FSH

**Structure & synthesis:** FSH is a glycoprotein with an alpha subunit shared with LH, TSH, and hCG, and a unique beta subunit conferring specificity. It is produced by gonadotroph cells of the anterior pituitary (basophils). Pulsatile GnRH from the hypothalamus (arcuate nucleus) stimulates release; slower GnRH pulses favor FSH, faster pulses favor LH. Continuous (non-pulsatile) GnRH, such as with leuprolide, suppresses FSH/LH release through receptor downregulation.

**Mechanism:** The FSH receptor is a Gs-coupled GPCR (increased cAMP and PKA).

**Female physiology:** - Acts on granulosa cells to promote follicular recruitment and growth. - Induces aromatase, which converts androgens (made by theca cells under LH) into estradiol. This is the "two-cell, two-gonadotropin" model: LH acts on theca cells to make androgens, and FSH acts on granulosa cells to make estrogen. - FSH rises in the early follicular phase (and late luteal phase), which recruits a cohort of follicles. - Granulosa cells also secrete inhibin B, which selectively inhibits FSH. - Estradiol exerts negative feedback on FSH/LH early in the cycle. A sustained high estradiol level triggers positive feedback and the LH surge (FSH rises modestly too), causing ovulation.

**Male physiology:** - Acts on Sertoli cells to support spermatogenesis. It stimulates androgen-binding protein (ABP), which keeps intratubular testosterone high, and supports the blood-testis barrier. - Sertoli cells secrete inhibin B, which negatively feeds back on FSH. - LH acts on Leydig cells to produce testosterone, which feeds back on LH (and GnRH). - Sertoli cells also secrete Müllerian inhibiting factor (AMH) in fetal life.

**Clinical correlations:** - **High FSH (hypergonadotropic hypogonadism, primary gonadal failure):** - Menopause (loss of inhibin and estrogen; FSH is the earliest and most sensitive rise). - Primary ovarian insufficiency (premature ovarian failure, <40 years). - Turner syndrome (45,XO; streak ovaries). - Klinefelter syndrome (47,XXY; small firm testes, tall stature, gynecomastia, high FSH/LH, low testosterone, and low inhibin B). - Gonadal dysgenesis, post-chemotherapy/radiation, and Sertoli-cell-only syndrome (isolated high FSH with normal LH and testosterone). - **Low FSH (hypogonadotropic hypogonadism):** - Kallmann syndrome (defective GnRH neuron migration; anosmia). - Hypopituitarism (Sheehan syndrome, pituitary tumors). - Hyperprolactinemia (suppresses GnRH). - Functional hypothalamic amenorrhea (low body weight, stress, excessive exercise). - Anabolic steroid use in males (suppresses gonadotropins and causes testicular atrophy). - **PCOS:** The LH:FSH ratio is elevated (often >2:1). FSH is relatively low or normal, leading to arrested follicle maturation, anovulation, and multiple peripheral follicles. Hyperandrogenism results from LH-driven theca cell stimulation. - **Infertility treatment:** - Recombinant FSH and hMG (menotropins) are used for ovulation induction and IVF. - Clomiphene (SERM) blocks hypothalamic estrogen receptors, which increases GnRH and thereby FSH/LH. - Letrozole (aromatase inhibitor) lowers estrogen, which increases FSH. - GnRH agonists (continuous) or antagonists are used to prevent premature LH surge. - **Complications of FSH therapy:** Ovarian hyperstimulation syndrome (ascites, pleural effusion, hemoconcentration) and multiple gestation.

**High-yield pearls:** - FSH, LH, TSH, and hCG share a common alpha subunit. - Inhibin B (from granulosa/Sertoli cells) selectively suppresses FSH. Activin stimulates FSH. - Elevated FSH with amenorrhea indicates a gonadal (ovarian) cause. Check hCG first to exclude pregnancy, then TSH, prolactin, and FSH. - In an amenorrhea workup, a high FSH points to ovarian failure; a low or normal FSH points to a hypothalamic or pituitary cause (progestin challenge and estrogen status help differentiate). - Testosterone suppresses LH more than FSH. Inhibin B is the main feedback regulator of FSH in males.