s41572-024-00511-3

nature reviews disease primers https://doi.org/10.
1038/s41572-024-00511-3
Primer Check for updates
Polycystic ovary syndrome

Elisabet Stener-Victorin 1 , Helena Teede2, Robert J. Norman3, Richard Legro4,5, Mark O. Goodarzi 6
, Anuja Dokras7,
Joop Laven8, Kathleen Hoeger9 & Terhi T. Piltonen10
Abstract Sections
Despite affecting ~11–13% of women globally, polycystic ovary syndrome Introduction
(PCOS) is a substantially understudied condition. PCOS, possibly Epidemiology

extending to men’s health, imposes a considerable health and economic Mechanisms/pathophysiology
burden worldwide. Diagnosis in adults follows the International
Diagnosis, screening and
Evidence-based Guideline for the Assessment and Management of prevention
Polycystic Ovary Syndrome, requiring two out of three criteria — clinical
Management
or biochemical hyperandrogenism, ovulatory dysfunction, and/or
Quality of life
specific ovarian morphological characteristics or elevated anti-Müllerian
hormone. However, diagnosing adolescents omits ovarian morphology Outlook
and anti-Müllerian hormone considerations. PCOS, marked by insulin

resistance and hyperandrogenism, strongly contributes to early-onset
type 2 diabetes, with increased odds for cardiovascular diseases.
Reproduction-related implications include irregular menstrual cycles,
anovulatory infertility, heightened risks of pregnancy complications
and endometrial cancer. Beyond physiological manifestations, PCOS
is associated with anxiety, depression, eating disorders, psychosexual
dysfunction and negative body image, collectively contributing to
diminished health-related quality of life in patients. Despite its high
prevalence persisting into menopause, diagnosing PCOS often involves
extended timelines and multiple health-care visits. Treatment remains
ad hoc owing to limited understanding of underlying mechanisms,
highlighting the need for research delineating the aetiology and
pathophysiology of the syndrome. Identifying factors contributing
to PCOS will pave the way for personalized medicine approaches.
Additionally, exploring novel biomarkers, refining diagnostic criteria
and advancing treatment modalities will be crucial in enhancing the
precision and efficacy of interventions that will positively impact
the lives of patients.
A full list of affiliations appears at the end of the paper. e-mail: [email protected]
Nature Reviews Disease Primers | (2024) 10:27 1

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Introduction years and several different doctor visits before diagnosis18. Moreover,
Polycystic ovary syndrome (PCOS) is a complex hormonal condition the treatment of PCOS is often ad hoc and is hampered by the lack of
characterized by signs of elevated androgens, irregular menstrua- knowledge regarding the aetiology and underlying mechanisms of the
tion and polycystic ovaries. PCOS is an understudied yet major health syndrome. We do know that hyperandrogenaemia and hyperinsulinae-
threat for women and, possibly, for men (Box 1). Worldwide, ~11–13% mia have key pathogenetic roles and that PCOS runs in families, with
of women suffer from PCOS1, resulting in a substantial health and an estimated heritability of 70%6,19,20. However, how PCOS is inherited
economic burden globally2–4. remains unclear; increasing evidence suggests that genetic and epi-
Based on the International Evidence-based Guideline for the genetic mechanisms act in concert to lead to a complex trait such as
Assessment and Management of Polycystic Ovary Syndrome1, PCOS PCOS, similar to T2DM21.
diagnosis in adults requires at least two of the following three criteria — The prevalence of anxiety and depression is increased in women
clinical hyperandrogenism and/or biochemical hyperandrogenism with PCOS, with increased eating disorders, psychosexual dysfunction
with elevated total testosterone, free androgen index, or bioavailable and negative body image likely contributing to the severity of depres-
testosterone; ovulatory dysfunction with irregular or absent men- sion and anxiety. Overall, the clinical features, together with these
strual cycles; or polycystic ovaries with multiple small antral follicles associated complications, contribute to poor health-related quality
and/or enlarged ovaries and/or elevated anti-Müllerian hormone (AMH) of life (HRQoL) in patients22–24.
levels1. In adolescents, a definitive diagnosis requires hyperandrogen- In this Primer, we highlight the latest advances related to diagno-
ism and irregular cycles but does not include ovarian morphology or sis, prevalence, associated comorbidities and current management
AMH levels as they are a normal part of development in adolescents. of PCOS. In addition, we identify knowledge gaps in the underlying
PCOS, hyperandrogenism and insulin resistance are strong con- aetiology, pathophysiology and associated comorbidities of PCOS
tributors to the development of early-onset type 2 diabetes mellitus to guide future research to improve diagnosis and screening and to
(T2DM)5,6, with preceding hyperinsulinaemia and insulin resistance7. develop preventive and novel therapeutic strategies.
The prevalence of cardiometabolic risk factors, including excess
weight, impaired glucose tolerance, T2DM, dyslipidaemia, hyperten- Epidemiology
sion and metabolic syndrome8–11, are consistently higher in women Prevalence
with PCOS, likely contributing to the increased odds for cardiovascular Being the most common lifelong endocrinopathy in women, the criteria
disease, including ischaemic heart disease, myocardial infarction, to diagnose PCOS has evolved from being a consensus Rotterdam cri-
stroke and, potentially, cardiovascular mortality12–14. teria25 to an evidence-based guideline criteria1. However, controversy
In individuals of reproductive age, PCOS is the most common surrounds the inclusion of polycystic ovarian morphology (PCOM) in
cause of irregular menstrual cycles and anovulatory infertility1. More- diagnostic criteria and relates to the lack of specificity of PCOM, the con-
over, PCOS causes considerably increased but poorly appreciated tinuum of follicle counts without a clear delineating cut point, changes
pregnancy complications, including early miscarriage1, gestational with age, methodological limitations with evolving technologies,
diabetes, hypertension and pre-eclampsia, and is associated with a and challenges with reporting26.
markedly increased risk of endometrial cancer15–17. Based on the Rotterdam criteria, population-based studies indi-
Despite the high prevalence of PCOS, with hyperandrogenism cate a prevalence of 14–19%27,28, although studies from the 2000s pro-
and hyperinsulinaemia persisting even after menopause13, it can take vided prevalence estimates of 10–13%24. Moreover, individuals with
Box 1
Male phenotype of PCOS

Although studies implicate that a male equivalent of polycystic dysfunction, suggestive of latent insulin resistance295. Moreover,
ovary syndrome (PCOS) exists, especially among men with a mother brothers of women with PCOS have increased anti-Müllerian hormone
and/or sister with the syndrome, no diagnostic criteria are available. levels, altered gonadotrophin and steroidogenic secretion296,297, and a
Furthermore, the mechanisms causing observed endocrine and metabolic phenotype characterized by dyslipidaemia, insulin resistance
metabolic alterations in men are unclear291. The early onset of and pancreatic β-cell dysfunction as well as an increased cardiovascular
androgenic alopecia (before 35 years of age) has been observed disease risk298–301. Current evidence indicates that genetic risk factors for
in men with a family history of PCOS292. Moreover, men with early PCOS contribute to an increased likelihood of obesity, type 2 diabetes
androgenic alopecia exhibit elevated circulating testosterone, mellitus, cardiovascular disease and androgenic alopecia in men96,
dehydroepiandrosterone sulfate, and luteinizing hormone and aligning with earlier observations of familial clustering of the metabolic
decreased follicle-stimulating hormone and sex hormone-binding phenotype in brothers of women with PCOS302.
globulin levels293. Reduced levels of follicle-stimulating hormone and Although genetic components likely play a role in the male
sex hormone-binding globulin may be potentially linked to insulin PCOS phenotype, clinical observations suggest that maternal
resistance294 — features equivalent to those in women with PCOS. obesity and PCOS may also impact the development of male fetuses,
Consistent with these findings, sons of women with PCOS predisposing them to reproductive and metabolic disorders later in
have greater obesity than sons of women without PCOS with lipid life, as observed in their female siblings106,109.

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Life course in women with PCOS

Adolescence Reproductive age Premenopause Postmenopause
• PCOS symptoms • PCOS symptoms • PCOS symptoms mitigate

• Increasing BMI • Subfertility but still present
• Psychological burden • Pregnancy complications • Higher BMI and metabolic burden
• Adverse pregnancy-related outcomes • Psychological burden
• Higher BMI and metabolic burden • Other health conditions accumulate
• Psychological burden
• Other health conditions start accumulating
Fig. 1 | Life course in women with PCOS. Illustration of life course trajectory of polycystic ovary syndrome (PCOS), from adolescence to postmenopause.
PCOS exhibit geographic and ethnic variability in symptom presenta- for overweight and obesity apply to Asian populations, warranting
tion, for example, Hispanic and African American people with PCOS consideration when making cross-ethnic comparisons42.
have greater insulin resistance than other ethnicities29,30. AMH levels
have been shown to correlate with PCOM and are now recommended Hyperandrogenism. Epidemiological data indicates that 40–80% of
in international guidelines for adult PCOS diagnosis with moderate women with PCOS exhibit hyperandrogenism24. The clinical manifes-
evidence certainty26,28. However, AMH levels have limitations similar tations of hyperandrogenism vary depending on ethnicity, obesity
to PCOM, with a lack of clear cut-off points for PCOS, changes with age, and age. Hirsutism (excess hair growth) affects ~70–80% of patients
variable assays, and challenges in reporting owing to a lack of global compared with 13% (range 8–20%) in the general population, with
standards and limited evidence across those of different ancestry. geographic variations24. Acne prevalence is ~43% (95% CI 41–45%) in
Obesity exacerbates endocrine abnormalities and symptoms in individuals with PCOS compared with 21% (95% CI 19–22%) in those
individuals with PCOS30,31 and increases prevalence32. Moreover, one without PCOS, with a higher rate of acne in adolescents than in adults
Chinese study suggests that the prevalence of PCOS increases with age, or those with hyperandrogenic PCOS, with some geographic varia-
being ~10% in adolescents between 10 and 20 years of age and 17% in tion43. Female pattern hair loss prevalence is estimated at 28% (95%
women 21–30 years of age29. Two population-based studies have also CI 22–34%) in women with PCOS44. Importantly, these manifestations
reported such high prevalence in adulthood27,28. Owing to the decline in are associated with substantial psychological distress, emphasizing
ovarian reserve and androgen levels towards menopause, the number the need for comprehensive treatment of women with the syndrome45.
of women presenting with PCOS symptoms or findings diminishes,
thereby lowering the prevalence of the syndrome with increasing Metabolic dysfunction. Approximately 50–80% of women with PCOS
age33. However, given that irregular menstrual cycles and PCOM are exhibit insulin resistance46,47. These individuals face an elevated risk
physiological in adolescents, evidence and guidelines recommend of pre-diabetes and up to fourfold increased risk for T2DM, with the
not including these features in adolescents to avoid overdiagnosis. condition developing at an earlier age than in women without PCOS35.
Although the underlying syndrome persists, ageing women with PCOS Although T2DM risk is increased in individuals with PCOS regardless
may eventually get increasingly regular cycles and PCOM is lost, making of BMI, variations in risk for insulin resistance and T2DM are noted in
diagnosis challenging in older women (>50 years of age)29. However, individuals with different BMI, geographical locations and ethnicities41,48.
long-term data suggests that PCOS-related comorbidity persists to
perimenopausal years and beyond34,35. Hence, PCOS prevalence in Cardiovascular disease. Current analyses have strengthened the evi-
fertile age likely reflects the true overall prevalence (Fig. 1). dence for increased risk for different cardiovascular disease outcomes
in individuals with PCOS13,49. Large data sets now indicate potentially
Comorbidities increased risk for major cardiovascular end points12,35, including myo-
Obesity. Obesity is a common comorbidity in PCOS, affecting 20–80% cardial infarction, stroke, heart failure and cardiovascular mortal-
of patients, where clinical cohorts tend to capture those with higher ity12,35,50. The analysis showed the hazard ratio (HR) for the composite
weight than non-selected populations26,31,36. In population-based stud- end point (that is, when combining two or more end points of interest
ies, clinical measures of obesity include BMI, waist circumference and within a single variable) of 1.26 (95% CI 1.13–1.41) in a UK data set and
waist-to-hip ratio37. Many of these indicators are elevated in PCOS, 2.33 (1.26–4.30, Rotterdam criteria) and 2.47 (1.18–5.17, NIH criteria)
although no optimal indicator has been established38. The develop- in population-based data from Finland35. Importantly, this risk seems
ment of overweight in PCOS starts early, possibly before 5 years of age, to accumulate at a relatively young age (~30–35 years onwards), even
supporting early onset of the syndrome39. Weight gain is particularly before menopause. Although the absolute risk is low as the populations
pronounced from puberty to adulthood, for example, 11% of individuals assessed have been relatively young (in most studies, women were
with PCOS have exhibited a high BMI trajectory, compared with 6.6% in aged <55 years), evidence from systematic reviews resulted in updated
controls without PCOS, resulting in a +2.6 kg difference over a 10-year guideline recommendations, which call for regular screening and early
follow-up31,40. However, the weight gap narrows towards menopause, prevention as well as research conducted in women in postmenopause1.
as women without PCOS also gain weight. Ethnic differences exist in
terms of weight gain associated with PCOS. For instance, American Metabolic dysfunction-associated steatotic liver disease. Studies
Hispanic people, African Americans and South Pacific Islanders show have demonstrated a close link between PCOS and major risk factors
the highest weight, whereas Europeans and South or East Asians have for the development of liver disease, including obesity, dyslipidaemia,
low BMIs but more central obesity41. Of note, different BMI cut-offs insulin resistance, cardiovascular disease and hyperandrogenism51.

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One meta-analysis indicates a 43% increased prevalence of meta- from some studies suggest an increased risk of ovarian cancer, although
bolic dysfunction-associated steatotic liver disease (MASLD)52 cervical cancer risk seems unaffected68,69.
(95% CI 35–52%) in women with PCOS53. Further analyses show that the
increased MASLD prevalence in these women could potentially be medi- Postmenopause, long-term morbidity and mortality. PCOS emerges
ated by a high prevalence of metabolic syndrome, elevated homeostatic as a risk factor for multimorbidity and chronic medication use, even
model assessment of insulin resistance (HOMA-IR), free androgen index at postmenopause34,63. Although gynaecological manifestations of
and circulating testosterone53. Although MASLD is highly prevalent in PCOS decline with age, metabolic issues and psychological distress,
relatively young women with PCOS, absolute risk is still low and evidence especially depressive symptoms, persist13,45,70. Studies also reveal an
is yet not strong enough to justify screening. Thus, further research into increase in major adverse cardiovascular end points like myocardial
underlying aetiology and pathophysiology is needed. infarction, stroke, heart failure and cardiovascular mortality beyond
menopause12,35,49,71, and hyperandrogenic status, at any point, seems
Infertility. Infertility risk is 15 times higher in women with PCOS than to drive metabolic morbidity risks14.
in women without PCOS54,55, yet the likelihood of having at least one Mortality data in PCOS is mixed72–74, but a large register study
child is similar between both groups of women56. Counselling should reports increased overall mortality in PCOS50, with contributions from
emphasize the potential for pregnancy, though it may take time, often cardiovascular outcomes and endometrial cancer.
requiring fertility treatments, especially in individuals with excess
weight or obesity54,55,57. Spontaneous ovulation can occur, necessitating Mechanisms/pathophysiology
contraception if pregnancy is not desired. As women with PCOS reach Genetic factors
~35–40 years of age, regular cycles and possible ovulation can emerge, Family and twin studies provide robust evidence for the genetic under-
but the implications for later fertility remain uncertain. pinnings of PCOS75. The correlation for PCOS between monozygotic
twin sisters was twice as high as the correlation in dizygotic twins;
Obstetric complications. Women with PCOS face a twofold to three- heritability of PCOS was estimated at >70% in this twin study76. Early
fold increased risk of pregnancy complications, including miscar- candidate gene research provided limited replicable genetic associa-
riage, pregnancy-induced hypertension, pre-eclampsia, gestational tions77. High-throughput genome-wide association studies (GWAS)
diabetes, prematurity and small-for-gestational-age offspring58. These have advanced our understanding, and initial GWAS in Han Chinese
risks underscore the long-term health implications in daughters and and European women identified 16 loci78–81 (Table 1).
likely also sons born to women with the syndrome. Although gesta- Since then, an international consortium assembled data from
tional diabetes risk is independent of BMI, a higher BMI increases >10,000 PCOS cases and 103,000 controls82. This GWAS meta-analysis
the risk in certain white populations59,60. By contrast, pregnancy- identified 14 loci, of which three (MAPRE1, ZBTB16 and PLGRKT) were
induced hypertension and pre-eclampsia seem to have stronger, novel. Regardless of diagnostic criteria (NIH, Rotterdam or self-reported
BMI-independent effects58. (hyperandrogenism and irregular cycles)), 13 of the 14 loci were consist-
ently associated with PCOS. Subsequent GWAS in electronic health
Psychological disorders. PCOS is associated with a high prevalence record-linked biobanks identified one locus (SOD2)83. In Northern
of mental health disorders. Independent of obesity, diagnostic crite- Europeans, two independent rare variants in CHEK2 and a common
ria or geographical region, 36.6% of women with PCOS present with variant in MYO10 were identified84. Overall, several genes near loci
moderate-to-severe depressive symptoms and 41.8% present with anxi- discovered by GWAS implicate neuroendocrine (FSHR, LHCGR and
ety symptoms compared with 13.2% and 8.5%, respectively, in con- FSHB) and metabolic dysfunction (INSR, THADA and HMGA2) in the
trols8. Adolescents also have higher odds of depression (OR 2.26, 95% pathogenesis of PCOS, whereas the role of other genes remains to be
CI 1.36–3.76) than controls, although evidence is limited for anxi- identified. Of note, although loci are named based on genes in the vicin-
ety symptoms according to the updated evidence-based guideline24. ity, functional studies are needed to establish the effector gene at each
Nevertheless, a systematic review and meta-analysis demonstrated locus. Studies in ovarian theca cells suggest that PA2G4 and ZNF217 may
that symptoms of both anxiety and depression are more prevalent be the effector genes at the 12q13.2 and 20q13.2 loci, respectively, and
amongst adolescents with PCOS than amongst adolescents without could be a potential target for the treatment of ovarian dysfunction85,86.
PCOS23. Moreover, the perinatal and postpartum periods may present Large-scale GWAS results have enabled Mendelian randomization
an additional risk for depression61. Individuals with PCOS also have analyses to examine causality between PCOS and other phenotypes87.
increased odds of binge eating disorder (OR 1.53, 95% CI 1.29–1.82)24. Mendelian randomization utilizes genetic variants associated with
PCOS-specific features that impact feminine identities, such as excess an exposure to assess the causality of an exposure with an outcome
weight, hirsutism and acne, lead to increased body image distress, without being affected by confounders that influence epidemiological
reduced sexual function and decreased sexual satisfaction24,62. Impor- studies. Mendelian randomization has suggested that high BMI79,82,88–90,
tantly, body image distress may be a mediator of anxiety and depressive insulin resistance79, increased fasting insulin5 and reduced levels of
symptoms in individuals with PCOS61. sex hormone-binding globulin (SHBG)6,79 may cause PCOS. However,
another Mendelian randomization analysis did not find a causal role
Cancer. PCOS is associated with a twofold overall increased risk for PCOS in T2DM, coronary heart disease or stroke, suggesting that
for cancer63, with the strongest evidence supporting elevated endome- PCOS and cardiometabolic disease share common underpinnings (for
trial cancer risk (fivefold) owing to anovulation, progesterone resis example, obesity) rather than a causal relationship91. Moreover, PCOS
tance, hyperinsulinaemia, overweight and low-grade inflammation15,64,65. seems to be associated with genetic variants that postpone menopause
Although Mendelian randomization analyses have linked PCOS to in women79,82. Conversely, PCOS may increase the incidence of oestro-
breast cancer66,67, clinical evidence is lacking13,68. Possible protective gen receptor-positive breast cancer66,67 and decrease endometrioid
effects of anovulation on breast tissue have not been studied. Findings ovarian cancer92.

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The existence of PCOS subtypes has been proposed, including Environmental and epigenetic factors
individuals with normal weight but an increased ratio of luteinizing Non-genetic factors may also be involved in the pathophysiology of
hormone to follicle-stimulating hormone (FSH) and individuals with PCOS97 and its inheritance could be attributed to genetic–epigenetic
overweight or obesity with insulin resistance93. A study performed interactions98 (Fig. 2). An aberrant maternal–fetal environment can con-
unsupervised hierarchical cluster analysis of anthropometric, repro- tribute to epigenetic changes, potentially affecting fetal development.
ductive and metabolic traits in 893 individuals with PCOS94 and iden- Such maternal factors could be weight gain during early pregnancy in
tified a distinct ‘reproductive’ cluster with high luteinizing hormone women with PCOS99 and sustained high levels of androgens and AMH
and SHBG levels and a ‘metabolic’ cluster with high BMI, glucose and throughout gestation100, negatively impacting placental aromatase
insulin levels. A GWAS stratified by BMI found shared as well as distinct activity101,102. Although exposure to environmental pollutants, including
genetic architecture in a lean PCOS subtype versus an obesity and over- pharmaceuticals and personal care products, microplastics, endo-
weight PCOS subtype95. Delineating specific subtypes of PCOS in large crine disruptors, and nanoparticles, could potentially increase the
prospective studies, with validation in independent cohorts, offers the risk of PCOS in the offspring, the evidence is still scarce, warranting
potential for precision medicine in PCOS. Notably, one study indicated further research103.
that men with high polygenic risk scores for PCOS had increased risk Consistent with the Developmental Origin of Health and Disease
for developing obesity, T2DM, cardiovascular disease and male-pattern hypothesis104, offspring of mothers with PCOS exhibit elongated
baldness, highlighting the impact of PCOS on both sexes96 (Box 1). anogenital distance, an indicator of in utero androgen exposure105.
Despite progress, the mechanistic details of how genetic variants Daughters have a major risk of developing PCOS themselves, includ-
contribute to PCOS, including the specific genes involved and their ing reproductive and metabolic dysfunction106–108, and sons have an
altered functions, remain unclear. A deeper understanding of these increased likelihood of developing obesity and dyslipidaemia, sug-
mechanisms is crucial for translating genetic discoveries into effective gesting in utero programming108,109 (Box 1). Global DNA methylation
PCOS therapies. patterns in umbilical cord blood from neonates born to mothers with
Table 1 | Findings from GWAS in polycystic ovary syndrome
Locus Index SNP Nearest gene First GWAS report GWAS replication Refs.
2p16.3 (A) rs13405728 LHCGR Chen, 2011 Shi, 2012 78,81

2p16.3 (B) rs2268361 FSHR Shi, 2012 Not applicable 81
2p21 rs13429458 THADA Chen, 2011 Shi, 2012; Day, 2015; Day, 2018 78,79,81,82
2q34 rs1351592 ERBB4 Day, 2015 Day, 2018; Zhang, 2020; Tyrmi, 79,82–84
2022
5p15 rs9312937 MYO10 Tyrmi, 2022 Not applicable 84
5q31.1 rs13164856 IRF1, RAD50 Day, 2015 Day, 2018 79,82
6q25.3 rs17186366 FNDC1, SOD2 Zhang, 2020 Not applicable 83
8p23.1 rs804279 GATA4, NEIL2 Hayes, 2015 Day, 2018 80,82
9p24.1 rs10739076 PLGRKT Day, 2018 Not applicable 82
9q33.3 rs2479106 DENND1A Chen, 2011 Shi, 2012; Day, 2018; Tyrmi, 2022 78,81,82,84
9p24.1 rs4385527 AOPEP, FANCC Shi, 2012 Hayes, 2015; Day, 2018 80–82
9p24.1 rs3802457 AOPEP Shi, 2012 Not applicable 81
11p14.1 rs11031006 FSHB Hayes, 2015 Day, 2015; Day, 2018; Tyrmi, 2022 79,80,82,84
11q22.1 rs1894116 YAP1 Shi, 2012 Day, 2015; Day, 2018 79,81,82
11q23.2 rs1784692 ZBTB16 Day, 2018 Tyrmi, 2022 82,84
12q13.2 rs705702 RAB5B, SUOX Shi, 2012 Day, 2018 81,82
12q14.3 rs2272046 HMGA2 Shi, 2012 Not applicable 81
12q21.2 rs1275468 KRR1 Day, 2015 Day, 2018 79,82
16q21.1 rs4784165 TOX3 Shi, 2012 Day, 2018 81,82
19p13.3 rs2059807 INSR Shi, 2012 Not applicable 81
20q13.2 rs6022786 SUMO1P1 Shi, 2012 Not applicable 81
20q11.21 rs853854 MAPRE1 Day, 2018 Not applicable 82
20q13.2 rs6022786 SUMO1P1 Shi, 2012 Not applicable 81
22q12 rs145598156 CHEK2 Tyrmi, 2022 Not applicable 84
22q12 rs182075939 CHEK2 Tyrmi, 2022 Not applicable 84
The index single-nucleotide polymorphisms (SNPs) listed are those from the first report of each locus. The SNPs in the above table are independent signals. Genome-wide association
study (GWAS) replication indicates reports in which the same variant or a linked variant reached genome-wide significance.

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Fig. 2 | Genetic and epigenetic inheritance

F0 mother Environment of PCOS. The inheritance of polycystic ovary
• Maternal androgen excess
syndrome (PCOS) likely involves genetic,
• Obesity, diet
environmental and epigenetic factors. F0, the
Structural and functional changes mother; F1, first generation (somatic cells and
germ cells); F2, second generation (germ cells).
• Neuroendocrine
F2 germ cells • Behaviour
F1 fetus • Obesity
• Insulin resistance
• Hyperinsulinaemia
• Polycystic ovary
morphology
• Anovulation
• Infertility
Genetics
Epigenetic changes
DNA methylation and RNA
PCOS suggests a unique PCOS-associated epigenetic signature110, variant identified by GWAS, DENND1A78, has been recognized in PCOS as
predisposing them to reproductive, metabolic and neuropsychiatric a significant stimulator of the androgen pathway with several microRNA
disorders97,106,109,111,112. variants also implicated in the pathophysiology117. The ovarian granulosa
Furthermore, studies have demonstrated the persistence of PCOS- cell layer is responsible for the aromatization of androgens to oestrogens
like traits across generations in mice offspring not directly exposed under the influence of FSH, and most patients with PCOS exhibit high
(that is, third generation) to in utero dihydrotestosterone or AMH, sug- circulating levels of androgens, with consequences on multiple organ
gesting epigenetic inheritance106,107,109. Transcriptional and mitochon- systems, including the skin, brain, adipose tissue and liver. Testoster-
drial changes in oocytes106, DNA methylation in ovaries107 and small one and androstenedione are the commonly elevated androgens and
non-coding RNA alterations in sperm109 accompany transgenerational are amplified by the resultant low levels of SHBG, leading to elevated
transmission of reproductive and metabolic phenotypic traits in mice, free androgens accessible to tissue androgen receptors118. Moreover,
suggesting that epigenetic modifications in germ cells may transmit women with PCOS have insulin resistance with hyperinsulinaemia, which
PCOS across multiple generations. Importantly, some of the epigenetic further decreases SHBG production in the liver and synergizes the effect
and transcriptomic signatures are detectable in the serum of daugh- of luteinizing hormone on theca cells, thereby contributing to elevated
ters and sons of women with PCOS, supporting the role of epigenetic circulating levels of androgens119.
inheritance in addition to genetic factors in the syndrome106,107,109.
Ovarian function
Hyperandrogenism The ovary contains many small follicles with oocytes that initially
Elevated adrenal production of dehydroepiandrosterone and dehy- develop under the control of intra-ovarian growth factors and later
droepiandrosterone sulfate, which through circulation reach peripheral under the influence of FSH following the development of appropriate
target tissues and are then converted to oestrogens or androgens, can receptors. Small (<9 mm) antral follicles produce large quantities of
contribute to hyperandrogenism in women with PCOS113,114. However, the AMH (whereas large ones do not), which regulates the passage of fol-
characteristic hyperandrogenism — the primary reproductive pheno- licular growth to preantral, larger follicles in association with androgen
type of PCOS — results from excess ovarian androgen production (Fig. 3). receptors preceding the expression of FSH receptors120 (Fig. 3). High
The theca cells of the ovary are the primary site of production of andros- levels of androgens, AMH and paracrine regulators tend to prevent
tenedione and testosterone and cells isolated from patients with PCOS the spontaneous growth of antral follicles that can ovulate; however,
show an intrinsic increase in androgen production in culture115. In vivo, this blockage can be overcome by exogenous FSH administration dur-
luteinizing hormone and insulin are the primary stimulators of androgen ing fertility treatment. Elevated levels of follistatin and diminished
production in combination with an absolute increase in the number of concentrations of activin A have been proposed to potentially con-
theca cells, which can be a consequence of increased follicle numbers tribute to the arrest of follicular development (that is, not growing
and increased theca cell thickness116. A previously unrecognized gene to >8–10 mm). This interplay may be partly responsible for the lack

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of pre-ovular follicle development in PCOS121. Early luteinization can luteinizing hormone and FSH are influenced by circulating oestra-
also occur under the influence of oestrogens and androgens and early diol, progesterone and leptin125. Kisspeptin neurons regulate GnRH
development of the progesterone receptor prevents normal maturation neurons and play a crucial part in regulating GnRH pulse frequency
of the preantral follicle122. The surrounding ovarian stroma is increased and amplitude126 (Fig. 3). Fast pulse frequencies favour luteinizing
in PCOS and is highly vascularized, partially under the influence of the hormone secretion whereas slow frequencies favour FSH secretion127.
VEGF family, which in turn is upregulated by androgens123. This phenom- In PCOS, an increased pulse frequency of GnRH leads to high levels of
enon likely explains why ovarian hyperstimulation syndrome is more luteinizing hormone in relation to FSH, thereby promoting the concept
common in fertility treatment incorporating the use of exogenous FSH of a higher ratio of luteinizing hormone to FSH in women with PCOS of
than in treatments that do not use FSH. Excess small antral follicles and normal weight than in women without PCOS128. By contrast, women
high AMH can be normal physiological findings in normo-androgenic with PCOS and obesity seem to have a luteinizing hormone-to-FSH ratio
women, especially during adolescence124, suggesting that additional that is less affected. Given the absence of androgen receptors in GnRH
stimuli to the ovary are required to fully develop PCOS. neurons, it is plausible that elevated androgens disrupt the progester-
one-induced negative feedback mechanism via a direct influence on
Gonadotropic derangement kisspeptin neurons126. Moreover, AMH receptors are also expressed in
Gonadotrophin-releasing hormone (GnRH) is secreted in a pulsatile man- the hypothalamus, raising the possibility that circulating levels of this
ner from the hypothalamus to the pituitary gland and concentrations of hormone may influence GnRH pulsatility129. Another feature of PCOS is
Hypothalamus–pituitary–ovarian axis ↑ AMH

Hypothalamus–pituitary–adrenal axis
Hypothalamus Adrenal gland
↑ GnRH
↑ DHEA/DHEAS
↑ Kisspeptin
Circulation
Pituitary gland
↑ LH ↓←→FSH Peripheral conversion →

androgens and oestrogens
Pancreatic islet
Pancreas
Impaired ovarian
steroid feedback
Accumulation of small antral follicles
↑ Insulin
↑ Testosterone ↓←→Oestradiol
Liver
↓ SHBG Theca cell

Granulosa cell
↑ AMH
Fig. 3 | Alterations in the hypothalamic–pituitary–gonadal axis in women amounts of anti-Müllerian hormone (AMH). The function of AMH is to exert an
with PCOS. In women with polycystic ovary syndrome (PCOS), the gonadotropin- inhibitory influence on the initial recruitment of follicles and the FSH-dependent
releasing hormone (GnRH) pulse frequency is elevated, increasing the luteinizing progression and selection of preantral and small antral follicles <9 mm. The
hormone (LH) frequency, whereas follicle-stimulating hormone (FSH) is elevated AMH levels in women with PCOS inhibit the conversion of testosterone
unchanged or slightly reduced. GnRH secretion requires the stimulatory action to oestradiol. Moreover, hyperinsulinaemia stimulates theca cells and suppresses
of kisspeptin, produced by kisspeptin neurons located primarily in the arcuate sex hormone-binding globulin (SHBG) production, further contributing to
nucleus of the hypothalamus. In PCOS, increases in kisspeptin likely trigger hyperandrogenaemia. In addition, the adrenal gland produces excessive amounts
the increased GnRH pulse frequency, leading to increased LH pulse frequency. of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate
LH in turn stimulates theca cells to increase androgen production. Increased (DHEAS), which via circulation reach peripheral organs (for example, adipose
testosterone inhibits follicular growth, leading to the accumulation of many small tissue, skeletal muscle and liver), where they are converted to oestrogens and
antral follicles. Granulosa cells in the small antral follicles produce excessive androgens. Altogether, steroid feedback is impaired.

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a degree of progesterone resistance to GnRH pulsatility, especially dur- insulin-dependent serine phosphorylation of insulin receptors, impair-
ing puberty, which predisposes to ovarian androgen overproduction130. ing insulin signalling in skeletal muscle151, a distinguishing feature not
These neuroendocrine changes in physiology offer opportunities for present in other insulin-resistant conditions like obesity and T2DM152.
lifestyle changes and pharmaceutical interventions to restore normal Skeletal muscle insulin receptor substrate 1 (IRS1) is also increased151,
pituitary function, thereby promoting ovarian follicular progression leading to dysfunctional insulin signalling through the activation of
to ovulation. MAPK pathways153.
Furthermore, patients with PCOS exhibit abnormal DNA methyla-
Endometrial dysfunction tion and gene and protein expression profiles in skeletal muscle154–157.
Endometrial dysfunction occurs in women with PCOS and anovula- These changes activate inflammatory response, lipid, glucose and
tion owing to the absence of the corpus luteum, leading to low pro- fibrotic pathways, contributing to insulin resistance154–157. Addition-
gesterone levels that compromise endometrial health over time131 ally, PCOS-related muscle dysfunction includes a reduction in insulin-
(Fig. 4). Reduced progesterone allows unhampered oestrogen activity, sensitive type I muscle fibres and ectopic lipid accumulation158 as well
increasing the expression of oestrogen receptor-α (ERα) and ERβ, as impaired mitochondrial function154, further aggravating insulin
which promote endometrial cell proliferation132 and hyperandro- resistance (Fig. 5).
genism via increased endometrial androgen receptor expression133. Despite these insights, the precise mechanisms and implications
Hyperinsulinaemia and insulin resistance decrease the expression of of PCOS on skeletal muscle dysfunction require further investigation,
insulin receptor and glucose transporter 4 (GLUT4)134. Importantly, including understanding the roles of specific cell types in driving
studies have shown compromised endometrial function during the insulin resistance.
secretory phase with altered steroid receptor expression and glu-
cose transportation — factors that are known to be involved in delayed Adipose tissue dysfunction
decidualization, impaired placentation, endometrial hyperplasia and Abdominal adipose tissue volume (including subcutaneous fat and
potential carcinogenic processes131,135. Moreover, reduced expression visceral fat), measured with MRI is comparable between women with
of uterine receptivity markers, for example, integrin, HOXA10 and PCOS and those without PCOS, matched for BMI149,159, and androgens
IGFB1, and increased expression of inflammatory factors, such as TNF exert no discernible impact on fat distribution160. Nevertheless, distinc-
and NF-κB, contribute to increased cell proliferation in PCOS134,136,137. tive morphological and functional abnormalities are evident within
However, in analyses of receptivity markers in samples collected in the the adipose tissue of women with PCOS, with dysfunctional adipokine
secretory phase, no discernible differences were observed between secretion resulting in increased circulating leptin and follistatin, and
the endometrium of those with PCOS and that of those without PCOS decreased adiponectin levels161,162.
with similar BMI138. Enlarged adipocytes and decreased adiponectin levels, which are
Despite this finding, global gene expression profiling reveals potent drivers of insulin resistance, are distinct features of PCOS149.
distinct patterns in endometrial stromal cells from women with PCOS Moreover, hyperandrogenism correlates with adipocyte hypertro-
with increased expression of SNCA, CDKN3, and CD58 and decreased phy163, inhibits adipose stem cell commitment to preadipocytes164 and
expression of PIBF1 and MICB139, which are linked to endometrial cancer, hinders their differentiation into mature adipocytes165. In addition,
endometriosis, delayed decidualization and increased inflammation140. differentiated adipocytes from women with PCOS have increased
Moreover, exposing endometrial stromal cells to dihydrotestosterone lipid content than those from women without PCOS, correlating with
disrupts gene expression associated with cell energy metabolism, androgen levels166,167.
proliferation, decidualization and inflammation139. Only few studies PCOS-specific adipose tissue dysfunction extends to impaired
exist on immune cell migration in the PCOS endometrium; however, insulin-stimulated glucose uptake, which is attributed to decreased
the current data suggest some changes even in well-matched samples, GLUT4 expression168,169. Moreover, subcutaneous adipocytes of women
thus warranting future studies141,142. with PCOS with normal weight are resistant to catecholamine-induced
Altogether, these findings underscore the multifaceted effect lipolysis due to a decreased number of β2-adrenergic receptors170,171.
of hormonal and molecular changes in the endometrium of women Together with diminished hormone-sensitive lipase and protein kinase A
with PCOS, potentially predisposing them to adverse reproductive (PKA) regulatory components, altered lipolysis is a possible link to insu-
outcomes such as early spontaneous miscarriage, pre-eclampsia and lin resistance170,172–174 (Fig. 6). Additionally, adipocytes in PCOS exhibit
endometrial cancer143–146. How specific cell types contribute to PCOS- dysfunctional lipid storage, release and energy regulation175,176.
specific endometrial dysfunction remains to be delineated, and these Increased intra-adipose production of testosterone and dihy-
insights will help identify therapeutic targets (Fig. 4). drotestosterone in PCOS via increased expression of androgen-
activating enzyme aldo-ketoreductase 1 C3 (AKR1C3) drives lipid
Insulin resistance accumulation, resulting in systemic lipotoxicity177 with ectopic
Women with PCOS, regardless of age, body composition and BMI, lipid deposition in tissues such as skeletal muscle and liver158, leading
exhibit insulin resistance, characterized by a substantial reduction to insulin resistance. Inflammation, macrophage accumulation, fibrosis
(35–40%) in insulin-stimulated glucose uptake, similar to that observed and adipose tissue expansion further exacerbate insulin resistance in
in individuals with T2DM147–149. This insulin resistance is accompa- PCOS178,179 (Fig. 5).
nied by compensatory hyperinsulinaemia, which strains pancreatic These findings underscore the specificity of adipose tissue dys-
β-cells and reduces hepatic insulin clearance, in turn exacerbating function in women with PCOS. Although various global protein, tran-
hyperinsulinaemia150. scriptional and epigenetic changes may contribute to PCOS-specific
dysfunctions158,180,181, the precise roles of specific cell types within adi-
Skeletal muscle dysfunction. The molecular basis of insulin resist- pose tissue, their molecular functions and inter-tissue communication
ance in PCOS is unique and tissue specific and involves increased are yet to be defined.

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Day of cycle 1 5 10 15 20 25 28
Follicular phase Ovulation Luteal phase
Ovarian cycle
Progesterone
Hormonal cycle
Oestrogen
Window of
Epithelium implantation
Macrophage Stroma
Ovulatory
cycle Endometrial Decidualized
gland stroma
NK cell
Lymphocyte
Functional endometrium
Uterine cycle
Basal endometrium
Myometrium
Menstrual phase Proliferative phase Secretory phase
Follicular phase
Ovarian cycle
Oestrogen
Hormonal cycle
Anovulatory
cycle in PCOS
Functional endometrium
Uterine cycle
Basal endometrium
Myometrium
Proliferation prolonged due to unbroken oestrogen exposure
Fig. 4 | The normal endometrium and the anovulatory endometrium. less stromal cells compared with the normal cycling endometrium. Endometrial
Endometrial development requires follicular maturation in response to ovarian proliferation is linked to increased expression of oestrogen receptor-α (ERα)
steroid hormone secretion (oestradiol and progesterone). In women with and ERβ as well as androgen receptor. Insulin resistance negatively affects
polycystic ovary syndrome (PCOS) and irregular cycles, the endometrium the expression of insulin receptor and glucose transporter 4 (GLUT4).
is exposed to oestrogen without counteracting progesterone action. The NK, natural killer.
endometrium of women with PCOS is characterized by more epithelial cells and
Altered immune function and inflammation circulating cytokines, such as TNF, IL-6, IL-18, MCP1 and high-sensitivity
Comorbidities in PCOS are linked to altered immune function, implying CRP, in women with PCOS183–185, indicating a systemic pro-inflamma-
low-grade inflammation182. Numerous studies have reported elevated tory status. These cytokines may originate from peripheral blood

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leukocytes, with increased levels of lymphocytes, monocytes, natural hyperandrogenaemia. Moreover, increased levels of fibrinogen
killer cells and neutrophils in PCOS186. and plasminogen activator inhibitor 1 (PAI1) suggest a prothrombotic
Cytokines are also produced in specific cells within tissues such state in women with the syndrome195. Together, these alterations
as adipose tissue, endometrium and ovaries. Subcutaneous adipose may contribute to their increased risk of cardiovascular disease and
tissue in women with PCOS shows elevated expression of CD11c and mortality. In addition, cardiovascular dysfunction is associated with
TNF, along with an increased density of crown-like structures, suggest- elevated muscle sympathetic nerve activity196. Of note, women with
ing altered macrophage activity178 and elevated CCR5 in omental fat187; PCOS have increased muscle sympathetic nerve activity independ-
however, another study found no differences in CD68+ macrophage ent of BMI197–199 and exercise. Electrical stimulation and renal den-
density149. The PCOS endometrium exhibits a dysfunctional immune ervation not only decrease muscle sympathetic nerve activity but
profile, with an increased proportion of specific immune cell popula- also improve hyperandrogenism, insulin resistance and hyperten-
tions, including macrophages, and increased expression of markers sion200–204. Yet, whether the mechanisms leading to impaired cardiac
such as TNF, IL-6 and NF-kB136,142, whereas studies on ovarian immune autonomic function in women with PCOS rely on direct or indirect
profile remain inconclusive182. effects of hyperandrogenism, hyperinsulinaemia and insulin resist-
Autoimmune components are implicated in PCOS, with reported ance205, arterial stiffness206, and/or lower baroreflex sensitivity with
autoantibodies targeting the thyroid and GnRH receptor188. Moreover, lower heart rate variability remains to be determined207,208. Understand-
B cell numbers are increased in PCOS, potentially contributing to ing the underlying mechanisms driving increased sympathetic output
increased inflammation and autoantibody production189, although is critical as these could be promising therapeutic targets in women
research suggests that B cells may not be central mediators of PCOS with PCOS.
pathology190.
In summary, PCOS is associated with low-grade inflammation Liver dysfunction
(Fig. 5), but its impact on disease progression and comorbidities Obesity together with impaired glucose metabolism, increased tri-
remains unclear and warrants further investigation. glyceride and cholesterol levels, and hyperandrogenism are major
risk factors for the development of MASLD, a condition where hepato-
Cardiovascular dysfunction cytes accumulate triglycerides owing to macrovesicular steatosis51.
Studies have reported structural alterations, such as increased left In women, high circulating testosterone levels increase lipid storage in
ventricular mass and increased left atrial diameter191, endothelial the liver and contribute to impaired glucose metabolism and develop-
dysfunction192, coronary and aortic calcification193, and increased ment of T2DM51. Moreover, hyperandrogenism in women with PCOS is
intima-media thickness of common carotid and femoral arteries194, linked to reduced hepatic SHBG production, which is suggested to be a
in women with PCOS, especially in those with insulin resistance and biomarker of MASLD in PCOS209. Liver dysfunction plays a central part in
Adipocyte hypertrophy
↑ Androgen production Hyperandrogenism
↑ Macrophage
Insulin resistance
Adipose Muscle
↑ Androgen
production
Liver ↓ SHBG
↓ MASLD
Adipocyte
hypertrophy
→ lipid
spillover and Lipotoxicity
inflammation in metabolic
tissues
Intramuscular
Fibrosis ↓ Adiponectin ↑ Inflammatory ↑ Fatty acids lipid accumulation Hyperinsulinaemia
cytokines ↓ Type I fibre
Fig. 5 | Proposed vicious circuit triggered by hyperandrogenism contributing adipokines such as adiponectin. Moreover, adipocytes cannot store lipids and
to insulin resistance in PCOS. Hyperandrogenism and hyperinsulinaemia a lipid spillover occurs that contributes to lipid accumulation in other tissues,
are two key features of polycystic ovary syndrome (PCOS), driving insulin including liver and skeletal muscle, leading to lipotoxicity. This leads to tissue-
resistance in the adipose tissue, skeletal muscle and liver. The ovaries not specific insulin resistance and tissue crosstalk. MASLD, metabolic dysfunction-
only produce excessive amounts of androgen but also the adipose tissue associated steatotic liver disease; SHBG, sex hormone-binding globulin. Adapted
contributing to adipocyte hypertrophy and infiltration of macrophages leads to from ref. 290.
systemic inflammation with an increased release of cytokines and a decrease in

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5 • ↑ CD11c
Adipocyte
• ↑ TNF ↑ Immune cell infiltration
Fibrosis
• ↑ IL-6 → Inflammation
• ↑ MCP1
Androstenedione
1 ↓ Adiponectin
↑ AKR1C3
Insulin resistance ↑ Testosterone 4

• ↑ Triglycerides Lipotoxicity
• ↑ Glycerol
• ↑ De novo
2 Glucose intolerance lipogenesis
• ↓ β-Oxidation ↓ HSL
• ↓ Lipolysis
↓ Insulin-stimulated
glucose uptake ↓ PKA
→ Hyperinsulinaemia ↓ GLUT4
↓ Catecholamine-induced
sensitivity
↓ β2-Adrenergic receptor
3 ↓ Catecholamine signalling sensitivity
Fig. 6 | Proposed mechanisms of adipose tissue dysfunction in PCOS. receptors as well as to protein kinase A (PKA) resulting in lower phosphorylation
(1) Adipocyte hypertrophy and decreased production and secretion of adiponectin of hormone-sensitive lipase (HSL). (4) Altered lipolysis results in altered lipid
are strong drivers of insulin resistance in polycystic ovary syndrome (PCOS), storage and increases in circulating triglycerides and glycerol, contributing
independent of obesity. However, current knowledge on insulin signalling to lipid accumulation in other tissues and lipotoxicity. (5) Moreover, increased
and lipolysis in subcutaneous adipose tissue in PCOS is limited. (2) Insulin cytokine secretion results in infiltration of immune cells, contributes to
resistance with reduced glucose transporter 4 (GLUT4) translocation and low-grade inflammation and is linked to fibrosis. (6) Finally, specific for PCOS
glucose uptake results in glucose intolerance. Moreover, the lipolysis in is the increased androgen production driven by increased expression of
PCOS adipose tissue is altered in both basal and catecholamine-stimulated androgen-activating enzyme aldo-ketoreductase 1 C3 (AKR1C3), which converts
conditions. (3) Catecholamine signalling sensitivity is reduced and the overall androstenedione to testosterone (and dihydrotestosterone), increasing
lipolytic stimulation in subcutaneous adipocytes is blunted in PCOS. Although de novo lipogenesis and decreasing β-oxidation and lipolysis. This further drives
many steps in the stimulation pathway are not yet explored in PCOS, part of ectopic lipid accumulation, lipotoxicity, fibrosis and insulin resistance. Adapted
the blunted response can be attributed to decreased levels of β2-adrenergic from ref. 37.
regulating the immune system, with accumulation of lipids in the liver critical brain development stages215 can mediate anxiety-like behav-
leading to lipotoxicity, which in turn stresses hepatocytes to generate iour via various factors, for example, ERα, serotonergic signalling,
inflammatory factors triggering the immune system210. Although not GABAergic signalling and activation of adrenoceptor α1B, in the
yet studied, lipotoxicity and MASLD likely trigger the immune system amygdala and hippocampus213,214. In support of preclinical observa-
and contribute to the observed low-grade inflammation in women with tions, maternal PCOS is suggested to be linked to increased autism
PCOS but need further investigation (Fig. 5). spectrum disorder in offspring of either sex216 and an increased risk
of attention-deficit/hyperactivity disorder in boys only217. Epidemio-
Psychological disorders logical studies also suggest associations between maternal PCOS and
The aetiology and pathophysiology of psychiatric disorders in women various psychiatric disorders, such as attention-deficit/hyperactivity
with PCOS likely involve a complex interplay of genetic and environmen- disorder, and autism spectrum disorder in children97,218,219. Moreover,
tal factors98. Twin and familial studies suggest substantial heritability anxiety disorders in mice can be transgenerationally transmitted in
of psychiatric disorders211, and Mendelian randomization analyses both sexes111.
indicate a causal link between PCOS and depression82. However, cur-
rent research has found no genetic correlation between PCOS and Psychosexual dysfunction. Additionally, women with PCOS often
psychiatric disorders212, and the association between depression experience psychosexual dysfunction, which may be related to external
and PCOS weakens when BMI is taken into account, emphasizing the factors such as body image concerns; however, the precise underlying
role of obesity. mechanism remains unknown62,220,221. Of note, adult women with PCOS
Non-genetic factors, such as an adverse maternal–fetal environ- and a mother with the diagnosis display impaired sexual function, indi-
ment owing to elevated androgens, can adversely impact fetal brain cating that maternal PCOS may trigger not only psychiatric disorders
development, leading to anxiety-like behaviour in the offspring111,213,214. but also sexual dysfunction222. Moreover, a preclinical mouse model of
Experimental rodent data indicate that androgen exposure during PCOS suggests a potential link between sexual behaviour impairment

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in female offspring and decreased hypothalamic expression of Screening for PCOS and prevention opportunities can improve
progesterone-sensitive neuronal nitric oxide synthase223. outcomes, including reproductive health (Box 2).
Diagnosis, screening and prevention Management

Diagnosis Metabolic dysfunction
Since the 2000s, PCOS diagnosis has changed as the understanding Lifestyle modification. Lifestyle interventions are a cornerstone in
of the condition has evolved from a crude description of macroscopic managing PCOS, particularly in individuals with excess weight. Modest
ovarian changes to a complex endocrine condition caused by polygenic, reductions in total body weight, as little as 5%, offer metabolic and pos-
epigenetic and environmental factors224. Ultimately, in 2018, building sibly reproductive benefits57,230–232. A meta-analysis of 18 randomized
on the American Society for Reproductive Medicine and the European controlled trials (RCTs) demonstrated that lifestyle interventions
Society of Human Reproduction and Embryology Rotterdam consensus improve various parameters, including waist circumference, waist-
criteria25, an international PCOS network with 40 organizations reach- to-hip ratio, modified Ferriman–Gallwey score (which evaluates hir-
ing across six continents upgraded these criteria from consensus to the sutism), fasting insulin, total cholesterol and LDL cholesterol compared
International Evidence-based Guideline Diagnostic Criteria225 (Fig. 7). with minimal intervention in PCOS24. Although RCTs investigating the
Changes to the International Guideline included a robust develop- effect of lifestyle interventions in the general population suggest a
ment process with patient and health professional groups; comprehen- prevention of T2DM in individuals at risk233, similar trials in PCOS are
sive evidence synthesis and refined individual diagnostic components, yet to be performed. Notably, studies involving lifestyle interventions
including increasing the cut-off for arrested ovarian follicle count resulting in weight loss demonstrated that women with PCOS achieve
(<9 mm) from >12 to ≥20 per ovary and/or the cut-off for enlarged similar weight loss improvements as those without PCOS24.
ovaries to >10 cm3 (ref. 225) (Fig. 7). Separate criteria for adolescents Notably, diet composition, including macronutrient components,
were developed requiring the presence of both oligoanovulation and does not significantly impact weight loss or metabolic outcomes in
hyperandrogenism, excluding ultrasound in the diagnostic criteria of women with PCOS or the general population in RCTs234–236. Currently,
adolescents owing to a lack of specificity for PCOS226. Adolescents ‘at no optimal lifestyle intervention exists for PCOS, with general popu-
risk’ were recognized when one of the two aforementioned features was lation guidelines applicable in this condition, tailored to personal
present, with reassessment recommended once they reach adulthood. preference237. Similarly, intensive exercise interventions alone do
These altered criteria for adolescents were validated in a well-character- not yield superior weight loss or metabolic improvements in PCOS24.
ized longitudinal cohort and dramatically reduced overdiagnosis at this Overall, evidence supporting any specific type or intensity of exercise
life stage227. Diagnosis in adults and adolescents requires biochemical for anthropometric, metabolic, hormonal, reproductive or psycho-
exclusion of thyroid dysfunction, hyperprolactinaemia, congenital logical outcomes is lacking238,239, although engaging in 150 min of
adrenal hyperplasia, primary and secondary ovarian failure, and clini- moderate-to-vigorous exercise per week is recommended for overall
cal exclusion of hypogonadotropic hypogonadism, as well as of other cardiometabolic risk improvement.
less common causes such as adrenal carcinoma or Cushing disease.
The International Guideline is updated every 5 years and, in 2023, Bariatric surgery. In individuals with BMI >35 kg/m2, lifestyle interven-
the evidence in PCOS was reviewed, synthesized, and appraised for tions are not as effective over the long term to maintain improvement
quality and integrity and a 6,000-page technical report was presented in weight and metabolic disease. In the general population, bariatric
with improved evidence certainty and strength of recommendations24. surgery or metabolic surgery has been demonstrated to provide sub-
Diagnostic criteria were expanded to include either ovarian ultrasound stantial and sustainable weight loss with accompanying improve-
or AMH levels in adults only1,24 (Fig. 7). This update is now a living guide- ment in metabolic health240,241. In a non-RCT comparing surgery, oral
line, responsive to the rapidly evolving advances in research, called the contraceptive and metformin management of PCOS, the greatest
‘International Guideline diagnostic criteria’. improvement in metabolic outcomes was observed with surgery, with
Another key advance in knowledge around diagnosis relates to regards to decreased weight, BMI, waist circumference, hip circumfer-
subgroups nested under the umbrella of PCOS. Traditionally defined ence, fasting glucose, fasting insulin, triglycerides, LDL, haemoglobin
as phenotypes A–D, based on Rotterdam diagnostic criteria25,224, these A1c (HbA1c), total testosterone and free androgen index242. In studies
original crude groups do not align to aetiology, genotype or patho- comparing surgical outcomes between women with and without PCOS,
physiology. Exploration of GWAS combined with sophisticated cluster similar improvements were observed in both groups concerning total
analyses in data sets has suggested grouping around core endocrine fea- weight loss, total testosterone, SHBG, AMH, total cholesterol, LDL,
tures across hyperandrogenaemia, hyperinsulinaemia, hypothalamic– triglycerides or HDL242,243, although improvement in fasting glucose
pituitary abnormalities and BMI19,94,224,228. Reproductive, metabolic and levels and BMI post-surgery was greater in women with PCOS than in
indeterminant subgroups have emerged and progress in understanding women without PCOS242,243.
the underlying aetiology and pathophysiology is likely to nuance these
distinctions further, similar to T2DM. T2DM has a similar complex poly- Medical treatment. Although no drugs are approved specifically for
genic aetiology to PCOS and extensive subgroups have been identified, the medical management of metabolic dysfunction in PCOS, met-
including many subtypes of maturity-onset diabetes of the young229 formin, a biguanide used to treat T2DM, has been used extensively in
and proposed subtypes of adult-onset diabetes. the management of PCOS. In RCTs investigating metformin and pla-
Evolving diagnostic criteria and lack of clarity on the subtypes, cebo, metformin significantly improved HOMA-IR and fasting glucose
alongside inadequate health professional education and patient and improved waist-to-hip ratio and lipid profiles244. In a meta-analysis
information, contribute to delayed PCOS diagnosis and patient dis- of RCTs conducted in women with PCOS, use of glucagon-like peptide 1
satisfaction18. Delayed diagnosis also limits screening, prevention and (GLP1) receptor agonists, such as liraglutide, yielded modest metabolic
treatment of the diverse features of PCOS, with health implications. improvements over a 12-week period compared with metformin alone.

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a Fig. 7 | Diagnosis of PCOS. a, The first step

First step; if yes, provide diagnosisa; if no, go to step 2 includes presence of irregular cycles and clinical
hyperandrogenism such as hirsutism and/or female
Irregular cycles and clinical hyperandrogenism
pattern hair loss; if yes, polycystic ovary syndrome
(PCOS) is diagnosed. The second step involves the
performance of biochemical testing of circulating
Second step; if yes, provide diagnosisa; if no, go to step 3
elevated total testosterone, calculation of free
Elevated total testosterone, free androgen index androgen index, or bioavailable testosterone; if levels
or bioavailable testosterone
are increased, PCOS is diagnosed. In the third step,
if isolated irregular cycles or hyperandrogenism are
reported, ultrasound is performed to assess antral
Third step; if yes, provide diagnosisa
follicle count (>20 that are <9 mm) or for enlarged
Isolated irregular cycles or hyperandrogenism ovary (>10 cm3) or elevated circulating anti-Müllerian
in adults, do ultrasound or measure AMH levels
hormone (AMH) levels. Importantly, the third step is not
performed in adolescents. b, Diagnostic criteria for PCOS
in adolescents (left) and in adult women (right). LC–MS,
liquid chromatography–mass spectrometry. aAfter
b Clinical or biochemical hyperandrogenism exclusion of other causes.
• Hirsutism: Ferriman–Gallway score ≥4–6
or
• Total or free testosterone measures
by LC–MS or calculated free androgen index
Adolescents
Fulfil two
Ovarian dysfunction
In adolescents, • Irregular menstrual cycles and/or
hyperandrogenism anovulation: <21 days or >35 days Adult
and ovulatory with >3 years after menarche Fulfil two out
dysfunction are of three
required
Polycystic ovarian morphology or AMH
• Antral follicles: ≥20 (2–9 mm)
or
• Enlarged ovaries: >10 cm3
or
• AMH
However, combination therapy with metformin demonstrated more Hyperandrogenism

substantial improvement in weight reduction, fasting glucose and Suppression of ovarian androgen secretion. In PCOS, common
fasting insulin than either treatment alone245. androgen-related features include hirsutism, acne and female pattern
The use of medications targeting weight loss alone in PCOS hair loss1. Low-dose ethinyl oestradiol combined oral contraceptive
remains uncertain although lifestyle interventions alone may prove pills (COCPs) are the preferred treatment for hirsutism in both adults
insufficient. Metformin has shown modest weight loss benefits and and adolescents as they increase SHBG levels and decrease lutein-
improved body composition compared with oral contraceptives alone izing hormone, serum testosterone and androstenedione levels249.
or in combination in women with PCOS246. Several anti-obesity drugs, Meta-analysis shows that cyproterone acetate and fourth-genera-
particularly GLP1 receptor agonists, are approved for use in adults but tion progestins result in greater reduction in serum androgen levels
face cost, access and availability challenges; anti-obesity drugs are not than earlier progestins250. However, fourth-generation progestins
recommended when pregnancy is desired. demonstrated no differences in their effect on hirsutism250. Given
Studies have explored the use of GLP1 receptor agonists, such as lira- the increased risk for venous thrombosis associated with ethinyl
glutide and semaglutide, for weight loss and metabolic improvements oestradiol plus cyproterone acetate, these preparations are consid-
in PCOS. In RCTs, liraglutide led to weight and fat mass reduction247. ered second-line therapy1. Addressing the primary symptoms and
However, liraglutide alone resulted in more lean body mass loss than considering cosmetic therapies are crucial. The choice of treatment
placebo, which improved when combined with lifestyle interven- should involve shared decision-making, addressing contraindications
tions247. A non-randomized study with semaglutide also showed weight and side effects.
loss and some metabolic improvements in women who had previously Combining COCPs with lifestyle management is more effective
undergone lifestyle modifications without success, although not across than COCP–metformin combinations1. Although metformin and
all parameters248. Although based on a limited number of small studies, COCPs can improve hyperandrogenism, a meta-analysis showed that
GLP1 receptor agonists are shown to reduce free androgen index247 and COCP treatment results in lower free androgen index, total and free
to normalize menstrual cycles248; large trials are needed in the future. testosterone, androstenedione, and dehydroepiandrosterone sul-
Of note, gastrointestinal side effects are common with GLP1 agonists fate levels along with higher SHBG levels than metformin treatment;
as well as weight rebound after cessation. however, hirsutism did not differ between the treatments251.
Inositol seems to have limited value in treating metabolic out-
comes in PCOS, with metformin being more effective. However, inositol Anti-androgens. Anti-androgens could be considered to treat hir-
could be used with informed consent and where access to metformin sutism in women with PCOS if suboptimal response is observed
or more effective medications is limited24. after a minimum of six months of COCP and/or cosmetic therapy24.

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If anti-androgens are used, the side effects should be weighed against cycle regulation. Progestin-only preparations can also be considered,
the possible benefits considering the extent and the impact of hirsutism although they lack the beneficial effect of COCPs to control hyperandro-
on the individual patient. genism. Levonorgestrel intrauterine devices are effective for endome-
Bariatric surgery could also be considered to improve hirsutism. trial protection, although some women may suffer from extrauterine
One large study reported a complete resolution of hirsutism after bari- levonorgestrel effects such as acne and hair loss253. Cyclic progestins,
atric surgery in 75% of all patients at the end of 6 months of follow-up252. like medroxyprogesterone or norethisterone, are also used, usually for
Another 20% experienced a moderate resolution whereas the remaining 10–14 days to induce menstruation over 8–6 cycles per year. Different
5% showed limited or no resolution of the extent of their hirsutism. weight loss strategies and metformin also support endometrial health
and should be considered in PCOS131,254. In cases where hyperplasia or
Cosmetic treatments. Mechanical laser and light therapies should be cancer are suspected, endometrial biopsy is indicated.
considered to reduce facial hirsutism and related depression, anxiety,
and quality of life in women with PCOS. A greater number of laser treat- Fertility
ment sessions may be required in women with PCOS than in women with Medication. Fertility treatment in women with PCOS should start with
idiopathic hirsutism to achieve hair reduction24. Adverse effects seem preconception counselling and optimizing maternal health before
limited in the hands of experienced and suitably qualified providers and pregnancy255. Preconception weight loss through lifestyle interventions
women should be encouraged to seek hair reduction therapies from or bariatric surgery may improve ovulation, enhance natural pregnancy
such providers. Wavelength and delivery of laser treatment varies by rates242,256, and may increase ovulation rates with first-line treatments257.
skin colour and hair colour. Moreover, laser is relatively ineffective in However, pregnancy in PCOS carries risks, including miscarriage, ges-
women with blond, grey or white hair. Finally, the addition of COCPs, tational diabetes, pregnancy-induced hypertension, pre-eclampsia,
with or without anti-androgens, to laser treatment may provide greater preterm delivery and the need for a Caesarean section1,258. The fetus is
hair reduction and maintenance than laser alone1. at risk for intrauterine growth restriction, with small-for-gestational-
age babies and low birthweight at birth1,258,259. Given the elevated risks,
Endometrial protection the primary goal of fertility therapy should be a singleton pregnancy to
Progestin-containing regimens offer endometrial protection. In PCOS, avoid complications associated with multiple pregnancies.
COCPs are commonly used as they are considered first-line therapy The first-line treatment for anovulation in PCOS involves ovula-
to manage irregular cycles1. Most COCPs have continuous progestin tion induction with letrozole over several cycles, with dose escalation
dosing, effectively controlling endometrial proliferation and offering if anovulation persists 1,260–262. Initial concerns about possible
Box 2
Screening and prevention

Infertility, time to conception and inter-conception intervals, rate For endometrial protection, monitoring cycle regularity
of fertility treatment and maternal age are all increased in women for those not on hormonal contraception is important to limit
with polycystic ovary syndrome (PCOS), with lower fecundity rate hyperplasia and endometrial cancer, especially in those with
and fewer children than in women without PCOS54,56. A delayed a high BMI. However, the absolute risk for cancer remains low
diagnosis of PCOS adversely impacts fertility and family size and and routine screening is not recommended unless clinically
increases advanced maternal age in a condition where pregnancy indicated1,24.
complications are already increased. In this context, a reproductive Given that anxiety and depressive symptoms are increased in
life plan is recommended to focus on timely diagnosis, screening, 70–80% of those with PCOS, screening for depression and anxiety are
prevention and family planning1. On the other hand, women should routinely recommended, using regionally validated and assessable
be informed about the chance of spontaneous pregnancies and that tools. For eating disorders, screening is not routinely recommended;
they are likely to have at least one child; however, this may require however, where these disorders are suspected, screening is
assisted reproductive technologies55,56,303. recommended1,24. Other psychological features, including body
Preconception offers additional screening opportunities. Nutritional image distress and self-esteem, should be considered for screening
status, prenatal vitamin use, smoking, alcohol, diet, exercise, sleep, and treatment if clinically indicated. Individualized screening,
and mental, emotional and sexual health as well as screening for identification and treatment of psychological features should be a
comorbidities such as excess weight, type 2 diabetes mellitus and priority to improve quality of life1,24. The frequency of psychological
high blood pressure, are important to improve maternal–fetal health screening should be based on clinical assessment and considered
and overall health. Risks for gestational diabetes and hypertension when other intersectional factors or life events occur such as
during pregnancy are increased in women with PCOS58. Screening, infertility or pregnancy304.
monitoring and prevention of complications in pregnancy are strongly Cardiometabolic screening is recommended routinely in PCOS
recommended in the International Guideline, including identifying PCOS from the time of diagnosis. Weight, glucose levels, blood pressure
status, high BMI, excess gestational weight gain, hypertension and type 2 and lipid profiles should be routinely and regularly screened to
diabetes mellitus, with a focus on improving maternal–fetal outcomes1,58. prevent complications1,24.

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teratogenicity have been allayed by a systematic review noting similar therapy along with lifestyle management may be an important strategy
rates of birth defects as other ovulation induction medications, although to address weight management in those with PCOS and high depres-
use of letrozole is still off-label263. Other oral medications, in order of sive scores276,277. A multidisciplinary holistic approach that provides
reduced effectiveness, include the combination of metformin and clo- education on long-term risks, lifestyle interventions, screening and
miphene citrate, clomiphene citrate alone, and metformin alone261. Preg- management of PCOS features is an essential component of improving
nancy rates often require six or more cycles with most medications, and outcomes, including psychological well-being and HRQoL in patients278.
the risk of multiple pregnancies ranges from 3% to 7%264. Some guidelines
suggest low-dose gonadotropin therapy as a second-line treatment but Quality of life
careful management is needed to prevent multiple follicle recruitment HRQoL scores related to hirsutism, menstruation and fertility are lower
and ovarian hyperstimulation. Continued use of oral medications with in women with PCOS than in the general population279,280. Identification
clomiphene citrate may also be effective in the long run264. of areas of key concern that affect quality of life in this multifaceted
disorder is critical to prioritizing treatment strategies. However, current
IVF and elective single embryo transfer. In vitro fertilization (IVF) has surveys do not capture all aspects of PCOS that impact quality of life,
gained popularity as a second-line fertility treatment in PCOS. Several and data for adolescents with PCOS is limited. Disease-specific HRQoL
modifications have improved its risk-to-benefit profile for patients questionnaires include questions specific to PCOS, such as menstrual
with PCOS. These modifications include enabling multiple follicular dysfunction, obesity-related matters and how symptoms of hyperan-
recruitment through gonadotropin stimulation whilst reducing the risk drogenism affect quality of life, and include the validated PCOS health-
of ovarian hyperstimulation syndrome by using less potent ovulation- related QOL questionnaire (PCOSQ)281,282 or the PCOS Quality of Life
triggering agents such as a GnRH agonist. The elective freeze-all strat- Scale (PCOSQOL). Studies have shown that PCOSQOL measures the
egy, where collected oocytes are fertilized and frozen for later embryo impact of PCOS on feminine identity and the negative impact of PCOS on
transfer, which allows the ovaries to recover from gonadotropin hyper- family and friends and on the feeling of pressure to have children in more
stimulation, is also employed to prevent exposure to endogenous detail than earlier questionnaires and is sensitive in both clinical and
human chorionic gonadotropin265. research settings in adult women283. In addition, the Adolescents’ PCOS
This approach lends itself to elective single embryo transfer of a health-related quality of life Questionnaire (APQ-20) was developed for
thawed cryopreserved embryo during a frozen embryo transfer cycle, adolescents and has been shown to be easy to use, valid and reliable284.
substantially lowering the likelihood of multiple pregnancies. However, PCOS-specific quality of life questionnaires capture the impact
a small chance (<2%) of monozygotic twins exists as a result of elective of PCOS-specific symptoms on HRQoL, and social, cultural and
single embryo transfer266. Although the freeze-all strategy reduces ethnic differences are observed in the responses279. For example,
ovarian hyperstimulation syndrome risk and potentially improves excess body weight is reported as a common concern in most patient
pregnancy rates compared with fresh embryo transfer, it may introduce surveys and has a strong association with lower quality of life scores
other risks such as an increased incidence of gestational hypertension whereas infertility, hirsutism and menstrual symptoms impact qual-
or pre-eclampsia and large-for-gestational-age babies267. The hyperten- ity of life in some studies279. Moreover, surveys in different world
sive problems may be avoided if frozen embryo transfer is performed in regions show that, in some cultures, fertility is a major stigma and
natural cycles with an intact corpus luteum268. Concerns about ovarian fertility-related quality of life scores are more affected; the same
hyperstimulation syndrome risk and the excessive use of fertility drugs holds for hirsutism.
have prompted the development of in vitro maturation, where oocytes
are retrieved after mild ovarian stimulation and matured in vitro before Outlook
undergoing standard IVF procedures269,270. Although commendable progress has been made in deciphering the intri-
cacies of PCOS in the past decades, considerable knowledge gaps remain.
Ovarian drilling. The original PCOS treatment by Stein and Leventhal, Our understanding of this complex syndrome is still incomplete and we
involving ovarian wedge resection (that is, removal of a wedge-shaped identify knowledge gaps and urgent research questions (Box 3). Of note,
portion in the ovary), improved hyperandrogenism and restored ovu- the questions highlighted represent only a fraction of the multifaceted
lation, enabling natural pregnancy271. Modified methods like ovarian areas that require further investigation. Overall, long-term health, quality
diathermy or drilling provide sustained reproductive benefits272, with of life and ability to work should be at the core of future studies.
potentially lower multiple pregnancy rates than low-dose gonadotro-
pin therapy273. Proponents have developed outpatient ablative pro- Management
cedures to lower costs and increase availability274. The invasiveness Metabolic dysfunction. Currently, data on the impact of specific life-
of this procedure and the risk of diminishing the ovarian reserve if the style interventions that are effective in the management of increased
operator is inexperienced warrant caution. weight and metabolic dysfunction in PCOS is limited. Preventive
therapies to control weight gain in adolescence and peripubertal and
Psychological disorders periconception interventions are needed. As there is now a growing
First-line treatments for PCOS, such as COCPs or lifestyle management, list of effective anti-obesity agents, the question of how these might
show some improvement or no difference in depressive or anxiety symp- be better utilized in weight management and investigation of the
toms, suggesting that traditional approaches, including psychological long-term metabolic impact of these agents are needed.
therapy and anti-depressants or anti-anxiety medications, should be Additionally, an improved understanding of the cardiovascular
used when indicated275,276. As depression, anxiety and eating disorders outcomes associated with PCOS and the impact that metabolic dys-
impact the ability of patients to effectively engage in lifestyle manage- function and its management may have on these outcomes is needed.
ment, screening for these disorders to individualize lifestyle recom- An understanding of how metabolic dysfunction impacts reproductive
mendations is needed24. Moreover, the use of cognitive behavioural function and vice versa is also needed.

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Reproductive dysfunction. The genesis of PCOM is unknown and the progestin types and dosages, whilst assessing efficacy on acne, hair loss
role of hyperandrogenism in the accumulation of small antral follicles and psychological outcomes. A thorough investigation into adverse
is unclear. Deciphering the intricate relationship between PCOM in the events linked to COCP usage, encompassing aspects such as weight
absence of hyperandrogenism and its impact on health and disease is gain, metabolic effects, increased insulin resistance and psychological
important. Moreover, challenging conventional norms by assessing impact, is imperative. Exploration of the relatively uncharted terri-
hyperandrogenaemia in cases where serum levels appear normative tory of progestin-only preparations, including intrauterine systems,
is needed. implants and pills, is warranted to enhance our understanding of
The accumulation of small antral follicles leads to excessive granu- their role in treating hyperandrogenism. The potential of anti-obesity
losa cell production of AMH, which in turn increases GnRH and lutein- drugs in addressing both biochemical and clinical hyperandrogenism,
izing hormone secretion, leading to ovarian hyperandrogenaemia either in isolation or in conjunction with COCPs, necessitates scrutiny
and contributing to the development of PCOS; this mechanism needs through adequately powered randomized trials.
further investigation. Whether PCOS is of neuroendocrine and/or
ovarian origin is still debated, and the respective contribution of each Psychological disorders. Current research strongly supports the
component to the manifestation of the syndrome needs further deline- integration of psychological well-being in the overall management of
ation. The efficacy of neuroendocrine manipulations, including inter- PCOS across the lifespan. Routine assessment of mental health condi-
ventions such as kisspeptin, in the treatment of anovulation associated tions in all adolescents and adults evaluated for PCOS is recommended.
with PCOS needs to be investigated. Further research in understanding the biological, genetic and envi-
ronmental determinants that impact emotional well-being is urgently
Hyperandrogenism. Conducting extensive population-based studies needed to better formulate individualized treatment strategies in this
is imperative to comprehensively capture the spectrum of side effects high-risk population. Incorporation of strategies to routinely screen
and risks associated with hyperandrogenism treatment in individuals patients, incorporate educational materials and access resources
with PCOS. To ascertain the optimal COCP preparation, particularly in might require a change in our current models of care delivery for this
adolescents, large-scale comparative studies are essential, focusing on chronic condition.
Box 3
Important research questions in PCOS

Management • Understand molecular mechanisms of insulin resistance, oxidative
• Define the best practice lifestyle management to improve stress and mitochondrial dysfunction.
reproductive and cardiometabolic risk in polycystic ovary • Define the role of the immune system in target tissues, including
syndrome (PCOS). reproductive and metabolic tissues.
• Investigate the effect and mechanisms of new anti-obesity and
diabetes drugs on reproductive and cardiometabolic features Inheritance and mechanisms
in PCOS. • Identify the effector gene at each locus and define how the
• Define the impact of peripubertal weight gain on long-term PCOS altered expression or function of each gene contributes to PCOS
risk and interventions that reduce risks. pathophysiology.
• Describe interventions for sons of mothers with PCOS. • Define the genetic architecture of PCOS in African or Hispanic
populations.
Reproductive dysfunction • Explore and define subtypes of PCOS.
• Origins of polycystic ovary morphology — is hyperandrogenism • Delineate neuroendocrine versus ovarian origins of PCOS.
essential? • Define key triggers (for example, androgens and anti-Müllerian
• Elucidate the relationship of polycystic ovary morphology in the hormone) and molecular pathways that drive PCOS-specific
absence of hyperandrogenism to health and disease. reproductive, cardiometabolic and psychiatric dysfunction.
• Assessment of hyperandrogenaemia when serum levels are normal. • Define how PCOS affects specific cell types in key target tissues
• Define age-specific anti-Müllerian hormone levels as a diagnostic such as ovary, endometrium, adipose tissue, skeletal muscle
criterion for PCOS. and liver.
• Evaluate whether neuroendocrine manipulation, including • Identify biomarkers to allow early diagnosis and development of
kisspeptin, is useful in the treatment of anovulation. novel drug targets as well as predictive markers.
• Define targeted prenatal interventions to influence fetal
Metabolic dysfunction programming.
• Delineate the role of metabolic dysfunction in cardiovascular risk • Define the male phenotype of PCOS for the assessment of male
in PCOS. relatives of women with PCOS.
• Define reliable tools for assessing cardiovascular risk in women
with PCOS.

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Mechanisms 3. Riestenberg, C., Jagasia, A., Markovic, D., Buyalos, R. P. & Azziz, R. Health care-related
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gaps persist in understanding the effector genes at these loci and in This paper highlights that early diagnosis and interventions could possibly reduce
deciphering how the altered expression or function of each gene con- the risk of developing comorbidities and the health-care-related economic burden
of PCOS.
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are prevalent in European and Chinese cohorts, the genetic architecture Polycystic ovary syndrome: systematic review and meta-analysis. eLife 12, e85338
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5. Liu, Q. et al. A genome-wide cross-trait analysis identifies shared loci and causal
explored. Investigating potential PCOS subtypes necessitates analysing relationships of type 2 diabetes and glycaemic traits with polycystic ovary syndrome.
larger cohorts for statistical robustness during sample subdivision. In Diabetologia 65, 1483–1494 (2022).
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in men and women. Nat. Med. 26, 252–258 (2020).
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guidelines. Endocrinol. Metab. Clin. North Am. 50, 83–95 (2021).
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10. Zhuang, C. et al. Cardiovascular risk according to body mass index in women
inflammation, cardiovascular disease and pregnancy complications
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189, R4–R5 (2023).
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treatment, and predict treatment response. increased risk of major cardiovascular events: a population study. J. Clin. Endocrinol.
Metab. 106, e3369–e3380 (2021).
This study shows that women with PCOS have a higher incidence of myocardial
Epidemiology infarction, angina pectoris and revascularization.
Large data sets and epidemiological studies are central to understand- 13. Millan-de-Meer, M., Luque-Ramirez, M., Nattero-Chavez, L. & Escobar-Morreale, H. F.
PCOS during the menopausal transition and after menopause: a systematic review and
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including routine clinical data, are also key to evaluating care and treat- 14. van der Ham, K. et al. Change in androgenic status and cardiometabolic profile of
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15. Johnson, J. E., Daley, D., Tarta, C. & Stanciu, P. I. Risk of endometrial cancer in patients
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sets should identify PCOS status, including self-report, PCOS symp- endometrial cancer.
16. Hanna, F., Wu, P., Heald, A. & Fryer, A. Diabetes detection in women with gestational
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of artificial or synthetic data, alongside advanced analytics to harness This study shows that women with PCOS have an increased risk for pregnancy
the power of data in PCOS are warranted. complications, including gestational diabetes and hypertension, independent of
coexisting metabolic conditions.
18. Gibson-Helm, M., Teede, H., Dunaif, A. & Dokras, A. Delayed diagnosis and a lack of
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in women with polycystic ovary syndrome: a pilot randomized clinical trial. Fertil. Steril. E.S.-V. is supported by the Swedish Medical Research Council: project no. 2022-00550 (ESV);
110, 161–171 e161 (2018). Distinguished Investigator Grant – Endocrinology and Metabolism, Novo Nordisk Foundation:
278. Melson, E. et al. A systematic review of models of care for polycystic ovary syndrome NNF22OC0072904 and project grant NNF19OC0056647; Diabetes Foundation: DIA2022-708;
highlights the gap in the literature, especially in developing countries. Front. Endocrinol. Karolinska Institutet KID funding: 2023-0005 and 2020-00990; and Regional Agreement
14, 1217468 (2023). on Medical Training and Clinical Research between the Stockholm County Council and the
279. Behboodi Moghadam, Z., Fereidooni, B., Saffari, M. & Montazeri, A. Measures of health- Karolinska Institutet: 20190079. M.O.G. is supported by the Eris M. Field Chair in Diabetes
related quality of life in PCOS women: a systematic review. Int. J. Womens Health 10, Research and NIDDK P30-DK063481. H.T. is supported by Australian NHMRC Fellowship
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satisfaction in women with PCOS symptoms. J. Clin. Endocrinol. Metab. 105, 1814–1826 Author contributions
(2020). Introduction (E.S.-V.); Epidemiology (T.T.P., H.T., A.D. and E.S.-V.); Mechanisms/pathophysiology
281. Cronin, L. et al. Development of a health-related quality-of-life questionnaire (PCOSQ) for (E.S.-V., M.O.G., J.L., R.J.N. and T.T.P.); Diagnosis, screening and prevention (H.T.); Management
women with polycystic ovary syndrome (PCOS). J. Clin. Endocrinol. Metab. 83, 1976–1987 (K.H., J.L., R.L., T.T.P. and A.D.); Quality of life (A.D.); Outlook (E.S.-V., H.T., R.J.N., R.L., M.O.G.,
(1998). A.D., J.L., K.H. and T.T.P.) and overview of the Primer (E.S.-V.).
282. Guyatt, G., Weaver, B., Cronin, L., Dooley, J. A. & Azziz, R. Health-related quality of life
in women with polycystic ovary syndrome, a self-administered questionnaire, was Competing interests
validated. J. Clin. Epidemiol. 57, 1279–1287 (2004). The authors declare no competing interests.

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Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden. 2Monash Centre for Health Research and Implementation,
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Monash Health and Monash University, Melbourne, Victoria, Australia. 3Robinson Research Institute, Adelaide Medical School, Adelaide, South Australia,
Australia. 4Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA, USA. 5Department of Public Health Science, Penn
State College of Medicine, Hershey, PA, USA. 6Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical
Center, Los Angeles, CA, USA. 7Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA. 8Division of Reproductive
Endocrinology & Infertility, Department of Obstetrics and Gynecology, Erasmus MC, Rotterdam, Netherlands. 9Department of Obstetrics and Gynecology,
University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. 10Department of Obstetrics and Gynecology, Research Unit of Clinical
Medicine, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.

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nature reviews disease primers https://doi.org/10.

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Polycystic ovary syndrome

Despite affecting ~11–13% of women globally, polycystic ovary syndrome Introduction

(PCOS) is a substantially understudied condition. PCOS, possibly Epidemiology

and anti-Müllerian hormone considerations. PCOS, marked by insulin

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Male phenotype of PCOS

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Life course in women with PCOS

• PCOS symptoms • PCOS symptoms • PCOS symptoms mitigate

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Table 1 | Findings from GWAS in polycystic ovary syndrome

2p16.3 (A) rs13405728 LHCGR Chen, 2011 Shi, 2012 78,81

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Fig. 2 | Genetic and epigenetic inheritance

DNA methylation and RNA

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Hypothalamus–pituitary–ovarian axis ↑ AMH

↑ LH ↓←→FSH Peripheral conversion →

↓ SHBG Theca cell

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Follicular phase Ovulation Luteal phase

Menstrual phase Proliferative phase Secretory phase

Proliferation prolonged due to unbroken oestrogen exposure

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Insulin resistance ↑ Testosterone 4

3 ↓ Catecholamine signalling sensitivity

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Diagnosis, screening and prevention Management

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a Fig. 7 | Diagnosis of PCOS. a, The first step

However, combination therapy with metformin demonstrated more Hyperandrogenism

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Screening and prevention

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Important research questions in PCOS

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