Polycystic ovary syndrome (PCOS)


Polycystic ovary syndrome (PCOS) is a hormonal disorder common among women of reproductive age.

Detailed clinical description

Polycystic ovary syndrome (PCOS) is a hormonal disorder common among women of reproductive age.

Women affected by PCOS experience infrequent or longer menstrual periods or increased levels of androgens. Follicles (cysts) containing fluid appear in the ovaries. Women with PCOS may fail to regularly release eggs.

The causes of PCOS remain unknown today. Some factors of susceptibility may include excess insulin (which may increase androgen production, causing difficulty in ovulation) increase androgen production, low-grade inflammation (which may stimulates polycystic ovaries to produce androgens) which can lead to heart and blood vessel problems, genetic factors, and excess androgen production by the ovaries, which may also lead to hirsutism and acne.

Early diagnosis include ultrasonographic (US) examination, while early treatment along with weight loss may reduce the risk of long-term complications such as type 2 diabetes and heart disease.

Complications of PCOS can include infertility, gestational diabetes or pregnancy-induced high blood pressure, miscarriage or premature birth, nonalcoholic steatohepatitis, metabolic syndrome (which includes high blood pressure, high blood sugar, and abnormal cholesterol or triglyceride levels, increasing the risk of cardiovascular disease), type 2 diabetes, sleep apnea, depression and anxiety, abnormal uterine bleeding, and endometrial cancer.


PCOS affects 4%–20% of women of reproductive age worldwide.

The prevalence of non-classic 21-OHD CAH (see below for explanation) in a general heterogeneous population has been estimated at 1:100. Population-speific prevalence data are available for Ashkenazi Jews (1:27), hispanics (1:40), slavs (1:50), and Italians (1:300).

Molecular genetics

There is generally poor understanding of PCOS etiology. PCOS tends to cluster in families and both female and male relatives can show signs of the syndrome, including metabolic abnormalities, which indicates that some genetic factors may play a role in susceptibility to PCOS. Candidate genetic loci of susceptibility have been isolated, although PCOS remains substantially a non Mendelian disorder, so genetic testing for this condition is generally not possible.

There’s actually only one genetic condition which may be confused with PCOS. It’s very important to be able to recognize it, due to the risk of a full syndrome in the progeny: it’s non-classic 21-hydroxylase deficiency Congenital Adrenal Hyperplasia (non-classic 21-OHD CAH), caused by CYP21A2 gene mutations. Many women with non-classic 21-OHD CAH develop polycystic ovaries. In addition, non-classic 21-OHD CAH may be identified in 2-10% of women with hyper-androgenism. Postnatal symptoms in females non-classic 21-OHD CAH with  may include hirsutism, frontal baldness, delayed menarche, menstrual irregularities, and infertility. However, it is important to highlight that approximately 60% of adult women with non-classic 21-OHD CAH have hirsutism only; approximately 10% have hirsutism and a menstrual disorder; and approximately 10% have a menstrual disorder only.

A classic form of 21-OHD CAH with severe enzyme deficiency and prenatal onset of virilization is distinguished from a non-classic form with mild enzyme deficiency and postnatal onset. The classic form is further divided into the simple virilizing form (~25% of affected individuals) and the salt-wasting form, in which aldosterone production is inadequate (≥75% of individuals). Newborns with salt-wasting 21-OHD CAH are at risk for life-threatening salt-wasting crises. Individuals with the non-classic form of 21-OHD CAH present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth.

Because 21-OHD CAH is transmitted in an automal recessive fashion, if a female affected by a non-classic form meet with a male partner who’s healthy carrier of a pathogenic mutation in the CYP21A2, there’s a consistent reproductive risk for 21-OHD CAH (even in the classic, salt-wasting form) in the offsrping.

The diagnosis of non-classic 21-OHD CAH is established by comparison of baseline serum 17-OHP and ACTH-stimulated serum 17-OHP or early morning elevated 17-OHP (however, baseline 17-OHP values in affected individuals are not always elevated). In some cases the diagnosis may be confirmed clinically, by the presence of polycystic ovary and hirsutism. Identification of biallelic pathogenic variants in CYP21A2 (usually a severe one plus a mild one) confirms the clinical diagnosis of non-classic 21-OHD CAH and allows for family studies and reproductive risk calculations, based on the partner genetic testing results.

So, with the exception of 21-OHD CAH, which may also be suspected clinically by the expert gynecologist, there’s no genetic testing possible for PCOS, unless the presence of other signs and symptoms indicate a rare genetic syndrome rather than pure PCOS.

Syndromic conditions, i.e. rare genetic disorders, characterized by polycystic ovary syndrome include:

Lipodystrophy, familial partial, type 4 (PLIN1 gene mutations): an autosomal dominant metabolic disorder characterized by childhood or young adult onset of loss of subcutaneous adipose tissue primarily affecting the lower limbs, insulin-resistant diabetes mellitus, hypertriglyceridemia, and hypertension. Other features may include hepatic steatosis, acanthosis nigricans, polycystic ovary syndrome, and renal disease.

Diabetes mellitus, insulin-resistant, with acanthosis nigricans (INSR gene mutations).

Lipodystrophy, congenital generalized, type 1 (AGPAT2 gene mutations): congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, is a rare autosomal recessive disease characterized by a near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia.

Blepharophimosis, epicanthus inversus, and ptosis, type 1 (FOXL2 gene mutations): blepharophimosis, ptosis, and epicanthus inversus syndrome, either with premature ovarian failure (BPES type I) or without (BPES type II), is caused by heterozygous mutation in the FOXL2 gene (but rare homozygous mutations have been described too). BPES syndrome includes a characteristic eyelid dysplasia, namely, small palpebral fissures (blepharophimosis), drooping eyelids (ptosis), and a tiny skin fold running inward and upward from the lower lid (epicanthus inversus).

Aromatase deficiency (CYP19A1 gene mutations): Endogenous estrogens synthesis is impaired and this results in virilization of both fetus and mother. Virilization manifests as pseudohermaphroditism in female infants. Cystic ovaries and delayed bone maturation can occur during childhood and adolescence in these girls. Affected males do not present with obvious defects at birth. Their clinical symptoms include tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions, and excess adiposity. Estrogen replacement therapy reverses the symptoms in males and females.

Hypoparathyroidism, sensorineural deafness, and renal dysplasia (GATA3 mutations): HDR syndrome (HDRS), also known as Barakat syndrome, is a heterogeneous disorder characterized by the triad of Hypoparathyroidism (H), nerve Deafness (D) and/or Renal disease (R). Variable clinical features include hypogonadotrophic hypogonadism, polycystic ovaries, congenital heart disease, retinitis pigmentosa, and cognitive disability.

Lipodystrophy, familial partial, type 3 (PPARG gene): Familial partial lipodystrophy is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution beginning in late childhood or early adult life. In some patients, adipose tissue accumulates on the face and neck, causing a double chin, fat neck, or cushingoid appearance. Metabolic abnormalities include insulin-resistant diabetes mellitus with acanthosis nigricans and hypertriglyceridemia; hirsutism and menstrual abnormalities occur infrequently.

Differential diagnosis

The differential diagnosis of PCOS includes: ovarian hyperthecosis, congenital adrenal hyperplasia (CYP21A2 gene mutations, late-onset, see above), iatrogen causes (use of drugs such as danazol orandrogenic progestins), hypothyroidism, patients with menstrual disturbances and signs of hyperandrogenism, idiopathic hirsutism, familial hirsutism, masculinizing tumors of the adrenal gland or ovary (rapid onset of signs of virilization), Cushing syndrome, hyperprolactinemia, exogenous anabolic steroid use, stromal hyperthecosis (valproic acid).

Genetic testing strategy

If non-classic 21-OHD CAH is suspected, CYP21A2 gene sequencing and MLPA are recommended by means of a special technique (CYP21A2 testing is quite difficult due to the presence of a pseudogene with a high sequence homolgy rate, CYP21A1P). Sequencing and MLPA should be performed in parallel, as large deletions/duplications detectable by MLPA represent 30% of all pathogenic mutations in this gene.

CYP21A2 testing may be done in parallel with a NGS panel for other rare female infertility causes or other forms of CAH not caused by deficiency of 21-OH.

If non-classic 21-OHD CAH canbe excluded and a pure form of PCOS is confirmed, then genetic testing is not possible and the patient should be counseled consequently.

If a rare syndrome including polycystic ovary among other important clinical signs is supected, than a wide high-thoughput approach by whole exome sequencing or whole genome sequencing is recommended.

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Ritu Deswal et al. The Prevalence of Polycystic Ovary Syndrome: A Brief Systematic Review. J Hum Reprod Sci. 2020 Oct-Dec; 13(4): 261–271. doi: 10.4103/jhrs.JHRS_95_18

Daniel A. Dumesic et al. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr Rev. 2015 Oct; 36(5): 487–525. doi: 10.1210/er.2015-1018

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