The ontogenesis of pituitary hormones and hypothalamic factors in the human fetus: maturation of central nervous system regulation of anterior pituitary function.
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Lutropin (LH), follitropin (FSH), and thyrotropin (TSH) from pituitary and human chorionic gonadotropin (hCG) from placenta are a family of glycoprotein hormones, each with an alpha and beta subunit. The alpha subunits of all four hormones have the same amino acid sequence, whereas biological specificity is determined by their unique beta subunits. The carbohydrate compositions of these hormones indicate the structures of their Asn-linked oligosaccharides are not identical. Sulfate is present on most, but not all, of these hormones, and for bovine LH is attached to GalNAc (Green, E.D., van Halbeek, H., Boime, I., and Baenziger, J.U. (1985) J. Biol. Chem. 260, 15623-15630). We used a reconstituted cell-free system to study sulfation of bovine (b) and human (h) glycoprotein hormones and its relationship to glycosylation. Exogenously added bLH, bTSH, bFSH, hLH, and hTSH are sulfated exclusively on the oligosaccharides of both alpha and beta subunits. The distribution of sulfated oligosaccharide structures varies among the hormones and appears to result from differences in the extent and/or pathway of oligosaccharide processing. Significant amounts of disulfated, dibranched complex oligosaccharides are present on all the sulfated hormones. Human FSH is not susceptible to sulfation unless first treated with neuraminidase. The sulfated oligosaccharides obtained from bovine FSH and desialylated human FSH are unlike those of the other hormones. Therefore, there is differential processing of the oligosaccharides on pituitary hormones. For FSH and LH, which are believed to be synthesized in the same cell, we would suggest that the unique beta subunits may regulate processing of all oligosaccharides present on the alpha-beta dimers.
We recently identified a novel set of Rab and its effector, Rab27a/granuphilin, that possibly regulates the exocytosis of insulin-containing, dense core granules in pancreatic beta-cells. In the present study we characterized another isoform, Rab27b, to further investigate the function of the Rab27 subfamily. Among the tissues examined, Rab27b is most abundantly expressed in pituitary tissue, where Rab27a is preferentially expressed. It is also significantly expressed in brain and spleen, where Rab27a is minimally expressed. Rab27a and Rab27b are differentially expressed in pituitary cell types that secrete different peptide hormones. Rab27b associates with secretory granules and granuphilin in the pituitary endocrine cell line AtT20. Furthermore, overexpression of its inactive mutant, Rab27b N133I, significantly inhibits basal and forskolin-induced ACTH secretion in AtT20 cells. These findings indicate that Rab27b is involved in pituitary hormone secretion, which further supports the idea that members of the Rab27 subfamily regulate the exocytosis of dense core granules containing peptide hormones in endocrine cells.
The hypothalamic hypophysiotrophic neurones are densely innervated by adrenergic and noradrenergic nerve terminals. Activation of alpha 1-adrenoceptors located in the brain stimulates the secretion of ACTH, prolactin and TSH. The effects of the alpha 1-adrenoceptors seem to be exerted on hypothalamic neurones that secrete vasopressin, CRH-41 and TRH. These mechanisms are important in the physiological control of the secretion of ACTH and TSH in humans. alpha 2-Adrenoceptors are not involved in the control of secretion of these hormones under basal conditions in humans. However, alpha 2-adrenoceptors exert an inhibitory effect that acts as a negative feedback mechanism, limiting excessive secretion of these hormones. There is no convincing evidence for the involvement of beta-adrenoceptors in the control of the secretion of these three hormones in humans. Studies on cultured anterior pituitary cells suggested that adrenaline and noradrenaline may influence the secretion of ACTH, prolactin and TSH directly at the level of the pituitary. However, these effects are not demonstrable in humans, and are likely to be due to alterations in the pituitary adrenoceptors during culture. In the case of growth hormone, activation of alpha 2-adrenoceptors located in the brain stimulates secretion of this hormone both by increasing the secretion of GHRH and by inhibiting the secretion of somatostatin. Activation of beta-adrenoceptors inhibits the secretion of growth hormone via an increase in the secretion of somatostatin. The effects of the central alpha 2- and beta-adrenoceptors are important in the physiological control of growth hormone secretion in humans. A considerable amount of evidence implicates brain alpha 1-adrenoceptors in the control of secretion of the gonadotrophins in experimental animals, but, despite intensive study, no convincing evidence has been found in humans of reproductive age.
The effect of chronic (3--9 months) therapy with metoclopramide on serum levels of pituitary and thyroid hormones was studied in 4 males and 1 female. The mean serum prolactin concentration during metoclopramide therapy was significantly higher than after discontinuation of metoclopramide. Serum prolactin concentrations increased acutely after each dose of metoclopramide. Serum prolactin concentrations increased acutely after each dose of metoclopramide, and gradually returned to normal by 6--12 h. There was no sifgnificant differences in the serum TSH, T3, T4, GH, and gonadotrophin levels during and after metoclopramide administration. In the male subjects the mean serum testosterone was normal, but significantly lower during metoclopramide therapy.
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The immunologically and biologically active molecular characteristics of human glycoprotein hormones were studied with the aid of previously produced and characterized monoclonal antibodies (MCA). Placentally derived human chorionic gonadotropin (hCG) and pituitary human follicle stimulating hormone (hFSH) were taken as examples for the use of MCA in the elucidation of molecular morphological and functional correlations and the diagnostic application of these findings. The immunological surface of hCG and of hFSH was probed by 26 MCA to these hormones and bovine luteinizing hormone. In 2-site immunoassays--resembling immunoradiometric assays (IRMA)--pairs of MCA were applied to simultaneous scanning of the molecules. Nine different recognition patterns were distinguished in the case of hCG and 5 for hFSH, reflecting the same number of immunological epitopes. These were either located on the alpha- or beta-subunit or expressed only by the conformationally intact molecule (c-epitopes). The construction of an immunological map revealed an equatorial cluster of alpha-, beta- and c-epitopes, with distinct epitopes on each subunit. This suggests a similar immunological arrangement of epitopes on all human glycoprotein hormones. Antigenic determinants of all 3 main specificities (alpha, beta, c) are involved in the expression of the biological activity of hCG. Surprisingly, hCG is not functionally neutralizable by means of MCA to one of the epitopes (beta 3)--although located on the hormone-specific beta-subunit which is evolutionary highly conserved throughout a large number of mammalian species. On the basis of the epitope map it was possible to establish IRMAs with predictable specificities for selective measurement of hFSH and hCG and its subunit.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration of d-fenfluramine, a serotonin-releasing drug, to male rats induced a dose-dependent increase in both serum prolactin and corticosterone concentrations. Serum growth hormone levels increased, but not significantly, at a dose of 1.25 mg/kg i.p. and decreased significantly at higher doses. When rats were pretreated with the serotonin uptake inhibitor fluoxetine (10 mg/kg i.p.) 30 min prior to injection of d-fenfluramine (5 mg/kg i.p.), the serum prolactin response to d-fenfluramine was partially inhibited, whereas the growth hormone response was not significantly modified. Fluoxetine pretreatment increased the serum corticosterone to the same level as did d-fenfluramine. d-Fenfluramine's effect on prolactin and growth hormone release was further tested in a hypothalamic-pituitary in vitro system. The addition of d-fenfluramine (5-500 ng/mL) for 30 min to rat hypothalami resulted in an enhancement of prolactin and growth hormone-releasing activities. These were expressed as the ability of the media in which the hypothalami had been incubated to stimulate prolactin and growth hormone release by cultured pituitary cells. The data suggest that the effect of d-fenfluramine on prolactin secretion is exerted through the hypothalamus and is probably mediated, at least partially, by a serotoninergic mechanism. The mechanism of d-fenfluramine's effect on corticosterone and growth hormone release needs further evaluation.
Data concerning the presence in the central nervous system of the anterior and intermediate lobe hormones ACTH, beta-lipotropin, alpha-melanocyte stimulating hormone, beta-endorphin, prolactin, growth hormone, gonadotrophic hormone, and thyrotropin stimulating hormone are reviewed. Available evidence for the ACTH-lipotropin family of peptides indicates that synthesis can occur in brain as well as in pituitary. Although behavioral effects have been described for some of these peptides and their fragments (ACTH, alpha-MSH, beta-endorphin, prolactin), the physiological relevance and the mechanisms of such effects, the nature of the biosynthetic pathways involved, and the factors regulating the brain concentrations of these peptides remain to be explored.
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Thirteen healthy postmenopausal volunteers were studied under basal conditions and at intervals (days 1, 5, 10, and 30) after intravaginal placement of a polysiloxane ring impregnated with 400 mg of estradiol. Mean serum estradiol concentrations rose 26-fold with a twofold increase in serum estrone concentrations. Serum delta 4-androstenedione, dehydroepiandrosterone sulfate, and total testosterone did not change, but absolute and percent free testosterone concentrations declined significantly by day 5. Concurrently, serum concentrations of immunoactive follicle-stimulating hormone declined progressively, while serum luteinizing hormone and free alpha-subunit concentrations exhibited a biphasic pattern of suppression. Serum levels of prolactin increased monophasically and those of growth hormone, somatomedin C, and thyroid-stimulating hormone did not change.
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