Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man

We have tested the participation of endogenous opiate pathways in the negative feedback actions of gonadal steroids on pulsatile properties of luteinizing (LH) hormone release in normal men. To this end, sex steroid hormones were infused intravenously at dosages that under steady state conditions selectively suppressed either the frequency or the amplitude of the pulsatile LH signal. The properties of pulsatile LH secretion were assessed quantitatively by computerized analysis of LH series derived from serial blood sampling over 12 h of observation. When the pure (nonaromatizable) androgen, 5-α-dihydrotestosterone, was infused continuously for 108 h at the blood production rate of testosterone, we were able to achieve selective inhibition of LH pulse frequency akin to that observed in experimental animals after low-dosage androgen replacement. Under these conditions, serum concentrations of testosterone and estradiol-17β did not change significantly, but serum 5α-dihydrotestosterone concentrations increased approximately two- to threefold, with a corresponding increase in levels of its major metabolite, 5α-androstan-3α, 17β-diol. In separate experiments, the infusion of estradiol-17β at its blood production rate over a 4.5-d interval selectively suppressed LH pulse amplitude without influencing LH pulse frequency. Estrogen infusion increased serum estradiol-17β levels approximately twofold without significantly altering blood androgen concentrations. We then used these schedules of selective androgen or estrogen infusion to investigate the participation of endogenous opiates in the individual inhibitory feedback actions of pure androgen or estrogen on pulsatile LH release by administering a potent and specific opiate-receptor antagonist, naltrexone, during the infusions. Our observations indicate that, despite the continuous infusion of a dosage of 5α-dihydrotestosterone that significantly suppresses LH pulse frequency, co-administration of an opiate-receptor antagonist effectly reinstates LH pulse frequency to control levels. Moreover, during the infusion of a suppressive dose of estradiol-17β, opiate receptor blockade significantly augments LH pulse frequency and increases LH peak amplitude to control levels. Thus, the present studies in normal men demonstrate for the first time that the selective inhibitory action of a pure androgen on LH pulse frequency is effectively antagonized by opiate-receptor blockade. This pivotal observation indicates that opiatergic and androgen-dependent mechanisms specifically and coordinately control the hypothalamic pulse generator for gonadotropin-releasing hormone (GnRH). Moreover, endogenous opiate systems susceptible to blockade by naltrexone also interact significantly with estrogen's negative feedback regulation of LH peak amplitude. We conclude that the negative feedback actions of gonadal steroids are integrally coupled to endogenous opiate pathways and that such functional coupling is ultimately expressed at least in part at the level of the hypothalamic pulse generator for GnRH. These observations suggest a model for the proximate regulation of gonadotropin secretion in man, in which the regulatory actions of two major inhibitory systems-opiates and gonadal steroids-are effectively integrated by neural mechanisms.