Abstract
Rat Leydig cells possess functional high affinity receptors for corticotropin-releasing factor (CRF). CRF inhibited human chorionic gonadotropin (hCG)-induced androgen production in cultured fetal and adult Leydig cells in a dose-dependent manner, but it had no effect on basal testosterone secretion. Comparable inhibitory effects of CRF were observed in the presence or absence of 3-isobutyl-1-methylxanthine. CRF treatment caused a marked reduction of steroid precursors of the androgen pathway (from pregnenolone to testosterone) during gonadotropin stimulation, but it did not influence their basal levels. The inhibitory action of CRF on hCG-induced steroidogenesis was fully reversed by 8-bromo-cAMP but was not affected by pertussis toxin. The action of CRF was rapid; and it was blocked by coincubation with anti-CRF antibody. CRF caused no changes in hCG binding to Leydig cells, and in contrast to other target tissues, CRF did not stimulate cAMP production, indicating that CRF receptors are not coupled to Gs in Leydig cells. These studies have demonstrated that CRF-induced inhibition of the acute steroidogenic action of hCG is exerted at sites related to receptor/cyclase coupling or cAMP formation. The inhibitory effects of CRF in the Leydig cell do not occur through the Gi unit of adenylate cyclase, but could involve pertussis toxin-insensitive G protein(s). These observations demonstrate that CRF has a novel and potent antireproductive effect at the testicular level. Since CRF is synthesized in the testis and is present in Leydig cells, it is likely that locally produced CRF could exert negative autocrine modulation on the stimulatory action of luteinizing hormone on Leydig cell function.
Highlights
From theEndocrinology and Reproduction Research Branch, Section on Molecular Endocrinology, National Instituteof Child Health and HumanDevelopment, National Institutes of Health, Bethesda, Maryland 20892
CRF-like immunoreceptorsforcorticotropin-releasingfactor (CRF) caused no changes in human chorionic gonadotropin (hCG) binding to the staining for CRF in adult rat testis is localized in the Leydig cells, and in contrast to other target tissues, Leydig cells, germ cells, and epididymal spermatozoa
These studies have demonstrated that CRF-in- were drastically reduced after hypophysectomy, indicating duced inhibition of the acute steroidogenic action of thatCRFproduction in thetestisisundergonadotropin hCG is exerted at sites related to receptor/cyclasceou- control [12]
Summary
Val. 264, No 4, Issue of February 5, pp. 2156-2163.1989 Printed in U.S.A. From theEndocrinology and Reproduction Research Branch, Section on Molecular Endocrinology, National Instituteof Child Health and HumanDevelopment, National Institutes of Health, Bethesda, Maryland 20892. In Leydig the levels of the peptide in the testicular extracts cells These studies have demonstrated that CRF-in- were drastically reduced after hypophysectomy, indicating duced inhibition of the acute steroidogenic action of thatCRFproduction in thetestisisundergonadotropin hCG is exerted at sites related to receptor/cyclasceou- control [12]. After 4 days of culture, media werecollected and cells were washed two times with medium 199 and incubated with or without hCG (10 pg/well) in the presence or in the absence of various concentrations of oCRF for an additional 3 hto monitor acute maximal steroidogenic responses to trophic hormone. In separate experiments the effect of CRF on hCG acute stimulation of the adult Leydig cells was studied by treating thecells in the presence or in the absence of 0.12 mM phosphodiesterase inhibitor, MIX. In some experiments the effect of CRF treatment on '"I-hCG binding in adult Leydig cells was studied. For in uitro assessment of steroidogenesis, three wells were used for each drug treatment, and each experiment was repeated at least three times
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