activin

STRUCTURE: Activin is a dimer of inhibin β subunits: activin A (βA-βA), activin B (βB-βB), activin AB (βA-βB). Inhibin is a heterodimer of an α subunit plus a βA (inhibin A) or βB (inhibin B) subunit. Both are members of the TGF-β superfamily.

SIGNALING: Activin binds the type II serine/threonine kinase receptor (ActRIIA/IIB), which recruits and phosphorylates the type I receptor (ALK4). This phosphorylates receptor-regulated SMAD2/3, which complex with SMAD4 (co-SMAD), translocate to the nucleus, and regulate gene transcription. Inhibin blocks activin by competing for ActRII binding (with betaglycan as co-receptor). Follistatin binds and neutralizes activin directly.

REPRODUCTIVE PHYSIOLOGY (high-yield): - Activin is produced by granulosa cells (females), Sertoli cells (males), and the pituitary. It stimulates FSH synthesis and secretion from gonadotrophs. - Inhibin B is secreted by Sertoli cells (in response to FSH) and granulosa cells, and selectively inhibits FSH by negative feedback. Inhibin A is secreted by the corpus luteum and rises in the luteal phase. - Sertoli cells: FSH drives inhibin B secretion, which suppresses FSH. Low inhibin B is a marker of impaired spermatogenesis or Sertoli cell dysfunction (for example, Klinefelter syndrome, which has high FSH and low inhibin B). - Women: Falling inhibin B and rising FSH are an early sign of diminished ovarian reserve and menopause. High FSH with low inhibin occurs in primary ovarian insufficiency. - Activin also promotes follicular development, granulosa cell FSH receptor expression, and oocyte maturation.

OTHER ACTIONS: - Embryology: Mesoderm induction and left-right axis patterning (Nodal, which is related, signals through the same receptors). - Stimulates erythroid differentiation (originally called erythroid differentiation factor). - Involved in wound healing, inflammation, and fibrosis. Activin A is raised in sepsis and some cancers (cachexia). - Bone and muscle: Activin and myostatin (GDF-8) negatively regulate muscle mass via ActRIIB. Activin ligand traps are being studied for muscle wasting.

CLINICAL CORRELATIONS: - Sluspatercept and sotatercept are activin/TGF-β ligand traps. Sluspatercept (a modified ActRIIB-Fc fusion) is used for anemia in β-thalassemia and myelodysplastic syndromes by promoting late-stage erythroid maturation. Sotatercept (an ActRIIA-Fc fusion) is approved for pulmonary arterial hypertension by rebalancing BMP and activin signaling. - Inhibin A is part of the second-trimester quadruple screen: Down syndrome (trisomy 21) shows ↑ inhibin A and ↑ hCG with ↓ AFP and ↓ estriol. - Inhibin B and inhibin A are tumor markers for granulosa cell tumors of the ovary (Call-Exner bodies, estrogen excess) and sex cord-stromal tumors. Inhibin is also elevated in some mucinous ovarian tumors. - Fibrodysplasia ossificans progressiva (ACVR1/ALK2 gain-of-function) causes aberrant response to activin A and heterotopic ossification.

HIGH-YIELD PEARL: FSH is stimulated by activin and GnRH, and suppressed by inhibin. LH is not directly inhibited by inhibin. Remember that activin = FSH ↑, inhibin = FSH ↓.