United States

Vanden Brink H1,2,3*, Burgert TS2, Barral R4,5,6, Gadiraju, M5, Lujan ME1*

1Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA; 
2Division of Endocrinology, Children’s Mercy Hospital, Kansas City, MO, USA; 
3Department of Nutrition, Texas A&amp;M University, College Station, TX, USA; 
4Adolescent Medicine, Children’s Mercy Hospital, Kansas City, MO, USA; 
5University of Missouri Kansas City School of Medicine, Kansas City, MO, USA; 
6 University of Kansas Medical Center, Kansas City, KS, USA

Introduction: Assessment of ovarian features are discouraged in the diagnosis of PCOS in adolescence owing to a lack of normative data and historically poor image quality via transabdominal ultrasonography. However, we have recently shown that ovarian morphology is adequately resolved via transabdominal ultrasound in adolescents and that follicle number and ovarian size reflect circulating AMH within the first gynecological year. Whether ovarian features at this early gynecological stage predict menstrual cycle status at two-years post-menarche (2YR-PM) is unknown. 

Methods: Menstrual records of 19 adolescent females who were evaluated at 6-10 months post-menarche (PM) were collected as a part of a prospective cohort study. Menstrual cycle status was determined at 2YR-PM as regular (three previous inter-menstrual intervals within 21-45 days) or irregular (at least one of the three previous inter-menstrual intervals &lt;21 or &gt;45 days). At 6-10 months PM, participants underwent a fasting blood draw, anthropometry, bioimpedance, and a transabdominal ultrasound of the ovaries. Differences in reproductive and metabolic features at 6-10 months PM were contrasted in those who were regular versus irregular at 2YR-PM via Mann-Whitney U-Tests. Whether reproductive features assessed at 6-10 months PM predicted menstrual cycle status at 2YR-PM was determined via logistic regression analyses.

Results: At 2YR-PM, 6/19 adolescents met the criteria for regular menstrual cycles and 13/19 met the criteria for irregular menstrual cycles. There were no differences in the metabolic profile nor in clinical or biochemical measures of androgens status at 6-10 months PM between those who ultimately achieved regular vs irregular menstrual cycles (P&gt;0.05). However, adolescents with irregular menstrual cycles at 2YR-PM had higher LH concentrations (4.8 [3.5-5.5] vs 3.0 [2.4-3.8] mIU/mL; P=0.025), AMH (5.6 [5.1-7.3] vs 3.0 [1.6-4.5] ng/mL, P=0.023), and tended to have higher numbers of antral follicles 2-5mm in diameter (FNPO 2-5mm) (19 [14-25] vs 10 [7-16], P=0.06) at 6-10 months PM. The likelihood of regular menstrual cycles at 2YR-PM decreased with higher AMH (Odds Ratio 0.49 [0.24-0.98], P=0.01), LH (OR: 0.33 [0.13-1.09], P=0.019) and tended to decrease with greater FNPO 2-5mm (OR: 0.89 [0.76-1.03], P=0.05) at 6-10 months PM. 

Conclusion: Ovarian features and serum LH may serve as early, clinically feasible biomarkers of future persistent menstrual irregularity with defective folliculogenesis preceding metabolic and androgenic derangements  in the timeline to aberrant reproductive maturation. Whether adolescents with persistent menstrual irregularity meet criteria for PCOS will be determined upon conclusion of the cohort study.  

Funding: National Institutes of Health (R21-HD095372), Canadian Institutes of Health Research (Postdoctoral Fellowship #171268). 


AE-PCOS 2022

Reproductive features captured within the first gynecological year predict persistent menstrual irregularity at two years post-menarche

### Welcome to the AE-PCOS Society's 20th Annual Meeting!


The AE-PCOS Society’s 20th Annual Meeting's theme will be Reflections and Directions. The meeting will aim to incorporate the perspectives of both long-time, contributing members of the Society and newer members of the Society, while highlighting the latest research findings in PCOS-related clinical and basic research.

The recorded content will be available to registrants only for three months after the meeting. 


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Please register for the AE-PCOS 2022 Conference to join the event.

The AE-PCOS Society’s 20th Annual Meeting's theme are Reflections and Directions. The meeting aims to incorporate the perspectives of both long-time, contributing members of the Society and newer members of the Society, while highlighting the latest research findings in PCOS-related clinical and basic research.

Vanden Brink H1,2,3*, Burgert TS2, Barral R4,5,6, Gadiraju, M5, Lujan ME1*

1Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA; 
2Division of Endocrinology, Children’s Mercy Hospital, Kansas City, MO, USA; 
3Department of Nutrition, Texas A&M University, College Station, TX, USA; 
4Adolescent Medicine, Children’s Mercy Hospital, Kansas City, MO, USA; 
5University of Missouri Kansas City School of Medicine, Kansas City, MO, USA; 
6 University of Kansas Medical Center, Kansas City, KS, USA

Introduction: Assessment of ovarian features are discouraged in the diagnosis of PCOS in adolescence owing to a lack of normative data and historically poor image quality via transabdominal ultrasonography. However, we have recently shown that ovarian morphology is adequately resolved via transabdominal ultrasound in adolescents and that follicle number and ovarian size reflect circulating AMH within the first gynecological year. Whether ovarian features at this early gynecological stage predict menstrual cycle status at two-years post-menarche (2YR-PM) is unknown. 

Methods: Menstrual records of 19 adolescent females who were evaluated at 6-10 months post-menarche (PM) were collected as a part of a prospective cohort study. Menstrual cycle status was determined at 2YR-PM as regular (three previous inter-menstrual intervals within 21-45 days) or irregular (at least one of the three previous inter-menstrual intervals <21 or >45 days). At 6-10 months PM, participants underwent a fasting blood draw, anthropometry, bioimpedance, and a transabdominal ultrasound of the ovaries. Differences in reproductive and metabolic features at 6-10 months PM were contrasted in those who were regular versus irregular at 2YR-PM via Mann-Whitney U-Tests. Whether reproductive features assessed at 6-10 months PM predicted menstrual cycle status at 2YR-PM was determined via logistic regression analyses.

Results: At 2YR-PM, 6/19 adolescents met the criteria for regular menstrual cycles and 13/19 met the criteria for irregular menstrual cycles. There were no differences in the metabolic profile nor in clinical or biochemical measures of androgens status at 6-10 months PM between those who ultimately achieved regular vs irregular menstrual cycles (P>0.05). However, adolescents with irregular menstrual cycles at 2YR-PM had higher LH concentrations (4.8 [3.5-5.5] vs 3.0 [2.4-3.8] mIU/mL; P=0.025), AMH (5.6 [5.1-7.3] vs 3.0 [1.6-4.5] ng/mL, P=0.023), and tended to have higher numbers of antral follicles 2-5mm in diameter (FNPO 2-5mm) (19 [14-25] vs 10 [7-16], P=0.06) at 6-10 months PM. The likelihood of regular menstrual cycles at 2YR-PM decreased with higher AMH (Odds Ratio 0.49 [0.24-0.98], P=0.01), LH (OR: 0.33 [0.13-1.09], P=0.019) and tended to decrease with greater FNPO 2-5mm (OR: 0.89 [0.76-1.03], P=0.05) at 6-10 months PM. 

Conclusion: Ovarian features and serum LH may serve as early, clinically feasible biomarkers of future persistent menstrual irregularity with defective folliculogenesis preceding metabolic and androgenic derangements  in the timeline to aberrant reproductive maturation. Whether adolescents with persistent menstrual irregularity meet criteria for PCOS will be determined upon conclusion of the cohort study.  

Funding: National Institutes of Health (R21-HD095372), Canadian Institutes of Health Research (Postdoctoral Fellowship #171268). 


technical paper

Objective: Polycystic ovary syndrome (PCOS) is a common condition with endocrine-metabolic dysfunction, and is highly heritable. Yet, there is limited research on how offspring are affected, and the age of onset, if any. We established a cohort of women with PCOS and matched controls along with their offspring to evaluate the effects of maternal PCOS on the offspring, as well as any differential impact between boys and girls. 
Methods: Among Chinese women from our PCOS registry (diagnosed based on the 2003 Rotterdam diagnostic criteria), we invited those who have children to participate in a follow-up study, and evaluated both the mothers and their sons (PCOSs) and daughters (PCOSd). For controls, we recruited women from the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study, who did not have PCOS or GDM, together with their sons (Cs) and daughters (Cd), for comparison. All offspring aged 15-25 years were included in the current analysis, and all have undergone a detailed assessment with questionnaire, anthropometric assessment, a standardized 75g OGTT for glycemic status evaluation and biochemical tests. Difference between groups were evaluated using independent sample t-test or Mann-Whitney U test for continuous variables, while Chi-square (X2) or Fisher’s exact tests were used for categorical variables. 
Result: A total of 21 PCOSs and 18 PCOSd (mean age 19.86 ± 3.98 and 18.33 ± 2.30, respectively) as well as 26 Cs and 45 Cd (mean age 17.27 ± 0.67 and 17.58 ± 0.84, respectively) were recruited to date. We noted a high prevalence of menstrual irregularity in PCOSd when compared with Cd (PCOSd: 8/18 (44.4%) vs Cd: 7/44 (15.9%), p<0.005). We also found that the frequency of elevated androgen levels was 8/18 (44.4%) and 11/33 (33.3%) in PCOSd and Cd, respectively (p=0.433). PCOSd were significantly more centrally obese than Cd (PCOSd: 5/18 (27.8%) vs Cd: 2/45 (4.4%), p=0.007). Yet, such significant difference was not observed when comparing between PCOSs and Cs. There was no significant difference in the prevalence of dyslipidemia (PCOSs: 13/21 (61.9%) vs Cs: 9/21 (42.9%), p=0.217; PCOSd: 3/18 (16.7%) vs Cd: 5/34 (14.7%), p=0.852), hypertension (none for both PCOSs and Cs; PCOSd: 1/18 (5.6%) vs Cd: 1/45 (2.2%), p=0.465) and metabolic syndrome (AHA/NHLBI) (PCOSs: 3/21 (14.3%) vs Cs: 0/26; Pd: 2/18 (11.1%) vs Cd: 0/45) in both gender between offspring of mothers with and without PCOS. There is a trend towards higher frequency of glucose abnormalities when comparing PCOSd vs Cd (PCOSs: 2/21 (9.5%) vs Cs: 1/21 (4.8%), p=0.549; PCOSd: 4/18 (22.2%) vs Cd: 2/34 (5.9%), p=0.079), although there was no significant difference.
Conclusion: PCOSd have increased risk of menstrual irregularity and central obesity compared to Cd. No difference in cardiometabolic traits were observed between PCOSs and Cs. Our preliminary results shed some light on the potential long-term cardiometabolic burden on PCOSd. 


Sexual dimorphism in cardiometabolic risk in offspring of mothers with PCOS

Natural history of PCOS

In women with PCOS receiving controlled ovarian stimulation for in vitro fertilization (IVF), follicular fluid and granulosa cells are dysfunctional, with hundreds of transcripts, proteins, lilpids and metabolites that differ significantly from controls with non-ovarian causes of infertility. However,  there is no evidence that oocytes are compromised: the proportion of metaphase II oocytes, the rate of development to blastocyst and the prevalence of aneuploid embryos are unchanged. Endometrial proteome is altered but receptivity is not affected in IVF treatments, where the implantation rates of single 'ideal' blastocysts are similar in PCOS and controls. During ovarian stimulation for IVF, protocols that use pituitary downregulation with GnRH antagonist followed by triggering with GnRH agonist are safer (lower incidence of ovarian hyperstimulation syndrome) and equally effective (same pregnancy rates) compared with long protocols that use GnRH agonist for pituitary downregulation and hCG for ovulation triggering. FSH receptor gene polymorphisms may affect ovarian response to exogenous FSH, but the clinical usefulness of this information to plan IVF treatments of women with PCOS is still uncertain. For women with PCOS treated with IVF, frozen embryo transfer is better than fresh embryo transfer. When preparing the endometrium for frozen embryo transfer, pituitary downregulation with GnRH agonist does not increase the odds of a live birth. Progestins are better than COC to induce menses before starting an IVF cycle in women with PCOS. Insulin sensitizers or weight reduction do not seem to improve IVF outcomes.

IVF and PCOS

PCOS is though to stem from prenatal exposures and seems to translate into increased comorbidity risk. The health insults, however, vary depending on the age. The presentation will go through the health risks related to PCOS over the lifespan.

PCOS over the lifespan

For the motion

Against the motion

Luteinizing hormone knockout alleviates anxiety in aged, but not in young mice

LH/CG Receptor activation protects mice from diet-induced obesity

OBJECTIVE: Polycystic ovarian syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is associated with cardiometabolic comorbidities. Information on cardiovascular disease (CVD) event risk associated with PCOS is mixed limited by sample size, diagnostic criteria, and years of follow up especially in US cohorts. Metformin, a drug traditionally used to treat patients with type 2 diabetes (T2D), is first line treatment for many women with PCOS We hypothesize that women with PCOS are at increased risk for developing cardiovascular diseases CVD and that metformin may play a protective role in disease progression.
METHODS: We leveraged the Penn Medicine electronic health record (EHR) which contains diagnosis information for 2,514,400 women. We calculated relative risk (RR) of being diagnosed with CVD or thrombotic disease (based on diagnosis codes) for women who were also diagnosed with PCOS or PCOS + T2D. For both RR calculations, our cases were women aged 15-50 who had at least one visit with PCOS diagnosis with or without T2D diagnosis. Controls were women aged 15-50 without a PCOS diagnosis but who had at least one visit for T2D. We also calculated RR of being diagnosed with CVD or thrombotic event for women aged 15-50 with at least one PCOS + T2D diagnosis who were treated with the drug metformin. Controls were women aged 15-50 with a PCOS +T2D diagnosis but were not treated with metformin.
RESULTS: Of the 945,670 women aged 15-50, 22,030 (2.3%) had at least one visit for PCOS diagnosis while 2,010 (0.2%) had PCOS and T2D. We found that the risk for CVD for women with PCOS was 1.35 times that of age matched controls (95% CI 1.29 ± 1.43, p = 1.76e-28) and the risk for thrombotic disease was 2.02 times that of age matched controls (95% CI 1.81 ± 2.26, p = 5.25e-37). We found that women with PCOS + T2D had decreased risk for CVD (RR = 0.26, 96% CI 0.23 ± 0.29, p = 6.21e-140) and thrombotic disease (RR = 0.60, 95% CI 0.47 ± 0.77, p = 3.02e-05). Because many women with T2D are prescribed metformin, we wanted to know if a metformin prescription had a protective effect on being diagnosed with CVD or thrombotic disease. By calculating RR, we found that women with PCOS + T2D who were prescribed metformin were 15% less likely of developing CVD (RR = 0.85, 95% CI 0.77 ± 0.93, p = 5.03e-05) and 4% less likely of developing TD (RR = 0.96, 95% CI 0.83 ± 1.12, NS) compared to patients that were never prescribed metformin.
CONCLUSIONS: In a large longitudinal cohort of women diagnosed with PCOS, we showed that a PCOS diagnosis was associated with an increased risk of CVD events. We also showed that PCOS patients who also had T2D diagnosis had decreased risk of CVD, which we observed was potentially associated by the protective effects of the drug metformin. Due to the high prevalence of CVD in women, longitudinal studies are needed to uncover the molecular, genetic, and pharmacogenomic pathways underlying disease progression in women with PCOS.

Cardiovascular events associated with PCOS diagnosis in large longitudinal cohort

Women with polycystic ovary syndrome (PCOS) have poorer work ability and higher disability retirement rate at midlife - A Northern Finland Birth Cohort 1966 Study

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Reproductive features captured within the first gynecological year predict persistent menstrual irregularity at two years post-menarche

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Sexual dimorphism in cardiometabolic risk in offspring of mothers with PCOS

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