GONADOTROPIN GENE-EXPRESSION AND SECRETION IN GONADOTROPIN-RELEASING HORMONE ANTAGONIST-TREATED MALE-RATS - EFFECT OF SEX STEROID REPLACEMENT

The possibility of direct pituitary effects of sex steroids on gonadotropin gene expression and synthesis was studied in male rats. The animals were treated with a potent GnRH antagonist, Ac-D-pClPhe-D-pClPhe-D-Trp-Ser-Tyr-D-Arg-Leu-Arg-Pro-D-Ala-NH2CH3COOH (Org 30276; 0.5 mg/kg BW, sc, twice daily) for 10 days. Groups of the antagonisttreated rats were implanted at the beginning of the injections with Silastic capsules containing testosterone (T), 5α-dihydrotestosterone (DHT), or diethylstilbestrol (DES). Groups treated with the antagonist alone or vehicle served as controls. The antagonist treatment decreased unoccupied pituitary receptors of GnRH by 93% (P < 0.001), serum LH by 34% (P < 0.01), and serum FSH by 30% (P < 0.05), and serum T became undetectable (<0.10 nmol/liter). Compared to antagonist treatment alone, no further effects on serum or pituitary LH levels were found after steroid replacements. In contrast, the antagonist-induced decreases in serum and pituitary FSH (30% and 70%, respectively; P < 0.05−0.01) were totally reversed by the T and DHT implants, but not by DES. Pituitary levels of the LH β-subunit mRNA were decreased by 60% (P < 0.01) after antagonist treatment. Combination treatment with androgens had no further effect on this mRNA, whereas DES partially reversed this suppression (P < 0.05). In contrast, the pituitary mRNA level of the FSH β-subunit, which decreased with antagonist treatment by 90% (P < 0.01), returned to the control level with T and DHT replacements, but only partially with DES. The pituitary mRNA level of the common α-subunit was significantly suppressed only by combined antagonist plus DHT treatment (P < 0.01). However, combination of DES with the antagonist increased α-subunit mRNA levels 2.4-fold (P < 0.05) compared to antagonist treatment alone. It is concluded that the suppression of gonadotropin secretion by GnRH antagonist treatment is accompanied in male rats by a parallel reduction in mRNA levels of the gonadotropin β-subunits. Sex steroid replacement of the antagonist-treated animals selectively reverses some of the mRNA changes. Androgens (T and DHT) increase the mRNA of FSH β-subunit, but have no effect on the LH β-subunit. Estrogen increases the mRNA levels of common α-and LH β-subunits and slightly increases that of FSHβ. Since the action of endogenous GnRH was blocked in these in vivo experiments, the observations indicate that gonadal steroids are able to directly stimulate gonadotropin gene expression at the pituitary level. © 1990 by The Endocrine Society.