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Research Article

Impact of polycystic ovary syndrome on quality of life of women in correlation to age, basal metabolic index, education and marriage

Roles Investigation

Affiliation Department of Pharmacology, Santosh Medical College, Santosh University, Ghaziabad, Uttar-Pradesh, India

Roles Data curation

Affiliation Department of Gynecology and Obstetrics, All India Institute of Medical Sciences, Patna, Bihar, India

Roles Project administration

* E-mail: [email protected] (KD); [email protected] (MSA)

Roles Formal analysis, Writing – original draft, Writing – review & editing

Affiliation College of Pharmacy, King Khalid University, Abha, Kingdom of Saudi Arabia

• Fauzia Tabassum, 
• Chandra Jyoti, 
• Hemali Heidi Sinha, 
• Kavita Dhar, 
• Md Sayeed Akhtar

• Published: March 10, 2021
• https://doi.org/10.1371/journal.pone.0247486
• Reader Comments

Polycystic ovary syndrome (PCOS) is the major endocrine related disorder in young age women. Physical appearance, menstrual irregularity as well as infertility are considered as a sole cause of mental distress affecting health-related quality of life (HRQOL). This prospective case-control study was conducted among 100 PCOS and 200 healthy control cases attending tertiary care set up of AIIMS, Patna during year 2017 and 2018. Pre-validated questionnaires like Short Form Health survey-36 were used for evaluating impact of PCOS in women. Multivariate analysis was applied for statistical analysis. In PCOS cases, socioeconomic status was comparable in comparison to healthy control. But, PCOS cases showed significantly decreased HRQOL. The higher age of menarche, irregular/delayed menstrual history, absence of child, were significantly altered in PCOS cases than control. Number of child, frequency of pregnancy, and miscarriage were also observed higher in PCOS cases. Furthermore, in various category of age, BMI, educational status and marital status, significant differences were observed in the different domain of SF-36 between PCOS and healthy control. Altogether, increased BMI, menstrual irregularities, educational status and marital status play a major role in altering HRQOL in PCOS cases and psychological care must be given during patient care.

Citation: Tabassum F, Jyoti C, Sinha HH, Dhar K, Akhtar MS (2021) Impact of polycystic ovary syndrome on quality of life of women in correlation to age, basal metabolic index, education and marriage. PLoS ONE 16(3): e0247486. https://doi.org/10.1371/journal.pone.0247486

Editor: Antonio Simone Laganà, University of Insubria, ITALY

Received: July 24, 2020; Accepted: January 1, 2021; Published: March 10, 2021

Copyright: © 2021 Tabassum et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Data cannot be shared publicly because of confidentiality. Data are available from the Ethics Committee, AIIMS, Patna for researchers who meet the criteria for access to confidential data. Contact information for the ethics committee: (The Chairman, Institutional review board, All India Institute of Medical Sciences, Patna, Bihar (India), PIN-801507).

Funding: This work is supported by the Dean of Scientific Research, King Khalid University for the financial support is greatly appreciated for the general research Project under grant number [GRP/190/42], awarded to MSA.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Polycystic ovary syndrome (PCOS) is a major endocrine disorder in young age women affecting their health-related quality of life (HRQOL) and their mental well-being as well [ 1 , 2 ]. Moreover, this develop into lifelong health condition that continues far beyond the young ages and affects around 5 million young age population in the United States of America [ 3 , 4 ]. In India, PCOS has been reported to vary between racial counterparts with an estimated prevalence of 9.13% in adolescents [ 5 ]. The major changes in physical appearance, obesity, along with menstrual irregularity have been found to be the main contributing factor of psychological dilemma [ 6 – 8 ]. PCOS negative impact is always underestimated and dominates on women’s life and may lead to a risk for serious anxiety and psychological disorder [ 9 , 10 ]. Importantly, the psychological burden greatly varies with the change in geographical areas and societal perceptions (Barnard et al., 2007; Brady et al., 2009). These patients may experience characteristics of PCOS as stressful and may be at higher risk for depression and anxiety disorders and even this may lead towards suicidal tendency [ 9 , 10 ].

Clinically, PCOS is characterized by either oligoovulation or anovulation and hyperandrogenism that may cause infertility, and other related metabolic disorders [ 11 ]. This progresses to increased risk of reproductive issues like infertility endometrial cancer, gestational as well as mental disturbances [ 12 ]. However, novel treatments and therapies can then be targeted toward improving those problems, which are most important for the individual concerned [ 13 , 14 ]. Recently, increased importance has been given on understanding the impact of PCOS symptoms and in particular about the feminine identity and thus their treatment from the patients’ perspective for the better quality of life (QOL). HRQOL is a self-perceived health status as a consequence of any disease that is measured by health status questionnaires [ 15 ]. Therefore, HRQOL questionnaires like Short Form Health Survey-36 (SF-36) for PCOS, was used to understand the impact of PCOS and evaluating individual patients’ health status and monitoring and comparing disease burden [ 16 , 17 ]. The SF-36 scale leaves out important detrimental issues linked to PCOS patients such as physical and emotional symptoms associated with menses [ 16 ]. PCOS questionnaire has reasonable internal reliability, good test-retest reliability, good concurrent and discriminated validity, and a reasonable factor analysis making PCOS questionnaire a useful and promising tool for HRQOL in PCOS cases.

At present, there is a paucity of information related to PCOS among women of the reproductive age group in India, in particular, North India. Thus, considering these factors into account, this prospective study was planned to compare socioeconomic status (SDS) and association of age, body mass index (BMI), education level and marital status between PCOS and healthy control cases among the women in the reproductive age group visiting the department of gynaecology and obstetrics of tertiary care hospital.

Material and methods

Ethical approval.

Ethical approval (SU/2017/1226-3) was obtained from the institutional review board of Santosh medical college, Uttar Pradesh, India. The institutional review board of All India Institute of Medical Sciences, Patna, India, granted study site approval (176/AIIMS/PAT/IEC/2017). Informed consent form was obtained from parents or guardians of the minors (<18 years).

Study design

This prospective, cross sectional, observational study was designed and conducted in the tertiary care teaching hospital of north India.

Study setting

Patients visiting the outpatients’ department of Gynecology and Obstetrics, All India Institute of Medical Sciences, Patna (India) were included in the study.

Participants

Patients diagnosed with PCOS, based on criteria derived from the 2003 ESHRE/ASRM (Rotterdam criteria) were arbitrarily enrolled in the study. PCOS is diagnosed as the presence of at least two of three of the following: 1) Oligo/anovulation, 2) hyperandrogenism, 3) Polycystic ovaries [ 18 ]. A healthy control (HC) was selected from participants of the same population and having regular menses and had no clinical features of hyperandrogenism as well as infertility.

Data sources

Data was collected after describing both written and verbal information about the study. After explaining, the informed consent form was signed by each participant and then they were requested to complete the questionnaires. Face-to-face interviews were conducted by investigators to the subjects meeting the inclusion criteria and consented for the participation into the study in three parts: Part A: Semi-structured, pre-validated questionnaires were used for collecting information on the socio-demographic, economic and reproductive history. Part B: Pre-validated SF-36 questionnaire is a standard diagnostic tool for evaluating various aspects of the HRQOL over the previous 4 weeks [ 19 ]. Its validity, sensitivity, reliability, internal consistency and stability, as well as test-retest reliability have frequently been confirmed in various studies [ 20 – 22 ]. SF-36 contains 8 domains: general health, physical functioning, and role limitations due to physical health, role limitation due to the emotional problem, body pain, social functioning, energy/fatigue and emotional well-being. The scores for each domain range from 0–100, where higher scores indicate better condition.

The sample size was estimated post assuming α-error of 0.05, power of 80%, percentage of controls having a poor quality of life to be 20% based on previous studies and odds of poor QOL among cases to be twice than among controls. Hence, a total of 100 PCOS cases and 200 healthy control cases were enrolled in the study.

Inclusion criteria

We included all diagnosed case of PCOS only, female from menarche to menopausal age between the age of 10–49 years, and those given informed consent.

Exclusion criteria

Patients having cognitive or developmental disabilities/another major illness that substantially influenced the HRQOL of women, confirmed malignancy and deformities, as well as breastfeeding women were excluded from the study.

Statistical analysis

Data were analyzed by using statistical software-Stata Version 14.0 (Stata Corp, Texas, USA). After checking for the normality condition for continuous variables, the appropriate statistical test was applied. Confounders like excessive body weight were taken into consideration. Quantitative data expressed as mean±SD, minimum and maximum followed normal and skewed distribution respectively. Analysis of covariance model (ANCOVA) was used to address potential confounders. Categorical variables expressed as frequency and percentage. Pearson Chi-Square test and Fisher exact test were used to checking the association between qualitative variables and categorical variables. Logistic regression analysis was used to estimate odds (95% CI) and models were robust for PCOS and other variables. Multivariable linear regression analysis was performed to observe the association between the variables. Independent t-test and One Way ANOVA used to compare normally distributed continuous variable between two and three categories respectively. Rank sum/Kruskal Wallis test used for comparing skewed continuous variables among categories and to look association between demographic categories. For all statistical tests, P-value < 0.05 is considered as statistical significant.

The outcome of socioeconomic status (SES) of a woman with PCOS and HC cases are mentioned in Table 1 . The women with PCOS and HC were comparable in respect of marital status and family type. Statistically significant differences were observed between PCOS and HC in terms of age (P<0.020), BMI (P<0.001), educational status (P<0.001), marital status (P>0.05) and work category (P<0.001). Total 97% of PCOS case was below the age of 30 years in comparison to 78% of control. Among all PCOS cases, 60% was student and almost 54% received higher education. Among the HC group, 39% was student and only 15% received higher education (P<0.001). A higher percentage of PCOS cases (16%) belong to greater BMI (>30) in comparison to HC (2%).

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https://doi.org/10.1371/journal.pone.0247486.t001

As shown in Table 2 , among the PCOS group, a significant percentage of women (33%) has menarche at age greater than 14 years and there was no any HC cases lies in this category (P<0.001). In respect of menstrual history, PCOS cases have a higher percentage of irregular (45%) and delayed (54%) menses and this comprises a signify`cant difference (P<0.001) in comparison to HC that was 8% irregular and no any delay in menses were observed. Around 64.3% of cases of PCOS women have no child (P<0.001) in contrast to HC cases (9.5%). However, 86.67% PCOS cases have less than ≤ 2 children in comparison to HC where 69.47% have less than ≤2 children (P<0.169). In terms of pregnancy, almost 77.27% PCOS women got pregnant ≤2 times in comparison to HC cases (P>0.05).

https://doi.org/10.1371/journal.pone.0247486.t002

As depicted in Table 3 , Overall differences of mean in PCOS and HC case comparable in respect of BMI (P<0.125).

https://doi.org/10.1371/journal.pone.0247486.t003

However, the highest range of BMI was more in PCOS cases in comparison to HC. Whereas, a statistically, significant differences in mean were observed in respect of age (P<0.009), age at marriage (P<0.001), age of menarche (P<0.001), number of children (P<0.001) and number of pregnancy (P<0.006) between PCOS and HC cases. In case of age, women with PCOS at age ≤19 showed significantly higher score for of general health (P<0.001), role limitation due to physical health (P<0.001), role limitation due to the emotional problem (P<0.022), pain (P<0.025) and social function (P<0.010) in comparison to age >30. However, comparable differences were observed in physical function (P<0.116), energy or fatigue (P<0.087) and emotional well-being (P<0.108). In HC cases, women of age ≤19 showed a statistically higher score in general health (P<0.001), physical health (P<0.001), role limitation due to the emotional problem (P<0.005) and energy/fatigue (P<0.001). Comparable differences were observed for role limitation due to physical health (P<0.818), pain (P<0.424), social functioning (P<0.110) and emotional well-being (P<0.147; Table 4 ).

https://doi.org/10.1371/journal.pone.0247486.t004

As per BMI is concerned, PCOS women scored high and statistically significant differences were observed in case of BMI those who have value <18 in comparison to >30. In addition, significant differences were observed for general health score (P<0.001), physical health (P<0.001), energy and emotion (P<0.001). Whereas, comparable differences observed in role limitation due to physical health (P<0.085), role limitation due to the emotional problem (P<0.565), pain (P<0.189), social function (P<0.549) and emotional well-being (P<0.127). In HC case, there no significant difference was observed in all the eight domains of SF-36 ( Table 5 ). As per the level of education is concerned, HRQOL score was higher in all eight domain of SF-36 in well-educated women in comparison to illiterate or women having education of primary level, but this difference was observed to be statistically non-significant and comparable. In case of HC women, HRQOL score in graduation level was higher and significant differences were observed in relation to the level of education for SF-36 domains like general health (P<0.001), physical health (P<0.039) and energy/fatigue (P<0.003). However, we observed comparable differences among all other domains of SF-36 ( Table 6 ).

https://doi.org/10.1371/journal.pone.0247486.t005

https://doi.org/10.1371/journal.pone.0247486.t006

We observed significant differences between married and unmarried PCOS cases in terms of general health (P<0.001), physical functioning (P<0.027), role limitation due to physical health (P<0.006), role limitations due to emotional problems (P<0.002), pain (P<0.001), social functioning (P<0.001), energy/fatigue (P<0.003) and emotional well-being (P<0.001). Whereas, in HC cases, no differences were observed between married and unmarried cases in regarding SF-36 domain score for role limitation due to physical health (P<0.538), role limitation due to the emotional problem (P<0.105), Pain (P<0.044), social functioning (P<0.225), emotional well-being (P<0.857). However, significant differences were observed for general health (P<0.001), physical health (P<0.002) and energy/fatigue (P<0.001) among married and unmarried HC cases ( Table 7 ).

https://doi.org/10.1371/journal.pone.0247486.t007

The Fig 1 and Table 8 exhibits the regression analysis data plot and we was observed strong association between infertility and menstrual irregularities (P<0.049) as well as emotional well being (P<0.001) of PCOS patients. We also observed infertility (P<0.001) and hirsutism (P<0.05) as a major predictor affecting in all domain scores ( Table 9 ).

https://doi.org/10.1371/journal.pone.0247486.g001

https://doi.org/10.1371/journal.pone.0247486.t008

https://doi.org/10.1371/journal.pone.0247486.t009

PCOS has no any constant treatment due to its multifaceted features. However, lifestyle modification, hormonal contraceptives and some other drugs like inositol, clomiphene, eflornithine, finasteride, flutamide, letrozole, metformin, spironolactone has been reported to ameliorate the PCOS symptoms [Williams T, Mortada R, Porter S. Diagnosis and treatment of polycystic ovary syndrome. American family physician. 2016; 94(2): 106–113; Lagana AS, Garzon S, Casarin J, Franchi M, Ghezzi F. Inositol in Polycystic Ovary Syndrome: Restoring Fertility through a Pathophysiology-Based Approach. Trends Endocrinol Metab. 2018;29(11):768–780; Lagana AS, Garzon S, Unfer V. New clinical targets of d-chiro-inositol: rationale and potential applications. Expert Opin Drug Metab Toxicol. 2020;16(8):703–710].

PCOS is an endocrine disorder and its long term complications affect various aspects of HRQOL in women [ 23 , 24 ]. Despite the various evidence about compromised HRQOL in women with PCOS, we further explored the other determinants that may help the clinician in care of the patient well-being [ 17 , 25 , 26 ]. Overall, we demonstrated the drastically compromised HRQOL in young women suffering from PCOS. As earlier reported, the woman with PCOS belongs to a lesser age group in relation to HC indicating a higher prevalence of PCOS cases in young age woman especially in adolescents [ 27 ]. As per SDS is concerned, the major difference between PCOS and control cases was observed in case of age, BMI and level of education [ 28 ]. Thus, all this indicated that PCOS affects HRQOL more in the young woman and the SDS definitely affect the prevalence of PCOS. The age of menarche in the majority of women was > 18 years as earlier reported [ 29 ]. This was in contrast to other reports [ 30 ]. Consistently, increased age of menarche was observed in PCOS cases indicating the impact of first menstruation in young women life and in the development of PCOS and another reproductive as well as metabolic disorder [ 31 , 32 ].

As previously reported, we observed a direct correlation between the PCOS and irregular or delayed menses and having no children that can be taken as a symptom of PCOS diagnosis [ 33 ]. The higher number of women having lesser than two children and lesser number of times get pregnant further supported this compromised HRQOL [ 30 ]. This compromised HRQOL in PCOS case was further supported by our study.

The overall decreased mean of BMI and age at menarche indicated as PCOS symptoms. Concurrently, mean age, age at marriage, number of children and frequency of pregnancy was less in PCOS cases than control. Consistent to the previous study, these indices corroborate above findings and strongly indicated the deterioration of HRQOL in PCOS women [ 28 ]. Altogether, higher fertility disorder in PCOS cases was observed that directly affects their HRQOL due to physical, social as well as emotional issues.

Furthermore, in PCOS cases, physical, social and emotional well-being more affected as evidenced from all eight domains of SF-36 indicating strongly compromised HRQOL than HC cases [ 34 ]. In particular, we also compare the mean score in relation to age, BMI, educational level and marital status. Consistent with the previous report, increasing the age had a more negative impact on different domains of SF-36 in PCOS cases than HC cases. Comparable scores in PCOS women with increasing age for physical health, energy and emotional well-being may be due to improved regular menses with age concurrent to improved PCOS features and loss of societal fear. Whereas, in HC cases, changes in normal life trend in the prospect of HRQOL was seen with increasing age indicating normal HRQOL [ 35 ].

In a similar fashion, with the increase in the BMI, physical activity was not affected in PCOS cases as observed from different domains of SF-36 but the emotional problem was more affected in PCOS cases in comparison to HC. This may be a major reason for compromised HRQOL in PCOS women [ 36 , 37 ]. In HC cases, none of the scores of SF-36 domains was different between BMI groups. Consistent to previous studies, with increasing the level of education, all the domains of SF-36 in PCOS cases have improved HRQOL. Similar to other HRQOL studies in different diseases, where well-qualified patients have better HRQOL than illiterate cases [ 38 ]. We also observed that well-qualified group probably have higher number of PCOS cases that directly support that improved SDS is a major contributing factor in developing PCOS. The differences in scores of all the domains of SF-36 were observed in married PCOS cases in contrast to unmarried. Thus, consistent to the previous report, the HRQOL of the unmarried cases was better in comparison to married women [ 39 ]. Whereas, in HC cases, all physical, social, as well as emotional wellness, were similar in both married and unmarried women. This may be due to their social independency and quality of education in young women with PCOS.

As reported earlier, infertility and hirsutism emerges as the major problem affecting the overall HRQOL and a strong association has been observed between infertility and emotional well-being [ 40 ].

Our data compares the relations between PCOS and HC cases of overall HRQOL. We explored the strong association between PCOS and SES, and suggest that with increasing age and BMI PCOS patients had lower scores on SF-36; opposite association was with education level. However, Infertility emerges as the major predictor affecting overall HRQOL in PCOS cases. The present study does have its limitations of not measuring biochemical assessment and ultrasonography indices.

Acknowledgments

The authors are thankful to Dean of Scientific Research, King Khalid University and the College of Pharmacy, Department of Clinical Pharmacy for providing facilities to carry out our research work. I also want to acknowledge Dr. R. M. Pandey, Professor & Head, Department of Biostatistics, All India Institute of Medical Sciences, Delhi (India) for supporting me to analyse and interpret my data.

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• Published: 11 February 2022

PCOS — a metabolic condition with health impacts on women and men

• Anju E. Joham 1 , 2 &
• Helena J. Teede 1 , 2  

Nature Reviews Endocrinology volume  18 ,  pages 197–198 ( 2022 ) Cite this article

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• Endocrine reproductive disorders
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A new paper explores genetic risk factors for polycystic ovary syndrome (PCOS) and non-reproductive PCOS phenotypes in women and men. This work affirms that PCOS is indeed a metabolic disorder, that ovarian function is not required for cardiometabolic features and that this condition has implications for both men and women.

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Joham, A.E., Teede, H.J. PCOS — a metabolic condition with health impacts on women and men. Nat Rev Endocrinol 18 , 197–198 (2022). https://doi.org/10.1038/s41574-022-00636-z

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• Published: 06 January 2021

Associations of diet, physical activity and polycystic ovary syndrome in the Coronary Artery Risk Development in Young Adults Women’s Study

• Annie W. Lin 1 , 2 ,
• David Siscovick 3 ,
• Barbara Sternfeld 4 ,
• Pamela Schreiner 5 ,
• Cora E. Lewis 6 ,
• Erica T. Wang 7 ,
• Sharon S. Merkin 8 ,
• Melissa Wellons 9 ,
• Lyn Steffen 10 ,
• Ronit Calderon-Margalit 11 ,
• Patricia A. Cassano 12 &
• Marla E. Lujan   ORCID: orcid.org/0000-0002-7203-5814 12  

BMC Public Health volume  21 , Article number:  35 ( 2021 ) Cite this article

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Current evidence supports the adoption of healthy diet and physical activity (PA) behaviors in patients with polycystic ovary syndrome (PCOS), given the positive effects of those behaviors on physical well-being. An improved understanding of the associations between diet and PA with PCOS is needed to ascertain whether tailored dietary and PA recommendations are needed for this population. Thus, we investigated the associations of diet and PA with PCOS and its isolated features.

Cross-sectional study. Of the 748 women who were included in this study from the Coronary Artery Risk Development in Young Adults (CARDIA) Women’s Study, 40 were classified as having PCOS, 104 had isolated hyperandrogenism (HA) and 75 had isolated oligomenorrhea (OA). Dietary intake was measured using the CARDIA diet history questionnaire and diet quality was scored using the Alternative Healthy Eating Index 2010; a higher score indicated a better quality diet. Self-reported PA was measured using a validated interviewer-administered questionnaire. Polytomous logistic regression analyses examined the associations between diet and PA with PCOS, HA, and OA status (outcomes), adjusting for age, race, total energy intake, education, and/or body mass index. The threshold for statistical significance was set at p  < 0.05.

Mean age of the participants was 25.4 years (SD 3.6) and 46.8% of participants were Black women. There was little to no association of total energy intake, nutrients, diet quality, and PA with PCOS, HA or OA status.

Energy intake, nutrient composition, diet quality, and PA were not associated with PCOS, supporting recent PCOS guidelines of using national recommendations for the general population to encourage health-promoting behaviors among women with PCOS. However, longitudinal studies evaluating changes in diet and physical activity in relation to the development and/or the progression of PCOS are needed to establish a causal association.

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Polycystic ovary syndrome (PCOS) is a complex endocrine condition traditionally characterized by ovulatory dysfunction and androgen excess [ 1 ]. In addition to reproductive complications, women with PCOS often present with overweight or obesity and associated obesity-related complications, such as insulin resistance, impaired glucoregulatory status, and cardiometabolic dysfunction [ 2 ]. Rates of overweight and obesity in PCOS (up to 88% of patients) well exceed that seen in the general population and suggest that obesity can either contribute to PCOS development and/or is a consequence of PCOS pathogenesis [ 2 ]. Accordingly, expert recommendations support modifications in diet and physical activity primarily targeted at weight loss or management as a means to improve health outcomes in PCOS [ 2 , 3 , 4 , 5 ]. Current diet and physical activity recommendations for women with PCOS reflect those for the general population or other clinical populations (e.g., diabetes mellitus) that do not necessarily account for the unique biology and/or psychosocial variables associated with PCOS [ 6 , 7 ]. An understanding of associations between dietary intake and physical activity levels with PCOS is ultimately needed to determine the relevance of tailored therapies for this patient population.

We previously noted inconsistent findings related to differences in energy intake and dietary composition between women with and without PCOS [ 8 ]. Approximately half of the 10 studies reviewed reported differences in total energy [ 9 , 10 , 11 , 12 , 13 ] and fat intake [ 9 , 10 , 13 , 14 , 15 ] in women with PCOS versus a reference group. Three studies did not detect any association(s) between diet and PCOS [ 16 , 17 , 18 ]. With respect to physical activity levels, only two studies reported longer sitting intervals in women with PCOS than the reference [ 11 , 14 ]. Most showed no differences in overall activity between groups [ 9 , 11 , 12 , 13 , 14 , 18 ]. Collectively, published studies do not provide definitive evidence on associations of diet, physical activity and PCOS [ 8 ].

Comparisons among previous studies of dietary intake and physical activity levels in relation to PCOS are limited by differences between studies in how PCOS phenotypes were defined [ 8 ]. Depending on the PCOS diagnostic criteria used, there are four distinct phenotypes. The National Institutes of Health (NIH) criteria define PCOS by the combined presence of oligomenorrhea (OA) and hyperandrogenism (HA) [ 1 ] to identify a relatively homogenous patient population with the most severe risk for reproductive and metabolic dysfunction [ 5 ]. The Rotterdam criteria define PCOS by the combined presence of two out of three cardinal features: OA, HA, and polycystic ovarian morphology [ 19 ]; the Rotterdam criteria captures a more heterogeneous patient population, including mild PCOS phenotypes (i.e., women with regular menstrual cycles and HA or women with OA and normal androgens) [ 20 ]. Milder phenotype(s) may reflect different etiologies and lower risks for metabolic and reproductive sequelae [ 5 ]. Differences in metabolic and reproductive risk across PCOS phenotypes may be attributed to the presence of isolated OA versus HA and/or the additive effects of these two features in conjunction with adiposity. Higher adiposity (an outcome closely linked with diet and physical activity) has been reported to be more prevalent in severe (i.e., those with HA) versus mild PCOS phenotypes [ 20 ]. There is an emerging consensus that studies should use a more homogenous definition of PCOS [ 21 ] or account for phenotypes in their analyses. Studies of usual dietary intake and physical activity levels that consider isolated versus combined cardinal features of PCOS while accounting for body mass index (BMI) are also needed.

While race influences the likelihood of adverse metabolic outcomes in women with PCOS [ 22 , 23 , 24 , 25 , 26 , 27 ], few prior studies investigated race as an effect modifier. To our knowledge, prior studies of the association of dietary intake or physical activity levels with PCOS do not investigate differences by race. Previous studies conducted in the United States (US) reported a higher odds and/or prevalence of obesity, hypertension [ 24 , 25 ], and elevated fasting glucose concentrations in Black versus White patients [ 23 , 26 ]. Although it is unclear whether race influences the etiology or pathogenesis of PCOS, food choice and medical experiences can vary by race and contribute to differential metabolic manifestations [ 28 ]. New recommendations from the international evidence-based guideline for the assessment and management of PCOS acknowledge this knowledge gap and endorse the need for further research on the impact of race/ethnicity in PCOS and the identification of best approaches for treatment across races and clinical phenotypes [ 29 ]. To that end, the primary objective of the present study was to investigate the cross-sectional associations of usual dietary intake and physical activity levels with (a) PCOS and (b) its isolated features (i.e. OA or HA alone) as defined by NIH criteria to include a more homogenous patient population. We hypothesized that high energy and fat intake, and high sedentary behavior, were associated with PCOS and its isolated features. We also explored whether race had a modifying effect on these associations as our secondary objective.

Study design and sample

The research questions were addressed using data from the Coronary Artery Risk Development in Young Adults (CARDIA) multi-center longitudinal prospective cohort study. From 1985 to 1986, CARDIA investigators enrolled 5115 Black and White men and women (Supplemental Figure 1 ) , ages 18 to 30 years of age, residing in one of four cities: Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California [ 30 ]. Participants visited research centers at years 2, 5, 7, 10, 15, 20, 25 and 30 after the initial examination (year 0), with a 71% retention rate of the surviving cohort at year 30. The CARDIA study was approved by the institutional review boards of the CARDIA coordinating center and the four participating field centers, and written informed consent was obtained from participants at all examinations. At year 16 (2002–2003), a subset of women was enrolled in an ancillary study (CARDIA Women’s Study; CWS) that investigated associations among androgens, polycystic ovaries and cardiovascular risk factors. Women were eligible if they had participated in the year 15 examination, had at least one ovary and were not pregnant. Eighty-six percent ( n  = 1163) of eligible women in the CARDIA cohort enrolled in the CWS (ages 34–46 years at enrollment to CWS). CWS participants completed questionnaires that retrospectively inquired about their reproductive health history and the occurrence of unwanted hair growth during the ages of 20s and 30s, an age range that for most of the participants coincided with the diet, physical activity, biochemical, and anthropometric data collected during years 0 and 2 of the CARDIA study. We excluded women who: had missing data on PCOS features ( n  = 294), were pregnant at year 2 ( n  = 103), and/or had implausible total energy (kcal) intake (defined as < 600 and > 6000 kcal) ( n  = 18). Thus, the analytic sample comprised 748 women (64% of the CWS cohort). The current study was deemed exempt by the Cornell University IRB since data was de-identified.

Group definitions

Participants were classified into four mutually exclusive groups: 1) PCOS; 2) isolated hyperandrogenism (HA); 3) isolated oligomenorrhea (OA); and 4) neither PCOS, HA, or OA. NIH criteria [both oligomenorrhea (irregular menstrual cycles) and hyperandrogenism (clinical and/or biochemical)] were used to identify women with PCOS. Oligomenorrhea was defined as self-reported menstrual cycle lengths ≥34 days during the woman’s 20s and 30s (retrospective data collected on reproductive history questionnaire at year 16). Hyperandrogenism was defined as self-reported unwanted hair growth at two or more regions of the body (with the exception of the lower leg and/or underarm) during the woman’s 20s and 30s (retrospective data collected on reproductive history questionnaire at year 16) or biochemical hyperandrogenemia based on assays in year 2 serum samples. Biochemical hyperandrogenemia was defined as total testosterone (T) ≥ 76 ng/dL and/or free T ≥ 0.69 ng/dL. Cut-off points were defined by the 95th percentile of androgen concentrations in CWS women with regular menstrual cycles (20 to 30 days) and no symptoms of unwanted hair growth during their 20s or 30s ( N  = 415). Androgens and sex hormone binding globulin were assayed by the OB/GYN Research and Diagnostic Laboratory at the University of Alabama, Birmingham as previously described [ 31 ]. Women who had only one of the two PCOS criteria were classified as either HA or OA.

Data collection

Diet and physical activity measurements.

Year 0 dietary data was used, given that the data was collected using the interviewer-administered CARDIA Diet History and was also in close proximity to the year 2 androgen concentrations [ 32 ]. Participants reported their dietary intake in the past 28 days, including the frequency and amount of food consumption and methods of food preparation. Forty-six food and beverage subgroups were defined by the Nutrient Data Software for Research (NDSR; University of Minnesota, Minneapolis, Minnesota). The intake of each food or beverage subgroup was calculated by summing the number of daily servings of items included in the subgroup.

Diet quality was scored using the Alternate Healthy Eating Index 2010 (AHEI-2010). The AHEI-2010 includes 11 dietary components (seven food groups, four nutrient groups) [ 33 ]. Each dietary component score ranged from zero to ten, with a higher score representing a healthier diet. The total AHEI-2010 score was calculated as the sum of all 11 components and ranged from 0 to 110. The 46 NDSR food and beverage subgroups were sorted into the seven AHEI-2010 food groups. Higher intakes of vegetables, fruits, whole grains, nuts/legumes, long chain omega 3 fatty acids (eicosapentaenoic and docosahexaenoic acids; EPA + DHA), polyunsaturated fatty acids (PUFAs without EPA + DHA) were assigned higher scores. Sugar-sweetened beverages and fruit juices, red and processed meats, trans -fats and sodium were assigned scores on a reverse scale due to their association with adverse health outcomes (thus, for these sub-scores a higher score indicates lower consumption). Given the complex and non-linear relation of alcohol to health outcomes, women who consumed 0.5 to 1.5 drinks/day were assigned the highest score (score of 10), women who consumed > 1.5 drinks/day were assigned the lowest scores, and non-drinkers were assigned a score of 2.5 [ 33 ].

Self-reported physical activity data were collected during year 0 with the CARDIA Physical Activity History questionnaire, which asked about the frequency of 13 types of moderate and vigorous intensity activities in the past year (e.g., jogging or running, recreational sports, home maintenance) [ 34 , 35 ]. Physical activity scores were calculated by multiplying the frequency and intensity of each activity and summing across all activities. Additional details on the calculation can be found in previous CARDIA publications [ 34 ]. Activity scores were expressed as ‘exercise units’ (EU) since the questionnaire did not ask specifically about the duration of each activity. A score of approximately 300 EU is approximately equivalent to moderate-to-vigorous exercise five times per week for 30 min [ 34 ].

Sociodemographic and clinical measurements

Sociodemographic data (age, race, education) were collected at year 0 using interviewer-administered questionnaires. For anthropometry data collection at year 0, participants changed into light clothing and removed their shoes prior to anthropometric measurements taken by trained research staff. Weight was obtained using a digital scale (Detecto model 439; Webb City, Missouri) and measured to the nearest 0.2 pounds. Height was collected using a vertical mounted ruler and measured to the nearest 0.5 cm. BMI was calculated as weight in kilograms divided by height in meters, squared.

Statistical analyses

Statistical analyses were completed using SAS 9.4 (SAS Institute, Cary North Carolina). The statistical significance threshold was set at p  < 0.05 for the bivariate (i.e., t-test and χ2 test) and logistic regression analyses to compare each of the PCOS, HA, and OA groups with the reference group for the overall sample. Polytomous logistic regression estimated the association of dietary and physical activity (continuous) variables with the odds of PCOS, HA and OA after adjusting for age, race, total energy intake and education in partial models, and extended to include BMI in the fully-adjusted models. To investigate whether associations with PCOS, HA and OA varied by race, regression models examined the interaction(s) between race and the dietary and physical activity variables using covariates from the fully adjusted models. The significance threshold for the effect modification of race on logistic regression models was set at p  < 0.10 and we did not adjust for multiple testing for the overall analyses given the exploratory nature of these aims to investigate whether diet and physical activity are linked with features of PCOS [ 36 ]. Interpretation focused on effect sizes and confidence intervals (CI) to address the precision of the estimates [ 37 ]. These results were reproduced by the Cornell Institute for Social and Economic Research.

Participant characteristics

Among the 748 participants included in this analysis, 40 (5.3%) women were classified as PCOS, 104 (13.9%) as HA, 75 (10.0%) as OA, and 529 comprised the reference group. Menstrual cycle status, unwanted hair growth and androgen levels differed across the four groups by definition. By contrast, mean age, BMI, diet, and physical activity were similar across groups (Tables  1 and 2 ). Compared to the reference group (i.e., no PCOS, HA, or OA), there were lower proportions of Black women in the PCOS and OA groups, and a higher proportion of women with advanced degrees in the PCOS group ( p  < 0.05).

Association of Dietary Intake and Physical Activity with PCOS and Isolated Features of PCOS

No statistically significant associations were found in models testing individual macro- or micronutrients intake, diet quality, nor physical activity with the odds of PCOS (Supplemental Tables  1 and 2 ). Further, we found no statistically significant associations of dietary intake and physical activity with isolated features of PCOS. In further analyses of the AHEI-2010 scores, we used a categorical approach and compared the highest and lowest total diet quality scores on their association with PCOS and its isolated features and found no significant associations. We also tested the association of the 11 subscores of the AHEI-2010 with the 3 PCOS phenotypes by race to explore whether there was evidence of race-specific associations. The AHEI-2010 vegetable intake score was inversely associated with the odds of PCOS in Black, but not White women [Table  3 ; β = − 0.37 (SE 0.20); P interaction  = 0.07]. Thus, a one-unit higher vegetable intake score (i.e., an additional ½ serving/day ) was associated with 31% lower odds of PCOS in Black participants compared to a 45% higher odds of PCOS in white participants. Differential associations by race were also found for whole grain intake scores [Table 3 ; β interaction  = 0.29 (SE 0.16); P interaction  = 0.07]. A one-unit higher whole grain intake score, which is ¼ serving/day, was associated with higher odds of PCOS in Black women [OR 1.34 (90% CI: 0.98, 1.84)], but lower odds of PCOS in White women [OR 0.75 (90% CI: 0.54, 1.02)]. Similar to the findings for PCOS, a ¼ serving/day higher whole grain intake was associated with higher odds of OA in Black women, but lower odds of OA in White women [β interaction  = 0.22 (SE 0.12); P interaction  = 0.07]. Further, a lower sugar-sweetened beverage and fruit juice score (i.e. approximately a ½ serving/week) was associated with higher odds of OA in Black women only [β interaction  = 0.15 (SE 0.09); P interaction  = 0.09]. Race interactions were not statistically significant for nutrient intake and physical activity with both isolated and combined features of PCOS.

This study investigated the associations of diet and physical activity with PCOS, an important topic given the use of health-related behavioral modifications to treat and prevent PCOS [ 38 ]. Cross-sectional analyses in the CARDIA cohort revealed total daily energy, nutrient intake, diet quality, and physical activity had no association with the odds of PCOS and isolated features. Further analyses also showed a potential impact of race, albeit these findings were from a small sample of women with PCOS.

There were no differences in macro- and micronutrient intakes between women with and without PCOS in the CARDIA cohort. Previous U.S. [ 14 , 17 ] and international studies [ 15 , 16 , 18 ] mainly reported no differences in total energy and/or macro- or micronutrient intake between women with and without PCOS, although three prior studies found that women with PCOS consumed more carbohydrates (ranged from 31 to 43 g) than comparison groups [ 9 , 10 , 14 ]. The conflicting evidence may be explained by the use of unexplained or unique criteria to define PCOS (i.e., luteinizing hormone: follicle stimulating hormone) in these earlier studies, and/or their comparison of women with PCOS to infertile women with various etiologies (rather than a comparison to reproductively healthy women). Our study of relatively younger women, taken together with another US study of older women [ 14 ], suggests that there are no differences in total daily energy intake between women with and without PCOS during the reproductive and peri-menopausal years. Additionally, when examining diet quality of women with PCOS in the US, our finding that there were no differences in diet quality between women with and without PCOS confirmed our observations from a recent study with a different US participant sample [ 39 ].

Our findings of no associations between nutrients with OA contrast with two longitudinal cohort studies that reported a greater intake of carbohydrate and folic acid was associated with a reduced risk of anovulatory infertility [ 40 , 41 ] but agree with findings of a longitudinal cohort study of B vitamins and self-reported anovulatory infertility, which reported no significant associations [ 41 ]. The inconsistencies between study findings may be attributed to the heterogeneity in the causes of HA and OA [ 42 ]. For example, anovulatory infertility can manifest secondary to stress and nutrient deficiency, and not all women with OA are at risk of progressing to PCOS due to differences in etiology [ 43 ]. We did not observe any associations of diet and physical activity with HA.

There was little to no association of physical activity behaviors with PCOS, which agrees with previous studies that noted no differences in self-reported moderate and vigorous intensity physical activity between women with and without PCOS [ 8 ]. Similar to previous studies that investigated physical activity in adult women with PCOS [ 11 , 12 , 13 , 14 , 18 ], our findings do not support the hypothesis that women with PCOS engage in less moderate and vigorous physical activity [ 38 ]. Other researchers reported differences in sedentary and physical activity patterns in women with PCOS (i.e. longer sitting intervals), which have been associated with increased risk of all-cause mortality [ 44 ]. The CARDIA measurement of physical activity did not capture patterns of exercise types and sedentary behaviors across time, and thus, objective physical activity data are needed to assess the full spectrum of movement intensity, from sedentary to vigorous activities.

Given that racial differences in the risk of glucoregulatory and cardiometabolic conditions have been identified in PCOS patients [ 23 , 24 , 25 , 26 ], a modifying effect of race on the associations between diet and physical activity with PCOS warranted consideration. We found that a higher whole grain intake, and a lower sugar-sweetened beverage and fruit juice intake, were associated with higher odds of PCOS and/or OA in Black women. These findings are paradoxical given that these two dietary patterns are typically associated with better health outcomes [ 45 ]. Our conclusions are limited by the small number of Black women with PCOS in this study and the multiple tests for interaction that may lead to type I errors.

Strengths of this study include the lower likelihood of reverse causality as an explanation for these findings because diet and physical activity data were collected prior to widespread recognition of PCOS, which mainly occurred after the establishment of formal NIH (1990) criteria for PCOS. The cohort also contained an equal proportion of Black and White participants, which provided the opportunity to explore differential diet, physical activity and PCOS associations by race. Notably, the CARDIA Women’s study was developed to identify those with PCOS features within the CARDIA cohort, thus allowing us and others to evaluate the isolated and combined features of PCOS using a well-established dataset [ 31 , 46 , 47 , 48 ]. A limitation of this study includes the potential residual confounding by AHEI-2010 groups that are highly correlated, although there will be minimal issue with groups that are not closely associated with one another. Additionally, there is greater potential for type I error due to multiple comparisons, therefore our study results should be considered exploratory. Further, self-reported and retrospective accounts of menstrual cycle history and clinical signs of androgen excess were not confirmed with clinical assessments. Our findings should also be viewed as being relevant for the most severe clinical phenotype of PCOS (defined as hyperandrogenism and irregular menses) because the absence of data on ovarian morphology meant we could not consider the association of diet and/or physical activity with the other phenotypes of PCOS. Future studies of how diet and physical activity associate with outcomes across the various PCOS definitions are needed particularly in light of the recent release of international evidence-based guidelines for PCOS, which support ovarian morphology as a PCOS criterion [ 29 ]. Previous studies have identified nutrient predictors of anovulatory infertility [ 40 , 41 ], but associations between food groups and physical activity with PCOS remained largely unexplored. Though nutrients are important components of the diet, evaluation of diet quality - particularly by race - provides further knowledge about the potential targets for intervention since alterations in foods and/or dietary patterns, rather than nutrients, are critical information for patients.

Conclusions

Overall, results from this study revealed no differences in diet and physical activity between those with and without isolated or combined features of PCOS. This study found preliminary evidence that associations between food groups and PCOS may differ by race. Findings from this study are formative and add to the current literature to promote greater understanding about the association of diet and physical activity on the development of PCOS.

Availability of data and materials

The data that support the findings of this study are available from the CARDIA field centers but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. The authors obtained permission from the CARDIA Coordinating Center to access the data needed to meet the study objectives.

Abbreviations

Alternate Healthy Eating Index 2010

Body Mass Index

Coronary Artery Risk Development in Young Adults

CARDIA Women’s Study

Eicosapentaenoic and Docosahexaenoic Acids

Exercise Units

Isolated Hyperandrogenism (elevated testosterone and/or hirsutism at 2 sites or more)

International Units; Reference (neither PCOS nor HA nor OA)

Monounsaturated Fatty Acid

National Institutes of Health

Nutrient Data Software for Research

Nanograms per Deciliter

Isolated Oligomenorrhea (≥34 days in menstrual cycle)

Polycystic Ovary Syndrome (hyperandrogenism and oligomenorrhea)

Physical Activity

Polyunsaturated Fatty Acid

Standard Deviation

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Acknowledgements

The authors are grateful to the CARDIA Coordinating Center, Kelley P. Gabriel, the CARDIA Publications and Presentations Committee, and BMC Public Health reviewers and editors for their support and input on this manuscript. The authors also thank the CARDIA participants for their dedication and years-long contribution to medical research. The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201800003I, HHSN268201800004I, HHSN268201800005I, HHSN268201800006I, and HHSN268201800007I, as was the CARDIA Women’s Study (R01-HL-065611). This manuscript is a revision from an unpublished dissertation chapter by AWL (Lin A. 2017. Dietary and physical activity behaviors, knowledge, and beliefs associated with polycystic ovary syndrome (unpublished doctoral dissertation). Cornell University, Ithaca NY. Retrieved from https://ecommons.cornell.edu/bitstream/handle/1813/56709/Lin_cornellgrad_0058F_10509.pdf?sequence=1&isAllowed=y ).

AW Lin was supported by a grant from the National Institutes of Health/National Cancer Institute (T32CA193193) during the writing of this manuscript.

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The authors’ responsibilities were as followed: AWL contributed to study design, analyzed and interpreted the data and wrote drafts of the manuscript. DS contributed to study design, interpreted the data, and reviewed and commented on manuscript drafts. BS contributed to study design, interpreted the data, and reviewed and commented on manuscript drafts. PS contributed to study design, interpreted the data, and reviewed and commented on manuscript drafts. CEL contributed to study design, interpreted the data, and reviewed and commented on manuscript drafts. EW contributed to study design, interpreted the data, and reviewed and commented on manuscript drafts. SSM contributed to study design, interpreted the data, and reviewed and commented on manuscript drafts. MW contributed to study design, interpreted the data, and reviewed and commented on manuscript drafts. LS contributed to study design, interpreted the data, and reviewed and commented on manuscript drafts. RCM contributed to study design, interpreted the data, and reviewed and commented on manuscript drafts. PAC contributed to study design, interpreted the data, wrote drafts of the manuscript, and had primary responsibility for final content. MEL contributed to study design, interpreted the data, wrote drafts of the manuscript, and had primary responsibility for final content. The author(s) read and approved the final manuscript.

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Lin, A.W., Siscovick, D., Sternfeld, B. et al. Associations of diet, physical activity and polycystic ovary syndrome in the Coronary Artery Risk Development in Young Adults Women’s Study. BMC Public Health 21 , 35 (2021). https://doi.org/10.1186/s12889-020-10028-5

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Article Contents

1. pathophysiology, 2. diagnosis of pcos, 3. treatment of adolescent pcos, acknowledgments, additional information, references and notes.

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Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls

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Selma Feldman Witchel, Sharon E Oberfield, Alexia S Peña, Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls, Journal of the Endocrine Society , Volume 3, Issue 8, August 2019, Pages 1545–1573, https://doi.org/10.1210/js.2019-00078

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Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. Depending on diagnostic criteria, 6% to 20% of reproductive aged women are affected. Symptoms of PCOS arise during the early pubertal years. Both normal female pubertal development and PCOS are characterized by irregular menstrual cycles, anovulation, and acne. Owing to the complicated interwoven pathophysiology, discerning the inciting causes is challenging. Most available clinical data communicate findings and outcomes in adult women. Whereas the Rotterdam criteria are accepted for adult women, different diagnostic criteria for PCOS in adolescent girls have been delineated. Diagnostic features for adolescent girls are menstrual irregularity, clinical hyperandrogenism, and/or hyperandrogenemia. Pelvic ultrasound findings are not needed for the diagnosis of PCOS in adolescent girls. Even before definitive diagnosis of PCOS, adolescents with clinical signs of androgen excess and oligomenorrhea/amenorrhea, features of PCOS, can be regarded as being “at risk for PCOS.” Management of both those at risk for PCOS and those with a confirmed PCOS diagnosis includes education, healthy lifestyle interventions, and therapeutic interventions targeting their symptoms. Interventions can include metformin, combined oral contraceptive pills, spironolactone, and local treatments for hirsutism and acne. In addition to ascertaining for associated comorbidities, management should also include regular follow-up visits and planned transition to adult care providers. Comprehensive knowledge regarding the pathogenesis of PCOS will enable earlier identification of girls with high propensity to develop PCOS. Timely implementation of individualized therapeutic interventions will improve overall management of PCOS during adolescence, prevent associated comorbidities, and improve quality of life.

The female hypothalamic–pituitary–ovarian (HPO) axis is a meticulously synchronized and tightly regulated network ultimately responsible for reproductive competence and survival of the species. The HPO axis responds to internal signals ( i.e. , hormonal and neuronal) and external factors ( i.e. , environment influences). Beginning during gestation, these factors impact future generations through epigenetic factors affecting the brain and the developing germ cells [ 1 ].

Polycystic ovary syndrome (PCOS), a disorder primarily characterized by signs and symptoms of androgen excess and ovulatory dysfunction, disrupts HPO axis function. Depending on diagnostic criteria, this disorder affects ∼6% to 20% of reproductive aged women [ 2 , 3 ]. Typical clinical features include hirsutism, irregular menses, chronic anovulation, and infertility. The persistent hyperandrogenism is associated with impaired hypothalamic–pituitary feedback, LH hypersecretion, premature granulosa cell luteinization, aberrant oocyte maturation, and premature arrest of activated primary follicles [ 4 ].

By the time the diagnosis is established, PCOS presents as a phenotype reflecting a self-perpetuating vicious cycle involving neuroendocrine, metabolic, and ovarian dysfunction. Over the years, numerous hypotheses have been proposed regarding the proximate physiologic origins for PCOS. PCOS reflects the interactions among multiple proteins and genes influenced by epigenetic and environmental factors ( Fig. 1 ) [ 5 ]. Specific sections of this article deconstruct the factors contributing to the development of PCOS in humans and preclinical models. Clinical and biochemical hyperandrogenism are major features of PCOS.

Factors contributing to PCOS phenotype. PCOS encompasses a woman’s life cycle. Factors potentially impacting the pathophysiology of PCOS are shown in circles. Not all factors affect each individual. PCOS epitomizes a biologic network of interacting neuroendocrine, hormonal, metabolic, genetic, and environmental influences.

PCOS develops during the early pubertal years [ 6 ]. However, most relevant information has been accrued through clinical studies involving adult women in which referral bias focuses on investigation of the more severe phenotypes [ 7 ]. Preclinical models involving animal and in vitro studies supplement clinical investigation and benefit from other approaches to study this complex disorder. Recent clinical, experimental, and genetic data emphasize neuroendocrine involvement in the pathophysiology of PCOS.

A. Ovary, Adrenal, and Androgen Excess

PCOS is characterized by excessive ovarian and/or adrenal androgen secretion. Intrinsic ovarian factors such as altered steroidogenesis and factors external to the ovary such as hyperinsulinemia contribute to the excessive ovarian androgen production. Characteristic features include more growing follicles in women with PCOS compared with normal controls with premature growth arrest of antral follicles at 5 to 8 mm. The classic ovarian phenotype of enlarged ovaries with string-of-pearl morphology and theca interstitial hyperplasia reflects androgen exposure; this morphology has also been observed in women with congenital adrenal hyperplasia (CAH) and female-to-male transgender individuals [ 8 ]. Distorted interactions among the endocrine, paracrine, and autocrine factors responsible for follicular maturation may contribute to ovarian dysregulation in PCOS.

The stages of follicular maturation are briefly reviewed ( Fig. 2 ). Developing during gestation, primordial follicles are comprised of meiotically arrested oocytes surrounded by pregranulosa cells. Hence, a woman’s ovaries have been exposed to the ambient maternal environment during gestation. Ovaries are relatively quiescent until the onset of puberty. Detailed knowledge regarding follicular morphology in prepubertal and early pubertal ovaries is lacking. Ovarian tissue obtained from prepubertal and early pubertal girls shows differences in follicle morphology and growth potential. Specifically, prepubertal ovaries contain a high proportion of abnormal nongrowing follicles, which are not found in pubertal ovaries [ 9 ]. The physiologic relevance of this finding is unclear.

Ovarian follicle development. This illustration shows ovarian follicular development during developmental periods.

The precise signaling mechanisms initiating follicular activation are poorly understood. Presumably a balance of factors influences the options—continuation in a resting state or activation. One such factor appears to be follicle density [ 10 ]. Following activation from the resting pool, initial follicular growth is gonadotropin-independent until the antral stage.

Anti-Müllerian hormone (AMH), a glycoprotein secreted by granulosa cells, inhibits initial follicular recruitment and indicates follicular reserve. In contrast to mice where AMH inhibits preantral follicle growth and antral follicle maturation, AMH appears to promote growth of preantral follicles to the antral stage in nonhuman primate (NHP) ovaries [ 11 , 12 ]. Peak AMH concentrations are found in antral follicles. Once FSH-stimulated granulosa cell estradiol concentrations achieve the necessary threshold, estradiol suppresses AMH expression [ 13 ].

Despite prior assumptions that androgens negatively impact follicles, androgens synthesized in preantral follicle theca cells promote growth of preantral and antral follicles and induce granulosa cell FSH receptor (FSHR) expression in early antral follicles [ 14 ]. Androgens promote aromatase expression and, ultimately, LH/chorionic gonadotropin receptor (LHCGR) expression in granulosa cells. As a follicle matures, androgens appear to inhibit proliferation and promote apoptosis. This biphasic androgen action was initially demonstrated in an NHP, the marmoset; androgens augmented FSH action in small antral follicles but had an inhibitory effect in larger follicles [ 15 ].

Androgen actions are mediated by androgen receptors (ARs), which are expressed in theca cells, granulosa cells, oocytes, and stromal cells [ 16 ]. Both canonical androgen signaling where AR functions as ligand-dependent transcription factor and nongenomic signaling occur. Peak AR gene expression occurs in small antral follicles (∼6 mm in diameter) and decreases in antral and preovulatory follicles [ 17 ].

Typically, one follicle is “selected” as the dominant follicle [ 18 ]. With increasing estrogen secretion, pituitary FSH secretion declines due to negative feedback. The dominant follicle compensates for this loss of FSH stimulation through increased LHCGR expression and increased responsiveness to LH stimulation. Subordinate follicles undergo atresia, presumably due to relative FSH deficiency and androgen excess. Upon achieving a sufficient estradiol concentration, neuroendocrine mechanisms trigger the LH surge to induce ovulation.

Under normal circumstances, the ovarian stroma provides a structural framework undergoing dynamic changes to support follicular growth. However, the ovarian stroma from women with PCOS tends to be more rigid. The developing oocyte and its surrounding scaffolding rely on endocrine, paracrine, and autocrine signaling mechanisms to maintain cell-to-cell communication and assure synchronized developmental progression. Aberrant development during these earliest stages of follicular growth likely contributes to the ovarian aspects of PCOS [ 19 ]. Another feature of PCOS ovaries is accelerated transition from primordial to growing follicles with increased numbers of 2- to 3-mm and 3- to 4-mm follicles [ 20 , 21 ]. AMH concentrations correlate with the number of these small antral follicles [ 22 ]. The growing follicle is exposed to an atypical environment with increased LH, insulin, androgen, and AMH concentrations accompanied by insufficient FSH concentrations [ 19 ]. Additional differences in PCOS ovaries include factors impacting vascular function and immune responsiveness [ 23 ].

Additionally, intrinsic alterations in ovarian steroidogenesis likely contribute to excessive ovarian androgen production. Available data document constitutively increased androgen production and CYP17A1 expression in cultured theca cells isolated from PCOS ovaries [ 24–26 ]. Steroidogenesis in the ovary involves both theca and granulosa cells. The theca cells produce ovarian androgens, which are converted to estrogens in the granulosa cell due to the actions of FSH-stimulated aromatase.

One interesting locus identified through genetic studies is DENND1A (see “H. Genetics” below). Overexpression of the alternative spliced variant, DENND1A.V2 , of this gene recapitulated a PCOS phenotype in cultured theca cells obtained from normal women, indicating a role for this variant in the excessive theca cell androgen production [ 27 ]. Overexpression of DENND1A.V2 in an adrenal cell line led to increased expression of the mRNAs for CYP17A1 and CYP11A1 . However, the mechanisms responsible for increased expression of this alternatively spliced variant of DENND1A remain to be elucidated [ 28 ].

The adrenal zona reticularis is responsible for biosynthesis of the C-19 adrenal androgens, including dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione, and testosterone. At least three distinct adrenal pathways contribute to androgen synthesis: (i) canonical/classical, (ii) “alternative backdoor,” and (iii) 11-oxo-androgens ( Fig. 3 ). In the canonical/classical pathway, progesterone is successively transformed by the enzyme 17 α -hydroxylase/17,20-lyase (P450c17) to DHEA, which is subsequently converted by 3 β -hydroxysteroid dehydrogenase type 2 to androstenedione. The alternative backdoor pathway bypasses the usual steroid hormone intermediates, DHEA, androstenedione, and testosterone, to produce dihydrotestosterone [ 29 ]. This pathway likely contributes to virilization of the external genitalia among girls with classical CAH and normal male external genital development [ 30 , 31 ]. The extent of the contribution of the alternative backdoor pathway to adrenal and ovarian steroid biosynthesis in PCOS is unclear [ 32 ].

Androgen biosynthesis. This illustration shows the classical/canonical, alternative backdoor, and 11-oxo-steroid pathways for androgen biosynthesis.

The adrenal steroidogenic enzyme, 11 β -hydroxylase (P450c11B1), encoded by CYP11B1 , is expressed in both zona fasciculata and zona reticularis; this enzyme converts androstenedione and testosterone to their respective 11 β -hydroxyl derivatives, 11 β -hydroxy-androstenedione and 11 β -hydroxy-testosterone. Both 11 β -hydroxy-androstenedione and 11 β -hydroxy-testosterone can be converted to their 11-keto counterparts, 11-ketoandrostenedione and 11-ketotestosterone. Testosterone, DHT, 11-ketotestosterone, and 11-ketodihydrotestosterone bind to the human AR and promote AR-regulated gene expression [ 33 ]. The concentrations of these 11-oxygenated steroids were reported to be higher in women with PCOS than among healthy premenopausal women [ 34 ]. Urinary steroid profiling using 24-hour urine collections in a relatively small number of women with PCOS and controls found androstanediol concentrations to discriminate between PCOS and controls; the overall pattern of steroid hormone excretion indicated enhanced androgen biosynthesis via canonical/classical, alternative backdoor, and 11-oxygenated steroid pathways rather than a specific steroid enzyme disorder [ 35 ].

A-1. Preclinical models

One unresolved conundrum regarding folliculogenesis is the regulation and interrelationships between androgens and AMH. Androgens and AMH are essential for normal cyclic ovulation. Using short hairpin RNAs to decrease AMH expression in macaques, preantral follicle growth and survival were reduced. Cotreatment with supplemental AMH overcame these effects. These results emphasize the important role of AMH as a critical factor to promote preantral follicle survival and growth in primates [ 36 ]. AMH treatment of cultured antral stage rhesus macaque follicles decreased estradiol production compared with untreated follicles despite similar follicle size [ 12 ]. Hence, AMH appears to have a dual role: whereas AMH promotes preantral follicle survival, it negatively impacts later stages of antral follicle maturation [ 12 ].

In a series of in vivo and in vitro experiments, a subset of hypothalamic GnRH neurons, both mouse and human, were shown to express AMR receptors; AMH treatment increased GnRH-dependent LH pulsatility and secretion [ 37 ]. Using a mouse model, AMH treatment of pregnant mice was associated with diminished placental metabolism of testosterone to estradiol, decreased aromatase expression, masculinization of exposed female offspring, estrus cycle disturbances, increased LH pulse frequency, brain masculinization, and infertility compared with unexposed mice; postnatal GnRH antagonist treatment reversed this PCOS-like phenotype [ 38 ]. These data suggest that excessive prenatal AMH exposure could promote the aberrant neuroendocrine function typical of PCOS and that AMH can modulate GnRH neuron function [ 37 , 38 ].

Knockout mice have been used to explore consequences of gene deletions. Using a postnatal androgen PCOS model, global AR knockout mice were protected from DHT-induced PCOS-like features. Curiously, neuron-specific AR knockout mice were protected from DHT-induced ovarian dysfunction and several metabolic traits, reinforcing a role for extraovarian tissues in the pathophysiology of PCOS [ 39 ]. Hence, intricate interrelationships exist between androgens, AMH, follicle growth, metabolism, and neuroendocrine factors in PCOS.

Recently, a group of naturally hyperandrogenic female rhesus monkeys have been described. The high testosterone animals had increased LH, AMH, and androstenedione concentrations. Additionally, five of the six high-testosterone monkeys had no live offspring [ 40 ]. Future study of these animals will provide insight into the pathogenesis of PCOS.

B. Neuroendocrine Factors

Increased LH pulse frequency, LH pulse amplitude, and increased LH/FSH ratios are described in women with PCOS. The initial features of PCOS emerge during the early pubertal years, concomitant with reactivation of the hypothalamic GnRH pulse generator, increased gonadotropin secretion, and subsequent increased ovarian estrogen production. Loci identified in the genome-wide association studies (GWASs) studies include LHCGR , FSHR , and FSH- β polypeptide ( FSHB ) genes, emphasizing neuroendocrine contributions to PCOS pathophysiology (see H. Genetics below).

Hypothalamic neurons in the arcuate nucleus secrete kisspeptin, neurokinin B, and dynorphin. These neurons, labeled as the KNDy neurons, are the leading contenders for the hypothalamic GnRH pulse generator because of the colocalization of these three peptides and their roles in episodic GnRH secretion [ 41 ]. Rather than initiating puberty, the GnRH pulse generator and GnRH neurons represent downstream nodes modulated by other hormones and neurosecretory factors [ 42 ]. In other words, activation of excitatory inputs and inactivation of inhibitory inputs moderated by multiple influences regulate the output of the GnRH pulse generator to govern the timing of puberty [ 43–45 ]. This process culminates in increased GnRH and gonadotropin secretion.

The hypothalamic GnRH neurons secrete GnRH in discrete pulses that travel through the median eminence to the pituitary gonadotrophs, resulting in pulsatile LH and FSH secretion [ 46 ]. LH and FSH pulse frequencies are modulated by GnRH pulse frequency. Increased GnRH pulse frequency increases LH pulse frequency and decreases FSH pulse frequency [ 47 ]. The GnRH neurons integrate diverse influences, decode metabolic signals, and serve as the output “managers” of the HPO axis [ 48 , 49 ].

Increased LH pulse amplitude and pulse frequency observed in PCOS are likely driven by increased pulsatile GnRH secretion. Manipulation of the hypothalamic kisspeptin–neurokinin B–GnRH pathway with an NK3 receptor antagonist, AZD4901, reduced serum LH pulse frequency and, subsequently, serum LH and testosterone concentrations. These data suggest the possibility of targeting neuroendocrine pathophysiology to treat HPO axis dysfunction in PCOS [ 50 ].

GnRH neurons express estrogen receptor- β , but they do not express AR, progesterone receptor, or estrogen receptor- α . Hence, steroid-mediated negative feedback is indirect and is mediated through the hypothalamic neuronal network upstream of the GnRH neuron. This negative feedback mechanism is impaired in some women with PCOS who appear to require higher progesterone and estradiol concentrations. This effect can be abrogated with androgen antagonist treatment [ 51 ].

One conundrum is that LH hypersecretion is less obvious in women with obesity with PCOS. Although GnRH and LH pulses generally exhibit a 1:1 ratio, preclinical data exist suggesting that a faster GnRH pulse frequency may be associated with decreased LH secretion [ 52 ]. Potential explanations for this mismatch between GnRH and LH pulses include the longer half-life of LH obscuring pulse detection, exhaustion of the pituitary pool of readily releasable LH, or lower amplitude GnRH pulses [ 53 ]. Measurement of circulating kisspeptin and LH concentrations showed temporal kisspeptin–LH pulse coupling in eumenorrheic women with PCOS; however, a greater frequency of kisspeptin pulses was associated with a loss of temporal coupling in women with oligomenorrhea with PCOS [ 54 ]. This study identified dissociated coupling of kisspeptin and LH pulses in women with oligomenorrhea with PCOS.

Tanycytes are specialized nonciliated cells lining the floor of the third ventricle. These polarized cells contribute to regulation of reproduction and metabolism in the median eminence. Specifically, tanycytes affect GnRH secretion, generate active forms of thyroid hormone, and influence exchange of signaling factors such as leptin between the blood and hypothalamic extracellular fluid [ 55 ]. Dynamic structural remodeling of tanycytes modulates GnRH neuron access to the pituitary portal system. Leptin and ghrelin enter the hypothalamus through the tanycytes [ 56 ]. Astrocytes, located at the interface between blood vessels and neurons, can function as metabolic sensors. This physical location enables them to modulate glucose fluxes between the periphery and the central nervous system [ 57 ]. Hence, dynamic tanycyte–neuron interactions and astrocytes orchestrate the ongoing communication between the neuroendocrine axis and the periphery [ 58 ]. Whereas the precise role of tanycytes in PCOS is indeterminate, these cells likely allow leptin, ghrelin, and AMH access to GnRH neurons.

B-1. Preclinical models

Numerous studies have described the development of neuroendocrine features reminiscent of PCOS following prenatal androgen exposure in rodents, sheep, and rhesus macaques [ 59–61 ]. Prenatal androgen exposure during early gestation (late first to second trimester) increased LH and androgen secretion in female rhesus monkeys [ 59 ]. Prenatally androgenized (PNA) female mice showed increased γ -aminobutyric acid (GABA)ergic transmission to GnRH neurons by 3 weeks of age, suggesting that prenatal androgen treatment affected neuronal development [ 62 ]. Questions regarding prenatal imprinting of the neuroendocrine components of the HPO axis persist.

C. Valproate and HPO Axis Function

Valproic acid (VPA), a branched short-chain fatty acid derived from valeric acid, is used to treat epilepsy, bipolar disorders, and prevent migraine headaches. VPA increases GABA levels by interfering with GABA degradation pathways [ 63 ]. GnRH neurons express both GABA A and GABA B receptors, implicating GABA signaling in the regulation of GnRH secretion. Signaling through the GABA A receptor can elicit an excitatory effect on GnRH neurons [ 64 ].

Women treated with VPA can develop PCOS-like symptoms. Lean women with PCOS had significantly higher CSF GABA concentrations compared with eumenorrheic lean control women; the women with PCOS also demonstrated increased LH pulse amplitude and LH pulse frequency on frequent blood sampling [ 65 ]. These clinical observations suggest that GABA signaling could influence the neuroendocrine changes associated with PCOS such as LH pulse frequency.

C-1. Preclinical models

PNA mice models have enabled investigation regarding the consequences of prenatal androgen exposure. In an elegant series of experiments, Silva et al. [ 66 ] demonstrated increased GABA synaptic input in prepubertal PNA mice. Their observations suggest that prenatal androgenization is associated with prenatal enhanced GABAergic structural wiring input onto GnRH neurons, that these changes are reversible with long term antiandrogen treatment, and that these structural changes precede postpubertal development of PCOS features [ 66 ].

D. Insulin Resistance, Hyperinsulinemia, and the β -Cell

The phenotype of female patients with insulin receptor gene mutations includes insulin resistance (IR), compensatory hyperinsulinemia, and hyperandrogenism [ 67 ]. Although IR and hyperinsulinemia are commonly detected in women with PCOS, insulin receptor gene mutations are extremely rare among women with PCOS.

Women with PCOS have intrinsic IR independent of the extent of obesity and magnitude of androgen concentrations [ 68 ]. Even lean women with PCOS manifest IR; increasing body mass index (BMI) exacerbates IR [ 69 ]. Normal-weight adolescent girls with PCOS have peripheral IR, increased liver fat, and muscle mitochondrial dysfunction compared with normal-weight girls [ 70 ].

Insulin is the hormone primarily responsible for glucose homeostasis and lipogenesis. In addition to its effects on carbohydrate, fat, and protein metabolism, insulin functions as a mitogenic hormone. Insulin actions are mediated by insulin receptors, which are found in numerous tissues of the HPO axis. In steroidogenic tissues such as the ovary and the adrenal cortex, insulin potentiates the cognate trophic hormones to promote steroidogenesis. The compensatory hyperinsulinemia associated with IR provokes excessive ovarian/adrenal androgen secretion and decreases hepatic SHBG synthesis with the net result of increasing circulating testosterone concentrations. This leads to the paradox of insulin signaling in PCOS; liver, skeletal muscle, and adipose tissue exhibit IR, whereas steroid-producing tissues and the pituitary retain insulin sensitivity [ 71 , 72 ]. This paradox is illustrated by differences in insulin actions in granulosa–lutein cells obtained from women with anovulation with PCOS; insulin-stimulated glucose uptake is impaired whereas insulin-stimulated progesterone production is preserved [ 73 ].

The central role of compensatory hyperinsulinemia has been established by improved clinical features with insulin-sensitizing medications and weight loss. The transient IR and hyperinsulinemia typical of early puberty may kindle the factors associated with development of PCOS [ 74 , 75 ].

The prevalence of the metabolic syndrome defined as obesity, hypertension, dyslipidemia, and hyperglycemia is approximately threefold higher in women with PCOS [ 76 ]. Although a consensus definition of metabolic syndrome in adolescents is lacking, published pediatric criteria are based on adult criteria and include a combination of elevated triglyceride concentration, elevated low high-density lipoprotein cholesterol concentration, fasting blood glucose ≥110 mg/dL, increased waist circumference, and hypertension for age [ 77 ]. A meta-analysis suggested that although IR is likely a common factor linking the metabolic and reproductive features of PCOS, the metabolic and reproductive features develop through independent mechanisms [ 78 ]. One relatively consistent finding is that obesity exacerbates the symptoms of PCOS, especially regarding the risk for development of T2D and the metabolic syndrome [ 76 ].

Primary hyperinsulinemia can precede the development of peripheral tissue IR. It is beyond the scope of this review to discuss arguments supporting the opposing viewpoints, that is, primary IR vs primary hyperinsulinemia [ 79 ]. Importantly, numerous genetic and epigenetic factors, nonheritable prenatal and extrauterine environmental influences, and varying adaptations to nutrient excess likely contribute to the development of IR and hyperinsulinemia.

D-1. Preclinical models

Preclinical data show β -cell dysfunction associated with hyperinsulinemia in monkeys and sheep prenatally exposed to androgens [ 80 , 81 ].

E. Obesity, the Adipocyte, and Nutrient Excess

Overweight and obesity are common among adolescent girls and adult women with PCOS. In response to nutrient excess, adipocytes can enlarge (hypertrophy) or form new adipocytes (hyperplasia). According to the adipose tissue expandability hypothesis, adipocyte hypertrophy establishes a microenvironment characterized by hypoxia, proinflammatory cytokine secretion, free fatty acid “spillover,” macrophage invasion, and IR [ 82 ]. IR decreases suppression of adipocyte lipolysis, resulting in increased serum free fatty acids and triglycerides, ultimately leading to increased hepatic de novo lipogenesis and hyperlipidemia [ 83 ]. Another consequence is increased fat storage in skeletal muscle, liver, and pancreas because the adipose tissue capacity to store lipid is exceeded. In the liver, ectopic fat storage is labeled hepatic steatosis, which can develop into nonalcoholic fatty liver disease [ 84 ].

White adipose tissue has several distinct locations, that is, visceral and subcutaneous. Partitioning of fat among different storage sites influences metabolic consequences: increased abdominal fat is associated with greater risk for dysglycemia and cardiovascular disease. Investigation of normal-weight women with PCOS showed increased total abdominal fat mass due to preferential deposition of intra-abdominal fat with an increased population of small subcutaneous abdominal adipocytes [ 85 ]. In a pilot study involving normal-weight women with PCOS, subcutaneous adipose IR correlated with serum androgen concentrations and the percentage of small subcutaneous abdominal adipocytes. These data support the hypothesis that expansibility of the subcutaneous abdominal adipose depot is limited and unable to expand sufficiently to meet the metabolic needs for most normal-weight women with PCOS [ 86 ]. Emerging pilot data in adolescent girls with PCOS showed that reduction of visceral fat improved menstrual irregularity [ 87 ].

In a small cross-sectional study, girls related to women with PCOS showed higher 17-hydroxyprogesterone concentrations, decreased insulin sensitivity, and decreased insulin-induced suppression of nonesterified fatty acid concentrations compared with healthy control girls. These findings suggest onset of adipocyte dysfunction, IR, and possible lipotoxicity among girls aged ∼9 to 15 years [ 88 ]. In another small study using frequently sampled IV glucose tolerance tests, the authors reported early β -cell dysfunction in first-degree female relatives with overweight/obesity of women with PCOS compared with control girls with overweight/obesity [ 89 ]. Small sample sizes limit the conclusions that can be drawn from these studies. Nevertheless, the studies hint that β -cell function and insulin sensitivity may differ beginning in childhood and early adolescent years among girls “destined” to develop PCOS.

Mismatches between prenatal and postnatal weights have led to the advance of the developmental origins of disease hypothesis [ 90 ]. The longitudinal prospective population-based study (Northern Finland Birth Cohort Study) found that women with PCOS had lower birth weights, experienced adiposity rebounds at younger ages, and had higher subsequent BMI values [ 91 ]. These findings are consistent with the concept that a mismatch between prenatal weight and postnatal weight gain is associated with increased risk for PCOS, ectopic fat storage, and hepatic steatosis [ 92–94 ].

Adipose tissue expresses enzymes that activate and inactivate androgen precursors. The enzyme aldo-ketoreductase type 1C, encoded by the AKR1C3 gene, is expressed in adipose tissue and converts the preandrogen androstenedione to testosterone. Additionally, the enzyme 5 α -reductase type 1, encoded by the SRD5A1 gene, converts testosterone to DHT and is expressed in adipose tissue. A deep in vivo metabolic phenotyping study showed increased AKR1C3 and decreased SRD5A1 mRNA expression in subcutaneous fat of women with PCOS [ 95 ]. Activation appears to regulate adipocyte proliferation and differentiation, insulin sensitivity, adipokine signaling, and lipid metabolism [ 96 ]. Using a human preadipocyte cell line, both testosterone and DHT increased de novo lipogenesis in the absence of insulin [ 95 ], whereas pharmacologic inhibition of AKR1C3 activity prevented androgen-mediated adverse effects on adipocyte lipogenesis. Using this model system, insulin increased AKR1C3 expression. Based on these data, O’Reilly et al. [ 95 ] proposed the existence of a vicious cycle linking adipocyte androgen biosynthesis and adipocyte lipid accumulation to IR and hyperinsulinemia.

Another situation demonstrating androgen effects on lipid metabolism was described in girls with obesity with and without PCOS. Girls with obesity with PCOS compared with those without PCOS demonstrated decreased lipid mobilization, diminished fat oxidation, and impaired ability to switch from lipid to carbohydrate oxidation during insulin stimulation (metabolic inflexibility) [ 97 ].

E-1. Preclinical models

In a treatment paradigm comparing a high-fat diet with/or without testosterone treatment in rhesus monkeys, the combination of a high-fat diet and testosterone treatment accelerated development of white adipose tissue dysfunction [ 98 ].

F. Developmental Hypothesis/Fetal Origins

The developmental theory of PCOS proposes that exposure of the female fetus to elevated androgen concentrations contributes to the development of PCOS. Potential mechanisms include effects on steroidogenesis, insulin signaling, pancreatic β -cell function, hypothalamic–pituitary organization, neuroendocrine secretory patterns, and epigenetic modifications [ 99 ].

Fetal, neonatal, prepubertal, and/or pubertal ovaries may be genetically predisposed to increased androgen secretion [ 100 , 101 ]. Women with classical CAH often develop a secondary PCOS phenotype; it is unclear whether this reflects prenatal imprinting of the hypothalamus and GnRH pulse generator or androgen effects on the ovary [ 102 ]. Available data support the hypothesis that prenatal androgen exposure programs the neuroendocrine, metabolic, and reproductive manifestations of PCOS [ 103 ]. Women with PCOS typically have higher androgen concentrations than do women without PCOS. One report involving 23 mothers self-reporting PCOS and 277 women reporting no PCOS indicated increased anogenital differences, a marker of prenatal androgen exposure, in daughters of women with PCOS [ 104 ]. How the fetus is exposed to androgen excess when placental aromatase and maternal SHBG limit fetal exposure to maternal androgens remains an enigma.

F-1. Preclinical models

Preclinical models involving androgen exposure in rodents, sheep, and NHPs recapitulate features of PCOS. Impaired adipocyte differentiation has been demonstrated in NHP models [ 105 ]. Among prenatally androgenized NHPs, when the capacity of subcutaneous adipocytes to store fat is exceeded, excess free fatty acids may be deposited in ectopic locations such a liver and muscle; consequences of ectopic fat deposition may include impaired tissue hypoxia, inflammation, and IR [ 106 ]. Curiously, transient pancreatic dysfunction manifested by hypoglycemia, an increased number of β -cells, small islets, and relative hyperinsulinemia have been observed in this NHP model of early gestational androgen exposure [ 80 ]. Early pubertal NHP treated with testosterone and a “Western style diet” with increased fat content showed increased larger visceral adipocytes, greater IR, and ectopic fat storage [ 106 ].

G. Microbiome

Bacteria, archaea, fungi, and viruses comprise the microbial community or microbiome of the gastrointestinal tract. These organisms play roles in fermentation of dietary fiber, bile acid metabolism, host defense, and modulation of metabolism. It has been suggested that the gut microbiome influences development of nonalcoholic fatty liver disease and is associated with insulin sensitivity [ 107 , 108 ]. Sex and sex steroids modulate the composition of the gut microbiome. Women are reported to show greater α -diversity. α -Diversity represents the number of species, and β -diversity indicates similarity between samples. Decreased α -diversity has been described in women with PCOS [ 109 , 110 ]. Numerous questions remain to be answered regarding the functional relationships, if any, between sex steroids, metabolic dysregulation, and the gut microbiome [ 111 ]. To the best of our knowledge, no data for adolescents are available.

H. Genetics

Twin studies suggest that the hereditability is ∼70% [ 112 ]. The few identified genetic loci explain only a modest proportion of estimated hereditability. GWASs involving women of Han Chinese and European origins have identified at least 16 susceptibility loci for PCOS [ 113–116 ]. Several genetic variants are similar in both Han Chinese and European populations, implying that PCOS is an ancient disease [ 117 ]. Several novel loci have recently been identified [ 118 ]. A meta-analysis showed that identified loci are linked to genes plausibly associated with the metabolic and reproductive characteristics of PCOS [ 118 ]. Linkage disequilibrium score regression analysis demonstrated genetic correlations with metabolic traits, that is, fasting insulin, lipid levels, and PCOS. With the exception of the GATA4/NEIL2 locus, the genetic architecture did not differ whether National Institutes of Health or Rotterdam criteria were used to diagnose PCOS [ 118 ]. Genes involved in HPO axis function, that is, LHCGR , FSHR , and FSHB , were identified in these GWASs implicating gonadotropins in the pathophysiology of PCOS [ 115 ]. Using family-based quantitative trait meta-analysis, rare DENND1A variants were associated with metabolic and reproductive traits in PCOS families; these data are consistent with the hypothesis that complex disorders such as PCOS are associated with genetic variations in noncoding regions [ 119 ]. Epigenetic modifications such as changes in methylation and miRNAs offer another level of regulation affecting the PCOS phenotype. Epigenetic variants have been reported for adipose tissue and muscle [ 120 , 121 ].

The classic features of PCOS include clinical or biochemical hyperandrogenism, oligomenorrhea or amenorrhea associated with chronic anovulation, and polycystic ovary syndrome morphology [ 122 ]. The current consensus is that use of the Rotterdam criteria is appropriate for adult women. For diagnosis of PCOS, women must fulfill two of the three characteristics: oligo-ovulation or anovulation, clinical and/or biochemical hyperandrogenism, or polycystic ovary morphology on ultrasound with exclusion of other disorders. The 2012 National Institutes of Health–sponsored Evidence-Based Methodology PCOS Workshop categorized PCOS into four phenotypes as follows: phenotype A, hyperandrogenism, ovulatory dysfunction, and polycystic ovary morphology; phenotype B, hyperandrogenism and ovulatory dysfunction; phenotype C, hyperandrogenism and polycystic ovary morphology; and phenotype D, ovulatory dysfunction and polycystic ovary morphology [ 123 , 124 ].

However, delineating appropriate diagnostic criteria for PCOS among adolescent girls has been problematic because irregular menses, cystic acne, mild hyperandrogenism, and multifollicular ovarian morphology occur during normal pubertal maturation. These similarities between normal pubertal development and the clinical features associated with PCOS confound the diagnosis in adolescent girls ( Table 1 ) [ 125–127 ]. Similar to the evaluation of adult women, other disorders associated with irregular menses and/or hyperandrogenism need to be excluded. These disorders include CAH, typically nonclassic 21-hydroxylase deficiency, androgen-secreting tumors, thyroid dysfunction, hyperprolactinemia, Cushing syndrome, exogenous use of steroid hormones/androgens, or severe IR syndrome [ 128 , 129 ].

Definition of Irregular Menses in Adolescent Girls

[Adapted from: Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018;110(3):364–379.].

With reactivation of the GnRH pulse generator, increased gonadotropin secretion stimulates ovarian estrogen secretion and follicular development. Estrogen promotes uterine growth and endometrial proliferation; endometrial estrogen exposure eventually culminates in vaginal withdrawal bleeding and menarche. A longitudinal study found that the median age at menarche for American girls was 12.25 years, with lower menarcheal ages in black and Hispanic girls compared with white and Asian girls [ 130 ]. By age 15 years, 98% of girls will have experienced menarche [ 131 ].

Contemporary understanding is that it takes 3 to 4 years postmenarche for adult menstrual cyclicity to mature. By the third year after menarche, 10 or more menses occur annually in 90% of adolescent girls [ 132 ]. Approximately 41% of girls have achieved ovulatory cycles by the fourth gynecologic year [ 133 ]. Importantly, ovulation may occur despite irregular menses [ 134 ].

Currently, evidence-based data regarding the first gynecologic year are limited and are largely derived from studies published prior to 2000. A 2018 systemic review of menstrual patterns during the first gynecologic year concluded that menstrual and ovulatory patterns are diverse during this time period. In 22 studies involving >2000 adolescents, frequent menstrual bleeding (<21 days) occurred in 23% and prolonged menstrual bleeding (>30 to 45 days) occurred in at least 33% [ 135 ]. A pilot study entailing serial hormone concentrations and ultrasound studies in ovulatory postmenarcheal girls revealed lower steroid (estrogen and progesterone) concentrations, slower dominant follicle growth rate, and longer follicular phases compared with adult women; these data suggest that coordinated development of all components of the HPO axis may take up to 5 years postmenarche [ 136 , 137 ].

Oligomenorrheic adolescents tend to have persistent oligomenorrhea [ 138 , 139 ]. Secondary amenorrhea for >90 days is uncommon and warrants additional consideration. Girls presenting with primary amenorrhea at ages 15 to 16 years merit further evaluation.

B. Hyperandrogenism

Hirsutism, defined as excessive terminal hair growth in male pattern distribution in women, is the primary clinical sign of hyperandrogenism. The modified semisubjective Ferriman–Gallwey scoring system is one widely used approach [ 140 , 141 ]. The extent of the clinical features of hyperandrogenism represents the interactions between circulating androgen concentrations, local androgen concentrations, and sensitivity of the pilosebaceous unit/hair follicle to androgens. The severity of hirsutism does not correlate with circulating androgen concentrations. Ethnic and genetic variations influence the development of hirsutism [ 141 ]. Depending on ethnicity, a modified Ferriman–Gallwey score ≥4 to 6 indicates hirsutism [ 125 ]. Other cutaneous signs of androgen excess include severe cystic acne and male pattern baldness.

Biochemical hyperandrogenism is confirmed by documentation of elevated serum androgen concentrations. One caveat is the importance of measuring androgens using high-quality assays such as liquid chromatography–tandem mass spectrometry or extraction/chromatography immunoassays [ 142 ]. Calculated free testosterone, free androgen index, calculated bioavailable testosterone, androstenedione, and DHEAS may provide helpful information. Testosterone determinations are confounded by several problems, including inadequate assay sensitivity to accurately measure low concentrations, limited evidence-based normal ranges, assay interference due to other steroid molecules or SHBG, and technical aspects of the assay methodology. In view of these constraints, the Canadian Laboratory Initiative in Pediatric Reference Intervals (CALIPER) project has developed sensitive and accurate liquid chromatography–tandem mass spectrometry methodology to simultaneously measure eight steroids [ 143 ]. Measuring 11-oxo-androgens shows promise as a method to assess for hyperandrogenism [ 144 , 145 ].

C. Polycystic Ovary Morphology

Polycystic ovary morphology (PCOM) is defined as enlarged ovaries with increased stroma and more small peripheral cysts. The Androgen Excess–PCOS Society Task Force recommended that PCOM is defined as ≥20 follicles per ovary using a transvaginal probe and high-resolution technology (transducer frequency ≥8 MHz) [ 146 ]. However, assessment of ovarian morphology is difficult in the adolescent girl because the increased gonadotropin stimulation leads to increased ovarian volume and follicular growth, giving rise to the appearance of multifollicular ovaries in adolescent girls. Additionally, use of transvaginal probes are problematic in adolescent girls. PCOM is an inconsistent finding in adolescent girls and is not associated with anovulation or metabolic abnormalities [ 147 ]. Hence, ovarian ultrasounds are unnecessary in adolescent girls.

D. Evaluation and Diagnosis

The approach to the evaluation of a girl with signs and symptoms suggestive of PCOS begins with a thorough history, including detailed family history and complete physical examination. The individualized laboratory evaluation typically includes thyroid function studies as well as the determination of prolactin, total testosterone, androstenedione, SHBG, DHEAS, and 17-hydroxyprogesterone concentrations. Direct free testosterone assays should be avoided due to inadequate sensitivity, accuracy, and reproducibility of available assays. Fasting glucose, HbA1c, and lipid concentrations should be determined. Ideally, the blood sample should be obtained prior to 8:30 am . If CAH is a diagnostic possibility, an ACTH stimulation test can be obtained. The cut point of a basal 17-hydroxyprogesterone >200 ng/dL has been suggested as the threshold for performing ACTH stimulation tests [ 148 ]. Nevertheless, when the clinical picture is highly suggestive of a steroidogenic enzyme deficiency, an ACTH stimulation test might be warranted. Adrenal and pelvic imaging may be considered depending on the clinical information, physical examination, and initial laboratory data.

AMH concentrations are often elevated in women with PCOS. AMH concentrations reflect ovarian reserve and are correlated with the number of growing follicles [ 149 ]. Although it is premature to use AMH concentrations to diagnose PCOS, AMH concentrations have been found to be elevated in nonobese girls with PCOS [ 150 , 151 ]. AMH concentrations were found to be higher in girls with obesity with PCOS compared to girls with obesity without PCOS of comparable age and pubertal status [ 152 ].

Insulin resistance, hyperinsulinemia, and obesity are commonly identified in women with PCOS. However, with the exception of a single publication, none of the current definitions, recommendations, or guidelines includes IR and/or hyperinsulinemia as a diagnostic feature [ 153 ].

Hence, the diagnosis of PCOS can be considered for the adolescent girl with persistence of oligoamenorrhea for 3 to 4 years postmenarche with clinical and/or biochemical hyperandrogenism after exclusion of other disorders associated with irregular menses or hyperandrogenism. When oligomenorrhea has not persisted for >2 years, these girls can be considered to be “at risk” for PCOS and require longitudinal evaluation to assess for ongoing features of PCOS. Deferred diagnosis attempts to avoid overdiagnosis with its potential for premature labeling, anxiety, and unnecessary interventions. Nevertheless, diagnostic labeling needs to be balanced with the patient’s desire for a diagnosis and specific therapeutic interventions [ 125–127 , 154 , 155 ].

Adolescents presenting with PCOS features, before the diagnosis is confirmed, often require management of their symptoms [ 125–127 ]. The management of adolescents with a clear diagnosis of PCOS should include education about the condition and lifestyle interventions. The interventions can be individualized to target the foremost complaints and symptoms. Interventions include metformin, combined oral contraceptive pills (COCPs), spironolactone, and local treatments for hirsutism and acne. Management should also include management of comorbidities, regular follow-up, and a plan for transition to adult care providers.

A. Education and Counseling

Education and counseling about the condition is very important. The explanation and discussion of PCOS should be culturally sensitive as well as appropriate, comprehensive, and tailored to the individual [ 125 ]. This discussion should use an empathetic approach, promote self-care, and highlight peer support groups, which are available in multiple countries ( www.pcoschallenge.org/ , www.verity-pcos.org.uk/ , and www.facebook.com/PCOSAustralia/ ). Counseling about fertility concerns is important, as adolescents with PCOS are more concerned than theirs peers about future fertility after diagnosis [ 156 ].

B. Lifestyle Interventions

Healthy lifestyle interventions must be incorporated in the management plan of all adolescents with PCOS [ 125–127 ] because a large proportion of these adolescents are overweight/obese or are at risk for gaining excessive weight [ 157 ]. Lifestyle interventions comprise multiple components, including healthy diets, physical activity, decreased sedentary behaviors, and behavioral strategies [ 158 ]. The interventions should also include the family, as parents’ involvement and their readiness to change affect adolescent outcomes [ 159 , 160 ]. Engagement and adherence to lifestyle interventions can be improved by management of psychological factors such as anxiety, body image concerns, and disordered eating, which are common in adolescents [ 125 , 161 ]. Two systematic reviews of lifestyle interventions in women with PCOS show improvements in weight, hyperandrogenism, and IR [ 162 , 163 ]. Lifestyle interventions in adolescents with PCOS have shown additional improvements in quality of life [ 160 , 164 , 165 ].

Limited data are available regarding the specific type of diet to achieve weight loss in PCOS [ 125 ]. Five randomized controlled trials (RCTs) have evaluated diets in the management of adolescents with overweight/obesity with PCOS, with only three that evaluated diet as a single intervention [ 160 , 164 , 166–168 ]. A low-carbohydrate diet (20 to 40 g/d) and a hypocaloric diet (<40 g of fat per day) during 12 weeks improved weight and menstrual irregularities with no difference between the diets. Similarly, both low–glycemic load and low-fat diets during 6 months improved weight with no difference between diets [ 168 ]. A low-energy diet compared with a healthy diet for 6 months was associated with weight loss, more regular menses, and decreased hirsutism [ 167 ]. Nutrition education in addition to exercise training and behavioral therapy for 12 months resulted in weight loss, as well as improvement of menstrual irregularities and androgen levels in adolescents with obesity and PCOS [ 160 ].

Physical activity of longer duration, frequency, and intensity results in better maintenance of health. Importantly, moderate to vigorous physical activity for at least 60 minutes per day is associated with better physical and psychosocial health in children and adolescents [ 169 ]. Sixty minutes of moderate to vigorous physical activity at least 3 times a week should be encouraged for the prevention of weight gain and maintenance of health in PCOS [ 125 , 170 ]. Exercise interventions can also improve cardiometabolic risk factors in women with PCOS [ 171 ]. Alternative exercise activities such as yoga for 12 weeks can also improve PCOS symptoms during adolescence [ 172 ]. Limiting sedentary behaviors such as watching television and the use of tablets, computers, and/or mobile phones to 2 h/d is advised for adolescents and relates to better health [ 173 ].

Data regarding behavioral interventions in adolescents with PCOS are limited [ 125 ]. However, family therapy in addition to other lifestyle interventions show beneficial effects on adolescent PCOS symptoms, and a small open trial shows that cognitive behavior therapy improved depressive symptoms [ 160 , 174 ].

Prevention of weight gain and effective weight management is important in adolescent PCOS, as obesity exacerbates metabolic and psychological comorbidities of PCOS [ 175 , 176 ]. Additionally, weight loss strategies up to 7% of body weight have resulted in improving menstrual irregularity and testosterone levels [ 164 , 167 ]. There are limited data for the use of weight loss medications in adolescents.

C. Metformin

Metformin is the single most studied insulin sensitizer in PCOS. It is commonly used in adolescents 15 to 19 years of age despite being “off label” for this indication [ 177 ]. Additionally, according to the recent international evidence-based guidelines for assessment and management of PCOS, “The use of metformin in addition to lifestyle could be considered in adolescents with a clear diagnosis of PCOS or with symptoms of PCOS before the diagnosis is made” [ 125 ].

A meta-analysis of metformin use with and without lifestyle changes in PCOS (including two RCTs in adolescents [ 164 , 178 ]) showed beneficial effects on BMI and menstrual cycles [ 164 , 178 , 179 ]. There have been multiple observational studies and six RCTs evaluating the effect of metformin on a total of 275 adolescents with PCOS. These studies have demonstrated short-term beneficial effects mostly in adolescents with overweight/obesity [ 164 , 180–183 ]. Metformin doses used ranged from 1000 to 2000 mg daily with the major side effect being mild gastrointestinal distress. Limitations are that the frequency of side effects and adherence to medications have not been fully reported. Side effects can be reduced by starting metformin at a lower dose with slow increments and the use of extended release preparations. RCTs were mostly of 6-month duration; only one study lasted 24 months, and no longer-term studies have been reported.

Metformin at a dose of 1700 to 2000 mg/d is associated with greater improvement of BMI, and COCPs are associated with improvement in menstrual irregularity and acne according to a meta-analysis of metformin vs oral contraceptives in adolescents with PCOS and including four RCTs (170 adolescents) [ 164 , 180–184 ]. Both metformin and oral contraceptives had similar beneficial effects on hirsutism, triglycerides, and high-density lipoprotein cholesterol, but the estimates of effect were derived from low-quality evidence involving small studies [ 184 ]. Meta-analyses including larger number of RCTs in women with PCOS showed limited or no benefit of insulin sensitizers on hirsutism [ 185 , 186 ].

Metformin also can be used in addition to COCPs, especially in adolescents with PCOS and BMI ≥25 kg/m 2 , as well as high–metabolic risk groups such as certain ethnicities and individuals at increased risk of type 2 diabetes [ 125 ].

COCPs (estrogen and progestin preparations) should be considered for management of menstrual irregularity and/or clinical hyperandrogenism in adolescents with a clear diagnosis of PCOS and in adolescents at risk of PCOS before the diagnosis is confirmed according to the recent international evidence-based guidelines [ 125 ]. There are limited evidence-based data regarding specific types or doses of progestins, estrogens, or combinations of COCPs for management of PCOS in adolescents and women, but the lowest effective estrogen dose (20 to 30 µg of ethinylestradiol) should be considered [ 125 ]. Contraindications such as thromboembolism risk should be assessed when prescribing COCPs by obtaining thorough medical histories of the patient and her family. In most instances, 35 µg of ethinylestradiol plus cyproterone acetate preparations should not be considered first line in PCOS [ 125 , 187 ]. Duration of treatment has not been evaluated beyond 24 months in adolescents with PCOS. However, COCPs have been used for contraception in longer periods of time.

COCPs improve menstrual irregularity in adolescents with PCOS [ 164 , 180–184 ]. COCPs should be also offered when contraception is required and/or medical treatment of hirsutism or acne is needed [ 184 ]. When no contraception is required, menstrual irregularity alone can also be managed with cyclical medroxyprogesterone acetate (10 mg per day for 10 days) [ 188 , 189 ]. This can be offered when there is a desire to have fewer menstrual cycles and/or a preference for not taking daily medications or being on COCPs due to cultural reasons.

E. Management of Hirsutism

Acknowledgment of the significance of the hirsutism, irrespective of the severity, for a particular adolescent is important when offering treatment options as well as understanding expectations of the treatment [ 125 ]. Long-term commitment is required for any topical and/or medical interventions. More severe hirsutism may require a combination of strategies. Current available therapies have been mostly evaluated in women and include physical hair removal methods, topical medications, light-based therapies, COCPs, and antiandrogens [ 190–192 ].

Physical hair removal methods include waxing, shaving, chemical epilation, plucking, bleaching, and electrolysis. All but electrolysis are temporary hair removal methods, easily available and commonly used by adolescents even before they are evaluated for PCOS. There have been no RCTs evaluating these methods. Electrolysis is a permanent hair removal method, as it causes destruction of hair bulb, but it requires an experienced technician and can cause scaring and pigmentation changes [ 193 ].

Topical medications such as 13.9% eflornithine cream, an irreversible inhibitor of ornithine decarboxylase, affects hair follicle growth and differentiation and can improve mild facial hirsutism in women with mild skin irritation [ 194 , 195 ].

Professional light-based therapies include lasers (alexandrite, diode, and neodymium-doped yttrium aluminum) and intense pulsed light. These light therapies provide wavelengths of 600 to 1100 nm that are absorbed by the melanin in the hair and destroy the hair. This approach provides a prolonged solution for hirsutism after multiple treatments. The light can also be absorbed by epidermal melanin, which is greater in darker skinned individuals, increasing the risk of blisters, dyspigmentation, and scarring [ 196 ]. The neodymium-doped yttrium laser has longer wavelengths, which is less absorbed by epidermal melanin of darker skinned individuals, decreasing side effects. Light-based therapies should be the first line of treatment of localized hirsutism [ 125 , 126 ]. Laser treatment was associated with a 50% reduction of hair at 6 months after treatment with mild side effects such as pain, skin redness, and perifollicular edema [ 197 ]. Uncommon side effects include burns, blisters, hyperpigmentation/hypopigmentation, and scarring that can be reduced by topical anesthetic creams prior to treatment and by cooling mechanisms after treatment. Sun exposure should be avoided before and after treatment. Improvement of hirsutism with laser has been associated with improvement in quality of life, anxiety, and depression in young women with PCOS [ 198 , 199 ].

Light-based home-use devices are also available and approved by the US Food and Drug Administration. These devices provide less optical energy and should be carefully used to avoid injuries to skin and eyes [ 200 , 201 ]. Fewer RCTs have evaluated the efficacy of these devices [ 202 ].

Hormonal therapies should be considered in moderate or severe forms of hirsutism and include COCPs and antiandrogens [ 192 ]. COCPs alone improve hirsutism in adolescents with PCOS [ 184 ]. Estrogens in the COCPs decrease free androgens by increasing hepatic production of SHBG and decrease ovarian and adrenal androgen production by suppressing LH levels [ 203 ]. Progestins in the COCPs also have some antiandrogenic properties by blocking the AR and inhibiting 5 α -reductase activity. A small RCT involving adolescents with PCOS showed no difference in hirsutism improvement when two COCPs were compared during 12 months (30 µg of ethinyl estradiol and 0.15 mg of desogestrel vs 35 µg of ethinyl estradiol and 2 mg of cyproterone acetate) [ 204 ]. However, cyproterone acetate is not available in the United States.

Spironolactone, cyproterone acetate (which can be part of COCPs), and flutamide are antiandrogens that have been evaluated and used to treat hirsutism in women [ 191 ]. Spironolactone is an aldosterone antagonist that blocks the AR. It should be used after 6 months of COCPs; monitoring for side effects such as volume depletion and electrolyte disturbances should be explained and performed [ 125 , 205 ]. The starting dose for spironolactone is ∼25 mg/d. Subsequently, doses can range from 100 to 200 mg/d divided in two doses. Flutamide at a dose of 250 to 500 mg/d divided in two doses during 12 months has shown beneficial effects on hirsutism in women, but there are no RCTs evaluating the effect of flutamide alone or in combination with COCPs in adolescents. Low doses of flutamide (125 mg/d) in combination with metformin have been used in adolescents with ovarian hyperandrogenism [ 206 ]. Flutamide has been associated with severe side effects such as liver toxicity [ 191 , 207 ]. Finasteride is a topical medication that inhibits 5 α -reductase that should be avoided in adolescents, as data are very limited even among adult women [ 190 ].

Antiandrogens alone could be considered to treat hirsutism or alopecia when COCPs are contraindicated or poorly tolerated. However, antiandrogens must be used with effective contraception in sexually active adolescents to avoid fetal undervirilization [ 125 , 126 ]. The combination of COCPs and antiandrogens is superior for management of hirsutism [ 186 ].

F. Management of Acne

Treatment will be guided by severity of acne with the following goals of treatment: reduction of sebum production, prevention of formation of microcomedones, suppression of Propionibacterium acnes , and reduction of inflammation to prevent scaring [ 208 ]. Mild acne can be managed initially with over-the-counter topical treatments such as benzoyl peroxide 0.1%/2.5% (Epiduo gel) or topical retinoids or the combination of the two agents as well as appropriate skin care. Moderate and severe forms of acne require the addition of systemic antibiotics (macrolides) for 3 or 4 months but discontinuation after new inflammatory lesions have stopped appearing [ 208 , 209 ]. COCPs can also be added for management of moderate to severe acne in adolescents [ 184 ]. Timely referral to a dermatologist should be considered when the response is poor or in severe cases, as acne has a major negative impact on adolescent psychosocial well-being.

G. Screening of Other Comorbidities

Additional comorbidities can occur in adolescents with PCOS that might be independent of overweight status. These comorbidities include impaired glucose tolerance and type 2 diabetes [ 125 , 126 , 210 , 211 ]. Additional comorbidities include decreased quality of life, depression, anxiety, eating disorders and disordered eating, and altered body image [ 192 , 212–214 ]. Identification of IR, hyperinsulinemia, and obesity galvanizes efforts to investigate and initiate treatment of associated comorbidities such as impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, and sleep apnea. Adequate screening for comorbidities should be guided by symptoms, clinical examination, and specific personal and family risks factors. This should be followed by appropriate management to avoid further complications [ 125 , 215 , 216 ].

As per management of any adolescent, the HEEADDSS screening tool should be used (that is, H, home environment; E, education and employment; E, exercise and healthy eating; A, activity and peers; D, drugs, smoking, and alcohol; D, depression and suicide ideation; S, sexuality and sexual health; S, sleep) [ 217 ]. Prompt referral to social work, psychology, and counseling in the presence of psychosocial comorbidities is necessary, as these comorbidities will affect adherence to any interventions. Self-management strategies such as mindfulness and yoga in PCOS are emerging and require more research [ 172 , 218 ]. Contraception should be discussed in sexually active adolescents with PCOS who are not taking COCPs for PCOS.

H. Transition to Adult Care Providers

Preparation for transition to adult care will require reinforcement of education about PCOS, its comorbidities, lifestyle interventions, medical treatment, and the need of long-term follow-up [ 125 , 126 , 219 ]. Women with PCOS are best managed by multidisciplinary health care teams comprised of endocrinologists, general physicians, gynecologists, family doctors, or general practitioners. Therapeutic options should be discussed with the adolescent or emerging adult. The selection of an appropriate specialist for adult care should be based on adolescent preferences and major complaints, local availability of health care professionals or specialized clinics, health care insurance, and the possible need of fertility management in the near future.

PCOS is a complex disorder involving multiple organ systems with onset during the early pubertal years ( Fig. 1 ). The list of factors involved in the pathophysiology continues to expand, with accruing evidence indicating that hyperandrogenism is a pivotal factor affecting multiple tissues [ 220 , 221 ]. GWASs have identified genes common to both Han Chinese and white populations that are involved in neuroendocrine, metabolic, and reproductive pathways [ 118 ]. Data obtained from animal models have consistently implicated testosterone as an important factor in the pathogenesis of PCOS. The important contributions of ectopic fat storage and adipocyte androgen biosynthesis are emerging. Promising clinical and preclinical data point toward neuroendocrine involvement with supporting roles for GABA signaling and neuronal ARs.

At this time, an individualized treatment plan can be developed for the adolescent girl with features of PCOS. Attention to the history, physical examination, and laboratory data is important to identify adolescent girls at risk to develop PCOS. Whereas deferring diagnostic labeling may be appropriate, treatment of clinical features and comorbidities is vital to the health and self-esteem of these patients. One future goal includes prevention through timely identification of at-risk prepubertal and early pubertal girls through lifestyle interventions.

Financial Support:  This work was supported in part by the Australian National Health and Medical Research Council Centre for Research Excellence scheme in the origins, outcomes, and optimal management of PCOS (Grant APP1078444 to A.S.P.).

Disclosure Summary: The authors have nothing to disclose.

Data Availability: Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

Abbreviations:

anti-Müllerian hormone

androgen receptor

body mass index

congenital adrenal hyperplasia

combined oral contraceptive pill

dehydroepiandrosterone

dehydroepiandrosterone sulfate

FSH receptor

γ -aminobutyric acid

genome-wide association study

hypothalamic–pituitary–ovarian

insulin resistance

LH/chorionic gonadotropin receptor

nonhuman primate

polycystic ovary morphology

polycystic ovary syndrome

prenatally androgenized

randomized controlled trial

valproic acid

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• Introduction
• Conclusions
• Article Information

PCOS indicates polycystic ovary syndrome.

a The exclusion criteria included studies of patients with gestational diabetes.

Size of boxes is proportional to weight of each study. Solid lines represent confidence interval for the prevalence value reported in each study. Dotted line represents the pooled estimate.

eTable 1. Sample Search Strategy: MEDLINE

eTable 2. Sample Search Strategy: Embase

eTable 3. Search Strategy: CINAHL

eTable 4. Search Strategy: Cochrane Library—Reviews and Trials

eTable 5. Search Strategy: Web of Science—Conference Proceedings Citation Index–Science (CPCI- S), 1990-Present

eTable 6. Summary of Guidelines for Diagnosing PCOS in Adolescents

eTable 7. Risk of Bias of Included Studies

eReferences

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Cioana M , Deng J , Nadarajah A, et al. Prevalence of Polycystic Ovary Syndrome in Patients With Pediatric Type 2 Diabetes : A Systematic Review and Meta-analysis . JAMA Netw Open. 2022;5(2):e2147454. doi:10.1001/jamanetworkopen.2021.47454

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Prevalence of Polycystic Ovary Syndrome in Patients With Pediatric Type 2 Diabetes : A Systematic Review and Meta-analysis

• 1 Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
• 2 Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada
• 3 Michael G. De Groote School of Medicine, McMaster University, Hamilton, Ontario, Canada
• 4 Health Sciences Library, McMaster University, Hamilton, Ontario, Canada
• 5 College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Division of Endocrinology, Department of Pediatrics, Ministry of the National Guard Health Affairs, Riyadh, Saudi Arabia
• 6 Department of Pediatrics, Division of Pediatric Endocrinology, King Abdullah bin Abdulaziz University Hospital, Princess Noura University, Riyadh, Saudi Arabia
• 7 Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
• 8 Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada
• 9 Centre for Evaluation of Medicines, St Joseph’s Health Care, Hamilton, Ontario, Canada
• 10 Biostatistics Unit, St Joseph’s Healthcare, Hamilton, Ontario, Canada

Question   What is the prevalence of polycystic ovary syndrome (PCOS) among adolescents with type 2 diabetes (T2D)?

Findings   In this systematic review and meta-analysis involving 470 girls across 6 studies, the prevalence of PCOS was 19.58%, a prevalence that is substantially higher than that of PCOS in the general adolescent population.

Meaning   These findings suggest that PCOS is a common morbidity in girls with T2D, and it is critical that active screening for PCOS in girls with T2D is initiated at diabetes diagnosis and follows international evidence-based guidelines for diagnosing PCOS in adolescents.

Importance   The prevalence of pediatric type 2 diabetes (T2D) is increasing globally. Girls with T2D are at risk of developing polycystic ovary syndrome (PCOS), but the prevalence of PCOS among girls with T2D is unknown.

Objective   To determine the prevalence of PCOS in girls with T2D and to assess the association of obesity and race with this prevalence.

Data Sources   In this systematic review and meta-analysis, MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science: Conference Proceedings Citation Index–Science, and the gray literature were searched from inception to April 4, 2021.

Study Selection   Two reviewers independently screened for studies with observational study design that recruited 10 or more participants and reported the prevalence of PCOS in girls with T2D.

Data Extraction and Synthesis   Risk of bias was evaluated using a validated tool, and level of evidence was assessed using the Oxford Centre for Evidence-Based Medicine criteria. A random-effects meta-analysis was performed. This study follows the Meta-analysis of Observational Studies in Epidemiology ( MOOSE ) reporting guideline.

Main Outcomes and Measures   The main outcome of this systematic review was the prevalence of PCOS in girls with T2D. Secondary outcomes included assessing the associations of obesity and race with PCOS prevalence.

Results   Of 722 screened studies, 6 studies involving 470 girls with T2D (mean age at diagnosis, 12.9-16.1 years) met the inclusion criteria. The prevalence (weighted percentage) of PCOS was 19.58% (95% CI, 12.02%-27.14%; I 2  = 74%; P  = .002). Heterogeneity was moderate to high; however, it was significantly reduced after excluding studies that did not report PCOS diagnostic criteria, leading to a calculated prevalence (weighted percentage) of 24.04% (95% CI, 15.07%-33.01%; I 2  = 0%; P  = .92). Associations with obesity and race could not be determined because of data paucity.

Conclusions and Relevance   In this meta-analysis, approximately 1 in 5 girls with T2D had PCOS, but the results of this meta-analysis should be considered with caution because studies including the larger numbers of girls did not report the criteria used to diagnose PCOS, which is a challenge during adolescence. The associations of obesity and race with PCOS prevalence among girls with T2D need further evaluation to help define at-risk subgroups and implement early assessment and treatment strategies to improve management of this T2D-related comorbidity.

Over the past 3 decades, type 2 diabetes (T2D) has made the transition from being an adult disease to being a pediatric disorder. 1 - 8 T2D in youth is an aggressive disease with multiple associated comorbidities and poor response to current therapies; it is also associated with higher morbidity and mortality rates than adult-onset T2D. 9 - 11

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that occurs in 1.14% to 11.04% of adolescent girls globally. 12 , 13 The diagnostic criteria for PCOS during adolescence include the combination of menstrual irregularities according to time since menarche and clinical or biochemical hyperandrogenism after excluding other possible causes. 14 - 18 Pelvic ultrasonography is not recommended for PCOS diagnosis in girls who are less than 8 years since menarche according to international evidence-based guidelines, 18 because it is associated with overdiagnosis of PCOS. 19 Insulin resistance and compensatory hyperinsulinemia are present in 44% to 70% of women with PCOS, 20 , 21 suggesting that they are more likely to develop T2D. 22 - 24

PCOS is also associated with a range of cardiometabolic diseases, including hypertension and dyslipidemia, as well as mental health disorders and future infertility. 25 - 28 Importantly, girls with T2D and PCOS are at an increased risk of depression. 29 However, although PCOS is associated with a range of conditions that are related to obesity, the association of PCOS with obesity is not well understood. PCOS is more common in adolescents with obesity, 12 yet insulin resistance is at times present in patients with PCOS regardless of their body mass index (BMI). 30 - 32

In addition, pediatric T2D disproportionately affects female patients, and its rates are increased among minoritized racial and ethnic groups. 1 , 2 , 4 , 5 Determining the scale of PCOS in T2D and the association of obesity and race with PCOS genesis can inform personalized screening and treatment strategies in this population. 33 , 34 The objectives of this systematic review and meta-analysis were to determine the prevalence of PCOS in girls with T2D and to assess the association of obesity and race with PCOS prevalence.

This systematic review and meta-analysis has been registered with PROSPERO. 35 Institutional review board approval and informed consent were not sought because the data were anonymous and publicly available, in accordance with 45 CFR §46. The manuscript was developed and reported in accordance with the Meta-analysis of Observational Studies in Epidemiology ( MOOSE ) reporting guideline. 36

Searches in MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews were developed by a senior health sciences librarian (L.B.) (eTable 1, eTable 2, eTable 3, and eTable 4 in the Supplement ). Gray literature searches were conducted in ClinicalTrials.gov, Cochrane Central Registry of Controlled Trials, and Web of Science Conference Proceedings Citation Index–Science (eTable 5 in the Supplement ). In addition, we searched the reference lists of eligible articles at the full-text screening stage for additional papers that fulfill the inclusion criteria.

The databases were initially searched from inception to February 4, 2019, and updated searches were run on February 20, 2020, and April 4, 2021. There were no language restrictions, but searches were limited to human studies. Terms for pediatrics and T2D were combined with language referencing PCOS, prevalence, and observational study design. Where a conference abstract was considered for inclusion, we searched the databases for a full-text publication and contacted the principal investigator if the publication could not be located.

Studies were included if they reported PCOS in girls diagnosed with T2D at age 18 years or younger. The studies included cross-sectional, retrospective, and prospective cohort studies, with a sample size of 10 or more patients, which reported the prevalence of PCOS in patients with T2D. We included all studies reporting on PCOS regardless of whether PCOS definition was reported.

The exclusion criteria included studies of patients with gestational diabetes. When encountering studies with serial reporting of data, we planned to include the report with the largest sample size.

Title, abstract, and full-text screening, data abstraction, risk of bias, and level of evidence assessments were performed by 2 independent reviewers in 3 teams (M.C., A.N., M.H., Y.Q., S.S.J.C., and A.J.R). Disagreements were resolved through discussion, or by a third reviewer (M.C.S.) if they persisted.

Data abstractions were done using a standardized form. We collected data including study title, author name, publication year, country, study design, age at diabetes diagnosis, age at study participation, duration of diabetes, sample size, and prevalence of obesity in participants, where available. We also extracted data on PCOS definition and total and race-based prevalence of PCOS. We contacted the principal investigators to collect any missing data.

Risk of bias was evaluated using a validated tool for prevalence studies. 37 The tool assesses the internal and external validity of the studies, rating overall risk of bias as low (score >8), moderate (score 6-8), or high (score ≤5).

Level of evidence was assessed using the Oxford Centre for Evidence-Based Medicine criteria. 38 The scale rates the appropriateness of each study to answer the research question, taking into account study design, study quality, imprecision, indirectness, and inconsistency. 38

We performed a meta-analysis using a random-effects model when 2 or more studies reporting the prevalence of PCOS used similar design, methods, and populations. 39 , 40 If studies could not be included in the meta-analysis, the results were reported as a narrative summary and tabulated. Prevalence values were calculated using raw proportions of the number of girls with PCOS and T2D divided by the total number of girls diagnosed with T2D. Study weights were calculated from the inverse of the variance of prevalence value. All studies were then pooled according to weight, and a pooled prevalence value was determined. Because no studies had prevalence values close to 0% or 100%, we did not use transformations in our calculations. 40

The primary outcome for this review was the pooled prevalence of PCOS with a 95% CI. Both inconsistency index ( I 2 ) and χ 2 test P values were used to quantify heterogeneity, with I 2  > 75% and P  < .10 considered as significant cutoffs for heterogeneity. 41

We had originally planned to perform subgroup analyses by race if 10 or more studies were included in the meta-analysis. However, these analyses could not be completed because of the limited number of eligible studies. Because of the number of included studies that did not report PCOS diagnostic criteria, we also conducted a post hoc sensitivity analysis excluding these studies to examine their impact on prevalence and heterogeneity. The meta-analysis was conducted using the metafor package in RStudio statistical software version 1.1.383 and R statistical software version 3.4.3 (R Project for Statistical Computing). 42 - 44

Of 722 screened articles, 6 studies 45 - 50 involving 470 girls met our inclusion criteria ( Figure 1 ). The Table reports the characteristics of the included studies. Five were retrospective cohort studies, 45 - 49 and 1 was a prospective cohort study. 50 The mean (SD) age at diagnosis of T2D ranged from 12.9 to 16.1 years, and the mean duration of T2D ranged from inclusion at diagnosis of T2D to 5.9 years after diagnosis.

The prevalence (weighted percentage) of PCOS across the included studies was 19.58% (95% CI, 12.02%-27.14%) ( Figure 2 ). 45 - 50 Heterogeneity was moderate to high ( I 2  = 74%; P  = .002).

There were variations in the PCOS definition in the included studies. The PCOS diagnostic criteria used in the included studies are summarized in eTable 6 in the Supplement . Common diagnostic criteria across the different guidelines included persistent oligomenorrhea and clinical and/or biochemical hyperandrogenism. Three studies used these criteria to make a PCOS diagnosis ( Table ). 47 , 49 , 50 The remaining studies reported PCOS diagnosis according to medical records review or clinical symptoms; however, the exact criteria were not defined. 45 , 46 , 48 In addition, none of the studies reported time to menarche, which is important for establishing PCOS diagnosis. 14 - 18

We conducted a sensitivity analysis excluding studies that did not report PCOS diagnostic criteria (87 girls) ( Figure 3 ). The pooled PCOS prevalence (weighted percentage) increased to 24.04% (95% CI, 15.07%-33.01%) with a substantial reduction in heterogeneity ( I 2  = 0%; P  = .92). 47 , 49 , 50

Only 2 studies 45 , 46 reported the prevalence of PCOS by race. The prevalence was 17.00% in White individuals (36 girls), 45 23.10% in Indian individuals (195 girls), 46 and 2.00% in Indigenous individuals in Canada (64 girls). 45

Although we originally aimed to determine the association of obesity and PCOS, none of the included studies provided information on the prevalence of obesity. Thus, the association between PCOS and obesity could not be evaluated.

Two studies had low risk of bias, 49 , 50 3 studies had moderate risk of bias, 45 - 47 and 1 had high risk of bias (eTable 7 in the Supplement ). 48 In 3 studies, 46 , 47 , 49 the study population was not representative of the national population, and in 3 other studies 45 , 47 , 48 the sampling frame was not representative of the target population. Cases were not selected using random selection or census data in 2 studies. 45 , 48 One study 48 had nonresponse bias and it was unclear what numerator and denominator were used to calculate PCOS prevalence.

In 3 included studies, 45 , 46 , 48 the diagnostic criteria used for PCOS assessment were unclear. In 1 study, 48 it was not clear whether all patients were assessed for PCOS using the same methods.

Studies had a level of evidence of 1 (1 study), 46 2 (3 studies), 47 , 49 , 50 or 3 (2 studies). 45 , 48 Level of evidence was rated down for studies that did not use random sampling, 45 , 48 and for those that did not have an adequate sample size. 47 , 49 , 50

The prevalence of pediatric T2D is increasing globally, and the majority of these patients are female. 6 , 7 , 51 PCOS is a comorbidity of T2D that is associated with substantial metabolic, cardiovascular, and psychological consequences. 23 , 26 , 52 - 54 Thus, the timely assessment and management of PCOS in this high-risk population is critical. 22 On the basis of studies with mostly moderate risk of bias, this systematic review and meta-analysis demonstrated that approximately 1 in 5 girls with T2D have PCOS. This figure is substantially higher than PCOS prevalence among the general female adolescent population, which is estimated at 1.14% to 11.04%. 12 , 13 There was moderate-to-high heterogeneity in the results of the studies included, although most of the heterogeneity may be attributable to the inclusion of studies that did not clearly report the PCOS diagnostic criteria. The prevalence of PCOS by race was reported in single studies, which precluded generalizability, and the association of obesity with PCOS could not be estimated because of the lack of data.

The association between PCOS and T2D in adults is bidirectional. 55 - 57 Insulin resistance plays a central role in the pathogenesis of PCOS, and studies in adolescents have shown that girls with PCOS have decreased insulin sensitivity and compensatory hyperinsulinemia. 23 , 30 , 58 Insulin increases the sensitivity of the pituitary gland to hypothalamic gonadotropin-releasing hormone, which, in turn, stimulates the production of luteinizing hormone. 59 Both insulin and luteinizing hormone act synergistically on the ovarian theca cells to upregulate androgen production, 21 , 55 which, in turn, reduces adipose tissue adiponectin secretion and insulin sensitivity and upregulates insulin production. 60 In addition, insulin increases androgen production within the subcutaneous adipose tissue via the upregulation of the aldo-keto reductase 1C3 activity. 61

Another mechanism that may lead to both insulin resistance and hyperandrogenism is lipotoxicity. 22 Increased ovarian exposure to fatty acids can lead to the overproduction of androgens, 62 , 63 and the enhanced delivery of fatty acids to nonadipose tissues is key to the development of insulin resistance and T2D. 64

Although earlier studies suggested that obesity-related insulin resistance and hyperinsulinemia can contribute to PCOS pathogenesis, 15 insulin resistance in patients with PCOS may be present independently of BMI. 30 - 32 Obesity seems to increase the risk of PCOS only slightly 65 and might represent a referral bias for PCOS. 12 Lipotoxicity is a potential mechanism in the development of both T2D and PCOS, and it can occur independently of obesity. 15 , 66 In addition, adipose tissue dysfunction is seen in both PCOS and T2D, 22 as women with PCOS have larger subcutaneous adipocytes for the same degree of total adiposity and BMI, and adipocyte hypertrophy is strongly correlated with insulin resistance and T2D. 67 , 68 Further studies are needed to clarify the association of obesity with PCOS pathogenesis in girls with T2D.

Because of the scarcity of studies reporting race-specific data, we could not address the association of race with PCOS prevalence comprehensively. However, our data demonstrate that Indian girls had the highest prevalence, followed by White girls, and then Indigenous girls in Canada. In a retrospective study 69 assessing PCOS prevalence in 250 adolescents without T2D, 60 patients were African American (65%) and 24 patients (26%) were White. African American patients had a higher BMI and hemoglobin A1 c and less dyslipidemia compared with White individuals. 69 A systematic review 70 in adult women reported that Chinese women have the lowest prevalence of PCOS, followed by White, Middle Eastern, and Black women. More studies are needed to evaluate the prevalence of PCOS in girls with T2D across different racial groups to aid the development of personalized screening and management strategies.

It is important for PCOS to be diagnosed early to prevent the development of ensuing complications when untreated. PCOS in adolescence is associated with features of the metabolic syndrome, including hypertension, hyperglycemia, and dyslipidemia. 26 In addition, adolescents with PCOS have higher prevalence of cardiovascular risk factors, 23 including higher carotid intima thickness, β stiffness index, and reduced arterial compliance compared with patients with obesity and no PCOS. 54 Psychiatric comorbidities are also prevalent in PCOS, such as anxiety (18%), depression (16%), and attention-deficit/hyperactivity disorder (9%). 53 Health-related quality of life is substantially reduced in patients with PCOS, with body weight concerns, menstrual irregularity, and a sense of lack of control over health being important contributors. 52 , 71 It is critical that PCOS in T2D is managed with a focus on biopsychosocial well-being to achieve positive health outcomes.

The limitations of this systematic review include that none of the studies had PCOS as a primary outcome. There was also a lack of a unified approach to diagnosing PCOS across studies and no reporting of the timing of menarche, which may have contributed to the high heterogeneity observed in the meta-analysis. Two of the largest studies did not report the criteria used for PCOS diagnosis. 45 , 46 However, this systematic review had a comprehensive search strategy across several databases, including the gray literature, which includes all available evidence to date on this outcome.

The results of this study reflect the lack of consensus and difficulty in diagnosing PCOS in adolescents. The European Society of Human Reproduction and Embryology/American Society of Reproductive Medicine, the Pediatric Endocrine Society, and the International Consortium of Paediatric Endocrinology guidelines suggest that ultrasonography showing increased ovarian size could be used to aid in diagnosis, but other guidelines are more conservative in using these findings to diagnose PCOS. 14 - 18 In addition, the European Society of Human Reproduction and Embryology/American Society of Reproductive Medicine guidelines state that biochemical hyperandrogenism needs to be present, and not just clinical signs of hyperandrogenism, whereas other guidelines state that either is sufficient for diagnosing PCOS. 14 - 18 There is a need for a consensus to establish the pediatric criteria for diagnosing PCOS in adolescents to ensure accurate diagnosis and lower the misclassification rates.

Given these limitations, the results should be interpreted with caution. Larger multiethnic, longitudinal cohort studies evaluating PCOS prevalence in girls with T2D and using standardized criteria for defining PCOS are urgently needed.

This study found that in girls with T2D, approximately 1 in 5 had PCOS. Identifying PCOS in this population is critical to allow for early screening and management of PCOS and its associated health concerns. Future studies are urgently needed to define the impact of obesity and race on PCOS prevalence in this population and to ensure the development of personalized assessment and treatment strategies.

Accepted for Publication: December 15, 2021.

Published: February 15, 2022. doi:10.1001/jamanetworkopen.2021.47454

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2022 Cioana M et al. JAMA Network Open .

Corresponding Author: M. Constantine Samaan, MD, MSc, Division of Pediatric Endocrinology, McMaster Children’s Hospital, 1200 Main St W, 3A-57, Hamilton, ON L8N 3Z5, Canada ( [email protected] ).

Author Contributions: Ms Cioana and Dr Samaan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Cioana, Deng, Banfield, Thabane, Samaan.

Acquisition, analysis, or interpretation of data: Cioana, Deng, Nadarajah, Hou, Qiu, Chen, Rivas, Alfaraidi, Alotaibi, Thabane, Samaan.

Drafting of the manuscript: Cioana, Deng, Alfaraidi, Samaan.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Cioana, Deng, Qiu, Thabane, Samaan.

Administrative, technical, or material support: Cioana, Deng, Rivas, Banfield, Alotaibi, Samaan.

Supervision: Banfield, Alfaraidi, Thabane, Samaan.

Conflict of Interest Disclosures: None reported.

Meeting Presentation: This article was presented as a poster presentation at the Pediatric Endocrine Society Annual Meeting; April 30, 2021; virtual meeting.

Additional Contributions: Mr Parm Pal Toor (undergraduate student at McMaster University) helped with the updated search of this systematic review; he was not compensated for this work.

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PCOS Forum: Research in Polycystic Ovary Syndrome Today and Tomorrow

Renato pasquali.

1 Division of Endocrinology, St. Orsola-Malpighi Hospital, University Alma Mater Studiorum of Bologna, Italy

Elisabet Stener-Victorin

2 Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden and Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China

Bulent O. Yildiz

3 Endocrinology and Metabolism Unit, Department of Internal Medicine, Hacettepe University School of Medicine, Hacettepe, 06100 Ankara, Turkey

Antoni J. Duleba

4 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of California, Davis, California, USA

Kathleen Hoeger

5 Department of Obstetrics and Gynecology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 668, Rochester, New York 14642, USA

Helen Mason

6 Division of Basic Medical, St George’s, University of London, Cranmer Terrace, London SW170RE, UK

Roy Homburg

7 Barzilai Medical Center, Ashkelon, Israel and Homerton Fertility Center, Homerton University Hospital, London E9, UK

Theresa Hickey

8 School of Medicine and School of Paediatrics & Reproductive Health, University of Adelaide, Adelaide, South Australia

Steve Franks

9 Imperial College School of Medicine, Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom

Juha Tapanainen

10 Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu FIN-90014, Finland

11 Department of Reproductive Medicine and Surgery, Leeds General Infirmary, Leeds, LS2 9NS, UK

David H. Abbott

12 Department of Ob/Gyn and Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA

Evanthia Diamanti-Kandarakis

13 Third Department of Medicine Medical School University of Athens, Sotirira Hospital, Athens, Greece

Richard S. Legro

14 Department of Ob/Gyn, Penn State College of Medicine, Hershey PA

To summarize promising areas of investigation into polycystic ovary syndrome (PCOS) and to stimulate further research in this area.

Potential areas of further research activity include the analysis of predisposing conditions that increase the risk of PCOS, particularly genetic background and environmental factors, such as endocrine disruptors and lifestyle. The concept that androgen excess may contribute to insulin resistance needs to be re-examined from a developmental perspective, since animal studies have supported the hypothesis that early exposure to modest androgen excess is associated with insulin resistance. Defining alterations of steroidogenesis in PCOS should quantify ovarian, adrenal and extraglandular contribution, as well as clearly define blood reference levels by some universal standard. Intraovarian regulation of follicle development and mechanisms of follicle arrest should be further elucidated. Finally, PCOS status is expected to have long-term consequences in women, specifically the development of type 2 diabetes, cardiovascular diseases and hormone dependent cancers. Identifying susceptible individuals through genomic and proteomic approaches would help to individualize therapy and prevention. A potential limitation of our review is that we focused selectively on areas we viewed as the most controversial.

INTRODUCTION

The polycystic ovary syndrome (PCOS) is a hyperandrogenic disorder associated with chronic oligo-anovulation and polycystic ovarian morphology 1 , 2 . It is often associated with psychological impairments, including depression and other mood disorders and metabolic derangements, chiefly insulin resistance and compensatory hyperinsulinemia, which is recognized as a major factor responsible for altered androgen production and metabolism 3 . Most women with PCOS are also overweight or obese, further enhancing androgen secretion while impairing metabolism and reproductive functions and possibly favoring the development of the PCOS phenotype. The definition of PCOS has led to an impressive increase of scientific interest in this disorder, which should be further directed to improve individualized clinical approaches and, consequently therapeutic strategies.

To further dialogue and exchange ideas on PCOS an international group of PCOS researchers, has gathered every other year to summarize the state of the field and stimulate further research. We have previously published our presentations in book form 4 , but elected here to create a shorter summary of our presentations. We designed the meeting to focus on specific areas of uncertainty in the pathophysiology and treatment of women with PCOS.

Defining alterations of steroidogenesis in PCOS

In normal women, androgen production rate (PR) is the result of adrenal and ovarian secretion and conversion from precursors in peripheral tissues, particularly the adipose tissue and skin 5 . Similarly, the metabolic clearance rate (MCR) of androgens may occur in both glandular and extraglandular tissues. Both PR and MCR of androgens in females depends on age and physiological status. All androgens exhibit a daily rhythm, less variable for androstenedione and testosterone than that of DHEA and cortisol. A few studies, all performed several decades ago, documented higher PRs for both androstenedione and testosterone in women with PCOS, associated with a less pronounced increase of their MCR 6 . In addition, it was shown that testosterone MCR was higher in obese PCOS women and varied according to its PR, whereas MCR of androstenedione was marginally different with respect to normal weight affected women, suggesting that factors [peripheral conversion or possibly binding to sex hormone binding globulin (SHBG)] in addition to body size influenced testosterone MCR in PCOS women. Notably, there are no studies in PCOS women with different obesity phenotypes, although there is evidence that in women with simple obesity, those with abdominal fat distribution have higher testosterone PR, but not higher androstenedione, with respect to those with the peripheral phenotype 7 . Similar studies should therefore be replicated in PCOS women with different obesity phenotypes. Estrogen and progesterone PRs in women with PCOS have been poorly investigated.

One of the main problems in the diagnosis of hyperandrogenic states such as PCOS is the accurate measurement of androgens and particularly testosterone. Many radioimmunoassays, especially platform assays, for androgens are decidedly unsatisfactory. Most of these intrisic methodological limitations are bypassed by the growing use of liquid chromatography-tandem mass spectrometry (LM/MS-MS), the modern gold standard for all steroid hormone measurement, particularly in women. By the use of LM/MS-MS it would be expected that additional kinetic studies in different phenotypes of this disorder may favour a better understanding of complex pathophysiological events leading to androgen excess in women with PCOS, as preliminary clinical studies seem to indicate.

Significance of adrenal androgen production

It has been estimated that 25% of androstenedione and testosterone production is of ovarian origin, 25% is of adrenal origin and 50% is produced in peripheral tissues, while the adrenal cortex accounts almost uniquely for the synthesis of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as well as that of androstenediol and 11β-hydroxy androstenedione 10 . In women androgens serve as precursors of estrogen biosynthesis, which starts to decrease 3–4 years before menopause 11 . At the same time basal serum levels of ovarian androgens decrease only slightly and remain relatively stable until menopause, while the decrease of adrenal androgens can already be observed after the age of 30 years 12 . Compared with healthy subjects, women with previous PCOS have an increased adrenal capacity to secrete androgens that remains until after menopause. These results confirm the adrenals contribute significantly to hyperandrogenism in PCOS and similarly to ovarian androgen secretion capacity, women with PCOS exhibit enhanced adrenal androgen production until their late reproductive years 13 . The pathophysiological mechanisms responsible for increased androgen production by the adrenals in women with PCOS remains, however, poorly elucidated and should require further investigation. Difficulty in obtaining viable and appropriate adrenal tissue has limited in vitro study of human tissue, but long term culture is possible, and the derivation of stem cell adrenal cortex tissue could significantly enhance studies of this important gland.

Specific steroidogenic enzyme defects in PCOS

The etiology of PCOS remains uncertain but intrinsic abnormalities in the synthesis and secretion of androgens are a plausible basis for the syndrome. There is clear evidence for constitutive hyper-secretion of androgen by ovarian theca cells 14 but abnormalities of adrenal androgen production have also been implicated in the etiology. It is therefore reasonable to pose the question “are specific primary enzyme abnormalities in the steroidogenic pathway an important cause of PCOS?”. On the basis of currently available evidence, the answer to this question is probably “no”. Amongst plausible candidate genes in genesis of hyperandrognemia are CYP17 (coding for P450c17, and the associated P450 reductase) and, because of evidence for a global increase in steroidogenic enzyme activity in PCO theca cells, CYP11a (P450scc) 15 , 16 . To date, case-control and family-based studies have shown no clear evidence that variants in these genes (or for that matter, many others involved in steroidogenesis) contribute to the pathogenesis of PCOS. Recent work has focused on metabolism of cortisol and adrenal androgens but, although specific enzyme defects may be associated with a PCOS phenotype (e.g. defects in cortisone reductase), the data from large association studies suggest that such defects are but a very minor contributor to the etiology of PCOS 16 .

In addition, extraglandular synthesis of androgens, particularly in the adipose tissue, has been found to be involved in the pathophysiology of PCOS. They involve alteration in the activity of 11β-hydroxysteroid dehydrogenase 17 and both 5α-reductase and 5β-reductase 10 , 18 , 19 . Alterations of these enzyme systems which are involved in peripheral cortisol metabolism may in turn activate the neuroendocrine drive to support adrenal steroidogenesis and may partly explain the increased androgen production in specific subsets of women with PCOS.

Sympathetic nerve activity and hyperandrogenism

Many factors associated with polycystic ovary syndrome (PCOS) are also associated with increased activity in the sympathetic nervous system 20 . The involvement of sympathetic nervous system in PCOS pathology is supported by the greater density of catecholaminergic nerve fibres in polycystic ovaries (PCO) 21 . Increased ovarian sympathetic nerve activity might contribute to PCOS by stimulating androgen secretion 22 . Nerve growth factor (NGF) is a strong marker for sympathetic nerve activity and recently it was demonstrated that women with PCOS has enhanced ovarian NGF production 23 . In a transgenic mouse model overexpressing NGF in the ovaries, they found that that a persistent elevation in plasma LH levels is required for the typical morphological abnormalities to appear 23 . These results suggest that overproduction of ovarian NGF is a component of PCO morphology.

Studies using indirect markers of autonomic function – heart rate variability and heart rate recovery after exercise – have shown that women with PCOS have increased sympathetic and decreased parasympathetic components 24 , 25 , 26 . Recently, for the first time it was demonstrated that women with PCOS have high general activity in the sympathetic nervous system which may be relevant to the pathophysiology of the syndrome 27 . Interestingly, testosterone was the strongest independent factor explaining high sympathetic nerve activity in women with PCOS 27 . As the degree of androgen concentration can reflect the severity of PCOS, the relationship between sympathetic nerve activity and testosterone concentration indicates that the degree of sympatho-excitation is related to the degree of PCOS severity.

Recently, a randomized controlled trial demonstrated that low-frequency electro-acupuncture (EA) and physical exercise (both known to modulate sympathetic nerve activity) decreases high levels of circulating sex steroid precursors, estrogens, androgens, and glucuronidate androgen metabolites and improve menstrual bleeding pattern in women with PCOS, and thus break the vicious circle of androgen excess 28 . In a subset of these women, low-frequency EA and physical exercise was shown to decrease high sympathetic nerve activity in women with PCOS 29 , which may at least in part explain the beneficial effects of these therapies. It may also be hypothesized that therapies such as ovarian wedge resection or laparoscopic laser cauterization 30 , utilize its effect by temporary disruption of ovarian sympathetic innervation, and thus increase ovulatory function and decrease androgen synthesis in women with PCOS.

Mechanism of follicle arrest

The finding that granulosa cells from anovulatory polycystic ovaries responded well to FSH in culture directed initial investigations into follicular arrest towards discovery of raised levels of a locally produced inhibitor. It is difficult to deduce cause and effect, however if the factor is causing follicular arrest, or did the follicular arrest elicit the production of the inhibitor. Androgens are an obvious candidate, but production is raised in theca from ovulatory PCO also 31 . Insulin causes premature acquisition of LH receptors possibly leading to early follicular luteinisation 32 , but the insulin signalling defect in the polycystic ovary remains to be clarified. More comprehensive investigation of insulin/glucose interactions in these cells has been undertaken utilising a metabolomic approach. Anti-Mullerian Hormone (AMH) is raised in women with PCOS and granulosa cell production is considerably higher in anovulatory than ovulatory women with PCOS. AMH’s suppressive effects on folliculogenesis may make this the sought-after local inhibitor 33 . Recent data indicated that it is those women in whom AMH levels fall who have the best response to methods to induce ovulation. Interestingly, the incubation of cells with metformin inhibited AMH production suggesting that this may be one mechanism of the action of this drug in PCOS 34 .

Intra-ovarian regulation of ovarian morphology

Kit ligand (KL) is an intra-ovarian cytokine that promotes multiple aspects of folliculogenesis in animal models including primordial follicle activation, follicle growth and survival, stromal cell differentiation, and theca cell proliferation and androgen biosynthesis 35 . Perturbation of these biological processes occur in PCO, particularly in anovulatory women with PCOS, in whom there is evidence for abnormal oocyte growth, increased follicle and stromal density, thecal hypertrophy, and increased thecal cell androgen biosynthesis. Therefore, KL may play a key role in the morphogenesis of PCO, particularly in women with PCOS. Androgen regulation of KL has been reported 36 , but the role of KL signalling, its regulation in human ovaries and its relevance to PCOS are currently unknown.

Determinants of ovarian morphology – Influence of gonadotropins

Initiation of growth and early differentiation of follicles are thought to be regulated independently of gonadotropin stimulation. The later stages of growth and differentiation, selection of the cohort and cyclic recruitment are largely dependent on FSH activity. In the PCO there is loss of the selection process from an increased pool to a dominant follicle. Enhanced steroidogenesis, excess androgens, hyperinsulinemia and lack of growth differentiation factor (GDF9) have all been implicated but FSH refractoriness may be key. FSH concentrations in PCOS are generally in the lower normal range. Adding FSH (with clomiphene or exogenous FSH) restores normal follicular growth, suggesting an endogenous inhibition of FSH action in PCOS. The source of this inhibition is probably ovarian as loss of ovarian tissue (wedge resection or laparascopic ovarian diathermy, or age >40 years old) 37 is capable of restoring normal follicular development and ovulation. Following laparoscopic ovarian drilling (LOD), there is a rapid steep rise in FSH in those who respond. Thus, it seems that the size of the 2–5mm follicle pool is an independent, important contributor to the follicular arres. Candidates for the source of FSH refractoriness include transforming growth factor (TGF)-alpha, epidermal growth factor (EGF), follistatin and, particularly the high concentrations of AMH in PCOS 38 . LH receptor over-expression in PCO granulosa cells leads to terminal differentiation and premature arrest of follicle growth 39 . Finally, the lack of circulating progesterone encourages high LH levels, exacerbating androgen excess, multiple small follicles and the consequences. These data highlight the role of appropriate gonadotropin action within the ovary in restoring follicular development and ovulation in women and PCOS, and provide evidence for the ovary as the primary determinant of inappropriate gonadotropin secretion in PCOS, though this remains an area of debate among researchers.

Clinical significance of polycystic ovaries in normal women

Polycystic ovaries (PCO) are the morphological ovarian phenotype in women with the polycystic ovary syndrome (PCOS). Several studies have been performed to attempt to determine the prevalence of PCO as detected by ultrasound alone in the general population, and have found prevalence rates in the order of 17–33% 40 . In 2003 a joint ESHRE/ASRM consensus meeting produced a refined definition of PCOS (1), and the morphology of the polycystic ovary, was defined as an ovary with 12 or more follicles measuring 2–9 mm in diameter and/or increased ovarian volume (>10 cm 3 ) 38 . It is interesting also to note that the presence of PCO is a marker for increased ovarian reserve and a reduced rate of ovarian aging 41 . The question of whether PCO alone are pathological or a normal variant of ovarian morphology is debated. It has been found that some women with hypogonadotropic hypogonadism (HH) also have polycystic ovaries detected by pelvic ultrasound and when these women were treated with pulsatile GnRH to induce ovulation they had significantly higher serum LH concentrations than women with HH and normal ovaries 42 . These results suggest that the cause of hypersecretion of LH involves a perturbation of ovarian-pituitary feedback, rather than a primary disturbance of hypothalamic pulse regulation. A consensus statement on defining the morphology of the PCO stated that “A woman having PCO in the absence of an ovulation disorder or hyperandrogenism (“asymptomatic PCO”) should not be considered as having PCOS, until more is known about this situation” 43 . Whilst the spectrum of “normality” might include the presence of PCO in the absence of signs or symptoms of PCOS, there is evidence that women with PCO morphology alone show typical responses to stresses such as gonadotropin stimulation during IVF treatment or to weight gain, whether spontaneous or as stimulated by sodium valproate therapy 44 . The difficulty in answering this question lies in the fact that to date there are no large scale, longitudinal prospective studies of women with polycystic ovaries.

Information about the prevalence of polycystic ovaries can be obtained from cross sectional studies of ovarian size and morphology in normal women without PCOS. For instance a large scale study of ovarian aging among women enrolled in the Kaiser Permanente Health Plan in California found a high prevalence of polycystic ovaries among younger women which resolved with aging.

However a better study design would be a prospective longitudinal study to examine via imaging changes in the size and morphology of the ovary over time to establish the permanence of the polycystic ovary in affected and unaffected women with PCOS. This would also address the important and understudied issue of the fate of the polycystic ovary in the perimenopause and menopause.

Hyperthecosis

Hyperthecosis is the development of nests of luteinized thecal cells, usually diffusely, in the ovary with the subsequent production of androgens and presentation with signs of androgen excess. Unlike PCOS there is not an abundance of antral follicles surrounded by theca, in fact it often develops in postmenopausal women devoid of follicles 46 . The cause of hyperthecosis is unknown. The phenotype in hyperthecosis can be more severe than PCOS, as women can present with markedly elevated testosterone levels and may develop frank signs of virilization. Hyperinsulinemia is also frequently part of the phenotype 47 . Though this condition responds to GnRH agonist suppression 48 , the usual treatment is oophorectomy, especially in a postmenopausal woman. Because this condition is rare, most publications are case reports and case series, however it offers an intriguing clinical model for hyperandrogenism and insulin resistance solely due to an ovarian factor. Hyperthecosis, especially as an acquired condition of sudden onset lends itself to the possibility of an infectious and/or autoimmune response to an infection or some external antigen, a possibility discussed below in relation to PCOS.

Impact of metabolic abnormalities on development of PCOS in a nonhuman primate model

A fetal testosterone excess model for PCOS manifests metabolic defects in adult female as well as adult male rhesus monkeys 49 . Testosterone treatment of monkey dams results in mild-to-moderate maternal glucose intolerance that adds a metabolic perturbation to in utero testosterone exposure and may explain why both female and male testosterone -exposed offspring exhibit metabolic defects in adulthood 50 , 51 . Testosterone -exposed female offspring also demonstrate subtle increases in fetal head growth and postnatal body weight, as well as indications of fetal hyperglycemia and neonatal hyperinsulinemia. Neonatal hyperinsulinemia may synergize with infant hyperandrogenism in testosterone -exposed females to increase lipogenesis and muscle protein synthesis 51 , thus enhancing insulin-sensitive tissue mass that may contribute to increased adiposity and insulin resistance found in testosterone -exposed adults 49 . Since insulin defects have been found in prepubertal daughters born to women with PCOS 52 , metabolic abnormalities during gestation may provide an important developmental contribution to the expression of PCOS phenotype.

The fetal programming hypothesis, however, while well defined in animal models, has yet to be confirmed in humans, despite two recent studies attempting to define fetal testosterone exposure in PCOS women. A long-term prospective study investigating a large cohort of unselected adolescents found that blood levels of testosterone from their mothers at 18 and 34–36 wk gestation, and from an umbilical cord sample, were not related to the subsequent development of PCOS 53 . A separate study examining umbilical cord blood levels in newborns found unchanged testosterone, but diminished androstenedione and estradiol levels, in girls born to women with PCOS 53 . These negative data are not surprising since human fetuses are protected from maternal androgen excess of PCOS by placental aromatase, and umbilical cord blood testosterone and androstenedione levels do not reliably distinguish boys from girls 53 , despite male fetal androgen excess earlier in gestation. This animal model offers a unique method to explore the effects of the intrauterine milieu on the development of future metabolic and reproductive abnormalities, and allows controlled manipulation and long term follow up of offspring in a manner that would be unethical and frankly impossibile in humans.

Dyslipidemia in PCOS

PCOS is frequently associated with various patterns of dyslipidemia including low high-density lipoprotein cholesterol (HDL-C), high levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol (LDL-C) 54 – 56 . Although the data from large series suggest that the mean values for circulating lipids in women with PCOS are in normal limits, up to 70% of patients have at least one abnormal lipid level according to NCEP-ATPIII criteria 57 . Body fat amount and distribution, presence and degree of insulin resistance, and androgen excess appear to have independent and interrelated effects on the type and extent of lipid abnormalities in PCOS 58 . Prevalence rates of dyslipidemia show significant variability in different studies. Several factors including age, race, glucose intolerance, and diagnostic criteria used to define PCOS might have an influence on this variation. Nevertheless, most of the studies assessing dyslipidemia in PCOS have certain limitations, including (but not limited to) small sample size and lack of information on environmental modulators of serum lipid levels such as diet, physical activity, smoking and alcohol consumption.

Large scale follow up studies are warranted to investigate lipid alterations in PCOS as well as to determine the impact of commonly used long term therapeutic interventions in the syndrome. There is debate at what age to institute therapy for dyslipidemia, as the treatment, for example with statins does include slight risk of a serious adverse side effect including rhabdomyolysis, whereas events are unlikely in younger women with PCOS. Further there is concern that treatment with these agents will improved reproductive aspects and result in increased and unexpected ovulation and potential undesired fetal exposure. Many of these drugs are given a categorical teratogenic designation because they interfere with cholesterol synthesis or metabolism, and LDL-C remains the primary precursor for sex steroid synthesis in the placenta.

Predisposing risk factors for PCOS and risk reduction

Evidence suggests there are contributions from both heritable and non-heritable factors in the development of PCOS. The typical presentation of PCOS in adolescence suggests that the predisposition to the endocrine and metabolic abnormalities of PCOS originates prior to puberty. There is likely a genetic heritability that is enhanced by environmental factors notably increased dietary consumption and development of obesity. Studies demonstrate that peripubertal obesity is associated with hyperandrogenism 59 , although prospective studies linking this to the development of PCOS are lacking. If indeed peripubertal obesity, acting either through increased insulin resistance or other adipocyte factors, increases the development of hyperandrogenism, reduction in adiposity should reduce this risk.

No long-term studies are available to demonstrate that reduction in body weight reduces the risk of PCOS development. Peripubertal weight reduction has been shown to be associated with a reduction in testosterone levels in the general population of obese pre-pubertal girls 60 . There are limited studies that demonstrate the induction of modest weight reduction, with or without concomitant oral contraceptives, improves serum androgens in adolescents diagnosed with PCOS 61 . Limited data have been reported on the use of insulin sensitizers in the management of PCOS in adolescence with mixed result 62 , 63 . Future research should focus on early identification of predisposing risk factors in PCOS development, and long-term studies that modify environmental factors to abrogate the risk.

The role of diet in the pathogenesis of PCOS: Focus on dietary Advanced Glycated End products (AGEs)

Lifestyle contributors to disease include not only calorie excess but also the dietary intake of specific nutrients. Advanced Glycated End products (AGEs) is a class of nutrients incriminated in the pathogenesis of diet-related diseases. AGEs are reactive derivatives of nonenzymatic glucose–protein reactions either produced endogenously or ingested from dietary sources. Cooking or processing at high temperatures such as broiling, grilling, frying, and roasting are the major sources of AGEs. By modulating the activity of protein kinases, AGEs promote oxidative stress and insulin resistance in peripheral tissues. PCOS women have increased serum AGEs levels and these have been positively correlated with serum androgen levels 64 . In women with PCOS dietary modification or use of a gastric lipase inhibitor may reduce serum AGEs and oxidative stress markers as well as serum testosterone levels 65 . PI3K mediates insulin signalling at the postreceptor level and also, mediates the clearance of AGEs via the Macrophage Scavenger Receptor (MSR) pathway. The inhibition of Phosphatidylinositol 3 kinase (PI3K) may play a dual role in the coexistence of AGE excess and insulin resistance in PCOS. By activating protein kinase C, AGEs may impair insulin action, thereby perpetuating insulin resistance, an intrinsic feature of PCOS 66 . Furthermore, a potential direct action of AGEs on ovarian function is suggested by their increased immunohistochemical localization in polycystic ovaries 67 . Overall, AGEs, both endogenously and exogenously derived, may play a part in the pathogenesis of PCOS. However, there are no data in comparing different ethnic populations with different diets regarding the impact of AGEs. The environmental source of AGEs can be reduced by dietary modifications.

PCOS: Inflammation and infection

Growing evidence supports the concept that PCOS is associated with increased oxidative stress and systemic inflammation. When compared to healthy control subjects, women with PCOS have increased markers of lipid peroxidation, elevated levels of c -reactive protein, inflammatory cytokines, as well as higher concentrations of blood lymphocytes and monocytes 68 , 69 . However, the cause/causes of these alterations have not yet been identified. This suggests a new hypothesis that chronic infections may be involved in the etiology of PCOS; such chronic infections may induce inflammation and oxidative stress, which in turn may contribute to insulin resistance, ovarian dysfunction and other alterations characteristic of PCOS. In support of this concept, there is evidence that PCOS is associated with greater risk of exposure to intracellular pathogens capable of inducing long-term inflammation including Chlamydia pneumonia and Chlamydia trachomatis 70 . A correlation between Chlamydia pneumonia and insulin resistance has also been observed 71 . Furthermore, Chlamydia pneumonia infection in mice resulted in increased ovarian size and a greater number of antral follicles 71 .

Long Term Outcomes in PCOS: Vascular Disease

The higher sex-specific coronary mortality observed in women compared with men, combined with a greater proportion of women in the population, has resulted in relatively more women dying of cardiovascular disease (CVD) each year than men. 72

Endogenous sex hormones including estrogen are hypothesized as the primary reason for the lower incidence of CVD among normal ovulatory premenopausal women compared with age-matched men and the subsequent age-related rise in women postmenopausally. 73 Moreover, there is a clear evidence from a large number of clinical studies that women with PCOS have a higher prevalence of classical and non classical risk factors, which are strictly related to the presence of insulin resistance, excess body fat, and low-grade inflammation, other than PCOS status per se . 74 However, despite risk factor clustering, studies published to date have failed to demonstrate a uniform association between PCOS and CV disease. 75 , 76 An apparent lack of association between PCOS and CVD may be due to inadequate PCOS characterization, inadequate CVD measurement, insufficient duration of follow-up, or a true lack of association. A recent study tested the hypothesis that women with clinical features of PCOS more often had angiographic coronary artery disease and CVD events in a carefully characterized group of postmenopausal women in USA. 77 This study confirmed that clinical features of PCOS were associated with more angiographic coronary heart disease (CHD) and worsening cardiovascular event-free servival, which suggests that the identification of postmenopausal women with clinical features of PCOS may provide an opportunity for risk factor intervention for the prevention of CAD and CVD events. However, this still require much more intensive reasearch and, possibly, longitudinal prospective studies.

Potential areas of further research activity include the analysis of predisposing conditions that increase the risk of PCOS, particularly genetic background and environmental factors, such as endocrine disruptors and diet 78 . In addition, defining alterations of steroidogenesis in PCOS needs to be re-examined to quantify ovarian, adrenal and extraglandular contribution, as well as a change in the blood androgen reference values due to the expanding use of mass spectrometry. Clearly identifying premenarchal and postmenopausal phenotypes of androgen excess and PCOS would significantly enhance our epidemiologic studies of natural history and intervention studies. Intraovarian regulation of follicle development and mechanisms of follicle arrest and the impact of metabolic abnormalities on these processes, as well as molecular mechanisms by which insulin excess regulates androgen secretion and metabolism and disrupts follicle development 79 are other potential issues for investigation. Current information would suggest androgens alone may be necessary but not sufficient to cause follicular arrest, and it is likely that other inhibitors and non-steroid directed pathways are implicated in follicular arrest. Future studies should utilize both existing cell culture and animal models discussed above, but also utilize ovarian follicles grown and matured in 3-D matrices or created out of stem cells.

The concept that androgen excess may be responsible for the development of insulin resistance also needs to be re-examined, since studies performed in the last decade in experimental animals have supported the hypothesis that early exposure to modest androgen excess may favor the development of insulin resistance and enlarged visceral adiposity, although available data in humans are still sparse and controversial 80 and preliminary prospective data in humans seem to not support this hypothesis 81 . There have been a number of recent well designed adequately powered trials examining infertility treatment in women with PCOS. While this is a positive development, it is only a start. PCOS status is expected to lead to many long-term consequences in women, specifically the development of type 2 diabetes, cardiovascular diseases and hormone dependent cancers. Identifying susceptible individuals would help to individualize therapeutic and, possibly, preventive strategies.

Is there a Broad Experimental Approach to PCOS?

Though it was beyond the scope of our meeting to formulate a unifying experimental approach to better understanding and treating polycystic ovary syndrome, the close interaction of basic and clinical scientists allowed speculation on future directions for research. The utilization of discovery “Omic” technologies should identify new and unsuspected proteins and metabolic pathways that could lead to new treatments for the disorder. A recent mathematical review of microarray data in women with PCOS identified 504 protein nodes and 1048 interactions among them, and theorized that there was a cell cycle protein in this network yet to be identified. 82

Several Genome Wide Association Studies (GWAS) devoted soley to PCOS are ongoing in the U.S., Europe and Asia, and should yield new candidate genes and proteins as intriguing (or baffling) as those discovered in other complex disorders such as type 2 diabetes. As discussed above a number of existing cell culture and animal models exist to identify pathways, pathophysiological perturbances, and interventions that normalize signal transduction in these pathways. These in turn may eventually be tested in randomized trials large and small in affected women with PCOS. Thus there is a potential beneficial cycle of bed to bench to bed studies ( Figure 1 ).

Acknowledgments

Acknowledgement of Financial Support: Supported in part by U54 HD034449; U10 HD 38992, R01HD056510.

Participation in the PCOS Forum was self-funded without industry support. We would also like to acknowledge the contributions of members of the group who participated in the meeting and discussions: Andrea Dunaif, M.D., Anuja Dokras, M.D., R. Jeffrey Chang, M.D., John C. Marshall, M.D., Ph.D., John E. Nestler, M.D. Robert J. Norman, M.D., Eva Dahlgren, M.D. and Silva Arslanian, M.D.

Financial Disclosure: None

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Causal relationships exist between polycystic ovary syndrome and adverse pregnancy and perinatal outcomes: a Mendelian randomization study

Affiliations.

• 1 Reproductive Medicine Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
• 2 The Key Laboratory for Reproductive Medicine of Guangdong Province, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
• 3 Guangdong Provincial Clinical Research Center for obstetrical and gynecological diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
• 4 Department of Neurology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
• 5 Reproductive Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
• 6 Department of Pulmonary and Critical Care Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
• PMID: 39006363
• PMCID: PMC11239544
• DOI: 10.3389/fendo.2024.1327849

Introduction: Previous observational studies have shown that polycystic ovary syndrome (PCOS) was associated with adverse pregnancy and perinatal outcomes. However, it remains controversial whether PCOS is an essential risk factor for these adverse pregnancy and perinatal outcomes. We aimed to use instrumental variables in a two-sample Mendelian randomization (MR) study to determine causality between PCOS and adverse pregnancy and perinatal outcomes.

Materials and methods: Summary statistics were extracted from a recent genome-wide association study (GWAS) meta-analysis conducted in PCOS, which included 10,074 cases and 103,164 controls of European ancestry. Data on Adverse pregnancy and perinatal outcomes were summarized from the FinnGen database of European ancestry, which included more than 180,000 samples. The inverse variance weighted (IVW) method of MR was applied for the main outcome. To assess heterogeneity and pleiotropy, we conducted sensitivity analyses, including leave-one-out analysis, weighted median, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier), and MR-Egger regression.

Results: Two-sample MR analysis with the IVW method suggested that PCOS exerted causal effects on the risk of hypertensive disorders of pregnancy [odds ratio (OR) 1.170, 95% confidence interval (CI) 1.051-1.302, p = 0.004], in particular gestational hypertension (OR 1.083, 95% CI 1.007-1.164, p = 0.031), but not other pregnancy and perinatal diseases (all p > 0.05). Sensitivity analyses demonstrated pleiotropy only in pre-eclampsia or eclampsia ( p = 0.0004), but not in other pregnancy and perinatal diseases (all p > 0.05). The results remained consistent after excluding two outliers (all p > 0.05).

Conclusions: We confirmed a causal relationship between PCOS and hypertensive disorders of pregnancy, in particular gestational hypertension, but no association with any other adverse pregnancy or perinatal outcome. Therefore, we suggest that women with PCOS who are pregnant should have their blood pressure closely monitored.

Keywords: Mendelian randomization; adverse pregnancy and perinatal outcomes; genetic role; gestational hypertension; hypertensive disorders of pregnancy; polycystic ovary syndrome.

Copyright © 2024 Ma, Cai, Liu, Wen, Huang, Hou, Wei, Xu, Xu, Wang and Mai.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Workflow of MR study revealing…

Workflow of MR study revealing causality from PCOS on adverse pregnancy and perinatal…

Odds ratio plot for PCOS…

Odds ratio plot for PCOS and adverse pregnancy and perinatal outcomes. OR, odds…

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