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Introduction Gonadotropin-releasing hormone (GnRH) is the master molecule that regulates reproductive function, being secreted from the median eminence (ME) to stimulate synthesis and secretion of the gonadotropins, luteinising hormone (LH
Department of Neurosurgery, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
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Introduction Encoded by the Kiss1 gene, kisspeptin and its receptor, G protein-coupled receptor 54, stimulate the release of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) in mammals and are crucial in ovulation regulation
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-1359 19022888 Chen MD O’Byrne KT Chiappini SE Hotchkiss J Knobil E 1992 Hypoglycemic ‘stress’ and gonadotropin-releasing hormone pulse generator activity in the rhesus monkey: role of the ovary . Neuroendocrinology 56 666 – 673 . ( https://doi.org/10
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We previously isolated a novel dodecapeptide containing a C-terminal -Arg-Phe-NH(2) sequence, SIKPSAYLPLRF-NH(2) (RFamide peptide), from the Japanese quail (Coturnix japonica) brain. This novel quail peptide was shown to be located in neurons of the paraventricular nucleus (PVN) and their terminals in the median eminence (ME), and to decrease gonadotropin release from cultured anterior pituitary in adult birds. We therefore designated this peptide gonadotropin-inhibitory hormone (GnIH). Furthermore, a cDNA encoding the GnIH precursor polypeptide has been characterized. To understand the physiological roles of this peptide, in the present study we analyzed developmental changes in the expressions of GnIH precursor mRNA and the mature peptide GnIH during embryonic and posthatch ages in the quail diencephalon including the PVN and ME. GnIH precursor mRNA was expressed in the diencephalon on embryonic day 10 (E10) and showed a significant increase on E17, just before hatch. GnIH was also detected in the diencephalon on E10 and increased significantly around hatch. Subsequently, the diencephalic GnIH content decreased temporarily, and again increased progressively until adulthood. GnIH-like immunoreactive (GnIH-ir) neurons were localized in the PVN on E10, but GnIH-ir fibers did not extend to the ME. However, GnIH-ir neurons increased in the PVN on E17, just before hatch, and GnIH-ir fibers extended to the external layer of the ME, as in adulthood. These results suggest that GnIH begins its function around hatch and acts as a hypothalamic factor to regulate gonadotropin release in the bird.
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Secretion of luteinizing hormone in response to gonadotropin releasing hormone (GnRH) has been described in the recently developed LbetaT2 gonadotroph cell line. We evaluated the expression of follicle stimulating hormone (FSH)beta mRNA and secretion of FSH from LbetaT2 cells in response to GnRH and activin A. LbetaT2 cells were treated with activin A in doses from 0 to 50 ng/ml, with or without a daily 10 nM GnRH pulse, or with GnRH alone. FSH secretion was stimulated over 6-fold by concomitant GnRH and activin A in a dose-responsive fashion at 72 h of treatment. FSHbeta mRNA was detectable by ribonuclease protection assay only in cells treated with activin A with or without GnRH. The demonstration of FSHbeta gene expression in LbetaT2 cells further validates these cells as mature, differentiated gonadotrophs and as an important tool for the study of gonadotroph physiology.
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We have previously demonstrated that the release of arachidonic acid (AA) from human chorionic gonadotropin (hCG)-stimulated Leydig cells occurs in a dose- and time-dependent manner. In addition, the amount of AA released was dependent on the hormone-receptor interaction and the concentration of LH-hCG binding sites on the cell surface. The present study was conducted to evaluate the involvement of phospholipase A(2) (PLA(2)) and G proteins in AA release from hormonally stimulated rat Leydig cells, and the possible role of this fatty acid in cAMP production. Cells were first prelabelled with [(14)C]AA to incorporate the fatty acid into cell phospholipids, and then treated in different ways to evaluate AA release. hCG (25 mIU) increased the release of AA to 180+/-12% when compared with AA released from control cells, arbitrarily set as 100%. Mepacrine and parabromophenacyl bromide (pBpB), two PLA(2) inhibitors, decreased the hormone-stimulated AA release to 85+/-9 and 70+/-24% respectively. Conversely, melittin, a PLA(2) stimulator, increased the release of AA up to 200% over control. The inhibitory effect of mepacrine on the release of AA was evident in hCG-treated Leydig cells, but not in the melittin-treated cells. To determine if the release of AA was also mediated through a G protein, cells were first permeabilized and subsequently treated with pertussis toxin or GTPgammaS, a non-hydrolyzable analog of GTP. Results demonstrate that GTPgammaS was able to induce a similar level of the release of AA as hCG. In addition, pertussis toxin completely abolished the stimulatory effect of hCG on the release of AA, indicating that a member of the G(i) family was involved in the hCG-dependent release of AA. Cells treated with PLA(2) inhibitors did not modify cAMP production, but exogenously added AA significantly reduced cAMP production from hCG-treated Leydig cells, in a manner dependent on the concentration of AA and hCG. Results presented here suggest an involvement of PLA(2) and G proteins in the release of AA from hCG-stimulated Leydig cells, and under particular conditions, regulation of cAMP production by this fatty acid in these cells.
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We have previously described the preparation, purification and partial characterization of recombinant (rec) forms of rat luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In the present study, the special functional features of these hormones were studied further, in vitro and in vivo, and compared with human recLH and recFSH, as well as with human urinary choriongonadotropin (hCG) and rat pituitary LH (NIDDK-RP3). In radioreceptor assay, the affinity of hCG binding to rat testis membranes was 5-fold higher than that of human recLH and 100-fold higher than that of rat recLH. In in vitro bioassay, using dispersed adult mouse interstitial cells or a mouse Leydig tumor cell line (BLT-1), hCG and human recLH were 10- to 20-fold more potent than rat recLH. Correspondingly, rat pituitary LH was about 10-fold less potent than rat recLH, and evoked a maximum testosterone response that was about half of that elicited by the other LH/CG preparations. Rat recFSH was about 10-fold less potent than human recFSH in stimulating cAMP production of a mouse Sertoli cell line (MSC-1) expressing the recombinant rat FSH receptor. The circulating half-times (T1/2) of rat and human rec hormones were assessed after i.v. injections into adult male rats rendered gonadotropin-deficient by treatment with a gonadotropin-releasing hormone antagonist. A novel immunometric assay was used for the rat FSH measurements. In the one-component model the T1/2 values of rat and human recLH were 18.2 +/- 1.9 min (n = 7) and 44.6 +/- 3.1 min (n = 7) respectively and those of rat and human recFSH were 88.4 +/- 10.7 min (n = 6) and 55.0 +/- 4.2 min (n = 6) respectively; the two-component models revealed similar differences between the rec hormone preparations. Collectively, rat recLH was eliminated significantly faster from the circulation than human recLH (P < 0.0001). In contrast, the elimination of rat recFSH was significantly slower than that of human recFSH (P = 0.02). In conclusion, rat recFSH and rat recLH display lower biopotencies per unit mass than the respective human hormones in vitro, and also in vivo for LH. This is paralleled by shorter T1/2 of rat recLH than the respective human hormone in the circulation, whereas human recFSH has a shorter T1/2 than human FSH. The special functional features of the rat rec gonadotropins emphasize the use of these preparations on studies of gonadotropin function in the rat, an important animal model for reproductive physiology.
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An estradiol-induced prolactin surge accompanies the LH surge in several species, including sheep. However, the neural mechanisms underlying this surge remain poorly understood. A first study on estradiol- and progesterone-treated ovariectomized ewes examined whether the prolactin surge, like the LH surge, is sensitive to progesterone. Our data clearly showed that the estradiol-induced prolactin surge in the ewe is blocked by continuous exposure to progesterone and, importantly, that this blockade is overcome by pretreatment with the progesterone receptor antagonist, RU486. In a second study, we established that the generation of the prolactin surge is not dependent on the co-secretion of a prolactin-releasing peptide in the hypophyseal portal blood or cerebrospinal fluid. The neuronal pathways targeted by estradiol and progesterone to modulate prolactin secretion at the time of the LH surge remain to be identified. Importantly, it has not been established whether there is any overlap in the neuronal systems generating the gonadotropin-releasing hormone and prolactin surges.
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The neuropeptide control of gonadotropin secretion is primarily through the stimulatory action of the hypothalamic decapeptide, GnRH. We recently identified a novel hypothalamic dodecapeptide with a C-terminal LeuPro-Leu-Arg-Phe-NH2 sequence in the domestic bird, Japanese quail (Coturnix japonica). This novel peptide inhibited gonadotropin release in vitro from the quail anterior pituitary; thus it was named gonadotropin-inhibitory hormone (GnIH). GnIH may be an important factor regulating reproductive activity not only in domesticated birds but also in wild, seasonally breeding birds. Thus, we tested synthetic quail GnIH in seasonally breeding wild bird species. In an in vivo experiment, chicken gonadotropin-releasing hormone-I (cGnRH-I) alone or a cGnRH-I/quail GnIH cocktail was injected i.v. into non-breeding song sparrows (Melospiza melodia). Quail GnIH rapidly (within 2 min) attenuated the GnRH-induced rise in plasma LH. Furthermore, we tested the effects of quail GnIH in castrated, photostimulated Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii), using quail GnIH or saline for injection. Again, quail GnIH rapidly reduced plasma LH (within 3 min) compared with controls. To characterize fully the action of GnIH in wild birds, the identification of their endogenous GnIH is essential. Therefore, in the present study a cDNA encoding GnIH in the brain of Gambel's white-crowned sparrow was cloned by a combination of 3' and 5' rapid amplification of cDNA ends and compared with the quail GnIH cDNA previously identified. The deduced sparrow GnIH precursor consisted of 173 amino acid residues, encoding one sparrow GnIH and two sparrow GnIH-related peptides (sparrow GnIH-RP-1 and GnIH-RP-2) that included Leu-Pro-Xaa-Arg-Phe-NH2 (Xaa=Leu or Gln) at their C-termini. All these peptide sequences were flanked by a glycine C-terminal amidation signal and a single basic amino acid on each end as an endoproteolytic site. Although the homology of sparrow and quail GnIH precursors was approximately 66%, the C-terminal structures of GnIH, GnIH-RP-1 and GnIH-RP-2 were all identical in two species. In situ hybridization revealed the cellular localization of sparrow GnIH mRNA in the paraventricular nucleus (PVN) of the hypothalamus. Immunohistochemical analysis also showed that sparrow GnIH-like immunoreactive cell bodies and terminals were localized in the PVN and median eminence respectively. Thus, only the sparrow PVN expresses GnIH, which appears to be a hypothalamic inhibitory factor for LH release, as evident from our field injections of GnIH into free-living breeding white-crowned sparrows. Sparrow GnIH rapidly (within 2 min) reduced plasma LH when injected into free-living Gambel's white-crowned sparrows on their breeding grounds in northern Alaska. Taken together, our results indicate that, despite amino acid sequence differences, quail GnIH and sparrow GnIH have similar inhibitory effects on the reproductive axis in wild sparrow species. Thus, GnIH appears to be a modulator of gonadotropin release.
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Abstract
To clarify the possible mechanisms regulating prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) synthesis, the effects of gonadotropin-releasing hormone (GnRH) and substance P (SP) on the release of these two prostaglandins were studied in the oocytes of the crested newt, Triturus carnifex. Full-grown oocytes of T. carnifex, freed from follicular cells, were incubated in the presence of GnRH or SP and of the inhibitors of several enzymes involved in the release of arachidonic acid (AA) and in the conversion of AA into PGE2 and PGF2α. In parallel, the same experiments were performed on oocytes with membrane phospholipids labelled with [3H] AA. In addition, the PGE2-9-ketoreductase activity was evaluated through the conversion of [3H]PGE2 into [3H]PGF2α. The results showed that GnRH and SP could regulate prostaglandin synthesis through the activation of phospholipase C and diacylglycerol lipase, and through the modulation of PGE2-9-ketoreductase in the oocytes of T. carnifex. In particular, GnRH enhances the activty of PGE2-9-ketoreductase with a consequent increase in PGF2α, while SP inhibits the enzyme which leads to an increase in PGE2. A similar mechanism could also be hypothesized for other vertebrate species.
Journal of Endocrinology (1995) 145, 235–241
