• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Q. What is the prevalence of PCOS?

  • 6-10% of women in the reproductive age group have PCOS based on the original NIH criteria

• Q. Which patients are at high risk of having PCOS?

  • First degree relative with PCOS
  • Obesity
  • Type 1, type 2 diabetes, or GDM history
  • Signs of insulin resistance / metabolic syndrome
  • Premature adrenarche
  • Women on antiepileptic drugs (especially valproate)
  • Anovulatory infertility

• Q. Who first described PCOS?

  • Stein and Levinthal

• Q. What is the most common source of androgens in PCOS?

  • It is mainly ovarian hyperandrogenism

• **Pathogenesis **

• Q. Summarize the pathogenesis of PCOS with a picture?

  • 
  • Ref: Witchel SF, Oberfield SE, Peña AS. Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. Journal of the Endocrine Society. 2019 Aug;3(8):1545-73.

• Q. Does PCOS have a heritable component?

  • Yes
  • Proven in Twin studies
  • The genetic component may be as high as 70% contributing to PCOS

• Q. What factors contribute to the genetic component of PCOS?

  • Difference in energy metabolism
  • Difference in gonadotropin secretion- LH predominance
  • Difference in secretion/action of insulin
  • Difference in androgen biosynthesis by the ovary

• Q. Which are the candidate genes for PCOS?

  • There are 100s of genes implicated
  • But two genes which have the strongest evidence-based on GWAS are
  • THADA gene
  • DENND1A

• Q. When does GnRH stimulate LH, and when does it stimulate FSH release?

  • More rapid GnRH pulse produces LH, and slower GnRH pulse produces FSH

• Q. What is the LH pulse frequency at various phases of the menstrual cycle?

  • Early follicular- 90 min
  • Late follicular (close of ovulation)- 60 min
  • Early luteal – 100 min
  • Late luteal – 200 min

• Q. What happens in PCOS in terms of GnRH pulse, and what is its consequence?

  • There is rapid GnRH release leading to predominant LH production in preference to FSH
  • Increase LH Theca cells have LH receptors so increase activation of Theca cell→ theca cells produce androgen so increase ovarian androgen production
  • Reduce FSH  granulosa cell have FSH receptor → reduced ovarian follicular development

• Q. Is this the only problem?

  • Not all women with PCOS have LH predominant response
  • Hence rapid LH pulsation is not the only reason for PCOS, and other things also have to be considered

• Q. Which drugs reduce insulin resistance?

  • Metformin
  • TZD
  • D-Chiro-Inositol

• Q. How does insulin contribute to the pathogenesis of PCOS?

  • Reduces SHBG
  • Theca cells have insulin receptor-activated → androgen production

• Q. What percentage of women with PCOS have insulin resistance?

  • 50-70%

• Q. Which molecular defect in PCOS links PCOS with diabetes?

  • There is a defect in serine phosphorylation
  • Abnormal serine phosphorylation in Insulin receptor  increase hyperinsulinemia
  • Abnormal serine phosphorylation in 17 alpha-hydroxylase (CYP17) → increase ovarian androgen production

• Q. What is the change in micro RNA seen in PCOS?

  • Increase of miR-93 RNA expression
  • This may contribute to the insulin resistance

• Q. Does weight gain contribute to PCOS or vice versa?

  • It could be either or both

• Q. What are some other factors implicated?

  • Role of Adrenal androgens
  • Role of Diet  androgenic content in the diet
  • Role of androgen exposure to the fetus during intrauterine life

• Q. Summarize the various factors involved in the pathogenesis of PCOS

  • Genetic component- DENND1A  and THADA
  • Role of GnRH pulsatility and LH predominance
  • Role of insulin resistance
  • Role of obesity
  • Role of other factors- adrenal androgen, diet, prenatal exposure to androgens

• Steroid hormone metabolism in polycystic ovary syndrome

• Q. What are the sources of various androgens in women?

  • DHEA/DHEAS- 100% from the Adrenal gland
  • Androstenedione- 50% from the ovary and 50% from adrenal
  • Testosterone- 25% - ovary, 25% adrenal, 50% from peripheral conversion of androstenadione

• Q. What is the difference in androgen source in normal premenopausal women vs. women with PCOS?

  • In normal premenopausal women, androstenedione and testosterone come 50,50% from the adrenal and ovary
  • In PCOS- they come mainly from ovaries instead of adrenals

• Q. Which product is an exclusive marker of peripheral androgen action?

  • Androstanediol
  • It is an indicator of androgen action on the skin and hence correlates well with hirsutism
  • It is derived from the metabolism of DHT

• Q. What happens to estrogen levels in PCOS women?

  • Estrogen, especially estradiol levels, are normal in women with PCOS
  • Estrone derived from androstenedione may be a little higher

• Q. Do statins reduce hyperandrogenemia by reducing the cholesterol substrate?

  • Yes
  • Statins can potentially reduce androgen levels in PCOS women by reducing the cholesterol available as substrate

• #Clinicalpearl

  • Remember Theca cells have LH receptors and produce androstenedione
  • Granulosa cells have FSH receptors and produce estrogen

• Q. What is the functional classification of PCOS based on the source of androgens?

  • Typical PCOS
    • Functional ovarian hyperandrogenism
    • Increase 17 OHP in response to GnRH analog (basically this is hyper-responsiveness to LH)
    • This is seen in 2/3rd of cases
  • Atypical PCOS
    • Functional ovarian hyperandrogenism with no increase of 17 OHP to GnRH
    • Functional adrenal hyperandrogenism
    • Hyperandrogenism from neither adrenal nor ovarian source

• Q. Which are the various tests done to find the source of androgen in PCOS?

  • GnRH agonsit test  - 17 OHP - >152 ng/dl – s/o of Funtional ovarian hyperandrogenism
  • HCG stimulation test- 17 OHP - >152 ng/dl – s/o of Funtional ovarian hyperandrogenism
  • Short dexamethasone suppression test- testosterone >26 ng/dl – suggestive of the ovarian source of androgen
  • ACTH stimulation test – DHEA – 1500 ug/dl – s/o of Functional adrenal hyperandrogenism