Isolated acquired ACTH deficiency and primary hypothyroidism: a short series and review.

Idiopathic isolated ACTH deficiency, congenital or acquired, is rare. It may be found in association with primary hypothyroidism. Here we describe four cases of acquired idiopathic isolated ACTH deficiency illustrating its importance and variable presentation. All cases had a structurally normal pituitary gland and persistently normal residual pituitary function. Three cases had co-existing primary hypothyroidism. We discuss the protean presentation of this rare but important condition, its treatment, associations, and possible aetiologies.

Gastric pacing for diabetic gastroparesis--does it work?

The management of diabetic gastroparesis resistant to medical therapy is very difficult Gastric electrical stimulation (GES) is a relatively new therapeutic modality which has shown some promise in international trials. It has seen use in four patients in Ireland. Our aim was to determine if GES improved patients' outcomes in terms of duration and cost of inpatient stay and glycaemic control. We reviewed the patients' case notes and calculated the number of days spent as an inpatient with symptomatic gastroparesis pre and post pacemaker, the total cost of these admissions, and patients' average HbA1c pre and post GES. Mean length of stay in the year pre GES was 81.75 days and 62.25 days in the year post GES (p=0.89). There was also no improvement in glycaemic control following GES. GES has been ineffective in improving length of inpatient stay and glycaemic control in our small patient cohort.

High-dose porcine galanin infusion and effect on intravenous glucose tolerance in humans.

The neuropeptide galanin inhibits glucose-stimulated insulin release in dogs and rodents and has been proposed as having a role in the control of insulin release in humans. The effect of infused galanin on intravenous glucose tolerance in humans was investigated by giving an intravenous glucose tolerance test (0.5 g glucose/kg body wt) alone and with infusions of synthetic porcine galanin at high-dose levels (80 and 160 pmol.kg-1.min-1) to seven healthy male volunteers. The results showed no effect of galanin infusion on plasma glucose or serum insulin, although a rise in serum growth hormone even in the face of the intravenous glucose load confirmed the potent growth hormone-stimulating effect of galanin. These results suggest that caution should be exercised in extrapolating a physiological role for galanin in humans from the results of animal studies.

The regulation of neuropeptide expression in rat anterior pituitary following chronic manipulation of estrogen status: a comparison between substance P, neuropeptide Y, neurotensin, and vasoactive intestinal peptide.

The neuropeptides substance P, neuropeptide Y, neurotensin, and vasoactive intestinal peptide are present in normal rat anterior pituitary gland and hypothalamus and can influence the secretion of classical pituitary hormones. We investigated the effects of estrogen manipulation on pituitary and hypothalamic expression of these four peptides by specific RIAs and cDNA probe analysis. Surgical ovariectomy produced a significant rise in the pituitary content of substance P immunoreactivity (IR) (130.2 +/- 4.8 fmol/gland vs. control 29.1 +/- 2.2, P less than 0.001), neuropeptide Y IR (34.9 +/- 3.9 vs. 19.6 +/- 2.0, P less than 0.05) and neurotensin IR (85.1 +/- 8.2 vs. 62.4 +/- 7.2, P less than 0.05), while vasoactive intestinal peptide IR showed a fall (201.2 +/- 18.8 vs. 285.4 +/- 25.9, P less than 0.05). These patterns were reversed with estrogen replacement or high dose estrogen treatment. Changes in peptide content were accompanied by parallel changes in the mRNA for each peptide. Treatment with an antiestrogen (tamoxifen) resulted in no change in substance P, neuropeptide Y, and neurotensin expression, while vasoactive intestinal peptide IR content decreased to below the assay detection limit. Hypothalamic expression of these peptides did not change with any of the treatments. These results indicate that: 1) the control of the pituitary expression of the four peptides under the influence of estrogen occurs predominantly at the level of gene transcription and 2) normalization of the castration induced changes by exogenous estrogen replacement suggests the changes to be mediated by the absence of this steroid. The regulation of the pituitary expression of these peptides by estrogen support the possibility of their having an autocrine or paracrine role.

Identification of bombesin-immunoreactive cells in rat, human, and other mammalian pituitaries, their ontogeny and the effect of endocrine manipulations in the rat.

Bombesin and gastrin-releasing peptide are homologous peptides which have biological activity in mammals. The distribution of bombesin immunoreactivity in rat, guinea pig, cat, dog, pig, cow, monkey, and human pituitaries was investigated using immunocytochemistry with various different antisera. Polyclonal antisera identified bombesin-immunoreactive (IR) cells in the anterior pituitaries of all species except monkey and human, although positive nerves were present in the human posterior lobe. In contrast, a monoclonal antibody demonstrated bombesin-IR cells in anterior and intermediate lobe (or equivalent) of all species. Both types of antibodies identified the anterior pituitary cells as somatotrophs, which may be significant because bombesin and related peptides influence pituitary growth hormone secretion. Differences in bombesin immunoreactivity were seen in male and female rats, with males having more positive cells, and females showing more intense immunoreactivity in those cells which were positive. Ontogenetic studies in rats revealed that bombesin-IR cells were first seen at birth. The effect of estrogen on bombesin-IR cells was studied using ovariectomized and estrogen-treated female rats. Estrogen treatment decreased very significantly the number of bombesin-IR cells, compared with controls, whereas ovariectomy increased significantly the frequency of bombesin-IR cells, so that the staining pattern began to resemble that seen in normal male rats. No bombesin-IR cells were detected in pituitaries from thyroidectomized rats. These results suggest that immunoreactive bombesin/gastrin-releasing peptide in the pituitary is modulated by endocrine status and this peptide may be involved in paracrine interactions in this tissue.

Effect of endocrine manipulation on anterior pituitary galanin in the rat.

Galanin is widely distributed throughout the rat neural and endocrine system. The highest concentrations are found in the anterior pituitary, and it can influence classical pituitary hormone secretion. The effects of endocrine manipulation on pituitary galanin content, mRNA, and immunostaining have been investigated in the rat. In females, medical (39 +/- 4 fmol/gland), surgical (33 +/- 2), or combined (28 +/- 6) castration resulted in a highly significant decrease in galanin content (control, 223 +/- 14; P less than 0.0001). Estrogen in physiological and pharmacological doses produced a significant increase in galanin content (368 +/- 14 and 373 +/- 13, respectively; P less than 0.01) associated with an increase in galanin mRNA content. In the male, high dose dexamethasone and thyroidectomy caused a fall in galanin content, while galanin mRNA levels showed a rise and fall, respectively. Adrenalectomy caused a rise in galanin content, while adrenalectomy and castration produced a dramatic decrease in tissue galanin content. No change in galanin mRNA was observed in these groups. Galanin immunostaining paralleled the results of tissue content in all groups examined, except in the medically castrated group, in which there was some intragroup variation in staining patterns. In normal and high-dose estrogen-treated females, galanin expression was seen mainly in lactotrophs, with a small number of somatotrophs and thyrotrophs staining. In the male, galanin expression was confined to somatotrophs and thyrotrophs. Galanin mRNA was localized at the cellular level by in situ hybridization. In the normal pituitary only scattered lactotrophs contained message, while in high-dose estrogen-treated animals the number of positive cells, mostly lactotrophs, was vastly increased. Thus, the cellular localization of galanin immunostaining varies between the sexes. Galanin peptide and mRNA levels in the pituitary are powerfully influenced by endocrine status.

The influence of thyroid hormone status on the hypothalamo-hypophyseal growth hormone axis.

Growth hormone (GH) synthesis is known to be impaired by either abnormally high or low levels of thyroid hormone. To determine the effects of these conditions on the central regulation of GH secretion, we have examined their effects on the hypothalamic regulatory peptides GH-releasing hormone (GH-RH) and somatostatin (SRIF). In thyroidectomized rat hypothalamus, a dramatic increase in GH-RH mRNA occurred in parallel with a decrease in peptide content. The significance of this phenomenon is uncertain and might possibly reflect some posttranscriptional derangement of GH-RH synthesis or an increased rate of GH-RH synthesis and release. In the hyperthyroid group, GH-RH showed significant decreases in both peptide and mRNA levels that might possibly reflect a decrease in GH-RH synthesis and secretion. No change was observed in SRIF peptide or mRNA levels in either thyroidectomized or T4-treated animals. As expected, GH mRNA levels in the anterior pituitary were dramatically decreased by thyroidectomy and unaffected by T4 treatment. In addition, in thyroidectomized pituitaries, the mature GH mRNA was observed to alter its structure, increasing in size by approximately 100 nucleotides. This increase in size was found to result from an increase in poly(A) tail length, the significance of which is as yet unclear.

Localization of immunoreactivity for calcitonin gene-related peptide in the rat anterior pituitary during ontogeny and gonadal steroid manipulations and detection of its messenger ribonucleic acid.

Localization of calcitonin gene-related peptide (CGRP) expression in the rat anterior pituitary and its changes during ontogeny and after gonadal steroid manipulations were studied by immunocytochemistry, RIA, and in situ hybridization. Colocalization studies and the combined use of immunocytochemistry and in situ hybridization revealed that CGRP immunoreactivity is localized mainly in gonadotropes and alpha- and beta-CGRP messenger RNAs were detected in CGRP-immunoreactive cells. Immunoreactivity for CGRP also was detected in nerve fibers and colocalized with substance P immunoreactivity. Cells immunoreactive to CGRP antiserum were first detected in fetal rats at gestational day 18, and the incidence considerably increased between postnatal days 5 and 14. CGRP immunoreactivity was low in control adults of both sexes and in pregnant and ovariectomized females but increased in lactating, estrogen-supplemented ovariectomized and high-dose estrogen-treated females, and in high-dose estrogen-treated and castrated males. Testosterone supplement suppressed the effect of castration on CGRP immunoreactivity in males. Quantities of extractable immunoreactive CGRP under conditions of estrogen manipulation corresponded well to the immunocytochemical findings (females: controls, 96.4 +/- 13.1 fmol/gland; ovariectomized, 107.6 +/- 19.2; high-dose estrogen-treated, 212 +/- 23.0; estrogen-supplemented ovariectomized, 680 +/- 42.1). The present study suggests that pituitary CGRP is synthesized and stored in gonadotropes, is modulated by gonadal steroids, and may have a functional link with gonadotropins.

A family pedigree exhibiting features of both multiple endocrine neoplasia type 1 and McCune-Albright syndromes.

The multiple endocrine neoplasia (MEN) type 1 and McCune-Albright syndromes share many clinical and biochemical characteristics. This report documents for the first time the occurrence and natural history of the McCune-Albright syndrome in a female with a strong family history of MEN type 1. There may be a functional link between both of these conditions, and there is a need to look for G-protein mutations as a mechanism for disease in MEN type 1.

Endothelin in human brain and pituitary gland: presence of immunoreactive endothelin, endothelin messenger ribonucleic acid, and endothelin receptors.

The presence of immunoreactive (IR) endothelin, endothelin mRNA, and endothelin receptors in human brain and pituitary gland has been studied by RIA, Northern blot hybridization, and receptor assay. IR endothelin was detected in all five brain regions examined (cerebral cortex, cerebellum, brain stem, basal ganglia, and hypothalamus) (6-10 fmol/g wet wt) and spinal cord (22 +/- 6 fmol/g wet wt, n = 7, mean +/- SEM). Higher concentrations of IR endothelin were found in the pituitary gland (147 +/- 30 fmol/g wet wt). Fast protein liquid chromatographic analysis of the IR endothelin in pituitary gland showed a large IR peak in the position of endothelin-3 and a smaller peak in the position of endothelin-1, whereas IR endothelin in the hypothalamus and brain stem was mainly endothelin-1. Endothelin messenger RNA was detected by Northern blot hybridization in the pituitary but not in hypothalamus. The receptor assay showed that 125I-endothelin-1 binding sites were present in large numbers in all five brain regions but were much less abundant in the pituitary gland. Binding capacity and dissociation constant were 5052 +/- 740 fmol/mg protein and 0.045 +/- 0.007 nM in brain stem and 963 +/- 181 fmol/mg protein and 0.034 +/- 0.009 nM in hypothalamus. In the pituitary gland, there were two classes of binding sites for endothelin with dissociation constants of 0.059 +/- 0.002 nM (binding capacity = 418 +/- 63 fmol/mg protein) and 0.652 +/- 0.103 nM (binding capacity = 1717 +/- 200 fmol/mg protein). Endothelin-1, -2 and -3 were almost equipotent in displacing the binding (IC50 approximately 0.04 nM). These findings are in accord with the possibility that endothelin acts as a neurotransmitter, neuromodulator or neurohormone in man.

Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deficiency.

The physiological role of GH in the adult skeleton is unknown. In this study, 12 adults (10 males and 2 females) with isolated GH deficiency were treated with GH as a single daily sc injection (0.125 IU/kg.week for the first 4 weeks and subsequently at 0.25 IU/kg.week) for 1 yr in a double blind, placebo-controlled manner. Bone mineral density of the spine (T12-L3) was measured by quantitative computed tomography, and bone mineral content (BMC) of the forearm by single photon absorptiometry at entry into the study and subsequently at 6 monthly intervals. All baseline bone mineral measurements were reduced compared with those in an age- and sex-matched control population. In the treatment cohort, quantitative computed tomography spinal trabecular bone mineral density increased by 7.8 g/L after 6 months of GH replacement (mean +/- SEM, 151.7 +/- 6.0 vs. 159.5 +/- 5.9 g/L; n = 11; P < 0.01), and this increment was maintained at 1 yr (160.7 +/- 6.3 g/L). Proximal forearm (cortical) BMC showed no change after 6 months of GH replacement, but there was a significant increase of 0.06 g/cm after 12 months of GH replacement (from 1.38 +/- 0.04 to 1.44 +/- 0.04 g/cm; n = 12; P < 0.05). Distal forearm (cortical and trabecular) BMC also increased significantly during the study period from 1.46 +/- 0.04 g/cm to 1.52 +/- 0.05 g/cm; n = 12, P < 0.05. No significant changes occurred in bone mineral measurements during 6 months of placebo therapy. Midthigh muscle and fat cross-sectional area increased and decreased, respectively, during the active treatment phase. These results demonstrate that GH plays an important role in maintaining the integrity of the adult skeleton.

The influence of adrenal hormone status on neuroendocrine peptides in the rat anterior pituitary gland.

Neuropeptide Y (NPY), neurotensin (NT), substance P (SP) and vasoactive intestinal peptide (VIP) are four structurally unrelated neuroendocrine peptides which affect anterior pituitary function. All four peptides appear to be locally synthesized in the anterior pituitary gland and have been shown to be regulated by thyroid and/or sex hormone status. We show here that NT, SP and VIP but not NPY are influenced by adrenal hormone status in the male rat pituitary gland. Adrenalectomy increased the content of VIP (35.4 +/- 4.0 (S.E.M.) vs control 11.9 +/- 1.1 pmol/g wet weight) but decreased that of SP (18.8 +/- 2.3 vs control 36.7 +/- 3.5 pmol/g wet weight). Adrenalectomy combined with castration decreased the content of SP (14.6 +/- 3.5 vs control 36.7 +/- 3.9 pmol/g wet weight) but had no effect on VIP content. Treatment with dexamethasone produced significant decreases in NT, SP and VIP contents (17.8 +/- 2.3 vs control 32.6 +/- 3.4 pmol/g wet weight, 5.5 +/- 0.9 vs control 36.7 +/- 3.9 pmol/g wet weight and 4.2 +/- 0.6 vs control 11.9 +/- 1.1 pmol/g wet weight respectively). The changes in pituitary peptide contents occurred in parallel with changes in mRNA levels, suggesting that alterations in glucocorticoid hormone status can alter the synthesis of these peptides. These results, together with the known effects of these neuroendocrine peptides suggest possible functions for locally produced SP and VIP in regulating the secretion of adrenocorticotrophin and/or other pro-opiomelanocortin-derived peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucagon-like peptide-1 (7-36)-NH2: a physiological inhibitor of gastric acid secretion in man.

Glucagon-like peptide (GLP)-1 (7-36)-NH2 is a peptide found in the mucosal endocrine cells of the intestine, and plasma levels of GLP-1 (7-36)-NH2 immunoreactivity show a rise after the ingestion of a fat or mixed-component meal. We investigated the effects of physiological infusion of GLP-1 (7-36)-NH2 on a submaximal gastric acid secretion in healthy volunteers at a rate known to mimic the observed postprandial rise in plasma concentrations. Corrected gastric acid output decreased to less than 50% and volume output to 33% of stimulated values. After the infusion, the secretion of gastric acid recovered immediately to preinhibition values. These results suggest a novel role for GLP-1 (7-36)-NH2 as a physiological inhibitor of gastric acid secretion in man.

Rat anterior pituitary neuropeptides following chronic prolactin manipulation: a combined radioimmunoassay and mRNA study.

Prolactin secretion is highly regulable, and the possibility exists that there are local intrapituitary factors controlling prolactin secretion. Recently, the neuropeptides vasoactive intestinal peptide (VIP), galanin and substance P (SP) have been co-localized to the lactotroph in the female rat. We investigated the effects of alterations in prolactin status in vivo on pituitary and hypothalamic expression of these peptides by specific radioimmunoassays and mRNA analysis. In the anterior pituitary, following haloperidol treatment, the contents of both VIP and galanin were suppressed to below detectable levels. Similarly, after bromocriptine treatment, the content of VIP was decreased to below the detection limit of the assay while galanin (14.2 +/- 1.3 vs control 21.0 +/- 2.1 fmol/mg, P less than 0.05) also showed a significant reduction. The levels of VIP mRNA and galanin mRNA in these groups showed the same qualitative change as their respective peptides. Concurrent treatment with high-dose oestrogen modified the VIP peptide response to bromocriptine (1368.7 +/- 149.2 vs bromocriptine 843.4 +/- 82.7 fmol/mg, P less than 0.05) but not to haloperidol. Oestrogen-induced decreases in galanin content were not influenced by either treatment. The pituitary content of SP showed a fall after oestrogen treatment (1.1 +/- 0.01 vs control 6.4 +/- 0.8 fmol/mg, P less than 0.05) which was not significantly altered by either bromocriptine or haloperidol. Likewise, SP mRNA levels in the pituitary were decreased by 90% following oestrogen treatment. Hypothalamic expression of these peptides did not change with any of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia.

Organisms survive by maintaining equilibrium with their environment. The stress system is critical to this homeostasis. Glucocorticoids modulate the stress response at a molecular level by altering gene expression, transcription, and translation, among other pathways. The effect is the inhibition of the functions of inflammatory cells, predominantly mediated through inhibition of cytokines, such as IL-1, IL-6, and TNF-alpha. The central effectors of the stress response are the corticotrophin-releasing hormone (CRH) and locus coeruleus-norepinephrine (LC-NE)/sympathetic systems. The CRH system activates the stress response and is subject to modulation by cytokines, hormones, and neurotransmitters. Glucocorticoids also modulate the growth, reproductive and thyroid axes. Abnormalities of stress system activation have been shown in inflammatory diseases such as rheumatoid arthritis, as well as behavioural syndromes such as melancholic depression. These disorders are comparable to those seen in rats whose CRH system is genetically abnormal. Thus, the stress response is central to resistance to inflammatory and behavioural syndromes. In this review, we describe the response to stress at molecular, cellular, neuroendocrine and behavioural levels, and discuss the disease processes that result from a dysregulation of this response, as well as recent developments in their treatment.

Coeliac disease and autoimmune Addison's disease: a clinical pitfall.

BACKGROUND: Coeliac disease has an increased prevalence in a number of autoimmune endocrine conditions. An association between coeliac disease and Addison's disease has been proposed in isolated case reports, but has not been formally studied. AIM: To investigate the extent of this association. DESIGN: Prospective screening of patients with confirmed Addison's disease. METHODS: From central computerized records, we identified all living patients with a diagnosis of autoimmune Addison's disease in the past 30 years and presently attending our affiliated hospitals. After exclusions, 44 were invited to attend for screening. RESULTS: Of 41 patients screened, five (12.2%) had coeliac disease: Three were previously diagnosed coeliacs and this was confirmed on review, including examination of biopsy material. A further two had positive IgA-endomysial antibodies. Histological confirmation was obtained in both cases. Neither had laboratory or clinical evidence of malabsorption. DISCUSSION: In this series of patients with Addison's disease, a higher co-morbidity with coeliac disease was observed than in any previously studied endocrine condition. We recommend that coeliac serology (anti-endomysial and tissue transglutaminase antibody) testing be incorporated routinely into the autoimmune screen for other conditions in patients with Addison's disease.

Increased serum lipoprotein(a) concentrations after growth hormone (GH) treatment in patients with isolated GH deficiency.

Fourteen post-pubertal subjects (11 male, 3 female) with isolated growth hormone (GH) deficiency were treated with a low dose (0.125 U/kg for the first 4 weeks and thereafter 0.25 U/kg/week) daily sc GH injection for 1 year. Fasting blood samples were collected at entry into the study and subsequently at 3 monthly intervals for estimation of serum cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol and lipoprotein(a) [Lp(a)]. Serum Lp(a) increased progressively during the treatment period (by analysis of variance) and was 41% higher at 12 months (P < 0.02) despite the fact that five patients showed little or no change. There was no significant change in any of the other lipid fractions. These observations are of concern as Lp(a) is an independent risk factor for cardiovascular disease and should introduce a cautionary note into the enthusiastic efforts to offer GH replacement to all GH deficient adults.