Where Are We in Understanding the Natural History of Polycystic Ovary Syndrome?

A Systematic Review of Longitudinal Cohort Studies

Sylvia Kiconco; Chau Thien Tay; Kate Louise Rassie; Ricardo Azziz; Helena J. Teede; Anju E. Joham


Hum Reprod. 2022;37(6):1255-1273. 

In This Article

Abstract and Introduction


Study Question: What is the natural history of reproductive, psychological and oncological features in women with polycystic ovary syndrome (PCOS) in comparison to those without PCOS across the life course?

Summary Answer: Existing longitudinal data on changes in reproductive, psychological and oncological features in PCOS are inadequate and conflicting, but the limited evidence suggests that total testosterone (T) and dehydroepiandrosterone sulphate (DHEAS) levels decline more significantly in women with PCOS than in those without PCOS, and the risk of gestational diabetes is higher in pregnant women with PCOS compared to their counterparts without PCOS.

What is Known Already: The progression of reproductive, psychological and oncological features in PCOS remains unclear, which limits prevention and early diagnosis strategies across the lifespan. Understanding the natural history of PCOS is one of the overarching priorities in PCOS research.

Study Design, Size, Duration: This is a systematic review of longitudinal cohort studies with a narrative presentation of findings. Databases MEDLINE, EMBASE, Ovid PsycInfo, CINAHL PLUS and EBM reviews were searched between 15 January 2020 and 11 February 2021 with no language restrictions. Only studies published from the year 1990 to February 2021 were included.

Participants/Materials, Setting, Methods: In line with current guidelines for the assessment and management of PCOS, we included studies where participants were females with PCOS diagnosed according to the 2003 Rotterdam or the 1990 National Institutes of Health (NIH) consensus criteria.

Main Results and the Role of Chance: A total of 21 longitudinal studies including 62 123 participants over four continents reported reproductive, psychological and/or oncological outcomes. Participants were females aged between 15 and 49 years at baseline, with follow-up periods ranging from 4 weeks to 32 years. Consistent evidence based on limited studies suggests that total T and DHEAS levels decline to a greater degree in women with PCOS compared to those without PCOS, and the risk gestational diabetes is higher in women with PCOS than in those without PCOS. Evidence reporting changes over time in the majority of the remaining outcomes was unclear due to conflicting and/or insufficient information.

Limitations, Reasons for Caution: There was extreme heterogeneity between studies in terms of study setting, population characteristics, follow-up period, effect measures used and laboratory testing approaches.

Wider Implications of the Findings: Understanding the natural history of PCOS and changes in diagnostic, reproductive, psychological and oncological features of PCOS across the lifespan is still a challenge and the existing literature is both limited and conflicting. It is important that future long-term prospective longitudinal studies are conducted in unselected and well-characterized populations.

Study Funding/Competing Interest(S): This specific study was not funded. S.K. is supported by scholarships from the Research Training Program of the Commonwealth of Australia and Monash University; H.J.T. is supported by an Australian National Health and Medical Research Council fellowship; and A.E.J. is supported by the Australian National Health and Medical Research Council's Centre for Research Excellence in Women's Health in Reproductive Life. R.A. was employed by the American Society for Reproductive Medicine and is a consultant to Spruce Biosciences and Fortress Biotech. The other authors have no conflicts of interest to declare.

Registration Number: Prospero registration number: CRD42020165546.


Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder diagnosed in adults based on the presence of at least two of three clinical features, including polycystic ovary morphology, oligo/amenorrhea and hyperandrogenism (clinical and/or biochemical). PCOS is a major public health issue that affects 5–15% women of reproductive age globally (Azziz et al., 2006; Diamanti-Kandarakis et al., 2006; March et al., 2010; Bozdag et al., 2016) but is complicated by diagnostic challenges including a lack of clear definitions for individual PCOS features. These contribute to misdiagnosis, delayed diagnosis and patient dissatisfaction (Dokras et al., 2017; Gibson-Helm et al., 2017), and up to 70% of women with the condition remain undiagnosed (March et al., 2010). The lack of information on changes in biochemical and clinical hyperandrogenism, cycle regularity and ovarian morphology, including the PCOS phenotype over the lifespan, also complicates diagnosis and warrants further investigation.

Women with PCOS are at increased risk of adverse reproductive, metabolic and psychological outcomes. Common reproductive features of the condition include biochemical hyperandrogenism, ovulatory and menstrual dysfunction, hirsutism, subfertility, endometrial hyperplasia and obstetrical complications (Teede et al., 2018a,b). Women with PCOS are also at a higher risk of infertility or reduced fertility than those without PCOS, which may be driven by changes in oocyte, endometrial and embryo function (Palomba, 2021). Metabolic features include increased risks for insulin resistance, dyslipidemia, impaired glucose tolerance, metabolic syndrome, gestational diabetes, type 2 diabetes and cardiovascular disease (Legro et al., 1999; Apridonidze et al., 2005). Psychological features include anxiety, depression, low self-esteem and poor body image (Moran et al., 2010; Teede et al., 2010; Deeks et al., 2011). Increased endometrial cancer risk has also been associated with PCOS (Charalampakis et al., 2016). These diverse PCOS features lead to a diminished quality of life in affected women (Dokras et al., 2018; Teede et al., 2018a,b). Overall, PCOS is associated with a substantial economic burden, conservatively estimated to exceed an annual total cost of $8 billion USD in the USA alone (2020 USD), including healthcare costs related to diagnosis, reproductive, metabolic, vascular and pregnancy-related morbidities (Riestenberg et al., 2022).

The recent international evidence-based guideline for the Diagnosis and Management of PCOS (Teede et al., 2018b) highlighted our limited understanding of the natural history of reproductive, psychological and oncological outcomes in PCOS and identified major gaps that currently limit the development of effective prevention strategies across the lifespan. Furthermore, understanding the natural history of PCOS emerged from the guideline process as one of the overarching priorities in PCOS research. Therefore, we now aim to explore the natural history of PCOS with a focus on reproductive and psychologic features as well as cancer risk, by conducting a systematic review of longitudinal cohort studies.