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 examine whether activin has similar actions in primates, female rhesus monkeys (n = 3/treatment) exhibiting regular menstrual cycles received sc injections of either vehicle or 60 μg/kg recombinant human activin-A at 0800 and 1600 h for 1 (acute) or 7 (chronic) days beginning in the early follicular phase. The vehicle-treated monkeys displayed menstrual cycles of normal length, with the follicular (11.3 ± 1.3 days, mean ± SE) and luteal (16.6 ± 1.8 days) phases demarcated by midcycle peaks in serum estradiol (E) and bioactive LH. After the first activin 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. Although serum E and FSH levels did not change, LH increased (273%, P < 0.05) within 8 h. Acute activin treatment increased (P < 0.05) serum E within 24 h to levels (1290 ± 330 pmol/L) typically observed at midcycle. 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 pmol/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) whereas 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 activin, the expected midcycle rises in serum E and gonadotropins were delayed to greater than or equal to day 20 (n = 4) or did not occur before menses (n = 2). Although an enlarged ovary with one greater than or equal to 4-mm follicle was observed by laparoscopy during the late follicular phase in vehicle-treated monkeys, medium-to-large follicles were not visible on ovaries during chronic activin treatment or later at the expected midcycle interval in activin-treated monkeys. Similar hormonal and ovarian events were obtained after activin treatment of amenorrheic monkeys having serum FSH, LH, and E levels that were comparable to those at menses in spontaneous menstrual cycles. Thus, exogenous activin stimulates pituitary LH and FSH secretion and ovarian estrogen secretion during the early follicular phase in intact monkeys. However, acute or chronic activin treatment did not promote complete follicular development and disrupted subsequent events in the menstrual cycle. The study identifies for the first time potent actions and possible roles for activin in the normal and dysfunctional reproductive cycle in primates.