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Hirsuitism (Pathologic (PCOS: Clinical syndrome characterized by: clinical…
Hirsuitism
Pathologic
Adrenal hyperplasia (Non-classic, late-to-onset)
Late-Onset CAH: Inherited LOF mutations that encode adrenal steroidogenic enzymes (partial enzyme deficiencies that decrease cortisol, loss of feedback inhibition increases ACTH secretion (ACTH -> adrenal gland hyperplasia))
21-hydroxylase deficiency: Hirsuitism, virilization, and oligo/amenorrhea. Low-normal FSH and LH
11-hydroxylase deficiency: Hirsuitism, virilization, and oligo/amenorrhea. Low-normal FSH and LH. Hypertension also present
3 B-hydroxysteroid dehydrogenase deficiency: Hirsuitism, virilization, and oligo/amenorrhea. Low-normal FSH and LH
Cushing syndrome: Hypercortisolism (ACTH-secreting pituitary tumor, cortisol-secreting adrenal adenoma), Hyperandrogenism (increased DHEA, DHEA-S, and ASD). Increased facial hair is the most common manifestation of androgen excess in Cushing syndrome.
Androgen-secreting tumors
: Rapidly progressive hisuitism, menstrual dysfunction, w/w/o masculinization.
Ovarian sex-cord tumors (Te)
Steroid cell tumor
Hilus cell tumor
Sertoli-Leydig tumor (most common androgen secreting ovarian tumor): Ages 20-40. extreme elevation of total Te (>12 mmol/L). DHEA-S is normal or slightly elevated (due to peripheral conversion to DHEA)
Adrenal tumors (DHEA-S)
Adenoma (rare)
Carcinoma
Hyperprolactinemia: Increases adrenal androgen secretion. Hirsutism and amenorrhea. Galactorrhea present in < 20%
Causes
Idiopathic
Medications: Increased Serotonin (SNRIs, SSRIs, and TCAs) -> VIP -> prolactin. Decreased dopamine (antipsychotics haloperidol and risperidone block dopamine -> no inhibition of prolactin release).
Prolactin-secreting microadenoma: Suprasellar and infundibular lesions, craniopharyngioma -> block dopamines inhibition of prolactin release.
Primary Hypothyroidism -> TRH -> increased prolactin
AKI and CKD: due to lack of renal clearance of prolactin.
Increased estrogen (i.e. pregnancy)
PCOS: Clinical syndrome characterized by: clinical or biochemical hyperandrogegism, ovulatory dysfunction (irregular menses), and ultrasound should polycystic ovarian morphology
Pathogenesis (3 synergistic mechanisms)
Hyperinsulinemia (most obese PCOS patients and 1/3 of non-obese PCOS patients)
Androgen excess
Hypothalamic pituitary-ovarian axis dysfunction: Increased GnRH pulse frequency which favors pituitary LH secretion over FSH secretion. I also increases ovarian ASD production (theca cells) over estradiol production (granulosa cells). Modestly elevated estrone levels (while estradiol is within a normal range still despite being elevated). Continuously elevated serum estrone -> stimulation of LH and inhibition of FSH (due to Inhibin B being produced by an increased number of arrested ovarian follicles also lowering FSH).
Lab tests: No lab tests are needed for Dx. Elevated Te confirms hyperandrogegism. LH and FSH usually in a normal ref range, but the 95% have an elevated LH: FSH ratio (>2.5 in non-obese PCOS patients, and between >1 and < 2.5 in obese PCOS patients).
Complications: Endometrial carcinoma (lifetime risk approx. 9%) (due reduced progesterone production and increased estrone levels), Metabolic syndrome, T2DM, Gestational DM and pre-eclampsia, Hyperlipidemia, HTN, CAD, LVH, HFpEF, OSA
HAIR-AN syndrome: subgroup of PCOS with clinical features that are more extreme. Severe IR -> acanthosis nigricans and a marked increased in ovarian androgen production -> hirsuitism.
Treatment:
Treating hirsutism: Diet, exercise and weight loss. Combined OCPs (decrease LH and ovarian ASD secretion, increase SHBG and lower free T). Spironolactone if OCPs fail (Blocks ARs in hair follicles, but can be teratogenic!)
Treating anovulation: Medications: Metformin (lowers insulin, lowers Te, and lowers estrone), Clomiphene (selective EsR modulator (SERM), decreases functioning hypothalamic EsRs, increases GnRH, and FSH secretion, restores ovulation and fertility)
Constitutional: Teenage onset, +FH,
FG score 8-15
, regular menstrual periods, normal androgen levels
Medication induced hair growth (hypertrichosis): Increased villus hair growth in androgen-dependent and independent areas. Meds include: minoxidil, phenothiazines, dilantin.
Onset at any age,
FG score > 15
, irregular menses or amenorrhea, elevated serum androgen levels, defeminization and/or virilization
Defeminization: loss of female body contour, breast atrophy
Virilization: Male pattern baldness, pustular acne or seborrhea, pectoral muscle hypertrophy, clitoromegaly (diameter > 4 mm)
Hyperinsulinemia -> Increased release of ASD from the adrenals and ovarian theca cells -> increased Te and Estrogens -> hyperandrogegism and hyperestrogenism
LH and FSH stay within a normal range, but the LH/FSH ratio is typically elevated (>2.5 in non-obese PCOS patients, and between >1 and < 2.5 in obese PCOS patients)
Look for: Hirsuitism, oligomenorrhea, and short stature (early epiphyseal closure due to excess androgens being aromatized to estrogen)
Thought to be due to increased 5-alpha reductase.