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The recent demonstration using genetic tracing that in the adult pituitary stem cells are normally recruited from the niche in the marginal zone and differentiate into secretory cells in the adenopituitary has elegantly confirmed the proposal made when the pituitary stem cell niche was first discovered 5 years ago. Some of the early controversies have also been resolved. However, many questions remain, such as which are the markers that make a pituitary stem cell truly unique and the exact mechanisms that trigger recruitment from the niche. Little is known about the processes of commitment and differentiation once a stem cell has left the niche. Moreover, the acceptance that pituitary cells are renewed by stem cells implies the existence of regulated mechanisms of cell death in differentiated cells which must themselves be explained. The demonstration of an apoptotic pathway mediated by RET/caspase 3/Pit-1/Arf/p53 in normal somatotrophs is therefore an important step towards understanding how pituitary cell number is regulated. Further work will elucidate how the rates of the three processes of cell renewal, differentiation and apoptosis are balanced in tissue homeostasis after birth, but altered in pituitary hyperplasia in response to physiological stimuli such as puberty and lactation. Thus, we can aim to understand the mechanisms underlying human disease due to insufficient (hypopituitarism) or excess (pituitary tumor) cell numbers., (© 2015 S. Karger AG, Basel.)

The RET receptor is a tyrosine kinase receptor implicated in kidney and neural development. In the adenopituitary RET and the co-receptor GFRa1 are expressed exclusively in the somatotrophs secreting GH. RET is implicated in a clever pathway to maintain at physiological levels the number of somatotrophs and the GH production. Thus, in absence of its ligand GDNF, RET induces apoptosis through massive expression of Pit-1 leading to p53 accumulation. In the presence of the ligand GDNF, RET activates its tyrosine kinase and promotes survival at the expense of reducing Pit-1 expression and downregulating GH. Recent data suggest that RET can also have a second role in pituitary plasticity through a second co-receptor GFRa2., (Copyright (c) 2010 S. Karger AG, Basel.)

Growth hormone secretion by the somatotroph cells depends upon the interaction between hypothalamic regulatory peptides, target gland hormones and a variety of growth factors acting in a paracrine or autocrine fashion. This review will be focused on recent data regarding the mechanism by which growth hormone-releasing hormone (GHRH) influences somatotroph cell function and the physiological role played by Ghrelin and leptin in the regulation of growth hormone (GH) secretion. It is well established that binding of GHRH to its receptor leads to activation of protein kinase A (PKA). More recently, it was found that GHRH can also activate mitogen-activated protein (MAP) kinase both in pituitary cells and in a cell line overexpressing the GHRH receptor. Whether somatotroph adenomas, either with or without a GS-alpha mutation, have alterations in some of the components of the activation of the MAP kinase pathway remains to be known. The recent isolation of Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, can be considered a landmark in the GH field, which opens up the possibility of gaining greater insight into our understanding of the mechanisms involved in the regulation of GH secretion and somatic growth. Indeed, preliminary evidences indicate that this peptide exerts a marked stimulatory effect on plasma GH levels in both rats and humans. Finally, it is well known that GH secretion is markedly influenced by nutritional status. Leptin has emerged as an important adipose tissue-generated signal that is involved in the regulation of GH secretion, thus providing an integrated regulatory system of growth and metabolism. Although the effects of leptin on GH secretion in humans remain to be clarified, indirect evidences indicate that it may play an inhibitory role., (Copyright 2001 S. Karger AG, Basel.)

Prothymosin alpha (PTA) mRNA and histone H4 (H4) mRNA levels were studied in various experimental conditions that affected GH1 pituitary tumor cell proliferation. Cell proliferation and progression through the cell cycle was assessed by counting cells, 3H-thymidine incorporation and flow cytometry. PTA mRNA levels were decreased in a time-dependent fashion following serum deprivation; when the cells were induced to grow by serum refeeding, PTA mRNA expression was greatly stimulated. Interestingly, after caprylic acid treatment (2.5 mM for 24 h) that arrested cells in the G0/G1 phase of the cell cycle, PTA mRNA and H4 mRNA levels were almost undetectable; conversely, following caprylic acid withdrawal, PTA mRNA and H4 mRNA expression were greatly stimulated. Furthermore, cells cultured in T3-deprived serum, which was found to decrease GH1 cell proliferation, had low levels of PTA and H4 mRNAs. This effect was reversed by the addition of nanomolar concentrations of T3 to the culture. On the other hand, IGF-1 addition to the culture did not substantially modify PTA mRNA levels. The present data clearly indicate that PTA mRNA expression is tied to the proliferating activity of GH1 cells and, thus, could be used as a marker of the action that various agents have on GH1 cell proliferation.

His-dTrp-Ala-Trp-dPhe,Lys-NH2(GHRP-6) is a synthetic compound that releases GH in a dose-response and specific manner in several species and that may well be related to an endogenous compound of similar structure. The aim of this study was to investigate the in vivo GH responses to GHRP-6 in pentobarbital anesthetized rats. Specifically and in order to avoid the influence of endogenous GHRH and somatostatin secretion we studied the GH responses to GHRP-6 in animals with surgical ablation of the hypothalamus, confirmed by histological assessment, as well as in hypophysectomyzed-transplanted rats bearing two hypophyses under the renal capsule. Since it has been previously reported that rats pretreated with GHRH (10 micrograms/kg i.p. every 12 h for 15 days) rather than saline-treated rats have greater GH responses to acutely administered GHRH, we compared the self-potentiating effect of chronic GH pretreatment with GHRP-6 (10 micrograms/kg i.p. every 12 h). Furthermore we also studied the influence of estrogens, glucocorticoids, free fatty acids (FFA) and bombesin on somatotroph responsiveness to GHRP-6 in intact rats. We found a greater GH response to GHRP-6 in rats that underwent a surgical ablation of the hypothalamus 36 h prior to the test than in sham-operated rats. A direct stimulatory effect of GHRP-6 on in vivo GH secretion was demonstrated by a clear GH response to GHRP-6 in hypophysectomyzed-transplanted rats. In addition, we found a similar response whether the animals were pretreated with GHRH or GHRP-6 over the previous 2 weeks. Finally, we found that both estrogen- and testosterone-treated rats have greater GH responses to GHRP-6 than untreated rats. On the other hand, chronic dexamethasone administration, acute elevation of circulating FFA levels and bombesin administration markedly inhibited GH responses to GHRP-6. In contrast to the effects exerted on GH responses to GHRP-6 estrogen administration led to a decrease in GH responses to GHRH while dexamethasone did not affect the GH responses to GHRH, highlighting a differential regulation of these hormones on somatotroph responsiveness to these peptides.

The aim of this study was to determinate whether elevations in circulating free fatty acids (FFA) inhibit in vivo growth hormone (GH) responses to GH-releasing hormone (GHRH) by increasing hypothalamic somatostatin release or by acting directly on the pituitary. Thus, we have studied the effect of an Intralipid-heparin infusion on in vivo GH responses to GHRH in normal rats, normal rats passively immunized with antisomatostatin antiserum, rats with medial hypothalamic ablation, and hypophysectomized rats bearing two hypophyses under the renal capsule. Administration of 1 ml of Intralipid (500 microliters at -30 min and 500 microliters at -25 min) plus heparin (50 IU at -15 min) induced a marked decrease in GH responses to both 1 and 5 micrograms/kg of GHRH (p less than 0.01 at 5, 10 and 15 min for GHRH alone vs. GHRH plus Intralipid). A similar degree of inhibition was obtained after the administration of antisomatostatin antiserum (750 microliters i.v. at -60 min) previous to a challenge with 5 micrograms/kg of GHRH plus 1 ml of Intralipid (p less than 0.05 at 5 and 15 min, and p less than 0.01 at 10 min for GHRH plus normal rabbit serum vs. GHRH plus Intralipid plus antisomatostatin antiserum). Furthermore, administration of 1 ml of Intralipid also markedly reduced GH responses to GHRH in rats with medial hypothalamic ablation (p less than 0.01 at 5, 10, 15 and 30 min for GHRH alone vs. GHRH plus Intralipid) as well as in hypophysectomized rats bearing two hypophyses under the renal capsule (p less than 0.01 at 5, 10 and 15 min for GHRH alone vs. GHRH plus Intralipid).(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies carried out in normal male or ovariectomized female rats have shown that bombesin plays an inhibitory role on growth hormone (GH) secretion. Since estrogens play an important role in the neuroregulation of GH secretion, we have studied the effects of bombesin on basal GH secretion and GH responses to GH-releasing hormone (GHRH) in untreated and estrogen-treated male rats (200 micrograms estradiol valerate s.c., 1 single dose 3 days before the experiment or every 3 days for 2 weeks). All the experiments were carried out in rats anesthetized with pentobarbital. GH responses to GHRH (1 microgram/kg) were inhibited by bombesin (100 micrograms/kg) in untreated rats, but were markedly increased in rats treated with estrogens either 3 days before or for the previous 2 weeks. Similarly, bombesin administration (25 or 100 micrograms/kg) in estrogen-treated rats induced a clear-cut, dose-related increase in basal GH levels. This stimulatory effect of bombesin was not affected by passive immunization with antisomatostatin antiserum (750 microliters i.v., 60 min before) and only partially blocked by anti-rGHRH antiserum (750 microliters i.v., 1 h before). In conclusion, our data show that bombesin exerts an inhibitory effect in normal male rats but a stimulatory one in estrogenized rats. This latter effect is independent of somatostatin and only partially blocked by anti-rGHRH serum.