Somatostatin-14 neurons in the ovine hypothalamus: colocalization with estrogen receptor alpha and somatostatin-28(1-12) immunoreactivity,and activation in response to estradiol

Pituitary gland growth hormone (GH) secretion is influenced by two hypothalamic neuropeptides: growth hormone-releasing hormone (GHRH) and somatostatin. Recent data also suggest that estrogen modulates GH release, particularly at the time of the preovulatory luteinizing hormone surge, when a coincident surge of GH is observed in sheep. The GHRH neurons do not possess estrogen receptor alpha (ERalpha), suggesting that estrogen does not act directly on GHRH neurons. Similarly, few somatotropes express ERalpha, suggesting a weak pituitary effect of estradiol on GH. It was hypothesized, therefore, that estradiol may affect somatostatin neurons to modulate GH release from the pituitary. Using immunocytochemical approaches, the present study revealed that although somatostatin neurons were located in several hypothalamic sites, only those in the arcuate nucleus (13% +/- 2%) and ventromedial nucleus (VMN; 29% +/- 1%) expressed ERalpha. In addition, we found that all neurons immunoreactive for somatostatin-14 were also immunoreactive for somatostatin-28(1-12). To determine whether increased GH secretion in response to estradiol is through modulation of GHRH and/or somatostatin neuronal activity, a final study investigated whether c-fos expression increased in somatostatin- and GHRH-immunoreactive cells at the time of the estradiol-induced LH surge in intact anestrous ewes. Estradiol significantly (P < 0.05) increased the percentage of GHRH (estradiol, 75% +/- 3%; no estradiol, 19% +/- 2%) neurons expressing c-fos in the hypothalamus. The percentage of somatostatin-immunoreactive neurons coexpressing c-fos in the estradiol-treated animals was significantly (P < 0.05) higher (periventricular, 44% +/- 3%; arcuate, 72% +/- 5%; VMN, 81% +/- 5%) than in the control animals (periventricular, 22% +/- 1%; arcuate, 29% +/- 3%; VMN, 31% +/- 3%). The present study suggests that estradiol modulates the activity of GHRH and somatostatin neurons but that this effect is most likely mediated through an indirect interneuronal pathway.     

Estrogen and androgen elicit growth hormone release via dissimilar patterns of hypothalamic neuropeptide secretion

The dimorphic pattern of growth hormone (GH) secretion and somatic growth in male and female mammals is attributable to the gonadal steroids. Whether these hormones mediate their effects solely on hypothalamic neurons, on somatotropes or on both to evoke the gender-specific GH secretory patterns has not been fully elucidated. The purpose of this study was to determine the effects of 17beta-estradiol, testosterone and its metabolites on release of GH, GH-releasing hormone (GHRH) and somatostatin (SRIF) from bovine anterior pituitary cells and hypothalamic slices in an in vitro perifusion system. Physiological concentrations of testosterone and estradiol perifused directly to anterior pituitary cells did not affect GH releases; whereas, dihydrotestosterone and 5alpha-androstane-3alpha, 17beta-diol increased GH. Perifusion of testosterone at a pulsatile rate, and its metabolites and estradiol at a constant rate to hypothalamic slices in series with anterior pituitary cells increased GH release. The androgenic hormones increased GHRH and SRIF release from hypothalamus; whereas, estradiol increased GHRH but decreased SRIF release. Our data show that estradiol and the androgens generated distinctly different patterns of GHRH and SRIF release, which in turn established gender-specific GH patterns.     

Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance

Growth hormone (GH) secretion is regulated by GH-releasing hormone (GHRH), somatostatin, and possibly ghrelin, but uncertainty remains about the relative contributions of these hypophysiotropic factors to GH pulsatility. Patients with genetic GHRH receptor (GHRH-R) deficiency present an opportunity to examine GH secretory dynamics in the selective absence of GHRH input. We studied circadian GH profiles in four young men homozygous for a null mutation in the GHRH-R gene by use of an ultrasensitive GH assay. Residual GH secretion was pulsatile, with normal pulse frequency, but severely reduced amplitude (<1% normal) and greater than normal process disorder (as assessed by approximate entropy). Nocturnal GH secretion, both basal and pulsatile, was enhanced compared with daytime. We conclude that rhythmic GH secretion persists in an amplitude-miniaturized version in the absence of a GHRH-R signal. The nocturnal enhancement of GH secretion is likely mediated by decreased somatostatin tone. Pulsatility of residual GH secretion may be caused by oscillations in somatostatin and/or ghrelin; it may also reflect intrinsic oscillations in somatotropes.     

Peripheral estrogen receptor-alpha selectively modulates the waveform of GH secretory bursts in healthy women

Estradiol (E(2)) drives growth hormone (GH) secretion via estrogen receptors (ER) located in the hypothalamus and pituitary gland. ERalpha is expressed in GH releasing hormone (GHRH) neurons and GH-secreting cells (somatotropes). Moreover, estrogen regulates receptors for somatostatin, GHR peptide (GHRP, ghrelin), and GH itself, while potentiating signaling by IGF-I. Given this complex network, one cannot a priori predict the selective roles of hypothalamic compared with pituitary ER pathways. To make such a distinction, we introduce an investigative model comprising 1) specific ERalpha blockade with a pure antiestrogen, fulvestrant, that does not penetrate the blood-brain barrier; 2) graded transdermal E(2) administration, which doubles GH concentrations in postmenopausal women; 3) stimulation of fasting GH secretion by pairs of GHRH, GHRP-2 (a ghrelin analog), and l-arginine (to putatively limit somatostatin outflow); and 4) implementation of a flexible waveform deconvolution model to estimate the shape of secretory bursts independently of their size. The combined strategy unveiled that 1) E(2) prolongs GH secretory bursts via fulvestrant-antagonizable mechanisms; 2) fulvestrant extends GHRH/GHRP-2-stimulated secretory bursts; 3) l-arginine/GHRP-2 stimulation lengthens GH secretory bursts whether or not E(2) is present; 4) E(2) limits the capability of l-arginine/GHRP-2 to expand GH secretory bursts, and fulvestrant does not inhibit this effect; and 5) E(2) and/or fulvestrant do not alter the time evolution of l-arginine/GHRH-induced GH secretory bursts. The collective data indicate that peripheral ERalpha-dependent mechanisms determine the shape (waveform) of in vivo GH secretory bursts and that such mechanisms operate with secretagogue selectivity.     

Effect of growth hormone-releasing hormone and clonidine on growth hormone release in type 1 diabetic patients

We administered growth-hormone releasing hormone (GHRH), clonidine or thyrotropin-releasing hormone (TRH) as intravenous boli each in three different randomized mornings to nine well-controlled Type 1 diabetic men and to six age-matched healthy men who served as controls. GHRH and clonidine evoked a prompt and brisk GH release both in diabetic and in control subjects with no significant difference being evident between the two groups. Only one diabetic subject showed a paradoxical GH release after TRH when he was under long-term poor metabolic control. These results indicate that in insulin-dependent patients with good control of the metabolic disease the response of somatotropes to pituitary- or central nervous system-directed stimuli is normal. These data are supportive of the idea that altered GH secretion in Type 1 diabetes rather than reflecting a primary hypothalamic and/or pituitary alteration may be a state-dependent phenomenon related to the metabolic state of the disease.     

Joint pituitary-hypothalamic and intrahypothalamic autofeedback construct of pulsatile growth hormone secretion

Growth hormone (GH) secretion is vividly pulsatile in all mammalian species studied. In a simplified model, self-renewable GH pulsatility can be reproduced by assuming individual, reversible, time-delayed, and threshold-sensitive hypothalamic outflow of GH-releasing hormone (GHRH) and GH release-inhibiting hormone (somatostatin; SRIF). However, this basic concept fails to explicate an array of new experimental observations. Accordingly, here we formulate and implement a novel fourfold ensemble construct, wherein 1) systemic GH pulses stimulate long-latency, concentration-dependent secretion of periventricular-nuclear SRIF, thereby initially quenching and then releasing multiphasic GH volleys (recurrent every 3-3.5 h); 2) SRIF delivered to the anterior pituitary gland competitively antagonizes exocytotic release, but not synthesis, of GH during intervolley intervals; 3) arcuate-nucleus GHRH pulses drive the synthesis and accumulation of GH in saturable somatotrope stores; and 4) a purely intrahypothalamic mechanism sustains high-frequency GH pulses (intervals of 30-60 min) within a volley, assuming short-latency reciprocal coupling between GHRH and SRIF neurons (stimulatory direction) and SRIF and GHRH neurons (inhibitory direction). This two-oscillator formulation explicates (but does not prove) 1) the GHRH-sensitizing action of prior SRIF exposure; 2) a three-site (intrahypothalamic, hypothalamo-pituitary, and somatotrope GH store dependent) mechanism driving rebound-like GH secretion after SRIF withdrawal in the male; 3) an obligatory role for pituitary GH stores in representing rebound GH release in the female; 4) greater irregularity of SRIF than GH release profiles; and 5) a basis for the paradoxical GH-inhibiting action of centrally delivered GHRH.     

Role of aging on growth hormone and prolactin release after growth hormone-releasing hormone and domperidone in man

Growth hormone (GH) and prolactin (PRL) secretion after GH-releasing hormone (GHRH) and domperidone (DOM), an antidopaminergic drug which does not cross the blood-brain barrier (BBB), was evaluated in 8 healthy elderly men (65-91 years) and in 7 young adults (23-40 years). All received in random order at 2-day intervals: GHRH(1-40) (50 micrograms i.v.) bolus, DOM (5 mg/h) infusion, GHRH(1-40) (50 micrograms i.v.) plus DOM (5 mg/h i.v.), saline solution. In elderly men GH increase after GHRH was significantly lower than in young men. DOM alone did not change GH secretion in either of these groups, whereas it increased the GH response to GHRH only in young adults. PRL levels increased in both young and elderly men during both DOM and GHRH plus DOM, but the PRL release was more marked in young than in elderly men. Both integrated secretion of GH after GHRH and of PRL after DOM were inversely correlated to chronological age. Our data show an impairment of GH rise after GHRH and of PRL after DOM in elderly adults. It is also stressed that peripheral blockade of dopamine receptors by DOM is unable to amplify the GH response to GHRH only in elderly men. A reduction in GH release after GHRH might be related to aging, perhaps through a reduction of dopaminergic tonus.     

Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion

Ghrelin is a native ligand for the growth hormone secretagogue (GHS) receptor that stimulates pulsatile GH secretion markedly. At present, no formal construct exists to unify ensemble effects of ghrelin, GH-releasing hormone (GHRH), somatostatin (SRIF), and GH feedback. To model such interactions, we have assumed that ghrelin can stimulate pituitary GH secretion directly, antagonize inhibition of pituitary GH release by SRIF, oppose suppression of GHRH neurons in the arcuate nucleus (ArC) by SRIF, and induce GHRH secretion from ArC. The dynamics of such connectivity yield self-renewable GH pulse patterns mirroring those in the adult male and female rat and explicate the following key experimental observations. 1) Constant GHS infusion stimulates pulsatile GH secretion. 2) GHS and GHRH display synergy in vivo. 3) A systemic pulse of GHS stimulates GH secretion in the female rat at any time and in the male more during a spontaneous peak than during a trough. 4) Transgenetic silencing of the neuronal GHS receptor blunts GH pulses in the female. 5) Intracerebroventricular administration of GHS induces GH secretion. The minimal construct of GHS-GHRH-SRIF-GH interactions should aid in integrating physiological data, testing regulatory hypotheses, and forecasting innovative experiments.     

Cell-specific distributions of estrogen receptor alpha (ERα) and androgen receptor (AR) in anterior pituitary glands from adult cockerels as revealed by immunohistochemistry

Estrogens and androgens play important roles in regulating the hormone-secreting functions of the pituitary gland by binding to their corresponding receptors. However, the expression of estrogen receptors (ERs) and the androgen receptor (AR) and the cell types containing ERs and AR in the anterior pituitary gland of adult chickens have not been well-studied. In this study, the distribution of ERα, AR and their corresponding cell types in the anterior pituitary gland of adult cockerels was detected by immunohistochemistry. The results showed that ERα was expressed in 68.63 % of luteinizing hormone (LH) producing cells but was not found in thyrotropes, lactotropes, somatotropes, corticotropes and folliculo-stellate (FS) cells. Pituitary hormone and AR double labeling results showed that about 37 % of LH cells and 50 % of thyroid-stimulating hormone (TSH) producing cells expressed AR, respectively. In contrast, less than 1 % of the somatotropes had an AR positive signal and AR signals were not detected in lactotropes, corticotropes or FS cells. In addition, there were only a few AR and ERα dual-labeled cells observed. These novel results provide evidence for a cell-specific distribution of ERα and AR in the anterior pituitary from adult cockerels by immunohistochemistry. The different distributions of ERα and AR in the LH cells suggest that the feedback-regulating mechanisms of estrogen and androgen on the pituitary hormones secretion are different. The functions and related mechanisms still need to be elucidated further.     

Enhanced growth hormone responses to growth hormone releasing hormone in male type I diabetic patients.

In a previous paper we have demonstrated that growth hormone (GH) responses to growth hormone releasing hormone (GHRH) are higher in premenopausal normal women than in age matched healthy men. As in type I diabetes mellitus various disturbances of GH secretion have been reported, the aim of our study was to assess the effect of sex on basal and GHRH stimulated GH secretion in type I diabetes mellitus. In 21 female and 23 male type I diabetic patients and 28 female and 30 male control subjects GH levels were measured before and after stimulation with GHRH (1 microgram/kg body weight i.v.) by radioimmunoassay. GH responses to GHRH were significantly higher in female than in male control subjects (p less than 0.02), whereas the GH levels following GHRH stimulation were similar in female and male type I diabetic patients. GH responses to GHRH were significantly higher in the male type I diabetic patients than in the male control subjects (p less than 0.001); in the female type I diabetic patients and the female control subjects, however, GH responses to GHRH were not statistically different. The absence of an effect of sex on GHRH stimulated GH responses in type I diabetes mellitus provides further evidence of an abnormal GH secretion in this disorder.     

Inhibition of prolactin and growth hormone secretion by nickel

Nickel (Ni++) is a potent inhibitor of prolactin (PRL) secretion from isolated rat pituitary quarters in vitro, suppressing both basal PRL release and the stimulation of PRL secretion due to theophylline and dibutyryl cyclic AMP. Stimulation of growth hormone (GH) secretion by synthetic GHRH is also blunted by Ni++, although basal GH release and stimulated GH release due to theophylline or dibutyryl cyclic AMP are not suppressed. Ni++ antagonizes the stimulation of both PRL and GH secretion by barium (Ba++) ion, suggesting that the inhibitory effects of Ni++ on hormone release are due to an antagonism of calcium uptake or redistribution.     

Diverse intracellular signalling systems used by growth hormone-releasing hormone in regulating voltage-gated Ca2+ or K channels in pituitary somatotropes

Influx of Ca2+ via Ca2+ channels is the major step triggering exocytosis of pituitary somatotropes to release growth hormone (GH). Voltage-gated Ca2+ and K+ channels, the primary determinants of the influx of Ca2+, are regulated by GH-releasing hormone (GHRH) through G-protein-coupled intracellular signalling systems. Using whole-cell patch-clamp techniques, the changes of the Ca2+ and K+ currents in primary cultured ovine and human somatotropes were recorded. Growth hormone-releasing hormone (10 nmol/L) increased both L- and T-type voltage-gated Ca2+ currents. Inhibition of the cAMP/protein kinase A (PKA) pathway by either Rp-cAMP or H89 blocked this increase in both L- and T-type Ca2+ currents. Growth hormone-releasing hormone also decreased voltage-gated transient (IA) and delayed rectified (IK) K+ currents. Protein kinase C (PKC) inhibitors, such as calphostin C, chelerythrine or downregulation of PKC, blocked the effect of GHRH on K+ currents, whereas an acute activation of PKC by phorbol 12, 13-dibutyrate (1 micromol/L) mimicked the effect of GHRH. Intracellular dialysis of a specific PKC inhibitor (PKC19-36) also prevented the reduction in K+ currents by GHRH. It is therefore concluded that GHRH increases voltage-gated Ca2+ currents via cAMP/PKA, but decreases voltage-gated K+ currents via the PKC signalling system. The GHRH-induced alteration of Ca2+ and K+ currents augments the influx of Ca2+, leading to an increase in [Ca2+]i and the GH secretion.     

Immunocytochemical localization of growth hormone and growth hormone-releasing hormone immunoreactivity in the brain and pituitary of the little brown bat

Anterior pituitary cells exhibiting growth hormone (GH) immunoreactivity and forebrain neurons containing growth hormone-releasing hormone (GHRH) immunoreactivity were identified in little brown bats (Myotis lucifugus) using light microscopic immunocytochemistry. Pituitary somatotropes appeared as ovoid or polyhedral cells that were distributed throughout most of the pars distalis, with the exception of its most rostral region where this cell type was scarce. GH-immunoreactive cells occupied approximately one-third of the total volume of the pars distalis; this proportion did not differ significantly between males and females or in bats collected at different times of year. Neuronal perikarya containing immunoreactive GHRH were observed in the hypothalamic arcuate and suprachiasmatic nuclei, as well as in the cortical and subcortical telencephalon. Fibers were most evident in the median eminence, paraventricular and periventricular nuclei, and molecular layer of the cerebral cortex. Fine fibers were also accumulated in the bed nucleus of the stria terminalis and in the amygdala.     

Feeding reduces activity of growth hormone-releasing hormone and somatostatin neurons

Secretion of growth hormone (GH) is synchronized among castrate male cattle (steers) around feeding when access to feed is restricted to a 2-hr period each day. Typically, concentrations of GH increase before and decrease after feeding. Our objectives were to determine whether i) concentrations of GH decrease in blood after start of feeding; ii) activity of immunoreactive growth hormone-releasing hormone (GHRH-ir) neurons decreases in the arcuate nucleus (ARC) after feeding; iii) activity of immunoreactive somatostatin (SS-ir) neurons in the periventricular nucleus (PeVN) and ARC increase after feeding; and iv) GHRH stimulates release of GH to a similar magnitude at 0900 and at 1300 hr, in steers fed between 1000 and 1200 hr. Blood samples were collected at 20-min intervals from 0700 to 1300 hr. Groups of steers were euthanized at 0700, 0900, 1100, and 1300 hr (n = 5 per group). Dual-label immunohistochemistry was performed on free-floating sections of hypothalami using antibodies directed against Fos and Fos-related antigens (Fos/FRA) as a marker of neuronal activity in immunoreactive GHRH and SS neurons. Concentrations of GH were high before and decreased after feeding. The percentage of SS-ir neurons containing Fos/FRA-ir in the PeVN was 50% lower (P<0.01) at 1100 hr and 36% lower (P<0.05) at 1300 hr than at 0900 hr. There was no change in percentage of SS-ir neurons containing Fos/FRA-ir in the ARC. The percentage of GHRH-ir neurons containing Fos/FRA-ir in the ARC was 66% lower (P<0.05) at 1100 hr and 65% lower (P<0.05) at 1300 hr than at 0700 hr. In contrast, the number of GHRH-ir neurons increased from 0700 to 1300 hr. GHRH-induced release of GH was suppressed at 1300 hr compared with 0900 hr. In conclusion, reduced basal and GHRH-induced secretion of GH after feeding was associated with decreased activity of GHRH neurons in the ARC and decreased activity of SS neurons in the PeVN.     

Increased growth hormone responses to growth hormone releasing hormone and thyrotropin releasing hormone in patients with metastatic testicular cancer

In 16 patients with metastatic testicular cancer and 10 age matched male control subjects growth hormone (GH) responses to growth hormone releasing hormone (GHRH; 1 microgram/kg body weight iv.) and thyrotropin releasing hormone (TRH; 200 micrograms iv.) were measured. Basal GH levels and GH levels following stimulation with GHRH or TRH were significantly increased in cancer patients compared to control subjects. 9 patients with testicular cancer were studied both in the stage of metastatic disease and after they had reached a complete remission. In complete remission GH responses to GHRH tended to decrease but the differences did not reach statistical significance. Our data suggest an alteration of hypothalamic and/or pituitary regulation of GH secretion in patients with metastatic testicular cancer.     

Role of central epinephrine in regulation of anterior pituitary hormone secretion

Hypothalamic regulation of anterior pituitary hormones is thought to be mediated by the release of stimulatory and/or inhibitory peptides that are, in turn, regulated by catecholaminergic neurons. The recent development of selective epinephrine (EPI) synthesis inhibitors has made it possible to disrupt central EPI neurotransmission without affecting norepinephrine or dopamine. These compounds were used in the present investigation to assess the involvement of brain EPI systems in regulation of GH, LH, and prolactin (PRL) in male and ovariectomized female rats. Inhibition of central EPI synthesis (1) inhibited episodic and morphine-, but not clonidine-induced GH release, and (2) blocked the LH surge induced by estrogen and progesterone, but did not affect episodic LH release in hormonally untreated rats. Inhibition of peripheral (adrenal) EPI synthesis had no effect on these hormones. Results of these studies suggest an excitatory role for EPI in regulation of GH and LH secretion, mediated by stimulation of GH-releasing hormone and LHRH, respectively. EPI does not appear to have a major function in regulation of PRL secretion.     

Growth hormone-releasing hormone neurons in the anestrus cat do not express progesterone receptors

Ovarian steroids have been implicated in the regulation of growth hormone (GH) secretion in several species and increased progesterone secretion has been associated with elevated circulating GH levels in the cat. These high GH concentrations may be due, at least in part, to a direct action of progesterone on growth hormone-releasing hormone (GHRH) neurons. Using standard immunocytochemical methods coupled to high-temperature antigen retrieval, the objective of this study was to determine whether progesterone receptors were colocalized in GHRH neurons of the anestrus cat. GHRH perikarya were restricted to the infundibular nucleus and the ventral ventromedial nucleus and although frequently surrounded by numerous progesterone receptor-immunoreactive cells, none was colocalized. This study, therefore, provides evidence that, in the adult anestrus female cat, GHRH neurons do not express nuclear progesterone receptors.     

Regulation of leptin mRNA and protein expression in pituitary somatotropes.

Leptin, the ob protein, regulates food intake and satiety and can be found in the anterior pituitary. Leptin antigens and mRNA were studied in the anterior pituitary (AP) cells of male and female rats to learn more about its regulation. Leptin antigens were found in over 40% of cells in diestrous or proestrous female rats and in male rats. Lower percentages of AP cells were seen in the estrous population (21 +/- 7%). During peak expression of antigens, co-expression of leptin and growth hormone (GH) was found in 27 +/- 4% of AP cells. Affinity cytochemistry studies detected 24 +/- 3% of AP cells with leptin proteins and growth hormone releasing hormone (GHRH) receptors. These data suggested that somatotropes were a significant source of leptin. To test regulatory factors, estrous and diestrous AP populations were treated with estrogen (100 pM) and/or GHRH (2 nM) to learn if either would increase leptin expression in GH cells. To rule out the possibility that the immunoreactive leptin was bound to receptors in somatotropes, leptin mRNA was also detected by non-radioactive in situ hybridization in this group of cells. In estrous female rats, 39 +/- 0.9% of AP cells expressed leptin mRNA, indicating that the potential for leptin production was greater than predicted from the immunolabeling. Estrogen and GHRH together (but not alone) increased percentages of cells with leptin protein (41 +/- 9%) or mRNA (57 +/- 5%). Estrogen and GHRH also increased the percentages of AP cells that co-express leptin mRNA and GH antigens from 20 +/- 2% of AP cells to 37 +/- 5%. Although the significance of leptin in GH cells is not understood, it is clearly increased after stimulation with GHRH and estrogen. Because GH cells also have leptin receptors, this AP leptin may be an autocrine or paracrine regulator of pituitary cell function.     

Acute effects of clonidine and growth-hormone-releasing hormone on growth hormone secretion in patients with hyperthyroidism

Patients with hyperthyroidism have reduced growth hormone (GH) responses to pharmacological stimuli and reduced spontaneous nocturnal GH secretion. The stimulatory effect of clonidine on GH secretion has been suggested to depend on an enhancement of hypothalamic GH-releasing hormone (GHRH) release. The aim of our study was to evaluate the effects of clonidine and GHRH on GH secretion in patients with hyperthyroidism. Eight hyperthyroid females with recent diagnosis of Graves' disease (age range 20-55 years, body mass index range 19.2-26.2 kg/m2) and 6 healthy female volunteers (age range 22-35 years, body mass index range 19-25 kg/m2) underwent two experimental trials at no less than 7-day intervals: (a) an intravenous infusion of clonidine 150 micrograms in 10 ml of saline, or (b) a bolus intravenous injection of human GHRH (1-29)NH2, 100 micrograms in 1 ml of saline. Hyperthyroid patients showed blunted GH peaks after clonidine (7.1 +/- 1.7 micrograms/l) as compared to normal subjects receiving clonidine (28.5 +/- 4.9 micrograms/l, p less than 0.05). GH peaks after GHRH were also significantly lower in hyperthyroid subjects (8.0 +/- 1.7 micrograms/l) as compared to normal subjects receiving GHRH (27.5 +/- 4.4 micrograms/l, p less than 0.05). No significant differences in the GH values either after clonidine or GHRH were observed in the two groups of subjects examined. Our data demonstrate that the GH responses to clonidine as well as to GHRH in patients with hyperthyroidism are inhibited in a similar fashion with respect to normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative effect of clonidine and growth hormone (GH)-releasing hormone on GH secretion in adult patients on chronic glucocorticoid therapy.

Glucocorticoids are thought to inhibit growth hormone (GH) secretion through an enhancement of endogenous somatostatin tone. The aim of our study was to evaluate the effects of GH-releasing hormone (GHRH) and clonidine, an alpha-2-adrenergic agonist which increases GH secretion acting at the hypothalamic level with an unknown mechanism, on GH secretion in seven adult patients (3M, 4F) with non endocrine diseases and on daily immunosuppressive glucocorticoid therapy. Eleven normal subjects (7M, 4F) served as controls. Steroid-treated patients showed a blunted GH response to GHRH (GH peak 8.3 +/- 3 micrograms/L) with respect to normal subjects (GH peak 19.3 +/- 2.4 micrograms/L). The GH responses to clonidine were also blunted (p less than 0.05) in steroid-treated patients (GH peak 5.8 +/- 2.8 micrograms/L) with respect to normal subjects (GH peak 17.6 +/- 2.3 micrograms/L). No significant differences between the GH responses to GHRH and clonidine were observed either in steroid-treated or in normal subjects. Clonidine is not able to enhance GH secretion similar to GHRH in patients chronically treated with steroids. It can be hypothesized that clonidine does not elicit GH secretion decreasing hypothalamic somatostatin tone.