HUMAN RECOMBINANT ACTIVIN-A ALTERS PITUITARY LUTEINIZING-HORMONE AND FOLLICLE-STIMULATING-HORMONE SECRETION, FOLLICULAR DEVELOPMENT, AND STEROIDOGENESIS, DURING THE MENSTRUAL-CYCLE IN RHESUS-MONKEYS

Activin, a stimulator of pituitary FSH secretion in nonprimate species , may also act in the ovary to modulate follicular development. To exa mine whether activin has similar actions in primates, female rhesus mo nkeys (n = 3/treatment) exhibiting regular menstrual cycles received s c injections of either vehicle or 60 mug/kg recombinant human activin- A at 0800 and 1600 h for 1 (acute) or 7 (chronic) days beginning in th e early follicular phase. The vehicle-treated monkeys displayed menstr ual cycles of normal length, with the follicular (11.3 +/- 1.3 days, m ean +/- SE) and luteal (16.6 +/- 1.8 days) phases demarcated by midcyc le peaks in serum estradiol (E) and bioactive LH. After the first acti vin injection, levels of human activin A peaked at 90 ng/mL within 1 h and returned to baseline before the second injection 8 h later. Altho ugh serum E and FSH levels did not change, LH increased (273%, P < 0.0 5) within 8 h. Acute activin treatment increased (P < 0.05) serum E wi thin 24 h to levels (1290 +/- 330 pmol/L) typically observed at midcyc le. With chronic treatment, serum E peaked on day 2 (2580 +/-338 pmol/ L; P < 0.05), then declined and rose to a second peak (1680 +/- 279 pm ol/L) on day 5. During chronic activin treatment, LH levels peaked on day 2 (603 +/- 270 ng/mL; P < 0.05 compared to day 0, 15 +/-7 ng/mL) w hereas FSH increased progressively until day 5 (937 +/- 320 ng/mL; P < 0.05 compared to day 0, 169 +/- 59 ng/mL). After acute or chronic act ivin, the expected midcycle rises in serum E and gonadotropins were de layed to greater than or equal to day 20 (n = 4) or did not occur befo re menses (n = 2). Although an enlarged ovary with one greater than or equal to 4-mm follicle was observed by laparoscopy during the late fo llicular phase in vehicle-treated monkeys, medium-to-large follicles w ere not visible on ovaries during chronic activin treatment or later a t the expected midcycle interval in activin-treated monkeys. Similar h ormonal and ovarian events were obtained after activin treatment of am enorrheic monkeys having serum FSH, LH, and E levels that were compara ble to those at menses in spontaneous menstrual cycles. Thus, exogenou s activin stimulates pituitary LH and FSH secretion and ovarian estrog en secretion during the early follicular phase in intact monkeys, Howe ver, acute or chronic activin treatment did not promote complete folli cular development and disrupted subsequent events in the menstrual cyc le. The study identifies for the first time potent actions and possibl e roles for activin in the normal and dysfunctional reproductive cycle in primates.