Pituitary Growth Hormone Secretion Research Articles

Regulation of Somatotroph Differentiation and Growth Hormone (GH) Secretion by Corticosterone and GH-Releasing Hormone during Embryonic Development

The role of extracellular factors in the regulation of anterior pituitary cell differentiation and GH secretion during embryonic development was investigated. Previously, we reported that somatotrophs become a significant population by embryonic day (e-) 16 of the chick and that corticosterone is the active compound responsible for the observed GH cell-differentiating activity of e-16 serum. More recently, the influence of hormone interactions on somatotroph differentiation and GH secretion during mid- to late embryogenesis was evaluated. Anterior pituitary cells from e-12, -14, and -17 chicks were cultured for 2, 3, and 6 days with corticosterone (10−9m) and GH-releasing hormone (GHRH; 10−10-10−7m) alone and in combination. Medium samples were analyzed for GH concentrations, and recovered cells were subjected to GH reverse hemolytic plaque assay for determination of somatotroph percentages and the relative amount of GH secretion from individual somatotrophs. GHRH significantly (P < 0.05) increased GH secretion from e-17, but not e-12 and e-14, pituitary cells during 2 and 3 days of culture. Corticosterone alone failed to increase GH secretion from e-12, -14, and -17 pituitary cells; however, corticosterone in combination with GHRH increased GH secretion from cells of all three ages. Culture with GHRH decreased percentages of e-17 GH-secreting cells in a concentration-dependent manner (from basal levels of 12.3 ± 2.4% to 3.2 ± 0.7% by 2 days), but did not affect percentages of e-12 and e-14 somatotrophs. Conversely, corticosterone increased percentages of e-12 and e-14 GH-secreting cells (by as much as 14- and 3-fold above basal levels, respectively), but did not alter the proportions of e-17 GH cells. Corticosterone in combination with GHRH was more effective than either hormone alone for increasing percentages of e-12 GH-secreting cells (from 9.6 ± 0.8% with corticosterone to 15.9 ± 1.5% with corticosterone plus GHRH), but this synergistic effect was not apparent until after 3 days of culture. Exposure to corticosterone in culture for 2, 3, and 6 days increased subsequent GH release from e-12 and e-14 pituitary cells during reverse hemolytic plaque assay. Combined treatment with corticosterone and GHRH further increased subsequent GH release from e-12 and e-14 cells. We conclude that glucocorticoids induce GH cell differentiation and that corticosterone and GHRH can interact at specific stages of embryonic development to regulate somatotroph differentiation and GH secretion.

Regulation of somatotroph differentiation and growth hormone (GH) secretion by corticosterone and GH-releasing hormone during embryonic development.

The role of extracellular factors in the regulation of anterior pituitary cell differentiation and GH secretion during embryonic development was investigated. Previously, we reported that somatotrophs become a significant population by embryonic day (e-) 16 of the chick and that corticosterone is the active compound responsible for the observed GH cell-differentiating activity of e-16 serum. More recently, the influence of hormone interactions on somatotroph differentiation and GH secretion during mid- to late embryogenesis was evaluated. Anterior pituitary cells from e-12, -14, and -17 chicks were cultured for 2, 3, and 6 days with corticosterone (10(-9) M) and GH-releasing hormone (GHRH; 10(-10)-10(-7) M) alone and in combination. Medium samples were analyzed for GH concentrations, and recovered cells were subjected to GH reverse hemolytic plaque assay for determination of somatotroph percentages and the relative amount of GH secretion from individual somatotrophs. GHRH significantly (P < 0.05) increased GH secretion from e-17, but not e-12 and e-14, pituitary cells during 2 and 3 days of culture. Corticosterone alone failed to increase GH secretion from e-12, -14, and -17 pituitary cells; however, corticosterone in combination with GHRH increased GH secretion from cells of all three ages. Culture with GHRH decreased percentages of e-17 GH-secreting cells in a concentration-dependent manner (from basal levels of 12.3 +/- 2.4% to 3.2 +/- 0.7% by 2 days), but did not affect percentages of e-12 and e-14 somatotrophs. Conversely, corticosterone increased percentages of e-12 and e-14 GH-secreting cells (by as much as 14- and 3-fold above basal levels, respectively), but did not alter the proportions of e-17 GH cells. Corticosterone in combination with GHRH was more effective than either hormone alone for increasing percentages of e-12 GH-secreting cells (from 9.6 +/- 0.8% with corticosterone to 15.9 +/- 1.5% with corticosterone plus GHRH), but this synergistic effect was not apparent until after 3 days of culture. Exposure to corticosterone in culture for 2, 3, and 6 days increased subsequent GH release from e-12 and e-14 pituitary cells during reverse hemolytic plaque assay. Combined treatment with corticosterone and GHRH further increased subsequent GH release from e-12 and e-14 cells. We conclude that glucocorticoids induce GH cell differentiation and that corticosterone and GHRH can interact at specific stages of embryonic development to regulate somatotroph differentiation and GH secretion.

Effect of bursal antisteroidogenic peptide (BASP) on chicken embryonic pituitary secretion of growth hormone (GH) and prolactin (PRL): evaluation in a reverse hemolytic plaque assay (RHPA)

Using the reverse hemolytic plaque assay described in the present investigation, a secretagogue activity of bursal antisteroidogenic peptide (BASP) for growth hormone (GH) or prolactin (PRL) secretion was observed in chicken Day 20e pituitary cell monolayers. Partially purified BASP (ppBASP), at all concentrations evaluated (0.25 BEQ/ml, 0.75 BEQ/ml, or 1.5 BEQ/ml), induced PRL secretion by isolated lactotrophs above (P < 0.05) basal levels during the 2- and 6-hr incubation. At the 18-hr time point, neither ppBASP nor vasoactive intestinal polypeptide (VIP) was efficacious (P < 0.05) in causing an elevation in PRL-secreting cells above basal levels. ppBASP, at all concentrations evaluated (0.25 BEQ/ml, 0.75 BEQ/ml, or 1.5 BEQ/ml), caused an increase in the percentage of GH-secreting cells above (P < 0.05) basal levels during the 18-hr incubation. When evaluating the 2-hr time point alone, ppBASP, at 0.75 or 1.5 BEQ/ml, significantly (P < 0.05) elevated the percentage of GH-secreting cells to above basal levels. After the 6-hr incubation, ppBASP at 0.25 or 0.75 BEQ/ml, was efficacious in causing elevated (P < 0.05) GH secretion above basal levels. The present study indicates a secretagogue activity of BASP on PRL or GH secretion by chicken embryonic anterior pituitary cells in vitro.

Intact leptin receptor is selectively expressed in human fetal pituitary and pituitary adenomas and signals human fetal pituitary growth hormone secretion.

Leptin, a circulating hormone secreted by adipocytes, communicates peripheral nutritional status to hypothalamic centers affecting satiety, energy expenditure, and body weight. The intact leptin receptor (OB-R), a single membrane-spanning peptide containing an approximately 300-amino acid intracellular domain, is highly expressed in the hypothalamus, whereas shorter OB-R isoforms with truncated cytoplasmic regions resulting from alternative splicing have also been identified. We studied expression of OB-R isoforms in human fetal pituitaries, adult anterior pituitaries, and human pituitary adenomas. Using RT-PCR, messenger ribonucleic acid expression of the OB-R intact isoform was detected in fetal anterior pituitary tissues, but not in adult anterior pituitary glands, whereas both fetal and adult tissues expressed the short forms. Messenger ribonucleic acid of both intact and short OB-R isoforms were expressed in 4 of 5 GH-secreting, all 9 PRL-secreting, and 26 of 29 nonfunctioning pituitary adenomas. Recombinant human leptin (3-6 nmol/L) specifically stimulated GH secretion from primary human fetal pituitary cultures by 40-90% (P < 0.05) without altering fetal ACTH, PRL, or gonadotropin secretion. Thus, the intact OB-R is selectively expressed in human fetal and adult pituitary tumor tissues, but not in normal adult pituitary. Leptin specifically stimulates GH release from normal fetal somatotrophs, substantiating the functionality of its intact receptor in the fetal pituitary. Thus, pituitary adenomas appear to revert to a fetal phenotype of leptin receptor expression.

Intact Leptin Receptor Is Selectively Expressed in Human Fetal Pituitary and Pituitary Adenomas and Signals Human Fetal Pituitary Growth Hormone Secretion

Intact Leptin Receptor Is Selectively Expressed in Human Fetal Pituitary and Pituitary Adenomas and Signals Human Fetal Pituitary Growth Hormone Secretion

Cafeteria diet-induced obesity is associated with a low spontaneous growth hormone secretion and normal plasma insulin-like growth factor-I concentrations

Pituitary growth hormone (GH) secretion has been shown to be blunted in human and animal obesity. With respect to human obesity, cafeteria diet-induced obesity might be an appropriate model to study spontaneous GH secretion. In 6 cafeteria diet-overfed obese male Wistar rats and 6 control rats with chronically implanted catheters, GH levels were measured every 15 min over 6 h by standard RIA. A significantly lower GH secretion, reflected by the integrated GH concentration, was found in the obese rats (median 16.46, [range 10.55-19.13] ng/ml x 6 h vs 35.63 [range 21.90-41.50] ng/ml x 6 h, P < 0.05). The GH secretion in the obese rats was significantly negatively correlated with the body fat percentage, assessed by dual X-ray absorptiometry (Rho = -0.95, P < 0.05). Median plasma insulin-like growth factor-I (IGF-I) concentration was comparable between the two groups, while the median insulin concentration was significantly higher in the obese group (1.95 [range 1.76-3.55] ng/ml vs 1.21 [range 0.86-2.13] ng/ml, P < 0.05). No significant correlation existed between GH secretion and the plasma insulin concentration. In conclusion, cafeteria diet-induced obesity is associated with a low spontaneous GH secretion and normal plasma IGF-I concentration. The hyperinsulinemia present in this model probably explains the normal IGF-I concentrations, but not the GH hyposecretion.

Octreotide in hepatocellular carcinoma

See article on page442 In this issue Kouroumalis et al (see page 442) report extended survival in patients with hepatocellular carcinoma (HCC) treated with octreotide, a somatostatin analogue. Somatostatin is...

Pituitary Growth Hormone-Secreting Adenoma Necrosis during an Oral Glucose Tolerance Test in Acromegaly

Pituitary Growth Hormone-Secreting Adenoma Necrosis during an Oral Glucose Tolerance Test in Acromegaly

Thyroid function in early pregnancy II: Paradoxical growth hormone response to thyrotropin-releasing hormone

A variant of growth hormone (GH) known as human placental growth hormone (hpGH) is found in maternal serum during pregnancy. It is well established that during the second half of normal pregnancy, pituitary GH secretion is suppressed; however, there are no data about maternal GH secretion during the first trimester of pregnancy, The present study reports the response of GH to thyrotropin-releasing hormone (TRH) in eight pregnant women in the first trimester of pregnancy (weeks 6-9) who had previously requested voluntary interruption of pregnancy. The TRH test induced a significant paradoxical GH response with a peak of 9.4 ± 0.5 ng/ml (mean ± SD) at 30 min and a higher thyroid-stimulating hormone (TSH) response in pregnant women. The increment was observed until 120 min and no response was observed in the control group.These data show the paradoxical response of GH to TRH, a releasing factor to which the hormone does not normally respond. This paradoxical secretion may be due to direct pituitary stimulation and can be explained on the basis of a state of gestational hypothyroidism.

Somatostatin decreases somatostatin messenger ribonucleic acid levels in the rat periventricular nucleus

Growth hormone (GH) secretion from the pituitary is known to be under the dual control of GH-releasing factor (GRF) and somatostatin (SRIF). Hypothalamic SRIF, the major inhibitor of pituitary growth hormone secretion, inhibits its own release by a negative ultrashort-loop feedback mechanism. However, it is not known whether this negative regulation is mediated by inhibition of SRIF mRNA production. GRF may also inhibit its own release, thereby modifying pituitary GH secretion, possibly through an ultrashort-loop feedback mechanism. Thus, SRIF production and GRF release are both regulated by SRIF. Periventricular nucleus (PeN) and mediobasal hypothalamus (MBH) from adult male rats were incubated for 6 h in Waymouth’s medium with either SRIF or the SRIF agonist analog RC 160 (10 −9 to 10 −6 M). Levels of SRIF mRNA were determined by an S1 nuclease protection assay using a 32[P]-labeled rat SRIF riboprobe. SRIF (10 −7 M) and RC 160 (10 −8, 10 −7 M) significantly ( p ≤ 0.01) decreased SRIF mRNA levels in the PeN. The levels of SRIF mRNA in the MBH were not modified by either SRIF or RC 160. SRIF (10 −7 and 10 −6 M) significantly ( p ≤ 0.01 and p ≤ 0.001, respectively) inhibited the release of GRF at 30 min in the MBH. Likewise, the release of GRF was slightly decreased by 10 −7 M RC 160, and significantly inhibited by 10 −6 M ( p ≤ 0.001) at 30 min. At 6 h, the levels of GRF were significantly reduced by 10 −7 M SRIF ( p ≤ 0.05) and by RC 160 (10 −7, 10 −6 M; p ≤ 0.001 and p ≤ 0.05, respectively). In contrast with these results, the SRIF analog was unable to alter SRIF release at 30 min. At 6 h incubation, RC 160 (10 −7 M) significantly ( p ≤ 0.001) reduced SRIF release from MBH fragments. These results demonstrate that SRIF and a SRIF analog decrease SRIF mRNA levels in the PeN and inhibit the release of SRIF from the nerve terminals of the MBH. Thus, SRIF appears to regulate its own gene expression by negative ultrashort-loop feedback. Therefore, when SRIF is secreted from these neurons in response to GRF, it down-regulates the preceding stimulatory input as well as its own secretion.

Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression.

The signal transducer and activator of transcription, STAT5b, has been implicated in signal transduction pathways for a number of cytokines and growth factors, including growth hormone (GH). Pulsatile but not continuous GH exposure activates liver STAT5b by tyrosine phosphorylation, leading to dimerization, nuclear translocation, and transcriptional activation of the STAT, which is proposed to play a key role in regulating the sexual dimorphism of liver gene expression induced by pulsatile plasma GH. We have evaluated the importance of STAT5b for the physiological effects of GH pulses using a mouse gene knockout model. STAT5b gene disruption led to a major loss of multiple, sexually differentiated responses associated with the sexually dimorphic pattern of pituitary GH secretion. Male-characteristic body growth rates and male-specific liver gene expression were decreased to wild-type female levels in STAT5b-/- males, while female-predominant liver gene products were increased to a level intermediate between wild-type male and female levels. Although these responses are similar to those observed in GH-deficient Little mice, STAT5b-/- mice are not GH-deficient, suggesting that they may be GH pulse-resistant. Indeed, the dwarfism, elevated plasma GH, low plasma insulin-like growth factor I, and development of obesity seen in STAT5b-/- mice are all characteristics of Laron-type dwarfism, a human GH-resistance disease generally associated with a defective GH receptor. The requirement of STAT5b to maintain sexual dimorphism of body growth rates and liver gene expression suggests that STAT5b may be the major, if not the sole, STAT protein that mediates the sexually dimorphic effects of GH pulses in liver and perhaps other target tissues. STAT5b thus has unique physiological functions for which, surprisingly, the highly homologous STAT5a is unable to substitute.

An urge to explain the incomprehensible: Geoffrey Harris and the discovery of the neural control of the pituitary gland.

Geoffrey Harris is responsible for our view that the brain controls the endocrine system by an exquisitely regulated pattern of synthesis and release of individual members of a family of peptide hormones. These hormones are carried through a portal vascular system that passes from the hypothalamus to the pituitary gland, where they selectively regulate the secretion of the six anterior pituitary hormones. This family of hypothalamic hormones is highly conserved in all vertebrates, including humans. They are essential for all aspects of reproduction--courtship, mating, pregnancy and young rearing--and they are responsible for the seasonal regulation of breeding. The hypothalamic control mechanism for reproduction is sexually dimorphic, with a basic female pattern that becomes masculinized under the influence of specific steroid hormones acting during development. Other members of the hypothalamic hormone family specifically regulate the secretion of pituitary growth hormone and the anterior pituitary hormones controlling the functions of the thyroid and adrenal glands. The secretion of the hypothalamic hormones is itself regulated by the feedback of the target gland hormones (such as estrogen and progesterone), which concurrently act on the brain to elicit appropriate behavior patterns. The hypothalamo-hypophysial axis plays a crucial role in the struggle for the survival of the species. By bringing the endocrine system under the control of the brain, it allows access to external environmental inputs, learned behavior patterns, and the whole of the central integrative machinery needed for the bodily functions to be sensitively and optimally adapted to the ever-changing challenges and opportunities in the outside world.

Hormones, Lymphohemopoietic Cytokines and the Neuroimmune Axis

The classical distinction between hormones and cytokines has become increasingly obscure with the realization that homeostatic responses to infection involve coordinated changes in both the neuroendocrine and immune systems. The hypothesis that these systems communicate with one another is supported by the ever-accruing demonstrations of a shared molecular network of ligands and receptors. For instance, leukocytes express receptors for hormones and these receptors modulate diverse biological activities such as the growth, differentiation and effector functions. Leukocyte lineages also synthesize and secrete hormones, such as insulin-like growth factor-I (IGF-I), in response to both growth hormone (GH) and also to cytokines such as tumor necrosis factor-alpha (TNF-alpha). Since hormones share intracellular signaling substrates and biological activities with classical lymphohemopoietic cytokines, neuroendocrine and immune tissues share a common molecular language. The physiological significance of this shared molecular framework is that these homeostatic systems can intercommunicate. One important example of this interaction is the mechanism by which bacterial lipopolysaccharide, by eliciting a pro-inflammatory cytokine cascade from activated leukocytes, modulate pituitary GH secretion as well as other CNS-controlled behavioral and metabolic events. This article reviews the cellular and molecular basis for this communication system and proposes novel mechanisms by which neuroendocrine-immune interactions converge to modulate disease resistance, metabolism and growth.

Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation.

Somatostatin (SRIF), a hypothalamic inhibitor of pituitary growth hormone (GH) and thyroid-stimulating hormone (TSH) secretion, binds to five distinct receptor (SSTR) subtypes. We therefore tested SSTR subtype-specific SRIF analogs in primary human fetal pituitary cultures (23-25-wk gestation) to elucidate their role in regulating human pituitary function. Using reverse transcription-PCR, mRNA expression of SSTR2 and SSTR5 were detected in fetal pituitary by 25 wk. SRIF analog affinities were determined by membrane radioligand binding in cells stably expressing the human SSTR forms. GH secretion was suppressed equally (40-60%, P < 0.005) by analogs preferential for either SSTR2 (IC50 for receptor binding affinity, 0.19-0.42 nM) or SSTR5 (IC50, 0.37 nM), and compounds with enhanced affinity for SSTR2 were more potent (EC50 for GH suppression, 0.05-0.09 nM) than Lanreotide (EC50, 2.30 nM) and SRIF (EC50, 0.19 nM). Similarly, analogs with high affinity for SSTR2 or SSTR5 decreased TSH secretion (30-40%, P < 0.005). However, prolactin was effectively inhibited only by compounds preferentially bound to SSTR2 (20-30%, P < 0.05). Luteinizing hormone was modestly decreased (15-20%) by SSTR2- or SSTR5-specific analogs. An SSTR5-specific analog also exclusively inhibited GH in acromegalic tumor cells. Thus, SRIF regulation of GH and TSH in primary human fetal pituitary cells is mediated by both SSTR2 and SSTR5, both of which are abundantly expressed by 25 wk. In contrast, suppression of prolactin is mediated mainly by SSTR2. These results indicate that SSTR5 is critical for physiologic regulation of GH and TSH. SRIF analogs with selective affinity for this receptor may therefore be more effective in the treatment of hormone-secreting pituitary adenomas.

Central Administration of a Growth Hormone (GH) Receptor mRNA Antisense Increases GH Pulsatility and Decreases Hypothalamic Somatostatin Expression in Rats

To test the hypothesis of the involvement of centrally expressed rat growth hormone receptors (rGH-R) in the ultradian rhythmicity of pituitary GH secretion, adult male rats were submitted to a 60 hr intracerebroventricular infusion of an antisense (AS) oligodeoxynucleotide (ODN) complementary to the sequence of rGH-R mRNA. Eight hour (10 A.M.-6 P.M.) GH secretory profiles, obtained from freely moving male rats infused with 2.0 nmol/hr of rGH-R AS, revealed a marked increase in GH peak amplitude (150 +/- 12 vs 101 +/- 10 ng/ml), trough levels (16.2 +/- 3.0 vs 5.4 +/- 1.4 ng/ml), and number of peaks (2.9 +/- 0.3 vs 1.8 +/- 0.2). No change was observed in rats treated with an ODN complementary to the prolactin receptor mRNA sequence (2.0 nmol/hr). Infusion of increasing ODN concentrations resulted in a dose-dependent stimulation of GH release. In parallel, somatogenic binding sites in the choroid plexus were decreased by 40%, and levels of rGH-R mRNA were increased in the periventricular nucleus (PeV) but unchanged in the arcuate nucleus (ARC). Levels of somatostatin mRNA, in the PeV but not in the ARC, were lowered by the treatment. Levels of GH-releasing hormone mRNA in the ARC were not affected. These data suggest that GH negative feedback results from a direct effect on central GH receptors and a subsequent activation of hypophysiotropic somatostatin neurons located in the anterior periventricular hypothalamus.

Acetylcholine Stimulates Growth Hormone Secretion in the Neonatal Rat Pituitary

The direct effect of acetylcholine on pituitary growth hormone secretion during the postnatal period of the rat was studied using a superfusion system. Acetylcholine elicited a dose related stimulatory effect on growth hormone (GH) secretion in the pituitaries from 2-day old rats. M1 muscarinic agonist McN A343 mimicked the GH releasing effect of acetylcholine, nicotine was ineffective. The GH release elicited by acetylcholine diminished with postnatal development, it was small by the end of the third postnatal week and was not demonstrable in the adult pituitaries. The effect of acetylcholine was potently antagonized by pirenzepine (M1 antagonist) and 4-DAMP (M3 and M1 antagonist) but not by methoctramine (M2 antagonist). It is concluded that unlike in the adult, in the newborn rat the cholinergic regulation of pituitary GH secretion plays a prominent role directly at pituitary level most likely via M1 receptors.

Long-term administration of acipimox potentiates growth hormone response to growth hormone-releasing hormone by decreasing serum free fatty acid in obesity

Obesity is associated with an impairment of normal growth hormone (GH) secretion and blunted responses to all stimuli. A high plasma free fatty acid (FFA) level is frequently observed in obesity. FFA participates in the regulation of pituitary GH secretion. To determine whether the derangement of GH secretion in obesity is associated with high plasma FFA levels, tests with GH-releasing hormone (GHRH) and acipimox (ACX), an antilipolytic agent able to decrease FFA, were undertaken in six obese subjects and seven normal control subjects. In addition, the effect of prolonged suppression of FFA level on GH response to GHRH after administration of ACX for 1 month was also examined in each of the obese subjects. The GH response in obese subjects (median, 9.1 μg/L) to GHRH (1–29) (1 μg/kg intravenously [IV]) was significantly blunted as compared with normal control subjects (23.5 μg/L, P < .05). Basal FFA levels were higher in obese subjects (855.2 μEq/L) than in normal control subjects (514.6 μEq/L, P < .05). One-dose ACX (500 mg) decreased FFA levels in both obese and normal subjects: the lowest FFA levels in obese subjects (158.3 μEq/L) 2 to 2.5 hours after ACX were similar to those of normal control subjects (108.7 μEq/L). One-dose ACX potentiated GHRH-stimulated GH response in both obese and normal subjects. GH responses potentiated by ACX in obese subjects (27.1 μg/L) were similar to GH responses to GHRH in normal control subjects, but lower than in normal subjects treated with ACX plus GHRH (58.5 μg/L, P < .05). Thereafter, all of the obese subjects were treated with ACX for 1 month, after which the ACX plus GHRH tests were repeated. After 1 month of acipimox administration in the obese subjects, GH responses (38.8 μg/L) were significantly higher than those of obese subjects treated with GHRH and one-dose ACX plus GHRH ( P < .05). They were similar to GH responses of normal control subjects receiving the one-dose ACX plus GHRH test. In conclusion, in obesity the prolonged suppression of FFA levels induced by long-term administration of ACX potentiated somatotrope responsiveness, likely acting at the pituitary level, suggesting that the duration of FFA suppression had an important relation to the magnitude of GH response.

Morphine withdrawal alters anterior pituitary hormone secretion, brain endopeptidase activity and brain monoamine metabolism in the rat.

Rats were made tolerant to morphine by a 5-day regimen with increasing doses. The time course of changes in serum anterior pituitary hormone levels, brain endo- and exopeptidase activity, levels of brain biogenic amines and body weight were studied during abrupt morphine withdrawal. Cold stimulated secretion of thyrotropin and the secretion of growth hormone were both decreased whereas that of prolactin was increased. In the hypothalamus both prolyl endopeptidase and dipeptidyl peptidase IV activities were concomitantly increased. The hypothalamic 5 hydroxyindole acetic acid levels were also increased. Changes in hormone secretion, peptidase activity and monoamine turnover had returned to baseline levels by 92 hr. Our results indicate that morphine withdrawal and the associated stress produce alterations in anterior pituitary thyrotropin and growth hormone secretion. Concomitant increases in hypothalamic prolyl endopeptidase and dipeptidyl peptidase activities may contribute to these changes.

Natural course of growth hormone hypersecretion in insulin-dependent diabetes mellitus

High growth hormone levels in patients with insulin-dependent diabetes were recognised 25 years ago. For many years this has been explained as an epiphenomenon of poor metabolic control. The natural course of the disease is characterised by gradual loss of residual beta-cell function and parallel elevations of plasma growth hormone and can be divided into three consecutive phases. It appears that the hormonal changes observed are determined by the IGF-1 generating capacity of the liver which, in turn, is dependent on the synergistic stimulating action of growth hormone and portal insulin. The first (initial) phase of insulin-dependent diabetes mellitus is characterised by the absence of insulin, high growth hormone levels and low plasma IGF-1. The pituitary growth hormone response to exercise and other stimuli is pathological. The second phase of disease ('C-peptide positive phase') is characterised by the return of some residual beta-cell insulin secretion, increased levels of growth hormone compared to non-diabetic subjects, physiological IGF-1 levels and near normal pituitary growth hormone responses to different agents. The third phase of the disease is characterised by complete loss of endogenous insulin secretion, very high plasma growth hormone levels, low normal plasma IGF-1 but impaired hepatic IGF-1 generating capacity. The control mechanisms of pituitary growth hormone secretion (long loop negative feedback and auto-feedback), are disturbed.

Reproductive Toxicity and Growth Effects in Rats Exposed to Lead at Different Periods during Development

The reproductive toxicity and growth effects of developmental lead exposure were assessed using a rat model in which 0.6% (w/v) lead acetate was administered in the drinking waterad libitum.Three series of experiments were conducted in which lead exposure was initiated beginningin utero,prepubertally, or postpubertally. Lead effects were measured on reproductive physiology and endocrinology, sexually dimorphic hepatic testosterone hydroxylation, and growth rates in both male and female animals. In male animals secondary sex organ weights were significantly decreased only in animals exposed prepubertally. In addition, serum testosterone levels were significantly suppressed, most severely in animals exposed fromin utero(in thein uterogroup). Little effect was observed in adult female rats. However, in female animals exposed prepubertally, delayed vaginal opening and disrupted estrus cycling was observed. More severe reproductive disruption was accompanied by suppression of circulating estradiol in thein uterogroup. Effects on circulating sex steroids were accompanied by variable effects on circulating luteinizing hormone (LH) levels, pituitary LH, and pituitary LHβ mRNA, suggesting a dual site of lead action: (a) at the level of the hypothalamic pituitary unit, and (b) directly at the level of gonadal steroid biosynthesis. Prepubertal growth in both sexes was suppressed 25% in thein uterogroup. However, pubertal growth rates were significantly suppressed only in male animals and postpubertal growth was not significantly different from controls in any of the experiments, despite continued exposure to high lead levels in the drinking water. In addition, at age 85 days, male-specific hepatic hydroxylation of testosterone at positions 2α and 16α, which is catalyzed by a cytochrome P450 isozyme CYP 2C11, itself regulated by sexually dimorphic growth hormone secretion, was unaffected. This suggests that the growth effects of lead are possibly due to a delay in the development of sex-specific pituitary growth hormone secretion patterns rather than a persistent developmental defect. Thus, the reproductive and growth effects of lead are complex and sex-dependent, and appear to involve multiple sites on the hypothalamic–pituitary–gonadal axis.