Legro, R. S., & Strauss, J. F. (2002). Molecular progress in infertility: polycystic ovary syndrome. Fertility and sterility, 78(3), 569-576. https://doi.org/10.1016/s0015-0282(02)03275-2
Legro, R. S., and J. F. Strauss. "Molecular progress in infertility: polycystic ovary syndrome." Fertility and sterility, vol. 78, no. 3, 2002, pp. 569-576.
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Penn State Milton S. Hershey Medical Center01h22ap11
To review the evidence that polycystic ovary syndrome is a genetic disease.
Design
Review of published literature.
Results
The existing literature provides a strong basis for arguing that PCOS clusters in families. However, the mode of inheritance of the disorder is still uncertain, although the majority of studies are consistent with an autosomal dominant pattern, modified perhaps by environmental factors. In addition, studies on PCOS cells (theca, muscle, and adipocytes) in culture have documented a persistent biochemical and molecular phenotype that distinguishes them from normal cells. Although several loci have been proposed as PCOS genes including CYP11A, the insulin gene, and a region near the insulin receptor, the evidence supporting linkage is not overwhelming. The strongest case can be made for the region near the insulin receptor gene, as it has been identified in two separate studies. However, the responsible gene at chromosome 19p13.3 remains to be identified. Association studies have provided a number of potential loci with genetic variants that may create or add to a PCOS phenotype, including Calpain 10, IRS-1 and -2, and SHBG.
Conclusions
Collectively, these findings are consistent with the concept that a gene or several genes are linked to PCOS susceptibility. Because the mutations/genotypes associated with PCOS are rare, and their full impact on the phenotype incompletely understood, routine screening of women with PCOS or stigmata of PCOS for these genetic variants is not indicated at this time. Currently the treatment implications for individually identified genetic variants is uncertain and must be addressed on a case by case basis.
Gao X et al., 2025·Nat Med·Free full text on PubMed Central
Polycystic ovary syndrome (PCOS) is a common and heterogeneous endocrine disorder that affects 11%-13% of women worldwide, with profound implications for fertility and long-term metabolic health. Here we identify four reproducible subtypes-PCOS with hyperandrogen, with obesity, with high-sex hormone-binding globulin and with high-luteinizing hormone-anti-Müllerian hormone-through unsupervised clustering of 9 clinical variables in 11,908 affected women, validated across 5 international cohorts. Prospective 6.5-year follow-up and in vitro fertilization treatment data revealed distinct reproductive and metabolic trajectories: hyperandrogenic PCOS showed the highest risk of second trimester pregnancy loss and dyslipidemia incidence; PCOS with obesity exhibited the most severe metabolic complications, lowest live birth rates and highest PCOS remission rate; PCOS with high-sex hormone-binding globulin demonstrated favorable reproductive outcomes and the lowest incidence of diabetes and hypertension; and PCOS with high-luteinizing hormone-anti-Müllerian hormone had the greatest risk of ovarian hyperstimulation and the lowest PCOS remission rate. These findings advance understanding of PCOS heterogeneity and provide a framework for subtype-based risk stratification and personalized management.
Wessel JA et al., 2022·Fertility & Reproduction·Free to read
Intrauterine insemination with ovarian stimulation (IUI-OS) is a first-line treatment for couples with unexplained infertility. Individual participant data meta-analysis (IPD-MA) is the gold standard for evidence synthesis. To compare the effectiveness and safety of ovarian stimulation with gonadotrophin, Letrozole and clomiphene citrate (CC) and to explore treatment-covariate interactions for important baseline characteristics in women undergoing IUI. We searched electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL). We included randomised controlled trials (RCTs) comparing IUI-OS with gonadotropins, Letrozole or CC among couples with unexplained infertility. We excluded dose comparing studies of the same drug. We contacted the authors of eligible RCTs to share the IPD and established the IUI IPD-MA collaboration. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. We used a one-stage approach using a random effects model. Six RCTs (n= 2299) provided IPD. Gonadotropins increased the chance of a live birth compared to both CC (5 RCTs, 1946 women, RR 1.28, 95%CI 1.10 to 1.49, I2 = 25%, moderate-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.77 95%CI 0.58 to 1.03). Gonadotropins increased the risk of a multiple pregnancy compared to both CC (4 RCTs, 1696 women, RR 2.17, 95%CI 1.33 to 3.55, I2 = 69%, low-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.71, 95%CI 0.33 to 1.56). No strong evidence on the treatment-covariate interactions (female age, BMI or primary versus secondary infertility) was found. Gonadotropins increased the chance of a live birth compared to both CC and Letrozole but also increased the chance of a multiple pregnancy. Further RCTs comparing Letrozole and other interventions in couples with unexplained infertility are needed.
Duffy JMN et al., 2020·Human Reproduction·Free full text on PubMed Central
Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed? A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility. Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret. STUDY DESIGN, SIZE, A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries). MAIN The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable. Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection and reporting of core outcomes. Research funding bodies, the SPIRIT statement, and over 80 specialty journals, including Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set.
Costello MF et al., 2019·Aust N Z J Obstet Gynaecol
Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence-based guideline on PCOS 2018. International evidence-based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first-line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first-line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second-line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third-line therapy where firstor second-line ovulation induction therapies have failed. This review provides the best available evidence informing recommendations (along with clinical expertise and consumer preference) which provide clinicians with clear advice on best practice for the management of infertile women with PCOS.
Over the past 20 years, it has been clearly documented that the polycystic ovary syndrome (PCOS) has major metabolic sequelae related to insulin resistance and that insulin resistance plays an important role in the pathogenesis of the reproductive disturbances of the disorder. Family studies have indicated a genetic susceptibility to PCOS. Polycystic ovaries and hyperandrogenemia are present in approximately 50% of sisters of affected women. Increased androgen secretion and insulin resistance persist in cultured theca cells and skin fibroblasts, respectively, from women with PCOS; this finding suggests that these are intrinsic, presumably genetic, defects. Insulin resistance and elevated low-density lipoprotein (LDL) levels also cluster in the sisters of women with PCOS, consistent with genetic traits. Moreover, the brothers of women with PCOS have insulin resistance and elevated dehydroepiandrosterone sulfate (DHEAS) levels, which supports a genetic basis for these findings. Family-based studies of linkage and association have implicated several genes in the pathogenesis of PCOS. The strongest evidence to date points to a gene in the region of the insulin receptor. Insulin-sensitizing therapy mitigates the reproductive disturbances of PCOS.
It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.
Aversa A et al., 2020·Frontiers in endocrinology·Free full text on PubMed Central
Polycystic ovary syndrome (PCOS) is a very common endocrine and metabolic disorder with the involvement of both genetic and environmental factors. Although much has been clarified on its pathogenesis, diagnosis, clinical manifestations, and therapy, there are still areas of uncertainty. To address fundamental concepts, novel aspects and hypotheses, and future perspectives, including the possible additional benefits of treatment with nutraceuticals, an expert consensus panel formed by endocrinologists and gynecologists was established. After an independent review of the literature, the panel convened electronically on February 3, 2020, and six resolutions were created, debated, and agreed upon discussion, and finally approved in their final form in a consensus livestream meeting held on April 15. The summary of the resolutions are: (1) PCOS is a well-established medical condition that negatively affects reproduction, general health, sexual health, and quality of life; (2) the symptoms and signs of PCOS appear early in life especially in female newborns from PCOS carriers; (3) women with PCOS have significantly increased risk of pregnancy-related complications including gestational diabetes mellitus; (4) a male PCOS equivalent exists, and it may impact on metabolic health and probably on reproduction; (5) the evidence supports that medical therapy for PCOS is effective, rational, and evidence-based; (6) the evidence supports a major research initiative to explore possible benefits of nutraceutical therapy for PCOS. The proposed resolutions may be regarded as points of agreement based on the current scientific evidence available.
Baptiste CG et al., 2010·The Journal of steroid biochemistry and molecular biology·Free full text on PubMed Central
Polycystic ovary syndrome (PCOS) is a very common endocrine disorder characterized by chronic anovulation, clinical and/or biochemical hyperandrogenism, and/or polycystic ovaries. But most experts consider that hyperandrogenism is the main characteristic of PCOS. Several theories propose different mechanisms to explain PCOS manifestations: (1) a primary enzymatic default in the ovarian and/or adrenal steroidogenesis; (2) an impairment in gonadotropin releasing hormone (GnRH) secretion that promotes luteal hormone (LH) secretion; or (3) alterations in insulin actions that lead to insulin resistance with compensatory hyperinsulinemia. However, in the past 20 years there has been growing evidence supporting that defects in insulin actions or in the insulin signalling pathways are central in the pathogenesis of the syndrome. Indeed, most women with PCOS are metabolically insulin resistant, in part due to genetic predisposition and in part secondary to obesity. But some women with typical PCOS do not display insulin resistance, which supports the hypothesis of a genetic predisposition specific to PCOS that would be revealed by the development of insulin resistance and compensatory hyperinsulinemia in most, but not all, women with PCOS. However, these hypotheses are not yet appropriately confirmed, and more research is still needed to unravel the true pathogenesis underlying this syndrome. The present review thus aims at discussing new concepts and findings regarding insulin actions in PCOS women and how it is related to hyperandrogenemia.
PMOS / PCOS › Pathophysiology › Insulin Resistance · Genetics and Immunology › Reproductive Genetics › Single Gene Conditions
Richard S Legro, Jerome F Strauss
Rick Legro, Dick Legro, Rich Legro, R Legro, J Strauss
PMID 12215335 12215335 DOI 10.1016/s0015-0282(02)03275-2 10.1016/s0015-0282(02)03275-2 Legro et al. 2002, Legro 2002
Cite this article
Legro, R. S., & Strauss, J. F. (2002). Molecular progress in infertility: polycystic ovary syndrome. Fertility and sterility, 78(3), 569-576. https://doi.org/10.1016/s0015-0282(02)03275-2
Legro, R. S., and J. F. Strauss. "Molecular progress in infertility: polycystic ovary syndrome." Fertility and sterility, vol. 78, no. 3, 2002, pp. 569-576.
