Hirsutism and Virilism

• Vellus hair


  Nonpigmented and soft, covers the entire body
• Terminal hair


  Pigmented and thick, covers the scalp, axilla, and pubic area
• Androgens


  Responsible for the conversion of vellus to terminal hair at puberty, resulting in pubic and axillary hair
• 5α-reductase


  Enzyme that converts testosterone to the more potent dihydrotestosterone (DHT)
• Hirsutism


  Increase in terminal hair on the face, chest, back, lower abdomen, and inner thighs in a woman
• Male escutcheon


  Diamond shaped pubic hair, as opposed to the triangular female escutcheon
• Virilization


  Development of male features, such as deepening of the voice, frontal balding, increased muscle mass, clitoromegaly, breast atrophy, and male body habitus
• The evaluation of hirsutism and virilism in the female patient is complex and requires the understanding of pituitary, adrenal, and ovarian function with detailed attention to the pathways of glucocorticoid, mineralocorticoid, androgen, and estrogen synthesis
• Adrenal cortex


  • Responsible for glucocorticoid, mineralocorticoid, and androgen synthesis
  • Composed of three layers: zona glomerulosa, zona fasciculata, and zona reticularis
• Zona glomerulosa


  Produces aldosterone, regulated primarily by the renin-angiotensin system
• Zona fasciculata and zona reticularis

  Produce both cortisol and androgens, regulated by ACTH
• ACTH


  Regulates the conversion of cholesterol to pregnenolone, which is then converted to progesterone, aldosterone, cortisol, or sex steroids
• Adrenal androgens


  Synthesized from the precursor 17α-hydroxypregnenolone, converted to DHEA, DHEAS, androstenedione, and finally to testosterone
• Ovarian androgens


  Produced by theca cells in response to LH, then aromatized to estrone and estradiol by granulosa cells in response to FSH
• Elevated LH:FSH ratio


  Leads to excess androgen production in the ovary
• Adrenal disorders leading to virilization

  • Nonneoplastic
  • Neoplastic (adrenal adenomas or carcinomas)
• Cushing syndrome


  Excess production of cortisol, leading to a concomitant hyperandrogenic state
• Cushing's disease


  Pituitary adenoma that hypersecrets ACTH, the most common cause of Cushing syndrome
• Overnight dexamethasone suppression test

  Used to diagnose Cushing syndrome, measures if adrenal gland decreases cortisol production in response to exogenous steroid
• Congenital adrenal hyperplasia (CAH)


  Enzyme deficiencies involved in steroidogenesis, most commonly 21α-hydroxylase deficiency
• 21α-hydroxylase deficiency


  Leads to accumulation of 17α-hydroxyprogesterone, which is shunted to the androgen pathway
• 11β-hydroxylase deficiency


  Leads to shunting of precursors to androstenedione and testosterone production pathways
• 3β-HSD deficiency


  Leads to accumulation of DHEA and its sulfate, which have mild androgenic effects
• ACTH stimulation test


  Used to confirm CAH diagnosis, measures 17-OHP response to ACTH administration
• Ovarian disorders leading to virilization

  • Nonneoplastic (polycystic ovarian syndrome, theca lutein cysts, stromal hyperplasia/hyperthecosis)
  • Neoplastic (functional ovarian tumors)
• Polycystic ovarian syndrome (PCOS)


  Common disorder involving excess LH stimulation leading to cystic changes and increased ovarian androgen secretion
• Theca lutein cysts


  Produce excess androgens that are secreted into the circulation, more common with elevated β-hCG
• Stromal hyperplasia and hyperthecosis

  Ovarian stromal lesions that can cause hirsutism and virilization
• Functional ovarian tumors


  • Sex-cord mesenchymal tumors
  • Sertoli-Leydig cell tumors
  • Granulosa-theca cell tumors
  • Hilar (Leydig) cell tumors
  • Germ cell tumors (gonadoblastomas)
• Luteoma


  Benign tumor that grows in response to hCG during pregnancy, can result in high testosterone/androstenedione and fetal virilization
• Functional ovarian tumors


  Tumors that can produce varying amounts of androgen, including sex-cord mesenchymal tumors, Sertoli-Leydig cell tumors (arrhenoblastoma), granulosa-theca cell tumors, hilar (Leydig) cell tumors, and germ cell tumors (gonadoblastomas)
• Sertoli-Leydig cell tumors


  • Usually occur in young women, account for less than 1% of all ovarian neoplasms
• Hilar cell tumors


  • Even rarer than Sertoli-Leydig cell tumors, usually seen in postmenopausal women
• Luteoma


  A benign tumor that grows in response to human chorionic gonadotropin during pregnancy
• Luteoma during pregnancy


  Can result in high levels of testosterone and androstenedione and virilization in 25% of patients, as well as virilization of 65% of female fetuses
• Nonfunctional ovarian tumors


  Can stimulate proliferation in the adjacent ovarian stroma, leading to increased androgen production
• Sex hormone binding globulin (SHBG)

  One of the major proteins that bind circulating testosterone, leaving a small proportion of free testosterone to interact at the cellular level
• Drugs that affect SHBG

  Androgens and corticosteroids decrease SHBG, leaving a greater percentage of free testosterone circulating
• Idiopathic hirsutism


  Hirsutism in the absence of adrenal or ovarian pathology, an exogenous source of androgens, or use of certain drugs
• Peripheral androgen production


  May be increased due to elevated 5α-reductase activity at the level of the skin and hair follicles in idiopathic hirsutism