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Testosterone Differentially Modulates Gonadotropin Subunit Messenger Ribonucleic Acid Responses to Gonadotropin-Releasing Hormone Pulse Amplitude^*

Division of Endocrinology and Metabolism, Department of Internal Medicine, and the Unit for Laboratory Animal Medicine (S.A.I.-S.), University of Michigan Medical Center Ann Arbor, Michigan 48109

Address requests for reprints to: Dr. John C. Marshall, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan Medical Center, 1500 East Medical Center Drive, 3920 Taubman Center, Box 0354, Ann Arbor, Michigan 48109-0354.

Abstract

Testosterone (T) inhibits GnRH secretion and can also modulate the effects of GnRH on gonadotropin synthesis and secretion. To assess the effect of T on GnRH stimulation of a, LHβ, and FSHβ mRNA expression, we replaced T at three levels to reproduce low (1.5 ± 0.5 ng/ml), medium (3.5 ± 0.3 ng/ml), and high (6.2 ± 0.6 ng/ml) physiological plasma concentrations. Additionally, as peripheral conversion to dihydrotestosterone (DHT) or estradiol (E2) may mediate T action, the effects of GnRH pulses in the presence of DHT and E2 were also studied. Male rats were castrated, and steroids were replaced via implants containing either T (three doses) or DHT or Ez (two doses each). GnRH pulses (10–250 ng/pulse) were administered iv at 30-min intervals for 48 h. Pituitary subunit mRNA concentrations, gonadotropin content, and LH and FSH secretion were determined.

The patterns of a, LHβ, and FSHβ mRNA responses to increasing GnRH pulse amplitude were similar at all concentrations of plasma T. a mRNA concentrations were increased 2- to 4-fold by GnRH pulses. At the same plasma T concentration, all doses of GnRH produced similar increases in a mRNA, but the response tended to be lower at the higher (6.2 ng/ml) levels of T. LHβ mRNA showed a clear dependence on GnRH pulse amplitude, with the maximum responses (2- to 3-fold) occurring after 10- to 25-ng GnRH pulses. At the higher (3.5 and 6.2 ng/ ml) T concentrations, the dose-response curve was shifted to the left. The lowest GnRH pulse dose (10 ng) produced maximum responses, and LHβ mRNA increments in response to the higher GnRH doses were suppressed. FSHβ mRNA concentrations were increased by T in saline-pulsed controls. FSHβ mRNA responses were similar (2- to 3-fold) after all GnRH doses and at all concentrations of T. Increasing GnRH pulse doses reduced the pituitary content of both LH and FSH at all levels of T. Acute LH secretion was maximal after 10- and 25-ng pulses of GnRH when plasma T was low, but increased progressively with GnRH dose at the highest plasma T concentrations. Plasma FSH did not show any differential responsiveness to GnRH pulse dose or to increasing plasma T. Thus, LH synthesis and secretion are affected more than those of FSH by changing plasma concentrations of T. T may modulate posttranslational events in LH secretion. The higher GnRH doses effected LH release without increasing LHβ mRNA in the presence of higher physiological concentrations of T.

Increasing plasma concentrations of DHT from 158 ± 10 to 241 ± 37 pg/ml did not alter the pattern of gonadotropin subunit mRNAs, pituitary gonadotropin content, or plasma gonadotropin responses to GnRH. The overall patterns were similar to those observed in T-replaced rats. E2 concentrations of 19.9 ± 2.0 or 39.9 ± 3.6 pg/ml also did not substantially change the apparent GnRH dose-dependent responses. Of note, E2 increased a-subunit mRNA concentrations (2-fold) in both the presence and absence of GnRH compared to those in animals treated with either T or DHT.

The results demonstrate that the GnRH pulse amplitude appears to be a more important determinant of subunit mRNA responses and hormone secretion than the gonadal steroid milieu. However, changes in T in the physiological range can directly modulate responses, particularly those of LHβ, to GnRH pulse ampitude. Higher T concentrations enhance LHβ mRNA and suppress LH release in response to low dose GnRH, but suppress mRNA and enhance LH release in response to high dose GnRH pulses. Thus, T appears to modify both pre- and posttranslational events in LH synthesis and secretion, with its actions dependent upon the GnRH pulse amplitude. (Endocrinology 127: 2876–2883, 1990)

Footnotes

^* This work was supported by USPHS Grants HD-11489 and HD-23736 (to J.C.M.), HD-23736 (to D.J.H.), and HD-07269 (to A.C.D.), NIH Laboratory Animal Science and Medicine Grant RR-07088, and NIH Animal Resource Branch Grant RR-00200 (to Daniel Ringler, Department of Veterinary Medicine, Unit for Laboratory Animal Medicine, University of Michigan.

Received June 21, 1990.

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