POLYCYSTIC OVARY SYNDROME

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 A. Background and classification :

 1. Can be a cause of infertility in up to 20% of infertile couples

 2. Mainly considered to be caused by androgen excess or hyperandrogenism 

 3. Underlying cause appears to be insulin resistance (in patients with and without obesity), with subsequent compensatory insulin hypersecretion or increased insulin action. This increased action stimulates androgen secretion by the ovaries or adrenal cells, leading to increased luteinizing hormone (LH) secretion but normal or low follicle-stimulating hormone (FSH) concentrations, with a subsequent decrease in follicular maturation and anovulation .

4. Has several potential comorbidities with endocrine and cardiovascular implications (e.g., T2D, obesity) 5. Can affect 6%–10% of women (or more depending on diagnostic criteria used), making it one of the most prevalent endocrine disorders in young women .

 6. No clear consensus on classifying polycystic ovary syndrome (PCOS), although some rate it from mild to severe 7. Endocrine Society has the only recent guideline on PCOS diagnosis and treatment.

B. Diagnosis 

 1. Still somewhat under debate; no clear consensus.

  2. 1990 National Institutes of Health criteria: 

 a. Hyperandrogenism or hyperandrogenemia

 b. Oligo-ovulation (infrequent or irregular ovulation)

 c. Exclusion of other secondary causes, particularly adrenal hyperplasia, Cushing syndrome, hyperprolactinemia.

 3. 2003 Rotterdam criteria: Presence of at least two of the following and ruling out secondary causes.

 a. Menstrual irregularity (oligo-ovulation or anovulation)

 b. Hyperandrogenism (clinical or biochemical signs)

 c. Polycystic ovaries (by transvaginal ultrasonography) 

 d. Recommended by the Endocrine Society guideline 4. 2006 Androgen Excess Society: Follow 1990 National Institutes of Health criteria, but recognize concerns brought about from the Rotterdam criteria .

C. Clinical presentation :

 1. Clinical signs of hyperandrogenism: Hirsutism, acne, pattern alopecia (can vary by ethnicity).

  2. Biochemical signs of hyperandrogenism (should not be used as the sole criterion because 20%–40% of patients with PCOS may be in the normal range) a. Elevated free or total serum testosterone b. LH/FSH ratio greater than 2.

 3. Infrequent, irregular (e.g., late), or no ovulation, leading to irregular menses.

  4. Infertility despite unprotected and frequent intercourse during the past year.

  5. In patients with obesity (50%–80% of cases), prediabetes (impaired glucose tolerance) or T2D may be present.

D. Therapy goals :

1. Normalize ovulation and menses.

 2. Improve fertility in those who want to become pregnant.

 3. Limit clinical signs. 4. Reduce progression to T2D (perhaps cardiovascular disease).

E. Non-pharmacologic therapy 

1. Weight loss (5%–10%) important in patients who are overweight or obese .
2. Mechanical hair removal for hirsutism.

F. Pharmacotherapy 

 Fertility improvement 

 a. Clomiphene citrate

 i. Mechanism of action: Induces ovulation as a selective estrogen receptor modulator that improves LH-FSH secretion .

ii. Dosing

 (a) 50 mg/day for 5 days starting on the third or fifth day of the menstrual cycle.

  (b) Increase to 100 mg if ovulation does not occur after first cycle of treatment. 

 (c) Maximal daily dosage 150–200 mg/day.

iii. Adverse effects: Flushing, GI discomfort, vision disturbances, vaginal dryness, multiple pregnancies iv. Drug of choice for infertility according to the Endocrine Society guideline.

 vi. Improved ovulation and pregnancy rates when used in combination with metformin.

b. Gonadotropin (e.g., recombinant FSH) or recombinant gonadotropin-releasing hormone therapy with or without clomiphene.

  i. Mechanism of action: Normalizes LH/FSH ratio to stimulate ovulation.

  ii. Dosing: Many dosing strategies used .

iii. Adverse effects: Multiple pregnancies, ovarian hypertrophy, miscarriage, mood swings, breast discomfort.

2. Symptomatic improvement

 a. Hormonal contraceptives (estrogen/progestin combination): Endocrine Society first-line therapy for menstrual abnormalities, hirsutism, or acne b. Metformin.

  i. Effective for metabolic and glycemic abnormalities, if present, but only modestly effective for hirsutism.

  ii. Alternative to hormonal contraception for irregular menses when hormonal contraceptives are contraindicated .

iii. Few data to support use for increased fertility (may improve pregnancy rate but not shown to improve rates of live births).

c. Spironolactone

i. Often added to hormonal contraceptives .
ii. Can help with hirsutism d. Pioglitazone: Questionable whether benefits outweigh risks in PCOS. Not recommended in Endocrine Society guidelines.