Context Antimüllerian hormone (AMH) level is strongly associated with ovarian response in assisted reproductive technology (ART) cycles but is a poor predictor of live birth. It is unknown whether AMH is associated with cumulative live birth rates (CLBRs) in women with diminished ovarian reserve (DOR). Objective To examine the association between serum AMH and CLBR among women with DOR undergoing ART. Methods Retrospective analysis of Society for Assisted Reproductive Technology Clinic Outcome Reporting System database 2014-16. A total of 34 540 index retrieval cycles of women with AMH <1 ng/mL. The main outcome measure was cumulative live birth. Results A total of 34 540 (25.9%) cycles with AMH <1 ng/mL out of 133 442 autologous index retrieval cycles were analyzed. Cycles with preimplantation genetic testing or egg/embryo banking were excluded. Data were stratified according to AMH and, age and regression analysis of AMH and CLBR was performed for each age stratum. Multiple logistic regression demonstrated that AMH is an independent predictor of CLBR (odds ratio [OR] 1.39, 95% CI 1.18-1.64). Serum AMH was strongly associated with number of oocytes retrieved, embryos cryopreserved, mean number of cumulative embryos transferred, and percentage of cycles that had an embryo transfer. Linear regression analysis demonstrated that AMH highly correlated with CLBR in each age stratum. Conclusion Serum AMH is highly correlated with CLBR in women with DOR independent of age. The addition of AMH to current age-based prognostication counseling particularly in women with DOR would provide more informative and personalized CLBR prediction prior to ART.

Serum antimullerian hormone (AMH) is frequently used to predict a woman's response to ovarian stimulation in assisted reproductive technology (ART). However, it has historically shown weak predictability for outcomes per embryo transfer (i.e. pregnancy and live birth rate) as traditionally reported by The Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SARTCORS) prior to 2014. We hypothesized that the association of AMH with ART cumulative live birth rate (CLBR) per cycle start as reported from 2014 onward by SARTCORS may be more informative as CLBR accounts for the entire embryo cohort (fresh and frozen) that are created and linked to a single identified index retrieval. The SART-CORS database was analyzed for CLBR by assessing outcomes of all linked fresh and/or frozen embryo transfer cycles from 2014 to 2016 from an individuals' index ART retrieval cycle (between 2014-2015). A total of 132,466 autologous ART index cycles were included. Cycles with preimplantation genetic testing, egg/embryo banking and those with embryo transfer/s from more than one ART index cycle were excluded. Multiple logistic regression was performed for the probability of CLBR per index cycle as the outcome variable using various predictor variables. Data was stratified according to AMH and age and linear regression analysis of AMH and CLBR were calculated for each age strata. Receiver operator characteristic (ROC) curve showed that AMH was predictive of CLBR (AUC 0.661, 95% CI 0.658-0.665, p<0.001). Multiple logistic regression demonstrated that AMH is an independent predictor of CLBR when controlling for age, BMI, race, total FSH dose and number of embryos transferred. Serum AMH was significantly associated with number of oocytes retrieved, number of embryos cryopreserved and percentage of index cycles that had a transfer, but was not associated with number of transferred embryos. Linear regression analysis demonstrated that AMH highly correlated with CLBR in all age strata (Table 1).Table 1Cumulative live birth rate (%)AgeAMH (ng/ml)<35N=61,26235-37N=28,36638-40N=23,85241–42N=11,52843+N=7,458< 1.0036.1%28.1%17.8%8.6%2.7%1.01 – 2.0049.0%37.6%25.4%11.9%5.2%2.01 – 3.0053.5%43.4%29.5%15.2%5.6%3.01 – 4.0058.1%46.4%32.5%16.7%4.8%4.01 – 5.0059.4%47.9%35.5%20.0%12.7%>559.7%51.5%38.4%20.5%12.8%Mean CLBR53.1%39.6%25.1%11.6%4.2%Linear correlation (R)0.970.990.990.980.85p-value0.001<0.000010.002<0.0010.015 Open table in a new tab Serum AMH is strongly associated with CLBR independent of age.

Accumulating evidence from animal and human studies indicates a role for vitamin D in female reproductive physiology, and numerous clinical studies have suggested its potential benefit for various aspects of human reproduction. Anti-Müllerian hormone (AMH) is an ovarian biomarker that plays an important role in folliculogenesis. It is the most sensitive ovarian reserve marker and is widely used clinically in reproductive medicine. While initial studies have suggested that vitamin D may be associated with ovarian reserve markers, including AMH, evidence has been conflicting. Currently, there is considerable debate in the field whether vitamin D has the capacity to influence ovarian reserve, as indicated by the AMH level. The current systematic review aims to evaluate and summarize the available evidence regarding the relationship between vitamin D and AMH. In total, 18 observational studies and 6 interventional studies were included in this systematic review. Cross-sectional studies have reported largely discrepant findings regarding an association between serum vitamin D and AMH levels, which are likely due to the heterogeneity in study populations, as well as the apparently complex relationship that may exist between vitamin D and AMH. However, meta-analysis of interventional studies performed herein that examined the effects of vitamin D supplementation on serum AMH levels indicates a cause-effect relationship between vitamin D and AMH, the direction of which appears to depend on a woman’s ovulatory status. Serum AMH was significantly decreased following vitamin D supplementation in polycystic ovarian syndrome (PCOS) women (standardized mean difference (SMD) −0.53, 95% CI −0.91 to −0.15, p < 0.007), while it was significantly increased following vitamin D supplementation in ovulatory women without PCOS (SMD 0.49, 95% CI 0.17 to 0.80, p = 0.003). In conclusion, the results of this systematic review demonstrate that the relationship between vitamin D and AMH is a complex one, and large, randomized trials of vitamin D supplementation focusing on different vitamin D status ranges are necessary to gain more insight into the nature of this relationship and the potential benefit of vitamin D to female reproduction in general.

Serum antimullerian hormone (AMH) is used to predict a woman’s response to ovarian stimulation. However, its ability to predict clinical outcomes per embryo transfer such as clinical pregnancy and live birth rate has been considered to be poor. We hypothesized that its association with cumulative live birth rate (CLBR) as reported by Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SARTCORS) from 2014 onward among women with diminished ovarian reserve (DOR) could be more informative as CLBR accounts for all embryos (fresh and frozen) linked to a single identified index retrieval. Retrospective cohort. The SARTCORS database was analyzed for CLBR by assessing outcomes of all linked fresh and/or frozen embryo transfer cycles (2014 to 2016) from an index retrieval cycle (between 2014-2015). A total of 34,540 (25.9%) of 133,442 autologous index cycles with DOR (i.e. AMH<1 ng/ml) were included and analyzed. Cycles with preimplantation genetic testing, egg/embryo banking and those with embryo transfer/s from more than one ART index cycle were excluded. Multiple logistic regression (MLR) was performed for the probability of CLBR per index cycle. Data was stratified according to AMH and age and linear regression analysis of AMH and CLBR were calculated for each age strata. Multiple logistic regression demonstrated that AMH is an independent predictor of CLBR (Odds ratio 1.46, 95% CI 1.28-1.66, P<0.0001) when controlling for age, body mass index, race, total FSH dose and number of embryos transferred. Serum AMH was associated with number of oocytes retrieved, number of embryos cryopreserved and percentage of index cycles that had an embryo transfer, but was not associated with number of embryos transferred. Linear regression analysis demonstrated that AMH highly correlated with CLBR in each age strata of women with DOR (Table 1), and most strongly in women <35 (R=0.95, p<0.001).Tabled 1AMH (ng/ml)Age<35N=8,29035-37N=7,50738-40N=8,99941 – 42N=5,54843+N=4,1960.00 – 0.122.1%18.7%9.2%6.1%1.2%0.11 – 0.229.1%19.8%12.5%6.4%1.7%0.21 – 0.330.3%26.1%16.3%7.9%1.9%0.31 – 0.432.0%26.1%17.8%7.4%2.4%0.41 – 0.535.9%27.6%17.7%7.3%3.2%0.51 – 0.634.0%26.7%19.1%9.2%3.9%0.61 – 0.736.7%30.8%18.9%10.1%2.6%0.71 – 0.838.2%31.2%21.8%11.1%3.0%0.81 – 0.942.7%30.2%19.0%10.7%4.1%0.91 – 1.0041.2%34.0%20.6%9.5%4.1%Mean CLBR36.1%25.5%19.3%5.7%1.4%Linear regression (R)0.950.880.870.890.88p-value<0.0001<0.00010.0010.001<0.001 Open table in a new tab Serum AMH is highly correlated with CLBR in women with DOR independent of age. The addition of AMH to current age-based prognostication counseling would provide more informative and personalized CLBR prediction.

We wish to respond to Mr Martinez-Portilla on his critique of our paper, "Vertical transmission of coronavirus disease 2019: a systematic review and meta-analysis."1Kotlyar A.M. Grechukhina O. Chen A. et al.Vertical transmission of coronavirus disease 2019: a systematic review and meta-analysis.Am J Obstet Gynecol. 2021; 224: 35-53.e3Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar Although several interesting points are raised, each of these points has been unfortunately handled with insufficient depth by the author. To his first point, case series have been previously validated as sources, which can be used for pooled prevalence analyses. Murad et al2Murad M.H. Sultan S. Haffar S. Bazerbachi F. Methodological quality and synthesis of case series and case reports.BMJ Evid Based Med. 2018; 23: 60-63Crossref PubMed Scopus (1220) Google Scholar described how proportions in case series can be combined in a quantitative synthesis using fixed or random effects models to obtain estimates of prevalence, similar to what we accomplished in our study using both case series and cohort studies. This same group cited how case series can be used in a meta-analysis to determine a prevalence estimate, for example, for mortality, following aortic transection. Therefore, we disagree with his argument that case series should not be included in determining prevalence estimates. Excluding case series would discard potential vital information in the setting of such a novel emerging disease, such as coronavirus disease 2019 (COVID-19), particularly in the absence of high-quality evidence regarding vertical transmission. As to our methodological quality assessment of study bias risk, Mr Martinez-Portilla's assessment misses a crucial point explicitly stated in our paper. We used the modified Newcastle-Ottawa Scale (NOS), which is designed to assess case series and has been validated in previous systematic reviews and meta-analyses cited in our methods section.2Murad M.H. Sultan S. Haffar S. Bazerbachi F. Methodological quality and synthesis of case series and case reports.BMJ Evid Based Med. 2018; 23: 60-63Crossref PubMed Scopus (1220) Google Scholar Although the Joanna Briggs Institute critical appraisal tool has been proposed as a method to assess bias in case series, we have not found any evidence that it is a superior tool than the modified NOS.3Munn Z. Barker T.H. Moola S. et al.Methodological quality of case series studies: an introduction to the JBI critical appraisal tool.JBI Database System Rev Implement Rep. 2019; ([Epub ahead of print])Google Scholar As far as the third point regarding our pooled estimate result (3.2%) for COVID-19 positivity in neonatal nasopharyngeal (NP) swabs, our meta-analysis was conducted using the most recent version of the MedCalc software (MedCalc Software Ltd, Ostend, Belgium), which uses the commonly used Freeman-Tukey transformation (arcsine-based square root transformation) to calculate the weighted summary proportion under the fixed and random effects model. The method used by Mr Martinez-Portilla in an attempt to replicate our results was based on adding an arbitrary continuity correction factor (0.5) to the number of observed COVID-19 cases in each study that has zero cases of COVID-19. However, this fixed correction method has been shown by Sweeting et al4Sweeting M.J. Sutton A.J. Lambert P.C. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data.Stat Med. 2004; 23: 1351-1375Crossref PubMed Scopus (1225) Google Scholar to have the undesirable effect of biasing study estimates toward no difference and artificially inflating the weight of each such zero study when the sample size is large. Here are 2 examples: using the arcsine square root transformation used in our study, the Ferazzi study (n=42; k=3) and the London study (n=48; k=0) have similar relative weights—4.41% and 5.03%, respectively (Figure 3).1Kotlyar A.M. Grechukhina O. Chen A. et al.Vertical transmission of coronavirus disease 2019: a systematic review and meta-analysis.Am J Obstet Gynecol. 2021; 224: 35-53.e3Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar In contrast, the 0.5 continuity correction factor method proposed results in 1.3% and 10.5%, respectively, which is counterintuitive and creates obvious bias. In another example using the arcsine square root transformation, the Yan study (n=86; k=0) has a weight of 8.93%, whereas the Knight study (n=244; k=12), which is the largest study in the meta-analysis, has a weight of 25.2% (Figure 3).1Kotlyar A.M. Grechukhina O. Chen A. et al.Vertical transmission of coronavirus disease 2019: a systematic review and meta-analysis.Am J Obstet Gynecol. 2021; 224: 35-53.e3Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar Moreover, the 0.5 continuity correction factor method results in a relative weight of 33.1% for the smaller Yan (zero) study and only 11.0% relative weight for the larger Knight study. Thus, using the 0.5 correction as proposed by Mr Martinez-Portilla is simply wrong and clearly inflates the relative weights of the zero studies, resulting in an underestimation of the pooled COVID-19 neonatal NP positivity proportion. In a recent Centers for Disease Control and Prevention report (November 2, 2020) representing the largest longitudinal data to date on pregnant women diagnosed as having COVID-19 from the Surveillance for Emerging Threats to Mothers and Babies Network (https://www.cdc.gov/mmwr/volumes/69/wr/mm6944e2.htm), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was found in 16 of 610 cases (2.6%) among neonates known to have been tested for SARS-CoV-2, which is very similar to the pooled estimates reported in our study (3.2%). Vertical transmission of coronavirus disease 2019American Journal of Obstetrics & GynecologyVol. 224Issue 3PreviewWith interest, I have read the article titled "Vertical transmission of coronavirus disease 2019: a systematic review and meta-analysis" published in the American Journal of Obstetrics and Gynecology by Kotlyar et al.1 Full-Text PDF

INTRODUCTION:Antimullerian hormone (AMH) strongly correlates with ovarian reserve and response to controlled ovarian stimulation. Emerging data suggests that serum AMH level may also predict ART outcomes. However, AMH is characteristically elevated in PCOS women and it is unknown whether it may predict live birth outcomes in this population. METHODS:This was a retrospective cohort study of 184 PCOS women (Rotterdam criteria) who underwent their first fresh IVF/ICSI cycle. Women were divided into 3 groups according to the <25th (low), 25 to 75th (average), or > 75th (high) percentile of serum AMH concentration. Cycle stimulation parameters and reproductive outcomes were compared between groups. RESULTS:Women in the low serum AMH group were older than those in the average or high AMH (p < 0.05), and required greater gonadotropin dose for stimulation compared to the high AMH group (p < 0.05). Women with high AMH had greater testosterone level compared to women in the low or average AMH groups. No differences were noted between groups in terms of maximal E2, oocytes retrieved and fertilization rate. However, low serum AMH women had significantly greater live birth rates (p < 0.05) and showed a trend towards greater clinical pregnancy rates compared to women in the average and high AMH groups (p = 0.09). The significant association of AMH with live birth rate remained after adjusting for age, BMI, day of transfer and number of embryos transferred. CONCLUSIONS:In PCOS women, elevated AMH concentrations are associated with hyperandrogenism and lower live birth rates.

Objective: To determine if serum antimullerian hormone (AMH) is associated with and/or predictive of live birth assisted reproductive technology (ART) outcomes. Design: Retrospective analysis of Society for Assisted Reproductive Technology Clinic Outcome Reporting System database from 2012 to 2013. Setting: Not applicable. Patient(s): A total of 69,336 (81.8%) fresh and 15,458 (18.2%) frozen embryo transfer (FET) cycles with AMH values. Intervention(s): None. Main Outcome Measure(s): Live birth. Result(s): A total of 85,062 out of 259,499 (32.7%) fresh and frozen-thawed autologous non-preimplantation genetic diagnosis cycles had AMH reported for cycles over this 2-year period. Of those, 70,565 cycles which had embryo transfers were included in the analysis. Serum AMH was significantly associated with live birth outcome per transfer in both fresh and FET cycles. Multiple logistic regression demonstrated that AMH is an independent predictor of live birth in fresh transfer cycles and FET cycles when controlling for age, body mass index, race, day of transfer, and number of embryos transferred. Receiver operating characteristic (ROC) curves demonstrated that the areas under the curve (AUC) for AMH as predictors of live birth in fresh cycles and thawed cycles were 0.631 and 0.540, respectively, suggesting that AMH alone is a weak independent predictor of live birth after ART. Similar ROC curves were obtained also when elective single-embryo transfer (eSET) cycles were analyzed separately in either fresh (AUC 0.655) or FET (AUC 0.533) cycles, although AMH was not found to be an independent predictor in eSET cycles. Conclusion(s): AMH is a poor independent predictor of live birth outcome in either fresh or frozen embryo transfer for both eSET and non-SET transfers. (C) 2017 by American Society for Reproductive Medicine.

Objective: To assess cycle outcomes when antimullerian hormone (AMH) is ultralow (<= 0.16 ng/mL) and to determine which parameters contribute to the probability of cycle cancellation and/or outcome.Design: Retrospective analysis.Setting: Not applicable.Patient(s): 5,087 (7.3%) fresh and 243 (1.5%) thawed cycles with ultralow AMH values.Intervention(s): Linear and logistic regression, comparison with age-matched cycles with normal AMH concentrations.Main Outcome Measure(s): Cancellation rate; number of retrieved oocytes, embryos, transferred embryos, and cryopreserved embryos; clinical pregnancy, live-birth, and multiple birth rates.Result(s): The total cancellation rate per cycle start for fresh cycles was 54%. Of these, 38.6% of the cycles were canceled before retrieval, and 3.3% of cycles obtained no oocytes at time of retrieval. Of all retrieval attempts, 50.7% had three oocytes or fewer retrieved, and 25.1% had no embryo transfer. The live-birth rates were 9.5% per cycle start. Cycles with ultralow AMH levels compared with age-matched normal AMH cycles demonstrated more than a fivefold greater pre-retrieval cancellation rate, a twofold less live-birth rate per cycle and a 4.5-fold less embryo cryopreservation rate.Conclusion(s): Refusing treatment solely on the basis of ultralow AMH levels is not advisable, but patients should be counseled appropriately about the prognostic factors for cancellation and outcomes. (C) 2016 by American Society for Reproductive Medicine.

Objective: To assess whether antimullerian hormone (AMH) is a predictor of implantation and/or clinical pregnancy in women undergoing assisted reproductive technology.Design: Systematic review and meta-analysis.Setting: Not applicable.Patient(s): Women undergoing IVF/intracytoplasmic sperm injection in nondonor cycles.Intervention(s): Measurement of serum AMH level.Main Outcome Measure(s): Diagnostic odds ratio (OR) and summary receiver operating characteristic curve (AUC) for AMH as a predictor of implantation and/or clinical pregnancy.Result(s): A total of 525 observational studies were identified, of which 19 were selected (comprising 5,373 women). Studies reporting clinical pregnancy rates in women with unspecified ovarian reserve (n = 11), diminished ovarian reserve (DOR) (n = 4), and polycystic ovary syndrome (n = 4) were included, together with studies reporting implantation rates (n = 4). The OR for AMH as a predictor of implantation in women with unspecified ovarian reserve (n = 1,591) was 1.83 (95% confidence interval [CI] 1.49-2.25), whereas the AUC was 0.591 (95% CI 0.563-0.618). The OR for AMH as a predictor of clinical pregnancy in these women (n = 4,324) was 2.10 (95% CI 1.82-2.41), whereas the AUC was 0.634 (95% CI 0.618-0.650). The predictive ability of AMH for pregnancy was greatest in women with DOR (n = 615), with OR and AUC of 3.96 (95% CI 2.57-6.10) and 0.696 (95% CI 0.641-0.751), respectively. In contrast, AMH had no significant predictive ability in women with PCOS (n = 414), with OR and AUC of 1.18 (95% CI 0.53-2.62) and 0.600 (95% CI 0.547-0.653), respectively.Conclusion(s): Antimullerian hormone has weak association with implantation and clinical pregnancy rates in assisted reproductive technology but may still have some clinical utility in counseling women undergoing fertility treatment regarding pregnancy rates, particularly those with DOR. (C)2015 by American Society for Reproductive Medicine.

ObjectivePolycystic ovary syndrome (PCOS) affects 5-10% of reproductive-aged women. There is an abnormal increase in transforming growth factor-beta1 (TGF-β1) bioavailability in women with PCOS due to increase in serum TGF-β1 and decrease in its soluble receptor, soluble endoglin (sENG), which has been suggested to play a role in the pathophysiology of this syndrome. Women with PCOS tend to have decreased vitamin D (VD) levels and VD supplementation has been shown to improve various clinical manifestations of PCOS. VD leads to a decrease in TGF-β1 levels in several diseases including myelofibrosis. Therefore, we investigated the effect of VD supplementation on TGF-β1 bioavailability in women with PCOS and assessed whether changes in TGF-β1/sENG levels would correlate with an improvement in PCOS clinical abnormalities.DesignProspective randomized placebo-controlled trial.Materials and Methods93 VD-deficient women with PCOS who were not pregnant or taking any exogenous hormones were recruited from October 2013 to January 2015. 54 participants completed the study: 36 women received 50,000 IU of oral vitamin D3 and 18 women received oral placebo once weekly for 8 weeks. The clinical parameters were evaluated before and four months after treatment. Lipid profile, 25-hydroxy-vitamin D (25-OHD), free testosterone, dehydroepiandrosterone, insulin resistance, TGF-β1, and sENG were measured in serum before and after treatment. Values were expressed as mean±SEM. A paired t-test and Pearson correlation were used as appropriate.Results73.1% of women with PCOS had VD deficiency (25-OHD<20 ng/mL). VD level significantly increased and normalized after VD supplementation (16.3±0.9 to 43.2±2.4 ng/mL; p<0.01) while it did not significantly change after placebo (17±1.8 to 17.4±1.9 ng/mL). In the VD treated group, there was a significant decrease in: the interval between menstrual periods (80±9 to 60±6 days; p=0.04), Ferriman-Gallwey hirsutism score (9.8±1.5 to 8.1±1.5; p<0.01), triglycerides (138±22 to 117±20 mg/dL; p=0.03), and TGF-β1/sENG (6.7±0.4 to 5.9±0.4; p=0.04). ΔTGF-β1/sENG was positively correlated with Δtriglycerides (r=0.59; p=0.03). However, no significant changes were observed in other measured parameters.ConclusionsVD supplementation in VD-deficient women with PCOS significantly decreases the bioavailability of TGF-β1 (TGF-β1/sENG) which correlates with an improvement in some abnormal clinical parameters associated with PCOS. This is a novel molecular explanation for the beneficial effects of VD supplementation in VD-deficient women with PCOS. These findings may support new treatment modalities for PCOS, such as the development of anti-TGF-β drugs.References: The effect of vitamin D on TGF-β1 in women with PCOS ObjectivePolycystic ovary syndrome (PCOS) affects 5-10% of reproductive-aged women. There is an abnormal increase in transforming growth factor-beta1 (TGF-β1) bioavailability in women with PCOS due to increase in serum TGF-β1 and decrease in its soluble receptor, soluble endoglin (sENG), which has been suggested to play a role in the pathophysiology of this syndrome. Women with PCOS tend to have decreased vitamin D (VD) levels and VD supplementation has been shown to improve various clinical manifestations of PCOS. VD leads to a decrease in TGF-β1 levels in several diseases including myelofibrosis. Therefore, we investigated the effect of VD supplementation on TGF-β1 bioavailability in women with PCOS and assessed whether changes in TGF-β1/sENG levels would correlate with an improvement in PCOS clinical abnormalities. Polycystic ovary syndrome (PCOS) affects 5-10% of reproductive-aged women. There is an abnormal increase in transforming growth factor-beta1 (TGF-β1) bioavailability in women with PCOS due to increase in serum TGF-β1 and decrease in its soluble receptor, soluble endoglin (sENG), which has been suggested to play a role in the pathophysiology of this syndrome. Women with PCOS tend to have decreased vitamin D (VD) levels and VD supplementation has been shown to improve various clinical manifestations of PCOS. VD leads to a decrease in TGF-β1 levels in several diseases including myelofibrosis. Therefore, we investigated the effect of VD supplementation on TGF-β1 bioavailability in women with PCOS and assessed whether changes in TGF-β1/sENG levels would correlate with an improvement in PCOS clinical abnormalities. DesignProspective randomized placebo-controlled trial. Prospective randomized placebo-controlled trial. Materials and Methods93 VD-deficient women with PCOS who were not pregnant or taking any exogenous hormones were recruited from October 2013 to January 2015. 54 participants completed the study: 36 women received 50,000 IU of oral vitamin D3 and 18 women received oral placebo once weekly for 8 weeks. The clinical parameters were evaluated before and four months after treatment. Lipid profile, 25-hydroxy-vitamin D (25-OHD), free testosterone, dehydroepiandrosterone, insulin resistance, TGF-β1, and sENG were measured in serum before and after treatment. Values were expressed as mean±SEM. A paired t-test and Pearson correlation were used as appropriate. 93 VD-deficient women with PCOS who were not pregnant or taking any exogenous hormones were recruited from October 2013 to January 2015. 54 participants completed the study: 36 women received 50,000 IU of oral vitamin D3 and 18 women received oral placebo once weekly for 8 weeks. The clinical parameters were evaluated before and four months after treatment. Lipid profile, 25-hydroxy-vitamin D (25-OHD), free testosterone, dehydroepiandrosterone, insulin resistance, TGF-β1, and sENG were measured in serum before and after treatment. Values were expressed as mean±SEM. A paired t-test and Pearson correlation were used as appropriate. Results73.1% of women with PCOS had VD deficiency (25-OHD<20 ng/mL). VD level significantly increased and normalized after VD supplementation (16.3±0.9 to 43.2±2.4 ng/mL; p<0.01) while it did not significantly change after placebo (17±1.8 to 17.4±1.9 ng/mL). In the VD treated group, there was a significant decrease in: the interval between menstrual periods (80±9 to 60±6 days; p=0.04), Ferriman-Gallwey hirsutism score (9.8±1.5 to 8.1±1.5; p<0.01), triglycerides (138±22 to 117±20 mg/dL; p=0.03), and TGF-β1/sENG (6.7±0.4 to 5.9±0.4; p=0.04). ΔTGF-β1/sENG was positively correlated with Δtriglycerides (r=0.59; p=0.03). However, no significant changes were observed in other measured parameters. 73.1% of women with PCOS had VD deficiency (25-OHD<20 ng/mL). VD level significantly increased and normalized after VD supplementation (16.3±0.9 to 43.2±2.4 ng/mL; p<0.01) while it did not significantly change after placebo (17±1.8 to 17.4±1.9 ng/mL). In the VD treated group, there was a significant decrease in: the interval between menstrual periods (80±9 to 60±6 days; p=0.04), Ferriman-Gallwey hirsutism score (9.8±1.5 to 8.1±1.5; p<0.01), triglycerides (138±22 to 117±20 mg/dL; p=0.03), and TGF-β1/sENG (6.7±0.4 to 5.9±0.4; p=0.04). ΔTGF-β1/sENG was positively correlated with Δtriglycerides (r=0.59; p=0.03). However, no significant changes were observed in other measured parameters. ConclusionsVD supplementation in VD-deficient women with PCOS significantly decreases the bioavailability of TGF-β1 (TGF-β1/sENG) which correlates with an improvement in some abnormal clinical parameters associated with PCOS. This is a novel molecular explanation for the beneficial effects of VD supplementation in VD-deficient women with PCOS. These findings may support new treatment modalities for PCOS, such as the development of anti-TGF-β drugs.References: The effect of vitamin D on TGF-β1 in women with PCOS VD supplementation in VD-deficient women with PCOS significantly decreases the bioavailability of TGF-β1 (TGF-β1/sENG) which correlates with an improvement in some abnormal clinical parameters associated with PCOS. This is a novel molecular explanation for the beneficial effects of VD supplementation in VD-deficient women with PCOS. These findings may support new treatment modalities for PCOS, such as the development of anti-TGF-β drugs.

CONTEXT:There is an abnormal increase in TGF-β1 bioavailability in women with polycystic ovary syndrome (PCOS), which might play a role in the pathophysiology of this syndrome. Vitamin D (VD) supplementation improves various clinical manifestations of PCOS and decreases TGF-β1 levels in several diseases including myelofibrosis.OBJECTIVE:The objective of the study was to determine the effect of VD supplementation on TGF-β1 bioavailability in VD-deficient women with PCOS and assess whether changes in TGF-β1/soluble endoglin (sENG) levels correlate with an improvement in PCOS clinical manifestations.DESIGN:This was a prospective, randomized, placebo-controlled trial.SETTING:The study was conducted at an academic-affiliated medical center.PARTICIPANTS:Sixty-eight VD-deficient women with PCOS who were not pregnant or taking any exogenous hormones were recruited between October 2013 and January 2015.INTERVENTIONS:Forty-five women received 50 000 IU of oral vitamin D3 and 23 women received oral placebo once weekly for 8 weeks.MAIN OUTCOMES MEASURES:Serum TGF-β1, sENG, lipid profile, testosterone, dehydroepiandrosterone sulfate, and insulin resistance were measured. The clinical parameters were evaluated before and 2 months after treatment.RESULTS:The VD level significantly increased and normalized after VD supplementation (16.3 ± 0.9 [SEM] to 43.2 ± 2.4 ng/mL; P < .01), whereas it did not significantly change after placebo. After the VD supplementation, there was a significant decrease in the following: the interval between menstrual periods (80 ± 9 to 60 ± 6 d; P = .04), Ferriman-Gallwey score (9.8 ± 1.5 to 8.1 ± 1.5; P < .01), triglycerides (138 ± 22 to 117 ± 20 mg/dL; P = .03), and TGF-β1 to sENG ratio (6.7 ± 0.4 to 5.9 ± 0.4; P = .04). In addition, the ΔTGF-β1 to sENG ratio was positively correlated with Δtriglycerides (r = 0.59; P = .03).CONCLUSIONS:VD supplementation in VD-deficient women with PCOS significantly decreases the bioavailability of TGF-β1, which correlates with an improvement in some abnormal clinical parameters associated with PCOS. This is a novel mechanism that could explain the beneficial effects of VD supplementation in women with PCOS. These findings may support new treatment modalities for PCOS, such as the development of anti-TGF-β drugs.