Physiological and Pharmacological overview of the Gonadotropin Releasing Hormone

Gonadotropin-releasing Hormone (GnRH) is a decapeptide responsible for the control of the reproductive functions. It shows C- and N-terminal aminoacid modifications and two other distinct isoforms have been so far identified. The biological effects of GnRH are mediated by binding to highaffinity G-protein couple receptors (GnRHR), showing characteristic very short C tail. In mammals, including humans, GnRH-producing neurons originate in the embryonic nasal compartment and during early embryogenesis they undergo rapid migration towards the hypothalamus; the increasing knowledge of such mechanisms improved diagnostic and therapeutic approaches to infertility. The pharmacological use of GnRH, or its synthetic peptide and non-peptide agonists or antagonists, provides a valid tool for reproductive disorders and assisted reproduction technology (ART). The presence of GnRHR in several organs and tissues indicates additional functions of the peptide. The identification of a GnRH/GnRHR system in the human endometrium, ovary, and prostate has extended the functions of the peptide to the physiology and tumor transformation of such tissues. Likely, the activity of a GnRH/GnRHR system at the level of the hippocampus, as well as its decreased expression in mice brain aging, raised interest in its possible involvement in neurogenesis and neuronal functions. In conclusion, GnRH/GnRHR appears to be a fascinating biological system that exerts several possibly integrated pleiotropic actions in the complex control of reproductive functions, tumor growth, neurogenesis, and neuroprotection. This review aims to provide an overview of the physiology of GnRH and the pharmacological applications of its synthetic analogs in the management of reproductive and non-reproductive diseases

Prolactin and Male Fertility: The Long and Short Feedback Regulation

In the last 20 years, a pituitary-hypothalamus tissue culture system with intact neural and portal connections has been developed in our lab and used to understand the feedback mechanisms that regulate the secretions of adenohypophyseal hormones and fertility of male rats. In the last decade, several in vivo rat models have also been developed in our lab with a view to substantiate the in vitro findings, in order to delineate the role of pituitary hormones in the regulation of fertility of male rats. These studies have relied on both surgical and pharmacological interventions to modulate the secretions of gonadotropins and testosterone. The interrelationship between the circadian release of reproductive hormones has also been ascertained in normal men. Our studies suggest that testosterone regulates the secretion of prolactin through a long feedback mechanism, which appears to have been conserved from rats to humans. These studies have filled in a major lacuna pertaining to the role of prolactin in male reproductive physiology by demonstrating the interdependence between testosterone and prolactin. Systemic levels of prolactin play a deterministic role in the mechanism of chromatin condensation during spermiogenesis

REVERSIBLE DOWNREGULATION OF HYPOTHALAMIC-PITUITARY-GONADAL AXIS IN THE STALLION WITH A THIRD-GENERATION GNRH ANTAGONIST

The objectives of this thesis were: (1) to evaluate the downregulation of the stallion hypothalamic-pituitary-gonadal (HPG) axis by a GnRH antagonist (acyline) based upon endocrine, seminal, testicular and behavioral effects, and (2) to assess recovery after treatment. Stallions were treated for 50 days (n=4; 330µg/kg acyline q 5d) and controls (n=4) received vehicle alone. Stallions were assessed pre-treatment and for 72 days after last treatment. Treatment induced declines (p\u3c0.05) in FSH, LH, testosterone (to castrate levels) and estrone sulfate. Gonadotropins and testosterone returned to control values within nine days and estrone sulfate by 14 days after treatment discontinuation. Acyline-treated stallions failed to respond with FSH, LH and testosterone increase after exogenous GnRH stimulation (25µg gonadorelin, IV) compared to pre-treatment and control stimulation. Total sperm numbers and motility were reduced in acyline-treated stallions, as well as total seminal plasma protein and testicular volume (p\u3c0.05). Time to ejaculation was increased in acyline group (p\u3c0.5). Testicular, sexual behavior and most seminal parameters regained normal levels within 72 days after treatment ceased. Sperm output of acyline-treated stallions was regained within seven months after ending treatment. Acyline reversibly suppressed the stallion HPG axis, thus has potential for treating the androgen-dependent Equine-Arteritis-Virus carrier state and as behavior modulator

Central mechanisms in the control of seasonal breeding in the Soay ram

The aims of the experiments described in this thesis were 1) to investigate the role of endogenous opioid peptides (EOP) in the control of pulsatile LH release in the ram, and 2) to study the generation of pineal melatonin rhythms and their role in relaying the effects of photoperiod on seasonal reproductive cycles in rams.A series of experiments was carried out on the effects of pharmacological opiate antagonists and agonists on LH secretion. Morphine significantly reduced LH pulse frequency in sexually active rams, and this effect was reversible by concurrent administration of the opiate antagonist naloxone, thus indicating the existence of specific opiate receptors. Naloxone injections alone increased LH pulse frequency in rams, showing that EOP mechanisms inhibit tonic LH secretion in a physiological situation. Effects of naloxone were studied at different stages of the seasonal reproductive cycle in rams maintained out -of- doors. Responses in intact rams were greater in the breeding season in September and December than when the rams were sexually quiescent in March and June. In pinealectomized rams which displayed a premature and attenuated reproductive cycle, LH responses to naloxone also correlated with testicular activity. These observations support the hypothesis that EOP mechanisms mediate the inhibitory effects of negative steroid feedback on LHRH secretion in the hypothalamus.Radioimmunoassay techniques were developed and validated for the extraction and measurement of poendorphin in tissue and plasma. Substantial levels of immunoreactive poendorphin (p0EP) were found in the preoptic area and median eminence /arcuate nucleas area in the hypothalamus of the sexually active ram. This distribution is similar Or) to that previously observed for LHRH, and is consistent with the view that the effects of naloxone on LH secretion result from antagonism of inhibitory EOP mechanisms on LHRH release. A considerable seasonal variation in peripheral blood plasma poEP concentrations was observed, levels being 5 -20 fold higher under short days than under long days. Studies suggest that this material is of pituitary origin, but its physiological function in peripheral target tissues is unknown.Studies were also made of melatonin rhythms and sexual responses in rams housed for prolonged periods under constant illumination (LL) and constant darkness (DD). After eight weeks under DD melatonin levels were not constantly elevated to normal nocturnal levels, though no clear 24 hour periodicity was evident. Likewise, under LL melatonin levels were not constantly suppressed. DD was unable to prevent gonadal regression in rams previously housed under photostimulatory short days, thus rams do not show the phenomenon of relative photorefractoriness. Paradoxically, stimulated testicular growth occurred in rams transferred from inhibitory long days to LL.A one hour light pulse per 24 hours re- established the melatonin rhythm in rams maintained in DD. The onset of the melatonin peak was shortly after the light pulse, suggesting that the pulse acts as an entrainment cue rather than by direct suppression of melatonin release. In a short term experiment a one hour light pulse was able to phase shift established melatonin rhythms free -running in constant darkness. A second light pulse given 7 hours after the first had only a transient suppressive effe ^t, thus the effect of light pulses on melatonin levels may depend on their temporal relationship to the endogenous melatonin rhythm. These observations are consistent with a model in which the (V1) environmental light -dark cycle regulates the melatonin rhythm by entraining two or more endogenous oscillators. The role of circadian rhythms in photoperiodic time measurement would appear to be in the generation of melatonin rhythms rather than in their ultimate interpretation by the hypothalamus

Secretory pattern of insulin-like peptide 3 and its regulation in male ruminants

Osaka Prefecture University (大阪府立大学)博士（獣医学）application/pdfThesis学位記番号：論獣第224号, 指導教員：玉田　尋通doctoral thesi