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

Abstract

As bstract. 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-a-dihydrotestosterone, was infused continuously for 108 h at the blood production rate of testosterone, we were able to achieve selective inhibition ofLH pulse frequency akin to that observed in experimental animals after low-dosage androgen replacement. Under these conditions, serum concentrations of testosterone and estradiol-1 7,3 did not change significantly, but serum 5a-dihydrotestosterone concentrations increased approximately two-to threefold, with a corresponding increase in levels of its major me- tabolite, 5a-androstan-3a, 17f-diol. In separate experiments, the infusion of estradiol-1 7#3 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-1 73 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 5a-dihydrotestosterone that significantly suppresses LH pulse frequency, co-administration of an opiate-receptor antagonist effectively reinstates LH pulse frequency to control levels. Moreover, during the infusion of a suppressive dose of estradiol-1 73, 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 oW servation indicates that opiatergic and androgen-dependent mechanisms specifically and coordinately control the hypothalamic pulse generator for gonadotropin-re- 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...

Expression of gonadotropin-releasing hormone receptors and autocrine regulation of neuropeptide release in immortalized hypothalamic neurons.

“…The receptor-mediated actions of GnRH on the neuronal network of GnRH cells (6,7), with decreases in the frequency and increases in the amplitude of GnRH pulses, lead to switching of the pattern of neuropeptide secretion from the basal pulsatile mode to one of episodic secretion and surge-like release as observed during the preovulatory period (34). Several other neuropeptides are known to modulate the activity of the GnRH pulse generator and may participate in the control of the preovulatory GnRH surge (8)(9)(10)(11)(12)(13)(14)(15)(16). There is also abundant evidence that estrogen promotes the development of the midcycle luteinizing hormone surge (35)(36)(37).…”

“…Recently, pulsatile neuropeptide secretion was found to be an intrinsic property of GnRH neuronal networks and to depend on voltage-sensitive Ca2+ influx for its maintenance (4-7). The activity of the GnRH pulse generator is influenced by several factors, including endothelin, N-methyl-D-aspartate, opiates, -aminobutyrate, and a-adrenergic input, as well as estrogens and androgens (8)(9)(10)(11)(12)(13)(14)(15)(16)). In addition, GnRH has been proposed to exert an inhibitory action on its own secretion (17-19); however, the mechanism and circuitry of such an ultrashort loop feedback effect have not yet been defined.…”

Association Between Genetic Polymorphisms of the ^|^beta;1-Adrenergic Receptor and Sensitivity to Pain and Fentanyl in Patients Undergoing Painful Cosmetic Surgery

“…A previous report demonstrated that the selective inhibitory effect of a pure androgen on luteinizing hormone pulse frequency was effectively antagonized by opioid receptor blockade (32). Therefore, sex hormones may affect endogenous opioid pathways, which may lead to sex differences in the sensitivity to pain and fentanyl.…”

Effects of decreasing the frequency of gonadotropin-releasing hormone stimulation on gonadotropin secretion in gonadotropin-releasing hormone-deficient men and perifused rat pituitary cells.

“…Secondly, the quantity of GnRH within each pulse is directly related to the magnitude of the ensuing luteinizing hormone (LH) response from the pituitary (3,4). Thirdly, the gonadotropin response to GnRH is modulated by the ambient levels of gonadal steroids (5)(6)(7)(8)(9). Finally, recent studies have demonstrated that the frequency of GnRH stimulation may itself be a critical determinant of the pituitary response to GnRH.…”