follicle-stimulating hormone

STRUCTURE/SYNTHESIS: FSH is a heterodimeric glycoprotein with an alpha subunit shared with LH, TSH, and hCG, and a unique beta subunit that confers specificity. It is made by basophilic gonadotroph cells of the anterior pituitary. Secretion is driven by pulsatile hypothalamic GnRH. Slow pulses favor FSH, and fast pulses favor LH. Continuous GnRH (e.g., leuprolide) suppresses FSH and LH through receptor downregulation. This is used for prostate cancer, endometriosis, fibroids, and precocious puberty.

RECEPTOR/SIGNALING: FSH binds a Gs-coupled GPCR, which raises cAMP and activates PKA.

FEMALE PHYSIOLOGY: FSH acts on granulosa cells. It recruits and grows follicles in the early follicular phase and induces aromatase, which converts androgens to estrogens. The androgens come from theca cells under LH control (the two-cell, two-gonadotropin model). FSH also induces LH receptors on granulosa cells before the LH surge. Rising estrogen and inhibin B give negative feedback on FSH, and this selects the dominant follicle. High sustained estrogen then produces positive feedback, causing the LH surge (with a smaller FSH surge) and ovulation. FSH is highest in the early follicular phase and at midcycle.

MALE PHYSIOLOGY: FSH acts on Sertoli cells, which are in the seminiferous tubules. It supports spermatogenesis and stimulates production of androgen-binding protein, which keeps intratubular testosterone high. Sertoli cells also secrete inhibin B, which selectively inhibits FSH. LH acts on Leydig cells to make testosterone. Remember: FSH goes to Sertoli, LH goes to Leydig.

FEEDBACK: Inhibin B (granulosa and Sertoli cells) inhibits FSH only. Estrogen and testosterone inhibit both FSH and LH. Activin stimulates FSH.

CLINICAL CORRELATES: - High FSH (hypergonadotropic hypogonadism, primary gonadal failure): menopause, premature ovarian insufficiency (FSH >25–40 mIU/mL on repeated testing before age 40), Turner syndrome (45,XO; streak ovaries, primary amenorrhea), Klinefelter syndrome (47,XXY; small firm testes, high FSH and LH, low inhibin B, low or normal testosterone), and gonadal damage from chemotherapy or radiation. Selective isolated FSH elevation with normal LH suggests seminiferous tubule damage in men, which is associated with infertility and low inhibin B. - Low FSH (hypogonadotropic hypogonadism): Kallmann syndrome (GnRH neuron migration defect with anosmia), Sheehan syndrome, pituitary adenoma or other mass, hyperprolactinemia, hypothalamic amenorrhea (low weight, athletes, stress), and anabolic steroid use (exogenous testosterone suppresses the axis). - PCOS: the LH:FSH ratio is increased (often >2:1) because FSH is relatively low. This gives follicular arrest, anovulation, and androgen excess. Diagnosis uses the Rotterdam criteria. - Infertility: recombinant FSH and hMG are used for ovulation induction and IVF. Clomiphene (a SERM) blocks hypothalamic estrogen receptors, which raises GnRH, FSH, and LH. Risks of FSH stimulation include ovarian hyperstimulation syndrome and multiple gestation. In men with hypogonadotropic hypogonadism, hCG (LH-like) plus FSH restores spermatogenesis. - Primary vs secondary: in amenorrhea or hypogonadism workup, high FSH points to a gonadal (primary) cause, and low or normal FSH points to a hypothalamic or pituitary (secondary) cause.

HIGH-YIELD PEARLS: The alpha subunit is shared with LH, TSH, and hCG. Pituitary tumors that secrete gonadotropins are usually clinically silent "null cell" or gonadotroph adenomas. Postmenopausal FSH is markedly elevated because of loss of estrogen and inhibin feedback. Oral contraceptives suppress FSH and LH, which prevents follicular development and ovulation.