EFFECTS OF CONTINUOUS INHIBIN ADMINISTRATION ON GONADOTROPIN-SECRETION AND SUBUNIT GENE-EXPRESSION IN IMMATURE AND ADULT MALE-RATS

To begin to examine inhibin as a male contraceptive, recombinant human (rh) inhibin-A was administered for 3 days via osmotic minipumps to m ale rats. Doses of inhibin of 0-150 mg/kg per day did not produce a co ncentration-dependent suppression of FSH secretion or pituitary FSH be ta mRNA levels in adult rats. Treatment of immature rats at a dose of 145 mu g/kg per day, which was without effect in adults, reduced plasm a FSH levels by 49% (p < 0.01), and FSH beta mRNA levels to 47 +/- 11% of control (p < 0.01). Inhibin also decreased levels of LH beta mRNA (63 +/- 8% of control; p < 0.01), alpha-subunit mRNA (86 +/- 10% of co ntrol; p < 0.05), and GnRH-receptor mRNA (77 +/- 17% of control; p < 0 .01) in immature rats. Rh inhibin-A was more effective in immature tha n in adult animals: plasma inhibin levels were increased (p = 0.03) by rh inhibin-A treatment only in immature rats. Pharmacokinetic studies revealed that the weight-adjusted clearance was greater (p < 0.01), a nd the elimination half-life of rh inhibin A was shorter (p < 0.01) in adult than in juvenile rats. These data indicate that partial suppres sion of FSH beta mRNA by inhibin is associated with a decline in GnRH receptor gene expression, suggesting that the notion that inhibin can act as a male contraceptive through selective and complete inhibition of FSH production, without effect on LH and Leydig cell function, may be mistaken. In addition, increased inhibin clearance appears to contr ibute to the fall in plasma inhibin levels with maturation in the male rat.