveats with the treatment include the fact that anesthesia and laparoscopy are required, and precise administration is required at 15 injection sites in 1-2 mm of the ovarian subcortical area, which can be difficult to achieve, Dr. Hsu said in an interview.
“If a new instrument could be developed in which physicians can carry out this treatment through a vaginal approach, like the transvaginal retrieval of eggs in IVF treatments,” the approach could become more acceptable, Dr. Hsu added.
The authors call for studies with larger sample sizes and say it will also be interesting to determine effects in different groups: For example, women with cancer who have undergone chemotherapy.
Dr. Faubion, who is director of the Mayo Clinic Women’s Health, Rochester, Minn., says the causes of early menopause could be important in determining the treatment’s efficacy.
“[The therapy’s] success may depend on the reason the woman experienced early menopause: For instance, due to chemotherapy, radiation, virus, autoimmune disease, genetic mutation, or other cause,” she said.
She also noted that cost could be an important factor.
“I don’t see a cost estimate, but it will be substantial,” she said. “So, even if the success rate improves as this technique is further studied, cost and the invasive nature of the treatment may prove to be substantial barriers to this therapy becoming mainstream,” she said.
The authors and Dr. Faubion have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.