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pcos

polycystic ovary syndrome (PCOS)

history:

  • 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

prevalence:

  • 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

pathophysiology:

  • appears to be 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)1)
    • note that the maternal IGF-2 allele is usually inactivated due to genomic imprinting - hence the paternal inheritance
  • 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).

clinical features:

  • 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:
  • 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)

clinical diagnostic criteria:

  • 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

diagnosis:

  • 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

management of polycystic ovary syndrome:

fertility Mx:

  • 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

Mx of hyperandrogenism - acne & hirsutism:

  • 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.

oligomenorrhoea Mx:

  • 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.

insulin resistance Mx:

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

preventive medicine:

  • 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
  • ref: Importance of Diagnosing PCOS. AnnIntMed 2000 132(12): 989-993
  • ref: PCOS. BMJ 1998 317(7154): 329-332
pcos.txt · Last modified: 2019/07/13 15:16 by wh