Action Of Pituitary Hormones Research Articles

Independent Skeletal Actions of Pituitary Hormones.

Over the past years, pituitary hormones and their receptors have been shown to have non-traditional actions that allow them to bypass the hypothalamus-pituitary-effector glands axis. Bone cells-osteoblasts and osteoclasts-express receptors for growth hormone, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), prolactin, oxytocin, and vasopressin. Independent skeletal actions of pituitary hormones on bone have been studied using genetically modified mice with haploinsufficiency and by activating or inactivating the receptors pharmacologically, without altering systemic effector hormone levels. On another front, the discovery of a TSH variant (TSH-βv) in immune cells in the bone marrow and skeletal action of FSHβ through tumor necrosis factor α provides new insights underscoring the integrated physiology of bone-immune-endocrine axis. Here we discuss the interaction of each pituitary hormone with bone and the potential it holds in understanding bone physiology and as a therapeutic target.

Actions of pituitary hormones beyond traditional targets.

Studies over the past decade have challenged the long-held belief that pituitary hormones have singular functions in regulating specific target tissues, including master hormone secretion. Our discovery of the action of thyroid-stimulating hormone (TSH) on bone provided the first glimpse into the non-traditional functions of pituitary hormones. Here we discuss evolving experimental and clinical evidence that growth hormone (GH), follicle-stimulating hormone (FSH), adrenocorticotrophic hormone (ACTH), prolactin, oxytocin and arginine vasopressin (AVP) regulate bone and other target tissues, such as fat. Notably, genetic and pharmacologic FSH suppression increases bone mass and reduces body fat, laying the framework for targeting the FSH axis for treating obesity and osteoporosis simultaneously with a single agent. Certain 'pituitary' hormones, such as TSH and oxytocin, are also expressed in bone cells, providing local paracrine and autocrine networks for the regulation of bone mass. Overall, the continuing identification of new roles for pituitary hormones in biology provides an entirely new layer of physiologic circuitry, while unmasking new therapeutic targets.

Chronic subcutaneous infusion of neurosecretory protein GM increases body mass gain in chicks

Recently we discovered a small hypothalamic protein in the chicken, named neurosecretory protein GL (NPGL), which is associated with body growth and energy metabolism in birds and rodents. Genome database analysis suggested that the NPGL gene has a paralogous gene in vertebrates, named neurosecretory protein GM (NPGM). However, the biological action of NPGM remains unclear. In this study, we investigated whether NPGM affects body growth in chicks. We found that subcutaneous infusion of NPGM for six days increased body mass gain in a dose-dependent manner. Despite the observed increase in body mass, infusion of NPGM did not alter food and water intake. Of note, we observed tendency of mass increase of several peripheral tissues, specifically. When we compared several tissue types, NPGM seemed to induce the largest growth increase in white adipose tissue mass. These results suggest that NPGM may accelerate fat accumulation and body growth. In addition, we analyzed whether NPGM increases body growth through the action of pituitary hormones. However, we observed no significant changes in mRNA expression of pituitary hormones or plasma levels of growth hormone in NPGM-treated chicks. This is the first report describing the biological action of NPGM in vertebrates.

Pituitary-bone connection in skeletal regulation.

Pituitary hormones have traditionally been thought to exert specific, but limited function on target tissues. More recently, the discovery of these hormones and their receptors in organs such as the skeleton suggests that pituitary hormones have more ubiquitous functions. Here, we discuss the interaction of growth hormone (GH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), prolactin, oxytocin and arginine vasopressin (AVP) with bone. The direct skeletal action of pituitary hormones therefore provides new insights and therapeutic opportunities for metabolic bone diseases, prominently osteoporosis.

Bone and hypopituitarism: not only a mass issue

Bone and hypopituitarism: not only a mass issue

Role of Pituitary Hormones on 17α-Ethinylestradiol-Induced Cholestasis in Rat

Estrogens cause intrahepatic cholestasis in susceptible women during pregnancy, after administration of oral contraceptives, or during postmenopausal hormone replacement therapy. 17alpha-Ethinylestradiol (EE) is a synthetic estrogen widely used to cause experimental cholestasis in rodents with the aim of examining molecular mechanisms involved in this disease. EE actions on the liver are thought to be mediated by estrogen receptor alpha (ERalpha) and pituitary hormones. We tested this hypothesis by analyzing metabolic changes induced by EE in livers from hypophysectomized (HYPOX) and hypothyroid rats. Microarray studies revealed that the number of genes regulated by EE was increased almost 4-fold in HYPOX rat livers compared with intact males. Little overlap was apparent between the effects of EE in intact and HYPOX rats, demonstrating that pituitary hormones play a critical role in the hepatic effects of EE. Consistently, hypophysectomy protects the liver against induction by EE of serum bilirubin and alkaline phosphatase, two markers of cholestasis and hepatotoxicity and modulates the effects of EE on several genes involved in bile acid homeostasis (e.g., FXR, SHP, BSEP, and Cyp8b1). Finally, we demonstrate a novel mechanism of action of EE through binding and negative regulation of glucocorticoid receptor-mediated transcription. In summary, pituitary- and ERalpha-independent mechanisms contribute to development of EE-induced changes in liver transcriptome. Such mechanisms may be relevant when this model of EE-induced cholestasis is evaluated. The observation that the pharmacological effects of estrogen in liver differ in the absence or presence of the pituitary could be clinically relevant, because different drugs that block actions of pituitary hormones are now available.

Luteinizing Hormone-Releasing Hormone-Induced Regulation of Gonadotropin and Prolactin Receptors in the Rat Testis

Regulation of LH receptors in the testis is highly sensitive to the circulating LH concentration, and marked loss of receptor sites has been demonstrated after treatment with exogenous gonadotropins such as hCG and ovine LH. Treatment with potent LHRH analogs has also been shown to cause loss of testicular LH receptors in rats, presumably due to elevation of endogenous gonadotropin secretion. To analyze the relationship between the changes in plasma gonadotropins and the receptor content of the testis, the effects of single doses (0.1, 1, and 10 μg) of the natural LHRH decapeptide on LH secretion and testicular receptors were examined in 55-day-old rats. After sc administration of LHRH, serum LH and testosterone values peaked at 15 and 60 min, respectively, and declined to normal values over the subsequent 4 h. In contrast with these rapid and transient plasma hormone responses, the gonadotropin (LH and FSH) and PRL receptor content of the testis exhibited delayed and protracted changes after single doses of LHRH. Between 8–48 h after administration of LHRH, there was a marked and consecutive loss of FSH-, PRL-, and LH-binding sites, each of which returned to control values after about 5 days. The magnitude and duration of receptor loss was related to the dose of LHRH administered, with almost total abolition of binding sites after treatment with 10 μg LHRH. The time sequence of plasma gonadotropin levels in relation to LH receptor regulation was similar to that caused by administration of exogenous gonadotropin, suggesting that the transient peak in serum LH initiated a process of negative regulation - that was manifested by the subsequent decrease in testicular receptor sites. The marked changes in gonadotropin and PRL receptors provide an explanation for the inhibitory effects of LHRH treatment on ovarian and testicular function. In addition, these actions of LHRH can be utilized to investigate the complex process of multiple receptor loss and regeneration that may accompany the physiological actions of pituitary hormones in the testis.

Hormonal Interactions in Regulation of Androgen Secretion

The action of pituitary hormones on testicular steroidogenesis is reviewed with particular focus on follicle stimulating hormone (FSH) and prolactin (PRL). Production of androgens by the testis depends on luteinizing hormone (LH) and the action of LH on the Leydig cells. There is evidence that FSH augments the action of LH on plasma testosterone (T) levels and on the growth of androgen-dependent male accessory reproductive glands. During sexual maturation FSH has a physiological role in increasing the responsiveness of the testes to LH stimulation. PRL augments the effect of endogenous or exogenous LH on testicular steriodogenesis. The effects of PRL seem to indicate direct action on the Leydig cells. PRL also seems to increase stores of cholesterol ester to provide a pool of precursors for steroidogenesis. PRL may be very important in sexual maturation. The review suggests that the regulation of testicular steroidogenesis depends on a complex of adenohypopyhseal hormones that FSH and PRL are both important components of this complex and that steroidogenesis regulation in the testis resembles steroidogenesis regulation in the ovary.

HYPOPHYSIS AND FUNCTION OF PANCREATIC ISLETS

The effects of the recognized diabetogenic hormones, growth hormone and ACTH, administered in vivo, on (pro-)insulin biosynthesis and secretion in isolated islets of normal rats were studied. Rats were treated with these hormones for 4 weeks. Afterwards, their collagenase-isolated islets were incubated with [3H]leucine for 3 h. (Pro-)Insulin biosynthesis was estimated for the incorporation data into islet protein fractions. Islets of treated rats released significantly more insulin and incorporated significantly less [3H]leucine into proinsulin and insulin compared with controls when tested at 100 mg glucose/100 ml. At 200 mg glucose/100 ml, no significant differences were found. The findings demonstrate an impact of these hormones on the B-cells derived from normal pancreas of intact rats. The alterations are, however, not very pronounced and can be easily compensated under a strong glucose stimulus. It appears that the mechanisms for (pro-)insulin biosynthesis and release in rats are more resistant against the diabetogenic actions of pituitary hormones than in other species.

Inhibition of action of pituitary hormones by animal sera

In these ‘Proceedings’ for 1934 (Thompson and Cushing, 1934) appeared the report of an experimental effort to reproduce the clinical syndrome of pituitary basophilism in a puppy by means of injections of a gonadotropic extract prepared from sheep-pituitaries. Certain striking effects were observed in the experimental animal, namely, obesity, a lowered metabolism, sexual inactivity, and retardation of growth with skeletal dystrophy. These effects, while in some respects suggesting the human disorder, basophilism, could in others be interpreted broadly as an inhibition of normal processes simulating hypophysectomy. Further experiments with other gonadotropic preparations have since been made, and each time some form of inhibition has developed in the animals. In order to investigate the nature of these reactions the blood sera of some of the injected dogs were tested by methods suggested by Collip and his co-workers in their several reports concerning “antihormones” (Anderson and Collip, 1934, a , b , c ; Bachman, 1935; Bach­man and Collip, 1934; Collip, 1934; Collip and Anderson, 1935). It will be recalled, briefly, that Anderson and Collip (1934, a ) first detected an antagonistic activity of the blood sera of animals which had become insensitive to injected thyrotropic extract. Bachman, Collip, and Selye (1934) shortly afterwards stated in regard to gonadotropic extract that “the loss of sensitivity is limited to the gonadotropic preparation with which the animals have been injected previously. Animals which become insensitive to pituitary implants remain sensitive to A. P. L.* and vice versa ”. The term “antihormone”, subsequently used by Collip and his co-workers to indicate this inhibitory action, is now well known and requires no explanation.

Normergic and allergic inflammation

The first, ordinary or normergic response of the body to a foreign protein (pollen, vegetable protein, bacteria, foreign animal protein) that has penetrated the body tissues varies from a negligible reaction to a severe inflammation depending upon the inherent toxicity of the substance and upon the dose. The body is then more or less sensitized to the foreign substance, and upon repeated exposure to it the inflammatory response differs from the original reaction in that the onset is more rapid, the course more violent, and the resolution of the process slower. Hyperergic reactions of this sort analogous in many respects to conditioned reflexes occur not only in the clinical allergies but also in other forms of anaphylaxis, in idiosyncrasy, and in immunity. In contrast to the hyperergic state of allergy there is a hypoergic or anergic state in which the body fails to react to an excitant, a condition not to be confused with acquired immunity. As is well known, allergic reactions are influenced by the number and size of the sensitizing and shocking doses and by the time intervals. They vary from functional, vascular responses and hypertonus or spasm of smooth muscle to the severe necrotizing inflammation characterizing the Arthus phenomenon. Under certain circumstances specific granulomatous lesions result. Although it is possible that all the cells in the body may be sensitized, allergic reactions are ordinarily exhibited by the arterial system, connective and lymphoid tissues, and synovial, ectodermal and entodermal membranes, whereas the parenchymatous tissues are usually spared. Evidence is accumulating that many of the drug idiosyncrasies with reversible and irreversible tissue changes are in reality true hyperergic allergic reactions, the drug as such or the drug as modified by the body acting as a hapten. The hyperergic reactions in immunity are completed without injury to the body health. They represent a perfect adaptation of the body to the various antigens. A further complicating factor influencing certain inflammations is the reaction of specifically sensitized tissues to a nonspecific allergen. A typical example of this sort is the transitory positive tuberculin reaction in certain individuals following vaccination with cowpox virus. Moro and Keller consider such reactions to be parallergic. Other parallergic reactions are likewise involved in mixed infections, superinfections, and complications of infections. The severe hemorrhagic lesions experimentally produced in the Sanarelli and Shwartzman phenomena are likewise parallergic reactions, as are also the severe vascular lesions with thrombosis and gangrene produced by Marcus and Schmidt-Weyland in rabbits sensitized with certain bacteria or bacterial toxins and then injected repeatedly with adrenalin. It is possible likewise that the hemorrhagic necrotic lesions in the liver in eclampsia may result from the action of pituitary hormone in excess after sensitization of the individual by some foreign excitant. In analyzing the tissue changes of inflammation the rôle of the factors outlined by Rössle and appearing above in diagrammatic form must be considered.