see also:

• gynaecology
• androgens and androgenic effects
• New Australian guidelines for PCOS 2011

• hyperandrogenism & insulin were linked as early as 1921 when Achard & Thiers published their classic description of bearded women with diabetes.
• polycystic ovary syndrome 1st described in 1935 & called Stein-Leventhal syndrome
• late 1960's & early 1970's, researchers noted deranged hypothalamic-pituitary axis & changed focus from a clinical diagnosis to endocrine by including diagnostic criteria such as raised LH or raised LH:FSH ratio.
• 1980, late complications related to insulin resistance
• by 1980's, with increasing use of USS, the recognition of a characteristic polycystic ovary complicated the diagnosis with some believing USS diagnosis was adequate

• 75% of hirsute women with normal menses but anovulatory cycles
• 40% of hirsute women with normal ovulatory cycles (mild form of polycystic ovary syndrome) (AmJMed 2001)
• up to 20% of unselected, apparently normal women if include mild form (Lancet 1988; 1:870-972)
• 4-7% of females in reproductive age have clinically evident PCOS
• prevalence of PCOS is significantly higher in the South Asian population, especially in Pakistan, as compared to Caucasians.

• see 2019: Genetic Basis of Polycystic Ovary Syndrome (PCOS): Current Perspectives
• anovulatory phenotypes:
  • Phenotype A:
    • numerous polycystic ovaries, oligoanovulation, tendency to hyperinsulinemia, metabolic syndrome and hyperandrogenism.
  • Phenotype B:
    • normal appearance of ovaries, oligoanovulation, tendency to hyperinsulinemia, metabolic syndrome and hyperandrogenism
  • Phenotype D:
    • polycystic ovaries, oligoanovulation, without hyperandrogenism
• ovulatory phenotype:
  • Phenotype C:
    • polycystic ovaries with normal routine menses and hyperandrogenism

• PCOS is an extremely heterogenetic and complex disease and may have many avenues to causation including¹⁾ :
  • Genes Involved in Ovarian and Adrenal Steroidogenesis
    • CYP11a, CYP21, CYP17, CYP19
  • Genes Involved in Steroid Hormone Effects
    • Androgen Receptor Gene
      • The “q” arm of chromosome X contains the AR gene, which is composed of 11 exons and encodes a 90-kb long tridomain protein.74 Mutations and structural disruption of the gene are reported to cause PCOS.
    • Sex Hormone-Binding Globulin Gene
      • SHBG gene is localized to chromosome 17p13-p12
  • Genes Involved in Gonadotropin Action and Regulation
    • Lutein Hormone (LH) and Its Receptor Gene
    • AMH
    • Follicular Stimulating Hormone Receptor (FSHR)
  • Genes Involved in Insulin Action and Secretion
    • The Insulin Gene
    • INSR
    • Insulin Receptor Substrate Proteins
    • Calpain10 Gene
    • IGF2 gene may have an autosomal dominant inheritance (male counterpart is thought to be premature baldness)
      • the A820G ApaI polymorphism in the IGF2 gene appears to confer significant risk for PCOS (G genotype has 7.6x risk of PCOS, GG genotype had 19.6x risk)²⁾
      • note that the maternal IGF-2 allele is usually inactivated due to genomic imprinting - hence the paternal inheritance
  • other genes
    • Fat Mass Obesity (FTO) gene
    • PCOS1
    • SRD5A2 and SRD5A1
  • Epigenetic alterations
    • animal studies have shown that an increased level of androgen during fetal life predisposes the offspring to PCOS-like symptoms in later stages
    • a differential CPG island methylation in PPARG1, NCOR1 of granulosa cells that causes hyperandrogenism-induced epigenetic alteration
• in 2020, a study³⁾ of women with European ancestry showed there were two distinct genetic and reproductive and metabolic “subtypes” of women with PCOS:
  • a reproductive group (21%–23%)
    • characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low BMI and insulin levels
    • associated with alleles in 4 loci (PRDM2/KAZN, P = 2.2 × 10−10; IQCA1, P = 2.8 × 10−9; BMPR1B/UNC5C, P = 9.7 × 10−9; CDH10, P = 1.2 × 10−8)
    • carriers of previously reported rare variants in DENND1A, a gene that regulates androgen biosynthesis, were significantly more likely to have the reproductive subtype of PCOS
  • a metabolic group (37%–39%)
    • characterized by higher BMI, glucose, and insulin levels with lower SHBG and LH levels.
    • associated with one allele (KCNH7/FIGN, P = 1.0 × 10−8)

• women with PCOS appear to fail to resume the normal insulin sensitivity that is interrupted during puberty
• normal puberty displays many of the features of PCOS:
  • insulin resistance
  • increased amplitude of LH pulses
  • increasing androgen concentrations
  • irregular menses
  • multiple small ovarian cysts on US are common
• pathogenesis of the insulin resistance remains unclear:
  • excessive up-regulation of IGF-2 due to a genetic polymorphism - IGF-2 is the co-hormone for both follicular and luteal phases of menstruation
  • excessive serine phosphorylation of insulin receptor (50% of pts)
  • dysfunction of beta cells
  • decreased action of chiroinositol (important in insulin signalling) - some pts successfully Rx with d-chiroinositol 
  • the chronic elevation of insulin levels &/or enhanced ovarian sensitivity to insulin combined with elevated LH concentrations results in ovarian thecal hyperplasia, increased androgen secretion, arrest of follicular development & thus anovulation resulting in menstrual disturbance & infertility
  • elevated insulin levels also act on liver to inhibit production of:
    • sex hormone binding globulin which thus leads to an increase in biologically available free testosterone
    • insulin-like growth factor 1 binding protein which leads to increased circulating insulin-like growth factor 1, further enhancing ovarian androgen production
  • some women may also have increased adrenal androgen production
  • elevated hepatic lipase activity converts large lipoprotein particles into smaller atherogenic species hence low HDL & high LDL
• rat studies:
  • adult female rodents can have relative hyperandrogenicity & also insulin resistance by either being treated with one dose on testosterone in the neonatal phase or administered androgens in adult life, thus hormonally imprinted in neonatal phase. (JClinInv 1998).

• most have some degree (usually mild) of insulin resistance:
  • high fasting & postprandial insulin levels
  • acute insulin response to a glucose load inappropriately low for the magnitude of peripheral insulin resistance
• glucose intolerance:
  • 31% of obese pts & 10% of non-obese pts
• centripetal obesity (40-50% pts)
• impaired fibrinolysis (circulating plasminogen activating factor levels) - assoc. with risk for vascular lesions
• endothelial dysfunction
• increased risk of:
  • type 2 diabetes mellitus:
    • 7.5% obese pts have overt DM (3x RR cw general population) cw 1.5% of non-obese pts
  • dyslipidaemia - low HDL cholesterol, high TG
  • hypertension (40% by perimenopause, 4x RR)
  • cardiovascular disease
  • ischaemic heart disease (IHD) (7x RR of acute myocardial infarction (AMI/STEMI/NSTEMI))
  • uterine cancer 3-4x risk ⁴⁾
• hyperandrogenism (primarily ovarian):
  • hirsutism
  • endothelial dysfunction:
    • impaired insulin-mediated vasodilation (degree in proportion to free testosterone levels) (Circulation Mar 2001).
• hyper-insulinaemic stimulation of ovaries:
  • polycystic ovaries
  • anovulation (most pts):
    • usually chronic & presents as oligomenorrhoea or amenorrhoea of perimenarchial onset, but a Hx of regular menses is possible
  • infertility
  • dysfunctional uterine bleeding
  • increased pregnancy loss & complications of pregnancy
  • elevated luteinising hormone:
    • may induce expression of LH receptor in adrenal cortex & thus elevated adrenal corticosterone production
  • elevated oestrone
  • endometrial hyperplasia
  • higher risk of uterine cancer (presumably due to chronic high oestrogen:progesterone balance(ie. unopposed oestrogen) as animal models so far do not suggest any role for hyperandrogenism in development of uterine Ca)

• hyperandrogenism with or without skin manifestations (ie. acne or hirsutism)
• irregular menses (anovulation or oligo-ovulation)
• absence of other androgen disorders (adrenal hyperplasia or tumor)
• +/- polycystic ovaries on US

• hyperandrogenaemia:
  • most appropriate test for ovarian hyperandrogenaemia is a serum total testosterone:
    • normally < 2 nmol/L but can vary from lab to lab & also during menstrual cycle
    • levels > 10nmol/L are suggestive of a testosterone producing tumour of the ovary or adrenal
    • measure free androgen index (ratio of testosterone to sex hormone binding globulin)
    • direct measurement of free testosterone is useless
  • NB. most appropriate test for adrenal hyperandrogenaemia is dehydroepiandrosterone sulphate level
  • NB. absence of skin manifestations does not exclude hyperandrogenism - some ethnic groups (eg. Asians) may have substantial biochemical hyperandrogenism without any skin manifestations
• transvaginal ultrasound during follicular phase (sensitivity > 90%):
  • > 10 peripherally oriented cysts in one US plane, each measuring 2-8mm diameter, arranged around dense stroma, usually ovary enlarged with volume > 9ml
• gonadotrophin-releasing-hormone-agonist test:
  • leuprolide acetate 1mg s/c then measure serum 17-hydroxyprogesterone at 0, 4, 8 & 24 hrs
    • ovarian hyperandrogenism suggested by when max. level - baseline level > 2.6ng/ml (usually @4-8hrs)
    • poor specificity & impractical & thus should only be used as an adjunctive test
• once a patient is menopausal, diagnosis of prior PCOS is very difficult
• pts on OCP for many years may have the clinical features of PCOS masked

• metformin 500mg bd/tds:
  • not if renal impairment;
  • improves menstrual patterns & ovulation rates within 2-3 months, but this indication is off-label & needs to be discussed with pt & documented.
  • may reduce miscarriage rate as well
• ovulation induction Rx eg. clomiphene

• anti-androgens (but not if trying to concieve):
  • cyproterone acetate (combined with ethinyloestradiol in an OCP)
    • may exacerbate menstrual irregularity
    • need to check LFTs 6mthly
    • less effective for hirsutism than for acne
  • spironolactone
    • not if renal impairment;
    • check U&E pre and at 3mths to excl. hyperkalaemia
  • flutamide:
    • not available in Aust.
    • may cause hepatotoxicity
  • finasteride:
    • not for general use in Aust.
    • teratogenic.

• low dose OCP:
  • lowers androgen profiles improving hirsutism & acne:
  • increases sex hormone binding globulin 
  • decreases LH secretion & thus reduces ovarian androgen production
  • decreases adrenal androgen production
  • improves endothelial-dependent vasodilation
  • reduces risk of endometrial hyperplasia & possibly produces regular uterine withdrawal bleeding, thus helps reduce risk of uterine Ca
  • helps reduce risk of ovarian Ca
  • some may raise HDL
  • but as tend to worsen insulin resistance, obesity is a relative C/I
  • not in smokers over age 35yrs
• cyclic progesterones:
  • eg. norethisterone 5mg/d for 14 days each month to induce a period & help reduce risk of Ca uterus
  • only if not planning to get pregnant & don't require hormonal contraception.

• weight reduction
• ? role for d-chiroinositol
• ? oral hypoglycaemic agents such as metformin - appears to improve most abnormalities & may restore ovulation

• encourage lifestyle to reduce cardiovascular risk & esp. to avoid obesity
• fasting lipids every 3-5yrs from age 35yrs
• glucose tolerance testing:
  • before pregnancy if obese
  • pregnancy
  • after 40yrs age
• monitor for hypertension esp. around perimenopause
• consider as a risk factor for IHD when Rx pts with chest pain
• it seems drinking 1-2 cups of coffee per day reduces symptoms:
  • those who drank two cups of coffee every day were at a 70% lower risk of developing PCOS symptoms than those who never drank coffee. Mechanistically, this protective role of coffee has been attributed to its effects on the metabolism of sex hormones like testosterone in the plasma. ⁵⁾
  • coffee contains high phenol levels that improve insulin sensitivity and alleviate hypersecretion. Reduced expression of the phosphatidylinositol 3-kinase (PI3K) pathway also decreases insulin sensitivity and improves β-cell function.
• ref: Importance of Diagnosing PCOS. AnnIntMed 2000 132(12): 989-993
• ref: PCOS. BMJ 1998 317(7154): 329-332