Disease relevance of GNRH

• Signaling and antiproliferative effects of type I and II gonadotropin-releasing hormone receptors in breast cancer cells [1].
• These data indicate that neonatal immunization does not affect the synthesis of GnRH in adulthood but reduces the secretion of GnRH, causing long-term sterility in these animals [2].
• Hypersensitivity (2-fold increase) to GnRH was briefly observed at the beginning of the period of E2beta-facilitated LH release [3].
• Eighteen prepubertal lambs (21 weeks of age, 34.2 +/- 1.5 kg body weight) were treated intravenously with either NMA (2 mg/kg, n = 6) or GnRH (68 ng/injection or approximately 2 ng/kg, n = 6) for 3 days, every 2 h on day 1 and every 1 h on days 2 and 3, or received no treatment (controls, n = 6) [4].
• Although application as a fertility control agent in men is unlikely, there is renewed interest in active immunization against GnRH as a means of treating prostate cancers and related steroid-dependent pathologies [5].

High impact information on GNRH

• During the follicular phase of the estrous cycle, cortisol reduces luteinizing hormone pulse frequency, most likely via the inhibition of gonadotropin-releasing hormone pulsatility [6].
• Using an estrogen (E)-free ovine model, we investigated the immediate GnRH and luteinizing hormone (LH) response to acute manipulations of circulating P concentrations and whether this response was mediated by the nuclear P receptor [7].
• Progesterone (P) powerfully inhibits gonadotropin-releasing hormone (GnRH) secretion in ewes, as in other species, but the neural mechanisms underlying this effect remain poorly understood [7].
• The negative feedback actions of progesterone on gonadotropin-releasing hormone secretion are transduced by the classical progesterone receptor [7].
• Taken together, these results suggest that GnRH metabolism in the hypothalamus may occur via a two-step process involving first removal of Gly10-NH2 by prolyl endopeptidase, followed by cleavage by endopeptidase 24.15 at the Tyr5-Gly6 bond [8].

Biological context of GNRH

• Direct effects of luteal regression on anterior pituitary response to GNRH [9].
• Estradiol profoundly influences GnRH secretion during the follicular phase of the estrous cycle of the sheep [10].
• In the luteal phase, LH was basal, indicating low GnRH secretion [11].
• Pattern of gonadotropin-releasing hormone (GnRH) secretion leading up to ovulation in the ewe: existence of a preovulatory GnRH surge [12].
• As a possible structural basis for seasonality, we examined the ultrastructure and synaptic inputs of GnRH neurons in the preoptic area of ewes during the breeding season and seasonal anestrus [13].

Anatomical context of GNRH

• We conclude that gonadotropin release from the pituitary gland requires the continual presence of GnRH during the ascending limb of the preovulatory gonadotropin surge, and that once the surge has been triggered, the ovaries do not appear to be required for further hypothalamic stimulation [14].
• There were no significant changes in the amount of GnRH contained in the preoptic area, the median eminence, or the hypothalamus [15].
• In the Suffolk ewe, seasonal reproductive transitions are due primarily to changes in the responsiveness of the GnRH neurosecretory system to the negative feedback influence of estradiol [13].
• When delivered to the anterior pituitary gland continuously, GnRH decreases numbers of GnRH receptors on gonadotropes [16].
• Simultaneous measurement of gonadotropin-releasing hormone in the third ventricular cerebrospinal fluid and hypophyseal portal blood of the ewe [17].

Associations of GNRH with chemical compounds

• Degradation of synthetic GnRH1-9 was more rapid than that of GnRH and was inhibited by CFP-AAY-pAB but not bacitracin [8].
• Indeed, both bacitracin and Z-Pro-prolinal, inhibitors of this enzyme, markedly reduced GnRH degradation to any product [8].
• The suppressive effect of estradiol on GnRH secretion, however, was delayed relative to that on LH [18].
• A gamma-aminobutyric acidB agonist reverses the negative feedback effect of testosterone on gonadotropin-releasing hormone and luteinizing hormone secretion in the male sheep [19].
• Effects of epinephrine, norepinephrine, and dopamine on gonadotropin-releasing hormone-induced secretion of luteinizing hormone in vitro [20].

Physical interactions of GNRH

• Estradiol and gonadotropin-releasing hormone (GnRH) interact to increase GnRH receptor expression in ovariectomized ewes after hypothalamic-pituitary disconnection [21].

Regulatory relationships of GNRH

• Extracellular signal-regulated kinase, Jun N-terminal kinase, p38, and c-Src are involved in gonadotropin-releasing hormone-stimulated activity of the glycoprotein hormone follicle-stimulating hormone beta-subunit promoter [22].

Other interactions of GNRH

• Does the type II glucocorticoid receptor mediate cortisol-induced suppression in pituitary responsiveness to gonadotropin-releasing hormone [23]?
• Thyroid hormone receptor (alpha) distribution in hamster and sheep brain: colocalization in gonadotropin-releasing hormone and other identified neurons [24].
• Are immediate early genes involved in gonadotropin-releasing hormone receptor gene regulation? Characterization of changes in GnRH receptor (GnRH-R), c-fos, and c-jun messenger ribonucleic acids during the ovine estrous cycle [25].
• Stimulating effect of glycoprotein hormone free alpha-subunit and daily gonadotropin releasing hormone treatment on prolactin release from 50-day ovine foetal pituitary explants [26].
• Regulation of gonadotropin releasing hormone release by neuropeptide Y at the median eminence during the preovulatory period in ewes [27].

Analytical, diagnostic and therapeutic context of GNRH

• The number of receptors for GnRH (GnRH-rec) can vary from 500 to 15,000-20,000/gonadotrope in ovine pituitary cultures after treatment with physiologically relevant combinations of gonadal hormones [28].
• We suggest that Fos expression in GnRH cells is markedly increased by the positive feedback action of estradiol (surge), whereas short-term removal of negative feedback (ovariectomy) has little, if any, effect, despite increased GnRH release in both states [11].
• Experiments were performed using an animal model in which GnRH secretion was blocked by progesterone, which in itself does not block the pituitary response to GnRH [29].
• Further studies on the radioimmunoassay of gonadotropin-releasing hormone: effect of radioiodination, antiserum and unextracted serum on levels of immunoreactivity in serum [30].
• Intact ewes treated with 100 micrograms GnRH also released an amount of LH similar to that in the control group [14].

References