Regulation of growth hormone release from cultured human pituitary adenomas by somatomedins and insulin

GH secretion is stimulated by hypothalamic GH-releasing factor (GHRH) and inhibited by somatostatin. Since GH induces the production of insulin-like growth factors (IGF) in liver and other tissues, it is of interest to learn whether IGF alters GH release through long loop feedback inhibition. Pituitary adenomas which had been removed from six acromegalic patients were processed for dispersed cell cultures and/or cell membrane preparations. Binding studies using 125I-labeled IGF-I, IGF-II, and insulin revealed specific hormone binding for each ligand to cell membranes derived from four somatotropinomas. A partially purified somatomedin preparation inhibited basal and/or GHRH-stimulated GH release from cultured pituitary cells derived from three of four adenomas; there was no effect of somatomedin in one tumor. In a single tumor, insulin also partially inhibited GHRH-stimulated GH release. Additionally, in one nonadenomatous pituitary removed from a patient with diabetes mellitus, insulin and somatomedin inhibited GHRH-stimulated GH release, and insulin inhibited basal GH secretion. These results indicate that specific cell membrane receptors for somatomedin peptides and insulin may be found on cell membranes from GH-secreting tumors, and that somatomedins and insulin can inhibit GH release in cultured human somatotropinoma cells. Thus, these data suggest that somatomedins may exert feedback inhibition of GH secretion in some patients with acromegaly.     

Effect of continuous somatostatin and growth hormone-releasing hormone (GHRH) infusions on the subsequent growth hormone (GH) response to GHRH. Evidence for somatotroph desensitization independent of GH pool depletion

Continuous infusions of growth hormone-releasing hormone (GHRH) attenuate the subsequent growth hormone (GH) response to GHRH. To test whether this phenomenon can occur in the absence of GH pool depletion, we examined the effects of continuous infusions of 10 nM GHRH and of 10 nM somatostatin (SRIH), separately or in combination, on dispersed, perifused rat anterior pituitary cells. Columns of these cells were given either GHRH alone for 5 h, GHRH and SRIH together for 3 h followed by GHRH alone, or SRIH alone for 3 h followed by GHRH or medium. SRIH blunted both basal GH release and the GH response to GHRH, without affecting the subsequent GH responses to GHRH. The GHRH infusions attenuated the subsequent GH response to GHRH, even when GH release was initially prevented by the concurrent infusion of SRIH. Furthermore, the degree of attenuation was similar in the presence or absence of SRIH, suggesting that pool depletion plays little role in the desensitization process under these experimental conditions. The results are consistent with the hypothesis that a short-term infusion of GHRH leads to attenuation of the GH response in rat anterior pituitary cells primarily through receptor effects rather than through GH pool depletion.     

Rat somatotroph insulin-like growth factor-II (IGF-II) signaling: role of the IGF-I receptor.

The anterior pituitary contains insulin-like growth factor-II (IGF-II) and expresses abundant IGF-II-binding sites, but the IGF-II signaling pathway in the pituitary has not been defined. We, therefore, tested the effects of recombinant human IGF-II on pituitary function by assessing the GH responsiveness of the primary rat somatotroph to IGF-II. IGF-II (3.3 nM) suppressed GH secretion by 50%, similar to the effect elicited by equimolar doses of IGF-I. In contrast, a low concentration of IGF-II (0.2 nM) did not attenuate GH secretion, while a similar IGF-I dose was sufficient to produce 50% inhibition of basal GH secretion. Fifty percent competition for [125I]IGF-I binding by IGF-I and IGF-II in GC rat pituitary cells demonstrated a 14-fold lesser affinity of the IGF-II ligand for the IGF-I receptor compared to IGF-I; therefore, the binding affinity of IGF-II for the IGF-I receptor correlates with the concentration of IGF-II required for 50% GH inhibition. Transfected GH-secreting cell lines derived from GC cells overexpressing intact human IGF-I receptors exhibited enhanced responsiveness to IGF-II. In contrast, cells transfected with a truncated IGF-I receptor cDNA lacking the cytoplasmic receptor beta-subunit (952STOP) failed to transduce the IGF-II signal, indicating that functional IGF-I receptors are required for IGF-II signaling. In addition, a mutant IGF ligand, [Leu27]IGF-II, which selectively exhibits high affinity for the type II receptor, but only minimal binding to the IGF-I receptor, did not attenuate GH secretion. However, the analog [Arg54,Arg55]IGF-II, which exhibits high affinity to the IGF-I receptor, but no binding to the type II receptor, appropriately suppressed GH secretion. This unique model of somatotroph signaling provides evidence for IGF-II regulation of polypeptide hormone secretion mediated by the IGF-I receptor.     

Suppressing actions of butyrate on growth hormone (GH) secretion induced by GH-releasing hormone in rat anterior pituitary cells

We assessed the inhibitory effects of butyrate on the growth hormone (GH) secretion in order to investigate the cellular mechanisms in rat somatotrophs. Isolated anterior pituitary cells were cultured in DMEM for several hours, either in the presence (1, 3, or 10mM) or absence of butyrate, and then stimulated with 10(-7)M GHRH for 30 min, in the presence of butyrate at the concentrations used for the previous culture. The increase in GHRH-induced GH release was significantly reduced in a time-dependent and concentration-dependent manner in the cells previously cultured with butyrate. GH content (the sum of GH released into the medium induced by GHRH stimulation and the GH remaining in the cells after stimulation) was reduced by the culture of cells in the presence of butyrate, which was also inversely dependent on the concentrations used for the culture. Simultaneous addition of an L-type Ca(2+) channel blocker, nifedipine (10 pM), to the medium during 10(-9)M GHRH stimulation significantly reduced the stimulated GH release, which was further significantly decreased by a simultaneous addition of 10 mM butyrate. Butyrate blunted the GHRH (10(-9)M)-induced increase in cellular cyclic AMP and calcium ion concentrations, the activity of protein kinases (A and C), and GHmRNA expression. The expression of mRNA for GPR 41 and 43, known as receptors for short-chain fatty acids, was confirmed in the anterior pituitary cells. These findings suggest that butyrate inhibits GHRH-induced GH release as well as GH production, and the cellular inhibitory actions of butyrate occur in diverse cellular signaling pathways of rat somatotrophs.     

Suppression of the growth hormone (GH) response to clonidine and GH-releasing hormone by exogenous GH

GH release in response to clonidine and human GH-releasing hormone-(1-44) (hGHRH-44) was assessed in 11 boys (aged 7-14 yr) with short stature, who had normal GH secretion. The response to these 2 provocative stimuli was repeated after, respectively, 2 and 3 days of treatment with human GH (0.1 U/kg, im). Exogenous GH significantly blunted the response to both clonidine [the mean 2-h integrated serum GH concentration falling from 1050 +/- 350 (+/- SEM) to 749 +/- 297 ng/ml X min; P = 0.03] and hGHRH-44, the 2-h integrated GH concentration falling from 1553 +/- 358 to 547 +/- 202 ng/ml X min; (P = 0.03). Plasma insulin-like growth factor (IGF-II) concentrations did not change after GH administration. In contrast, plasma IGF-I (somatomedin-C) concentrations increased from 97 +/- 16 ng/ml before administration of GH to 142 +/- 32 ng/ml (P = 0.05) after two days and 149 +/- 23 ng/ml (P less than 0.01) after the third treatment day. However, no correlation was found between the changes in response to clonidine or hGHRH-44 and changes in circulating levels of IGF-I. Our data confirm the existence of GH-dependent feedback inhibition of GH release during childhood and suggest that this inhibition operates, at least in part, at the level of the pituitary. While participation of the IGFs/somatomedins in this feedback loop cannot be excluded, the inhibitory effects of exogenous GH do not depend directly on circulating plasma IGF-I or IGF-II levels.     

Normal and growth hormone (GH)-secreting adenomatous human pituitaries release somatostatin and GH-releasing hormone

Neuropeptides such as vasoactive intestinal peptide, LHRH, or TRH have been found in rat pituitary tissue and could act via paracrine or autocrine actions in this tissue. In this study we investigated whether normal human pituitary tissue and GH-secreting human pituitary adenomas could release somatostatin (SRIH) and GHRH. Fragments from three human pituitaries and dispersed cells from six GH-secreting adenomas (four adenomas were studied for GHRH release and five for SRIH release) were perifused using a Krebs-Ringer culture medium, and the perifusion medium was collected every 2 min (1 mL/fraction for 5 h). GH, GHRH, and SRIH were measured by RIA under basal conditions and in the presence of 10(-6) mol/L TRH or SRIH. Both normal pituitaries and GH-secreting pituitary adenomas released SRIH and GHRH. SRIH release commenced 90-180 min after initiation of the perifusion, at which time GH secretion had decreased significantly. TRH stimulated SRIH release from normal pituitary tissue and inhibited SRIH release from adenoma tissue. GHRH was present at the start of the perifusion, but rapidly disappeared. However, SRIH stimulated GHRH release from normal pituitary tissue, but not from adenoma tissue. Significant amounts of GHRH and SRIH were released during the experiments, suggesting their local synthesis. These results indicate that pituitary cells can release hypothalamic peptides. The liberation of these neuropeptides is regulated, and moreover, their regulation differs between normal and adenomatous pituitaries.     

The interrelationship between the effects of insulin-like growth factor I and somatostatin on growth hormone secretion by normal rat pituitary cells: the role of glucocorticoids

Both insulin-like growth factor I (IGF-I) and somatostatin (SRIH) have been shown to directly inhibit GH release and the total GH content of cultured pituitary cells. In the present study we evaluated the interrelationship between the effects of a recombinant human IGF-I analog ([Thr59]IGF-I) and SRIH on GH release by cultured normal rat pituitary cells together with the effects of glucocorticoids. In all experiments anterior pituitary cells were preincubated for 24 h without or with IGF-I, SRIH, and/or dexamethasone. Thereafter, 24-h incubations without or with IGF-I, dexamethasone, SRIH, and GHRH were performed. Both IGF-I and SRIH inhibited basal and GHRH-stimulated GH release in a dose-dependent manner; the maximal inhibitory concentrations were 5 nM IGF-I and 10 nM SRIH. These concentrations inhibited basal and GHRH-stimulated GH release by 23% and 40% (IGF-I) and 80% and 85% (SRIH), respectively. The combination of IGF-I and low concentrations of SRIH exerted an additive inhibitory effect on GHRH-stimulated GH release; IGF-I (1 nM) and SRIH (10 pM) together inhibited GH release by 50%, while the maximal inhibitory concentrations of 5 nM IGF-I and 10 nM SRIH virtually completely inhibited GH release (by 93%). Preincubation with 5 and 100 nM dexamethasone attenuated the sensitivity of somatotrophs to SRIH and completely abolished the inhibitory effects of IGF-I. This effect of dexamethasone could be reversed by coincubation with the glucocorticoid receptor antagonist RU 38486. High concentrations of 5-10 nM of the recombinant human IGF-I analog stimulated PRL cell content (5 and 10 nM) and release (10 nM), while a purified IGF-I preparation extracted from human blood exerted a parallel inhibitory effect on GH and PRL release. We conclude that 1) IGF-I and SRIH exert an additive direct inhibitory effect on basal and GHRH-stimulated GH secretion by normal cultured pituitary cells; 2) glucocorticoids directly attenuate the sensitivity of somatotrophs to SRIH, but completely prevent the inhibitory effects of IGF-I on GH secretion; and 3) in contrast to a purified IGF-I preparation extracted from human blood (which inhibits GH and PRL release) high concentrations of the recombinant IGF-I preparation (which inhibit GH release) stimulate PRL production.     

The effects of insulin-like growth factor-I (IGF-I), IGF-II and des(1-3)IGF-I, a potent IGF analogue, on growth hormone and IGF-binding protein secretion from cultured rat anterior pituitary cells.

The effects of insulin-like growth factor-I (IGF-I), IGF-II and des(1-3)IGF-I, a potent IGF-I analogue, on the secretion of GH and IGF-binding protein (IGFBP) from cultured rat anterior pituitary cells were measured. IGF-I and des(1-3)IGF-I stimulated GH secretion at low concentrations (maximally effective at 1 and 0.1 micrograms/l respectively) and inhibited GH secretion at higher concentrations. The half-maximal inhibitory concentrations (IC50) were approximately 20 micrograms/l and 1 microgram/l for IGF-I and des(1-3)IGF-I respectively. Thus des(1-3)IGF-I was more potent than IGF-I in these effects on GH secretion. We postulate that the increased potency of des(1-3)IGF-I in affecting GH secretion is due to decreased binding of this peptide by pituitary IGFBP compared with IGF-I. In contrast with IGF-I and des(1-3)IGF-I, IGF-II did not stimulate GH secretion at low concentrations, but did inhibit GH secretion from pituitary cells with an IC50 of approximately 20 micrograms/l. Several IGFBPs ranging in molecular mass from 22,000 to 52,000 were detected in medium conditioned by cultured anterior pituitary cells. When measured by Western-ligand blotting and competitive ligand-binding techniques, these IGFBPs exhibited decreased binding of des(1-3)IGF-I compared with IGF-I and IGF-II. The production of IGFBP by anterior pituitary cells was stimulated by the addition of IGFs to the culture medium.     

Acromegaly due to ectopic growth hormone (GH)-releasing hormone (GHRH) production: dynamic studies of GH and ectopic GHRH secretion

Dynamic studies of GH and GH-releasing hormone (GHRH) secretion were performed in a man with a GHRH-producing carcinoid tumor and acromegaly. Insulin hypoglycemia stimulated and metoclopramide inhibited both GH and GHRH acutely. Bromocriptine suppressed GH both acutely and chronically without altering circulating GHRH levels and also blunted the GH response to exogenous GHRH. TRH acutely stimulated GH, but not GHRH, secretion, and iv bolus doses of synthetic GHRH-(1-40) stimulated GH release acutely. Somatostatin infusion decreased both GH and GHRH concentrations and blunted the GH responses to TRH and GHRH-(1-40). We conclude that prolonged exposure of the pituitary gland to high concentrations of GHRH is associated with chronic GH hypersecretion and may be accompanied by a preserved acute GH response to exogenous GHRH; a paradoxical response of GH to TRH may be mediated at the pituitary level, consequent to prolonged pituitary exposure to GHRH; bromocriptine suppression of GH in acromegaly is due to a direct pituitary effect of the drug; and somatostatin inhibits both ectopic GHRH secretion as well as GH responsiveness to GHRH in vivo. Since GH secretory responses in patients with somatotroph adenomas are similar to those in this patient, augmented GHRH secretion may play a role in development of the "classic" form of acromegaly.     

Growth hormone regulation in primary fetal and neonatal rat pituitary cell cultures: the role of thyroid hormone

GH is first detectable in the fetal rat pituitary between gestational days 18 and 19. The reasons for the GH surge soon after birth and subsequent postnatal decline to adult levels remain unclear. We therefore determined whether GH gene regulation in the developing pituitary could be distinguished from adult rat somatotroph function. In primary cultures of fetal and neonatal rat pituitary cells, GH secretion was detected by the 20th gestational day. These cells were stimulated by GH-releasing hormone (GHRH), but not by T3 or the morphogen retinoic acid. The stimulatory effect of T3 (0.25 mM) on GH secretion was detected only on the 2nd neonatal day and was similar to that seen in mature rat pituitary cell cultures. GHRH (10 nM) treatment for 24 h caused a 5-fold induction of GH secretion in pituitary cells derived from 2-, 5-, and 12-day-old neonatal rats. The presence or absence of T3 in the culture medium did not alter the response to GHRH. In contrast, only 2-fold induction of GH was observed in adult male pituitary cells during the same time course. Insulin-like growth factor-I (IGF-I; 6.5 nM), the peripheral target hormone for GH, resulted in a modest (20%) attenuation of GH secretion from pituitary cells derived from 20-day-old fetuses. IGF-I, however, produced a 70% reduction in GH levels in adult male pituitary cells grown under similar conditions. The effects of IGF-I on adult pituitary cells grown in T3-depleted medium were blunted. Addition of T3 partially restored the responsiveness of these cells to IGF-I. The results suggest that the high circulating GH levels in the fetal and neonatal rat may be secondary to relative insensitivity of the immature somatotroph to the inhibitory actions of IGF-I in addition to enhanced responsiveness to GHRH compared with the adult rat pituitary. Relative thyroid hormone deficiency in the immature rat may be contributory to this early transient state of pituitary IGF-I resistance.     

Effects of elevated serum insulinlike growth factor-II on growth hormone and insulinlike growth factor-I mRNA and secretion

The insulinlike growth factors (IGF) appear to exert feedback control over their own production. In an effort to determine the physiologic mechanisms for this feedback modulation, we utilized a previously developed in vivo model in which rIGF-II secreting tumor cells are transplanted into immunodeficient rats to form IGF-II secreting tumors. The tumor-bearing rat have serum IGF-II concentrations sevenfold greater than those in controls (119 +/- 16 ng/mL [mean +/- SE] v 17 +/- 2 ng/mL, P less than .0001). Serum IGF-I concentrations were reduced among the tumor-bearing rats (438 +/- 42 ng/mL v 606 +/- 32 ng/mL, P = .002) and were negatively correlated with IGF-II concentrations (r = -.47, P = .025), suggesting that IGF-II suppressed the secretion of IGF-I. Increased serum IGF-II concentrations, however, did not affect basal growth hormone concentrations (tumor-bearing, 44 +/- 12 ng/mL; control 33 +/- 6 ng/mL, P = 0.96). The GH response to GH releasing factor was likewise similar in both groups. Moreover, pituitary GH mRNA level were not different in the two groups, suggesting that IGF-II does not have a significant effect on GH secretion in this in vivo model. There was no association between serum glucose and serum IGF-I or IGF-II concentrations. To examine the effect of IGF-II on IGF-I production from the liver, we measured IGF-I mRNA levels in a subset of animals. Despite these differences in serum IGF-I concentrations, the tumor-bearing rats did not have significantly lower liver IGF-I mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Administration of adrenocorticotropic hormone during chicken embryonic development prematurely induces pituitary growth hormone cells

Treatment of fetal rats and embryonic chickens with exogenous glucocorticoids induces premature GH cell differentiation. However, it is unknown whether the developing adrenal gland is capable of mounting this response autonomously. The present study determined whether stimulation of the adrenal gland in developing chicken embryos through administration of ACTH could induce a premature increase in GH cells. We found that plasma corticosterone and ACTH levels increased between embryonic day (e) 11 and e17, consistent with GH cell (somatotroph) ontogeny. Injection of ACTH into eggs on e9, e10, or e11 increased somatotrophs on e14. In contrast, thyroid-stimulating hormone, CRH, alpha-MSH, GHRH, and TRH were ineffective. Culture of e11 pituitary cells with ACTH failed to induce somatotrophs, suggesting an indirect action of ACTH on GH cells in vivo. Intravenous administration of ACTH dramatically increased plasma levels of corticosterone within 1 h and increased the percentage of pituitary somatotrophs within 24 h. Although ACTH administration increased the relative abundance of pituitary GH cells, there was no effect on plasma levels of GH, IGF-I, or IGF-II, or in hepatic expression of IGF-I or IGF-II mRNA. We conclude that ACTH administration can increase the population of GH cells in the embryonic pituitary. However, this treatment alone does not lead to downstream activation of hepatic IGF production. These findings indicate that the embryonic adrenal gland, and ultimately anterior pituitary corticotrophs, may function to regulate pituitary GH cell differentiation during embryonic development.     

Characterization of high affinity receptors for insulin-like growth factors I and II on rat anterior pituitary cells

Primary cultures of rat anterior pituitary cells were assessed for the presence of specific receptors for insulin and for the somatomedin peptides, insulin-like growth factors I and II (IGF-I and IGF-II). Specific binding per 100,000 pituitary cells averaged 9.45 +/- 1.69% (mean +/- SD) for [125I]IGF-II, 0.83 +/- 0.06% for [125I]IGF-I, and only 0.11% for [125I]insulin, IGF-II was twice as potent as IGF-I in displacing [125I]IGF-II, while insulin was totally nonreactive, IGF-I was 5-fold more potent than IGF-II at displacing [125I]IGF-I and 1000-fold more potent than insulin. Scatchard analysis of [125I]IGF-II binding revealed a curvilinear plot, which could be resolved into a high affinity receptor with a Ka of 7.0 X 10(8) M-1 and 120,000 receptor sites/cell, and a low affinity receptor with a Ka of 1.1 X 10(8) M-1 and 720,000 receptor sites/cell. The existence of abundant high affinity somatomedin receptors (especially for IGF-II) on rat anterior pituitary cells is consistent with a potential role for these peptides in the regulation of GH secretion.     

Growth hormone (GH) response to GH-releasing hormone by perifused pituitary cells from male, female, and testicular feminized rats

To determine whether a normal complement of androgen receptors is required to permit full expression of sex-related differences in pituitary GH secretion, we compared the GHRH-stimulated GH secretory responses of continuously perifused anterior pituitary cells from normal male, normal female, and androgen-resistant testicular feminized (Tfm) rats. In each experimental replicate, acutely dispersed pituitary cells were exposed to GHRH (0.03-100 nM) administered as 2.5-min pulses in random order at 30-min intervals. The eluate was collected in 5-min fractions for GH determination by RIA. Basal unstimulated secretion of GH by cells from male rats was greater than that by cells from female (P = 0.007) and Tfm (P = 0.03) rats; basal secretion by the other two groups was similar (P = 0.55). Linear concentration-response relationships between GHRH and GH release were defined for cells from male (P = 0.0002), female (P = 0.0001), and Tfm (P = 0.0002) rats. Overall GHRH-stimulated GH secretion by cells from male rats was greater (P less than 0.0001) than that by cells from female rats. Overall secretion by cells from Tfm rats was less (P less than 0.001) than that by cells from male rats but greater (P less than 0.001) than that by cells from female rats. For all experimental groups, body weight was strongly correlated with both basal (r2 = 0.42; P = 0.001) and GHRH-stimulated (r2 = 0.53; P = 0.0001) GH secretion by the dispersed pituitary cells. These data suggest that a deficiency of androgen receptors results in a diminution of the in vitro GH secretory capability of anterior pituitary cells to a level below that by cells from normal males, but not to the level in normal females. The intermediate position of cells from the Tfm rat may represent a partial masculinization or defeminization within this generally female phenotype.     

Growth hormone-releasing hormone stimulates cAMP release in superfused rat pituitary cells.

The release of growth hormone (GH) and cAMP was studied in superfused rat pituitary cells by infusing growth hormone-releasing hormone (GHRH) at different doses or a combination of GHRH and somatostatin 14 (SS-14). Three-minute pulses of GHRH caused a dose-dependent GH and cAMP release (effective concentration of 50% of the maximal biological effect is 0.21 nM and 52.5 nM, respectively). The lowest effective doses of GHRH in the superfusion system were 0.03 nM for GH release and 0.3 nM for cAMP discharge when 3-min pulses were applied. The amount of cAMP liberated from the cells was not proportional to GH release: cAMP responses to low doses of GHRH were disproportionally small, and the gradual increase in the release of cAMP after high doses of GHRH was not followed by a parallel rise in GH release. The desensitization induced by repeated pulses or prolonged infusion of GHRH resulted in a greater reduction in GH release than in cAMP liberation. A simultaneous infusion of SS-14 completely blocked GH release stimulated by GHRH but did not inhibit the immediate release of cAMP caused by GHRH. An abrupt decrease in GHRH-stimulated GH release induced by SS-14 was followed by only a minimal reduction in cAMP liberation 9 min later. Our findings indicate that a discharge of cAMP is stimulated after a GHRH pulse, but this effect alone cannot maintain the release of GH. Other steps of the signal transduction mechanisms that are independent of the cAMP route may participate in the process of GH release. The nature of the mechanisms involved in the mediation of GH release may vary with the doses of GHRH used.     

Leptin stimulates growth hormone secretion via a direct pituitary effect combined with a decreased somatostatin tone in a median eminence-pituitary perifusion study

The aim of this study was to examine the effect of recombinant human leptin on growth hormone (GH) secretion in perifused anterior pituitary slices from adult pigs. Anterior pituitary slices from sows were perifused and treated with recombinant human leptin (10 nM) and GH-releasing hormone (GHRH; 1 nM). In some experiments, pituitary slices were coincubated with stalk median eminence (SME). In a subset of the coincubation experiments, immunoneutralization of endogenous GHRH and somatostatin (SRIH) release was performed with antisera to GHRH and SRIH. Leptin increased GH secretion in pituitary slices alone (up to 100% vs. control at 40 min) as well as in pituitary slices coincubated with SME (up to 122% vs. control at 40 min). A significant difference was observed in GH secretion from pituitary slices when the tissue was coincubated with leptin and GHRH at a low concentration (0.1 nM), but not when GHRH was used at 1 and 10 nM. Furthermore, anti-SRIH antiserum increased GH release from pituitary slices in coincubation experiments with SME. Finally, SRIH secretion was significantly reduced by leptin (down by 35% vs. control from 0 to 30 min of treatment) in cultured SME. These data show that leptin is effective in stimulating GH secretion by acting at two different levels: (1) it stimulates GH secretion directly from pituitary slices, and (2) it reduces SRIH tone from the median eminence and, indirectly, increases GH secretion from the pituitary. These results support the hypothesis that leptin may be an interesting hormonal mediator of growth and related metabolic effects by acting directly on the hypothalamic-pituitary axis.     

Effect of dexamethasone on growth hormone (GH) response to growth hormone releasing hormone in acromegaly

The effect of dexamethasone on the GH response to GH-releasing hormone (GHRH) was studied in vivo in six patients with acromegaly as well as in vitro in monolayer cultures of GH-secreting pituitary tumor cells obtained from three of these patients. Oral administration of 9 mg/day dexamethasone for 2 days decreased plasma GH responses to iv injection of 100 micrograms GHRH-(1-44 amide) in all six patients. Blood glucose levels were significantly increased, while plasma somatomedin-C levels were significantly decreased by this regimen of dexamethasone treatment. On the other hand, 2-day pretreatment with 50 nM dexamethasone of monolayer cultures of pituitary adenoma cells potentiated GH release basally and/or in response to 100 pM to 1 nM GHRH in vitro. These results indicate that the potentiating action of 2-day treatment of dexamethasone in vitro is overwhelmed in vivo by some extra-pituitary action, probably on the central nervous system, of glucocorticoids in patients with acromegaly.     

Pioglitazone treatment increases spontaneous growth hormone (GH) secretion and stimulated GH levels in polycystic ovary syndrome

BACKGROUND: Low GH levels, probably due to insulin resistance and increased abdominal fat mass, are well described in polycystic ovary syndrome (PCOS). GH acts as an important ovarian cogonadotropin, and GH disturbances may be an additional pathogenic factor in PCOS. Decreased abdominal fat mass and improved insulin sensitivity during pioglitazone treatment may affect GH secretion. OBJECTIVE: The objective of the study was to investigate the effect of pioglitazone on GH levels in PCOS. DESIGN: Thirty insulin-resistant PCOS patients were randomized to either 16 wk pioglitazone (30 mg/d) or placebo treatment. Before and after intervention, levels of fasting insulin, GH, total IGF-I, free IGF-I, IGF binding protein-1, IGF-II, free fatty acids, testosterone, and SHBG were measured. Patients underwent whole-body dual x-ray absorptiometry scans, pyridostigmine-GHRH tests, and 24-h 20-min integrated blood sampling for measurement of GH. RESULTS: Peak GH and area under the curve for GH in pyridostigmine-GHRH tests and 24-h mean GH concentrations and pulsatile GH secretion significantly increased after pioglitazone treatment. No significant changes were observed in GH pulse frequency, pulse duration, approximate entropy levels, or basal GH release. Levels of IGF binding protein-1 significantly increased, whereas no significant differences were measured in total IGF-I and free IGF-I. Pioglitazone treatment significantly decreased fasting insulin and homeostasis model assessment levels. No significant changes were observed in Ferriman Gallwey score or androgen levels. CONCLUSION: Pioglitazone treatment significantly increased GHRH-stimulated GH levels and 24-h pulsatile GH secretion, probably directly or indirectly due to improved insulin sensitivity.