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Acromegaly and hyperprolactinemia have been described in association with polyostotic fibrous dysplasia; the pathogenetic mechanisms involved in the development of the endocrinopathies is unknown. We report a 26-year-old man with polyostotic fibrous dysplasia and hypersecretion of GH and PRL. Plasma GH, PRL, and insulin-like growth factor-I (IGF-I) were elevated. Glucose-non-suppressible plasma GH concentrations, GH responsiveness to TRH and GHRH, and GH suppression after a test-dose of somatostatin, octreotide, and bromocriptine were found. Plasma GHRH levels were within the normal range (< 25 ng/l). Computed tomography of the sella turcica and visual fields were normal. [111In-DTPA-D-Phe1]-octreotide scintigraphy were used to localize a possible tumor; no radioactivity was visualized at the site of the hypothalamus, the pituitary or elsewhere in the body but a considerable accumulation of radioactivity was found in the os frontalis. Therapy with octreotide by continuous sc infusion partially suppressed GH and IGF-I (and normalized PRL). The results suggest that hypersecretion of GH in our patient is not due to a GH-secreting pituitary tumor, eutopic or ectopic hypersecretion of GHRH or autonomous somatotroph function. The origin of the disease in this patient might be an abnormal hypothalamic regulation of somatotrophs and/or an alteration in the transmembrane signalling systems.

Objective: Little is known about the relative circulating concentrations of growth hormone releasing hormone (GHRH) 1-44 NH2 and 1-40 OH in response to dynamic GH stimulation. We therefore studied the concentrations of growth hormone-releasing hormone (GHRH) 1-44 NH2 and 1-40 OH in the peripheral plasma of normal male subjects during GH stimulation tests., Design: Tests were performed at 0900 h after an overnight fast. Stimulation tests, commenced at 0 minutes, included alpha-adrenergic activation with adrenaline (10 micrograms/min from 0 to 30 minutes) following beta-blockade with propranolol (1.5 mg/min from -10 to 0 minutes), alpha 2-adrenergic activation with clonidine 150 micrograms i.v., insulin hypoglycaemia (0.15 U/kg soluble insulin), L-arginine infusion (30 g from 0 to 30 minutes), L-dopa (500 mg orally) and oral glucose (100 g)., Subjects: Groups of healthy male volunteers aged 20-42 years, all within 10% of ideal body weight., Measurements: Serum GH and plasma GHRH 1-44 NH2 and 1-40 OH were measured at intervals for between 60 and 390 minutes, depending on the stimulation test., Results: There were no significant changes in either GHRH 1-44 or 1-40 following alpha-adrenergic activation with propranolol/adrenaline infusion, alpha 2-adrenergic activation with i.v. clonidine, insulin-induced hypoglycaemia or arginine infusion despite the expected rise in GH levels. After oral glucose, GH was initially suppressed with a late rise. There were no changes in GHRH 1-44 or 1-40 levels during either phase of this response. After L-dopa GH levels peaked at 90 minutes, 24.5 +/- 11.0 mU/l (mean +/- SEM). At 0 minutes GHRH 1-44 and 1-40 levels were 3.25 +/- 0.89 and 4.93 +/- 1.28 pmol/l respectively and rose in both cases, peaking at 60 minutes at 4.23 +/- 1.01 and 7.55 +/- 1.80 pmol/l (P < 0.05). At no time was there any evidence of differential secretion of GHRH 1-44 or 1-40., Conclusions: We have confirmed previous studies demonstrating a small rise in GHRH before the GH response to L-dopa. However, in all other situations of pharmacological stimulation of GH release we were unable to detect any significant changes in GHRH 1-44 or 1-40 levels. It seems most likely that peripheral GHRH does not reflect hypothalamic secretion. As yet there is no evidence for differential release of GHRH 1-44 and 1-40.

A corticotropin-releasing hormone (CRH) stimulation test with four cumulative doses of human CRH (0.01, 0.06, 0.2 and 1 microgram/kg body weight) and infusion of a low dose of [Arg8]-vasopressin (0.004 U/kg body weight/30 min) was performed in five depressed patients and six healthy subjects. Plasma samples for the measurement of cortisol, ACTH and beta-endorphin were taken at regular intervals and considered as measures of pituitary-adrenal function. A dose-response relationship between CRH and the hormones measured was found in patients and controls. Depressed patients already responded to the lowest dose of CRH with respect to cortisol release, whereas ACTH and beta-endorphin responded to the second and third doses, respectively. In control subjects the cortisol and ACTH response started after the third dose of CRH, whereas beta-endorphin responded significantly to the highest dose only. When both groups were compared, differences in response were found to the higher doses of CRH with respect to cortisol, ACTH and, less markedly, beta-endorphin and to the lowest dose of CRH with respect to cortisol. Although numbers are small, the data show 'blunting' of the ACTH response to the higher doses of CRH in patients with an enhanced cortisol response of the adrenals to lower and higher doses of CRH. There was no significant difference in response when CRH was used with vasopressin as compared to treatment with CRH alone. Thus, in this design vasopressin did not contribute significantly to CRH activity. The data suggest that pituitary cell sensitivity might be changed in depression as part of HPA dysfunction.

The steroid hormone status of 27 female patients (15 premenopausal and 12 postmenopausal) and 11 male patients with rheumatoid arthritis (RA) was investigated before and after a clinically significant deterioration in disease activity. In postmenopausal patients the serum level of cortisol decreased significantly with the progression of disease activity. No significant change in the serum levels of oestrone, oestradiol, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate or prolactin was found within the groups. In premenopausal patients serum cortisol levels also decreased, with progression of disease activity, but this difference did not reach statistical significance. In male patients with RA none of the measured steroid hormone levels changed significantly after exacerbation of disease activity. Our data indicate that the synthesis and/or utilization of cortisol might be abnormal in female patients with active rheumatoid arthritis.

Glucocorticoid (GC) has been shown to stimulate potassium (K) excretion in various conditions, but it is still incompletely resolved whether its presence is essential for the normal K homeostasis. We addressed this question in patients with selective GC deficiency (panhypopituitarism) and with combined GC and mineralocorticoid deficiency (Addison's disease), studied 24 hours after withdrawal of their regular substitution therapy. Compared to data in healthy subjects, both basal K excretion and the kaliuresis after a KCl load (1 mmol/kg body wt orally) were impaired in either patient group (P < 0.05). Physiological cortisol supplementation (20 mg 3 hr prior to test, and 1 mg/hr during test) increased basal K excretion (from 10.6 +/- 1.8 to 19.2 +/- 1.9 mmol/5 hr, P < 0.01) and KCl stimulated kaliuresis (from 47.9 +/- 6.1 to 54.8 +/- 4.7 mmol/5 hr, P = 0.06) to normal levels in panhypopituitarism. Cortisol also improved basal K excretion (from 10.2 +/- 1.5 to 16.9 +/- 3.5 mmol/5 hr, P < 0.05) and KCl-stimulated K excretion (from 31.6 +/- 2.5 to 45.2 +/- 3.8 mmol/5 hr, P < 0.05) in Addison's disease, although KCl-stimulated K excretion remained below normal (P < 0.01). The effects of cortisol on sodium excretion differed between the two patient groups (P < 0.05) in that only in Addison's disease the improved K excretion was associated with sodium retention. Additional experiments with the purely GC compound dexamethasone (0.5 mg 3 hr prior to test, and 0.03 mg/hr during test) in the patients with Addison's disease also improved K excretion (P < 0.05), but without the concomitant sodium retention observed after cortisol.(ABSTRACT TRUNCATED AT 250 WORDS)

A plasma insulin and amino acid-mediated mechanism is thought to modulate brain serotonin concentration, thereby regulating carbohydrate consumption on a meal to meal basis. It has been suggested that obesity is associated with a defect in the appetite control system. Furthermore, post-absorptive plasma levels of several amino acids are increased in obese subjects, which is ascribed to obesity-associated insulin resistance and/or hyperinsulinemia. We studied breakfast-induced changes in plasma ratios of tryptophan to other large neutral amino acids and associated differences in macro-nutrient composition of lunch food in normal weight and obese human subjects. The study was randomized, double blind and cross-over with a 2 x 2 factorial design with drug/placebo and type of breakfast as factors. Nineteen healthy, non-obese (body mass index (BMI) 22.5 +/- 1.9 kg/m2, mean +/- s.d.) and 19 obese (BMI 34.7 +/- 6.2 kg/m2) female volunteers were treated with either 60 mg fluoxetine (FXT), a serotonin re-uptake blocker specifically acting in the brain, or placebo for four days with a wash-out period between treatments of four weeks. The subjects received either a carbohydrate (CHO) breakfast (80 g maltodextrin, 300 kcal) or a protein-rich (PROT) breakfast (60% milk protein and 40% CHO, 300 kcal) on two consecutive days (days 4 and 5 of each treatment period). Plasma glucose, insulin and amino acids were measured at several time points after breakfast. Three hours after breakfast, subjects were able to choose from 29 different food items. Total energy content and weight of lunch food and energy percentage of each macronutrient were calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

Repeated daily injections of the somatostatin analogue, octreotide (SMS201-995, Sandostatin) are an effective treatment for acromegaly, but lead to gall stone formation in about 50% of cases during longterm treatment. This is probably because of impaired gall bladder contraction. This study examined whether the timing of intermittent injections in relation to meals, or alternatively, continuous 24 hour subcutaneous octreotide infusion (CSOI) might avert adverse effects on gall bladder contraction. In six patients with active acromegaly, gall bladder volume, plasma cholecystokinin (CCK), and pancreatic polypeptide (PP) were measured in the fasting state and after consumption of a fatty meal. Measurements were made on five separate days: (a) without treatment, (b) 45 minutes after 100 micrograms octreotide given subcutaneously, (c) four hours after 100 micrograms octreotide given subcutaneously, (d) eight hours after 100 micrograms octreotide given subcutaneously, and (e) during CSOI of 300 micrograms/24 h for two weeks. Without treatment, postprandial gall bladder contraction was 86.2 (2.1%). Fasting gall bladder volume increased after octreotide injection and was almost doubled during CSOI. Octreotide injections impaired postprandial gall bladder contraction as well as CCK and PP release for at least four hours. Eight hours after injection and during CSOI, postprandial gall bladder contraction was partly restored (43.4% and 50.8% respectively). Postprandial CCK release was normal at eight hours after injection but very low during CSOI. PP release was suppressed by each mode of octreotide treatment. This study indicates that octreotide injections impair postprandial gall bladder contraction for at least four hours. Eight hours after injection and during CSOI, gall bladder contraction is partly restored.

To both patients and physicians it seems natural to attribute adverse premenstrual phenomena to cyclic fluctuations of hormones produced by the ovary. This seems so plausible that, although the endocrine mechanism that causes premenstrual syndrome remains unknown, the condition itself is often treated with hormonal substances. Psychosocial factors are thus considered to be of only secondary importance. They may play a role as a contributing factor, to the 'real' cause of premenstrual syndrome they are not an essential ingredient. The aim of this review article is to examine how strong the evidence is for the possible existence of an endocrine factor as the causative agent in premenstrual syndrome. Using an epidemiological approach we conclude that the continuing search for the responsible mechanism that causes premenstrual syndrome may very well be an endocrine 'Holy Grail'. Human behavior cannot be understood within a single (hormonal) frame of reference. Cyclical ovarian activity is only one of the etiological factors in premenstrual syndrome. Unravelling the pathogenesis of premenstrual syndrome requires a multidisciplinary approach.

In this study the effect of fluoxetine versus placebo treatment on body weight, body composition and abdominal fat areas, assessed from three magnetic resonance imaging scans at umbilicus level, was investigated. Thirty-eight abdominal overweight men aged 41 +/- 7 years (mean +/- s.d.), BMI 27.9 +/- 1.2 kg/m2 and WHR 0.97 +/- 0.03 were given dietary advice and a placebo (n = 20) or fluoxetine treatment (n = 18, 60 mg/day) for 12 weeks after a placebo run-in of two weeks. Measurements were carried out during run-in and at week 12 of treatment. The treatment groups did not differ at the start of the study. After treatment, weight loss (on average) was observed in both groups: -2.4 +/- 0.6 kg and -5.9 +/- 0.7 kg for the placebo and fluoxetine groups, respectively. Weight loss was significantly larger in the fluoxetine group (P = 0.0004). The reduction of fat mass tended to be larger (P = 0.08), and the reduction of fat-free mass was considerably larger in the fluoxetine group (P = 0.0005). Absolute (and proportional) changes in visceral and subcutaneous fat areas (cm2) were +2 +/- 26 (+1%) and -9 +/- 26 (-4%) in the placebo group, and -9 +/- 30 (-3%) and -30 +/- 27 (-13%) in the fluoxetine group. In both groups the proportional change in subcutaneous fat area was larger than the change in visceral fat (P < 0.02). Only in the fluoxetine group was the decrease in subcutaneous fat area significant, and larger compared to the placebo group (P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

It has been suggested that a defect in hypothalamic serotonergic neurotransmission may be partly responsible for the impaired pituitary hormone release in obese subjects. In this study we investigated basal serum pituitary hormone concentrations and pituitary hormone release in response to the sequential injection of four hypothalamic releasing hormones before and after a seven-day course of fluoxetine, which inhibits serotonin re-uptake by presynaptic neurons and acts specifically in the brain. Ten obese women (body mass index (BMI) 35.6 +/- 1.0 kg/m2) and nine women of normal weight (BMI 22.9 +/- 0.9 kg/m2) were studied in the early and mid-follicular phases of the menstrual cycle. Basal concentrations of pituitary hormones were measured at 09.00. Subsequently 200 micrograms of TRH and 100 micrograms of CRH, GnRH and GHRH were injected intravenously. The pituitary hormone response was measured at regular intervals until 180 min after the four injections. The experiment was repeated after a seven-day course of 60 mg fluoxetine orally. We found the basal concentrations of prolactin (PRL) and growth hormone to be significantly lower in obese subjects than in the normal controls. Basal concentrations of ACTH, beta-endorphin, TSH, LH and FSH in the two groups were comparable. Releasing hormone-induced responses in the two groups were not significantly different. Administration of fluoxetine "restored" the basal PRL concentrations in obese subjects. It did not affect the other basal hormone concentrations. Furthermore, fluoxetine treatment reduced TRH-induced TSH release in both normal and obese subjects. It did not influence the other releasing hormone-induced responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Graded doses arginine-vasopressin (AVP) were administered to depressed patients and control subjects to compare the sensitivity of the pituitary-adrenal system of these subjects for this compound. The plasma levels of cortisol, adrenocorticotropic hormone (ACTH) and beta-endorphin were measured before and after intravenous AVP injection. The hormonal output was taken as a measure of pituitary-adrenal function. In control subjects 3 doses AVP and placebo were used, whereas in patients two doses AVP, a low and a high dose, and placebo were tested. All tests were carried out in the afternoon when the pituitary-adrenal system is stable and more susceptible for stimulation. Patients were subdivided into dexamethasone suppressors and nonsuppressors based on their DST status before testing to look for differences among these groups. Control subjects showed no response of the hormones to the lowest dose AVP and a moderate response to the higher doses. Interestingly, depressed patients as compared to controls responded more to the lowest dose AVP in particular with respect to ACTH. DST status did not influence the results. These findings suggest an enhanced sensitivity of the pituitary to low doses AVP in depressed patients. Thus, AVP might play a role in HPA dysfunction in depression.

Objective: The objective of this study was to investigate the effect of plasma GH-levels on the high affinity growth hormone binding protein (GHBP)., Patients: We studied plasma samples of eight patients with acromegaly and eight age and sex matched healthy subjects., Design: Patients with acromegaly were treated with octreotide administered by continuous subcutaneous infusion. Levels of growth hormone binding protein (GHBP) were measured in plasma samples before therapy and 3, 6 and 12 months after starting treatment. During this period, octreotide was administered in doses of 300-800 micrograms/day. The mean dose per patient over the study period ranged from 300 to 575 micrograms/24 h. The GHBP levels of patients with acromegaly were compared with those in the healthy subjects., Measurements: Bound and free 125I-GH in plasma were measured using FPLC gel chromatography on a Superose 12 column, after an overnight incubation period. The binding data were used for a Scatchard plot analysis. Wilcoxon's signed rank test was used for statistical analysis., Results: We found lower GHBP levels in acromegalic patients (P = 0.01) than in the control subjects. Octreotide treatment resulted in IGF-I levels < 300 micrograms/l in four patients. In these patients GHBP levels increased., Conclusions: We conclude that growth hormone binding protein levels are down regulated in acromegaly, indicating an important role for GH in the regulation of this protein.

A 19-year-old female with ectodermal dysplasia, lipoatrophy, diabetes mellitus, and amastia is described. This complex of symptoms is very similar to that of a case published by Pinheiro et al [1983] under the acronym of AREDYLD syndrome.

Calcitonin gene-related peptide plasma levels were measured during four different phases of ovulatory menstrual cycles, in eight women suffering from the premenstrual syndrome and in eight controls. No significant fluctuations in calcitonin gene-related peptide levels occurred during the menstrual cycle. Neither were there significant differences in calcitonin gene-related peptide levels between the premenstrual syndrome and control groups.

Background: Multiple endocrine neoplasia (MEN) type IIb is an autosomal dominantly inherited disorder associated with medullary thyroid cancer, pheochromocytoma, and a characteristic phenotype. The present study was performed to investigate the natural course of the syndrome and to describe its expression., Methods: The medical records of 18 patients with MEN IIb, seven male and 11 female, were reviewed., Results: The mean age at diagnosis of MEN IIb was 18 years (range, 8 to 41 years). All 18 patients had medullary thyroid cancer. In three patients, medullary thyroid cancer was diagnosed via screening. In two of these patients, the calcitonin value normalized after thyroidectomy. One patient died of metastases from medullary thyroid cancer at the age of 20 years (median duration of follow-up, 10 years). Eight of the 18 patients had pheochromocytomas. All of our patients had neuromas and bumpy lips, and all but one had a marfanoid habitus. A large proportion of the patients had intestinal abnormalities (75%), thickened corneal nerves (69%), skeletal abnormalities (87%), and delayed puberty (43%)., Conclusions: The course of medullary thyroid cancer in MEN IIb is not always as aggressive as is generally thought. Periodic examination of relatives who are at risk may lead to early diagnosis and curative treatment. Intestinal abnormalities, skeletal abnormalities, and delayed puberty are commonly found in association with MEN IIb.

Objective: We wished to investigate the interaction of arginine, GHRH and insulin stress on GH secretion., Design: Six healthy, non-obese volunteers underwent seven separate studes in random order. They received (1) insulin alone at 0 minutes; (2) GHRH alone at 15 minutes; (3) arginine alone at 0-30 minutes; (4) arginine at 0-30 minutes and GHRH at 15 minutes; (5) insulin at 0 minutes and arginine at 0-30 minutes; (6) insulin at 0 minutes, GHRH at 15 minutes and arginine at 0-30 minutes; (7) insulin at 0 minutes and GHRH at 15 minutes., Measurements: GH and PRL were measured from -30 to 150 minutes at intervals of 15 minutes., Results: Arginine increased GH responses to GHRH and decreased GH responses to hypoglycaemia, but this inhibitory effect of arginine was reversed by GHRH., Conclusions: The findings suggest that arginine-induced GH release is mainly mediated by a decrease in somatostatinergic tone, while GH responses to insulin stress are probably mediated by both an increase in hypothalamic GHRH release and inhibition of somatostatin.

The aim of this study was to investigate the seasonal behaviour of the plasma free testosterone: cortisol ratio (FTCR) and to relate hormonal changes to daily training volume and performance parameters on a rowing ergometer in elite female rowers. During 9 months of training preceding the 1988 Olympic Games the resting values of the FTCR in six elite female rowers were regularly (ten times) studied. Daily training volume was analysed in terms of rowed distance (lrowed) and time (t). In addition, two performance parameters, the power at 4.0 mmol.l-1 lactate concentration in the blood and the maximal power, were determined by a test on a rowing ergometer. The results indicated that the mean FTCR test value did not differ significantly from the level of the initial test or from the mean value of the directly preceding test. A significant negative correlation (r = -0.98, P less than 0.01) between FTCR and lrowed was found in a period i.e. at a training camp, when there was a sudden increase in training volume. When FTCR was related to t a significant positive correlation (r = 0.88, P less than 0.05) was found only for the period at the training camp. Our data further suggested that the FTCR alone was not an adequate indicator for the anabolic/catabolic balance in elite female rowers. This finding was contrary to previous findings in elite male rowers. However, in training practice the FTCR seems useful as an indicator of the hormonal training status of elite female rowers when complemented with data about total and free testosterone, performance parameters and knowledge concerning cyclic variations of the FTCR.

Preceding the 1988 Olympic Games 6 elite female rowers were regularly subjected to an exercise test on a rowing ergometer (REM-test) with a time interval of about 5 weeks. Daily training volume was analysed in terms of rowed kilometres (RKM) and training time (TOTMIN, rowing and land training). The purpose of this study was to investigate the training volume during a season and to study possible changes in the working capacity of elite female rowers. The REM-test consisted of 3 consecutive blocks: 3 min warming up, 5 min standard load at anaerobic threshold and 2 min "all-out". Blood lactic acid concentration (LA) was determined for the construction of a LA-power curve. The power at 4.0 mmol/l (P4) was estimated as a measure of the aerobic capacity. The "all-out" score was used for calculating the maximal power (PM). Results show that both RKM and TOTMIN increase (range resp. 40-400% and 20-25%) when compared with the initial value. P4 also increases, in parallel with changes in both RKM and TOTMIN, with 8-10% of the initial value. PM increases continuously during the season up to 10% of its initial value. However, based on maximal heart rate and lactate values, it is concluded that PM was maximal in only 15% of the tests. Our data suggests that evaluation of training volume in elite female rowers is better done with P4 than with PM. The behaviour of P4 shows a parallel with the seasonal changes in the training load.(ABSTRACT TRUNCATED AT 250 WORDS)

Body weight and weight history in association with hormone levels were studied retrospectively in 47 patients with prolactinoma; macroprolactinoma was diagnosed in 36, microprolactinoma in 11 patients. At the time of diagnosis a weight history could be traced in 14 patients, 9 patients having gained weight (11.8 +/- 2 kg), 1 with a weight loss of 5 kg, and 4 reporting unaltered body weight. Body weight and Body Mass Index before treatment were 83 +/- 2.4 kg and 27.3 +/- 0.6 kg/m2, respectively. In the male patients the prevalence of BMI greater than or equal to 25 was greater than in the average Dutch male population (p less than 0.001). After 6 months of treatment, mainly with bromocriptine, patients with macroprolactinoma had lost 5.5 +/- 1.6% (p less than 0.002) of initial body weight. No significant weight change occurred in patients with microprolactinoma. Weight loss did not correlate with degree of hyperprolactinemia, nor with decrease of prolactin levels during treatment, in either group of patients. Thyroid or gonadal function were not associated with weight loss either. It appears that prolactinoma is associated with a higher frequency of overweight, as far as patients with macroprolactinoma are concerned.

Objective: To test the hypothesis that the hyperendorphinaemia in obesity originates from outside the pituitary., Design: Intravenous administration of corticotrophin-releasing hormone (CRH) after overnight suppression with 2 mg of dexamethasone in normal-weight controls and in obese subjects before and after weight reduction., Patients: Eleven obese females, age (mean +/- SEM) 30 +/- 2.1 years, body mass index (BMI) 41.2 +/- 1.9 kg/m2. Eight normal-weight females served as controls, age 26 +/- 2.1 years, BMI 21.4 +/- 0.5 kg/m2. Five obese subjects were also studied after weight loss of 18.4 +/- 1.0% of original weight., Measurements: Plasma beta-endorphin, ACTH and cortisol. Cortisol production rate in 24-hour urine. Basal (without dexamethasone suppression) plasma beta-endorphin levels., Results: Basal (without dexamethasone suppression) beta-endorphin levels were 7.7 +/- 0.8 pmol/l in the obese and 3.8 +/- 0.5 pmol/l in the control subjects (P less than 0.005). The degree of suppression of beta-endorphin after dexamethasone was similar in the obese (23.2 +/- 3.7%) and in the control subjects (28.2 +/- 0.12%). Administration of CRH following dexamethasone suppression resulted in a small but significant increase of plasma beta-endorphin in both obese (from 1.55 +/- 0.12 to 2.32 +/- 0.28 pmol/l) and control subjects (from 0.98 +/- 0.24 to 1.69 +/- 0.33 pmol/l). The groups did not differ regarding this response, nor regarding the release of ACTH and cortisol after CRH. Cortisol production rate was higher (P less than 0.001) in the obese (68.7 +/- 3.3 mumol/24 h) than in the controls (40.0 +/- 3.0 mumol/24 h). No correlation between cortisol production rate and basal beta-endorphin levels was found. Weight loss appeared to have no influence on cortisol production rate, basal beta-endorphin levels, or on the responses to dexamethasone or CRH., Conclusions: Plasma beta-endorphin in obese subjects can be affected by manipulations of the hypothalamic-pituitary-adrenocortical axis; the hypothesis that the hyperendorphinaemia of obesity originates from outside the pituitary cannot be confirmed.

We studied plasma calcitonin gene-related peptide (CGRP) levels in obese women before (n = 24) and after (n = 13) weight loss, and in normal weight controls (n = 15). Furthermore, the influence of two isocaloric meals (high carbohydrate vs. high fat) on plasma CGRP concentrations was studied. The CGRP concentration in the obese group (32.26 +/- 2.01 pg/ml) was significantly (p less than 0.0001) higher than in the control group (21.64 +/- 0.15 pg/ml). After weight loss (14.3 +/- 0.72% of original weight) CGRP concentrations remained unchanged. Only the high-fat meal caused a significant (p less than 0.02) rise in CGRP levels. Our results indicate that elevated plasma CGRP levels may constitute a primary phenomenon in obese women, and that fat intake may be associated with increased CGRP secretion.

The efficacy of subchronic (3 weeks) treatment with the long-acting somatostatin analogue octreotide was studied in four patients with symptomatic benign insulinoma. No clinical or biochemical effect on serum glucose, insulin, C-peptide or glucagon was observed in all four patients despite clearly detectable serum levels of octreotide. The resistance to octreotide therapy in these patients might be explained by the absence of somatostatin analogue receptors on their tumours.

The effect of fluoxetine on body weight and spontaneous food choice was studied in twenty-three healthy, non-depressed, obese females on an outpatient basis. After a one week placebo run-in period, subjects were randomized to receive either fluoxetine (FXT) 60 mg daily (n = 11) or placebo (P) (n = 12) for 6 weeks in a double blind study design. BMI (35.2 +/- 0.8 vs 36.4 +/- 1.3 kg/m2, mean +/- s.e.m.) and age (38.1 +/- 239 vs 37.3 +/- 2.7 years) were not different in either group. No specific diet was prescribed. On four separate days per 14 days food records were collected. Data were analysed with the use of food composition tables. Statistical analysis was performed using Student's t test for independent samples for data on body weight and calorie intake. Macro-nutrient composition of the diet was analysed using multivariate analysis of variance and post hoc Student's t test for independent samples. All subjects lost weight during fluoxetine treatment. Mean (+/- s.e.m.) weight loss in the fluoxetine treated group was 3.6 +/- 0.5 kg, compared to a mean weight gain of 0.3 +/- 0.5 kg in the placebo treated group (P less than 0.001). In all patients food intake was reduced during fluoxetine treatment and this reduction could fully account for the observed weight loss. The mean total caloric intake per day was significantly lower during fluoxetine treatment compared with placebo (FXT 1123 +/- 118 kcal vs P 1845 +/- 87 kcal, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The responses of plasma beta-endorphin, insulin and glucose to two different isocaloric mixed meals--high carbohydrate (CHO meal) and high fat (fat meal)--were assessed in women with android obesity before (n = 11) as well as after (n = 5) weight reduction, and in normal-weight controls (n = 8). Basal plasma beta-endorphin concentrations in the obese subjects (7.7 +/- 1.2 pmol/l) were significantly (p less than 0.005) higher than in the controls (3.8 +/- 0.5 pmol/l) and were not influenced by weight loss. Fasting plasma levels and the integrated releases of insulin and glucose, both after the CHO meal and after the fat meal were significantly higher in the obese subjects than in the controls. The fat meal induced no changes in beta-endorphin levels in either group. After the CHO meal a significant decrease in plasma beta-endorphin concentration was observed only in the obese group before weight reduction. An influence on beta-endorphin release by macronutrients is hypothesized.

In the multiple endocrine neoplasia syndrome type I (MEN-I syndrome), periodic screening of patients and their close relatives may improve prognosis and life expectancy. Although there is diffuse involvement of the pancreas with microadenomatosis, insulinomas in the MEN-I syndrome usually occur as single tumours. This is illustrated here by two patients with insulinomas and the MEN-I syndrome. Preoperative localization of the tumours was achieved accurately by digital subtraction angiography combined with dynamic computerized tomography after a bolus injection of contrast medium. At present, two and three years after elective surgery both patients are asymptomatic. The early detection and treatment of insulinomas is extremely important because of the high risk of cerebral damage associated with late diagnosis. Periodic investigation of MEN-I family members can promote the early diagnosis and treatment of insulinomas, especially in young patients, whose life expectancy and quality of life may be improved.

Screening of androgens and estrogens in blood and a GnRH test were performed in 20 female patients with anorexia nervosa and in 10 lean and 10 normal weight healthy control subjects. Both control groups had regular ovulatory menstrual cycles. The investigation was performed in the mid-follicular phase. Several variables showed significant differences between the groups; the levels of PRL, estrone, estradiol, progesterone, testosterone, androstenedione, and LH were lowest in the patients with anorexia nervosa. The lean control group showed intermediate values for progesterone, androstenedione, and, to a smaller extent, testosterone. The FSH response to GnRH was significantly higher in the patient group, corresponding to the pattern of late prepubertal girls. Ten patients were seen in a follow-up study. Five had resumption of the menstrual cycle, and the others still had amenorrhea. The two subgroups did not differ in either weight gain or the basal hormonal variables investigated. After weight gain an increased LH response to GnRH was observed in both subgroups. Patients who had resumption of the menstrual cycle showed a higher response of LH to GnRH, both before and after weight gain. The mean increase in LH after GnRH administration was significantly different between the two subgroups. The results suggest that the GnRH test may be useful to assess the stage of the disease and to predict the outcome, especially with regard to restoration of the menstrual cycle.

Pseudohypoparathyroidism is a condition in which for some reason the normal effect of PTH in the target organ fails to occur. In the Ia type here described the signal transmission is impaired due to abnormal genetic development of the stimulating G protein (Gs) in the cell membrane resulting in insufficient cAMP production after binding of PTH on the membrane receptor. The failure to occur of the normal PTH effect impairs the calcium homeostasis. In many cases this type of pseudohypoparathyroidism is associated with phenotypical characteristics such as short stature, round face, obesity, brachydactyly, subcutaneous and intracerebral calcifications and sometimes bradyphrenia. Since the Gs protein aspecifically also brings about production of cAMP after binding of other polypeptide hormones to this hormone-specific receptor, several hormone resistances may be present concurrently.

Some patients with Cushing's disease respond to neuropharmacological treatment, whereas others do not. This apparent heterogeneity has been attributed to the existence of a separate form of Cushing's disease of putative neurointermediate lobe origin as opposed to Cushing's disease of anterior pituitary origin. The present review summarizes recent observations in human and canine Cushing's disease which mitigate against this view. We propose that heterogeneity in Cushing's disease is related to heterogeneity of the normal anterior pituitary corticotroph. However, the most fundamental questions concerning the pathogenesis of Cushing's disease remain unanswered.

Metabolic responses during a very-low-calorie diet, composed of 50 per cent glucose and 50 per cent protein, were studied in 18 grossly obese subjects (relative weights 131-205 per cent) for 28 d. During the last 14 d (period 2) eight subjects (Gp B) served as controls, while the other ten subjects (Gp A) in the low T3 state were treated with triiodothyronine supplementation (50 micrograms, 3 times daily). During the first 14 d (period 1) a low T3-high rT3 state developed; there was an inverse relationship between the absolute fall of the plasma T3 concentrations and the cumulative negative nitrogen balance as well as the beta-hydroxybutyrate (BOHB) acid concentrations during the semi-starvation period, pointing to a protein and fuel sparing effect of the low T3 state. Weight loss in the semi-starvation period was equal in both groups; during T3 treatment the rate of weight loss was statistically significant (Gp A 6.1 +/- 0.3 kg vs Gp B 4.2 +/- 0.2 kg, P less than 0.001). In the control group there was a sustained nitrogen balance after three weeks; in Gp A the nitrogen losses increased markedly during T3 treatment. Compared to the control group, on average a further 45.4 g extra nitrogen were lost, equivalent to 1.4 kg fat free tissue. Thus, 74 per cent of the extra weight loss in the T3 treated group could be accounted for by loss of fat free tissue. During the T3 treatment period no detectable changes occurred regarding plasma triglycerides and plasma free fatty acids (FFA) concentrations; the plasma BOHB acid concentrations decreased significantly as compared to the control group. Plasma glucose concentrations and the immunoreactive insulin (IRI)/glucose ratio increased in Gp A in the T3 treatment period, reflecting a state of insulin resistance with regard to glucose utilization. Our results warrant the conclusion that there appears to be no place for T3 as an adjunct to dieting, as it enhances mostly body protein loss and only to a small extent loss of body fat.

Cholinergic receptor blockade has been shown to abolish GH secretion in a variety of physiological and pharmacological situations in normal subjects. We have investigated the effect of pirenzepine on nocturnal GH secretion in young adult patients with Type I insulin-dependent diabetes mellitus. Five patients (three male, two female; aged 20-27 years) were studied in a randomized order on two days separated by at least 1 week. All patients showed episodes of slow wave sleep on each occasion and this was followed by peaks of GH release when placebo alone was administered (range of GH peaks 6-115 mU/l). In contrast, cholinergic muscarinic receptor blockade with pirenzepine (100 mg orally at 2200 and 2400 h) completely abolished nocturnal GH release in each individual without altering the occurrence of slow wave sleep itself. Mean plasma glucose levels at each sampling time between each study did not differ significantly. The ability to abolish nocturnal GH secretion may be important in the field of diabetes, since excess GH secretion is implicated in several acute metabolic and chronic microvascular complications of the disease.

A direct radioimmunoassay for the determination of ACTH in a small volume of serum was developed using a commercially available antiserum and tracer. A single-stage radioimmunoassay with an incubation period of 4 days gave reliable and reproducible ACTH values. In the incubation medium 0.1% 2-mercaptoethanol was used as the antioxidant. During a 15-month period the assay has been used routinely in the laboratory. The coefficient of variation was less than 10% in the physiological and pathological range. A normal range of 12 to 60 ng/L was found. The reliability of the assay is demonstrated by results obtained in patients with disorders of the pituitary-adrenal axis.

The effect of a low calorie diet (200 kcal/0.8 MJ) composed of 50 per cent glucose and 50 per cent protein was studied on blood pressure and sympathetic activity in eight normotensive obese subjects. The study lasted 21 days; during the first seven days (period I) a weight maintaining diet was given; this was followed by 14 d (period II) of modified fasting (200 kcal/0.8 MJ). Sodium and potassium intakes of 20 and 80 mmol per d respectively were maintained constant throughout the study. In period I blood pressure decreased slightly until day 5; this occurred concomitantly with a marked natriuresis. Thereafter blood pressure and sodium excretion remained stable. No significant change was observed in the urinary excretion of total catecholamines, noradrenaline and 4-hydroxy-3-methoxy mandelic acid. From the start of period II blood pressure decreased markedly, together with a significant decrease in the urinary excretion of the catecholamines and 4-hydroxy-3-methoxy mandelic acid. Both blood pressure and urinary excretion of catecholamines and 4-hydroxy-3-methoxy mandelic acid stabilized after day 7 of period II. These changes preceded the maximal sodium diuresis of severe calorie restriction. The results suggest a primary role for the sympathetic system in the hypotensive effect of short term calorie deprivation although some influence of natriuresis cannot be excluded.

Four immunometric kits for thyrotropin with detection limits below 0.1 milli-int. unit/L were evaluated with respect to accuracy, precision, specificity, matrix effects, and high-dose "hook" effect. We also studied variations of values related to the patients' sex and age and time of the day and season when samples were collected. Correlation among the four methods was excellent, except for a few samples, and the interference in these samples could be abolished by adding mouse serum or "suppression medium." These phenomena can also be expected to occur in other immunometric assays involving monoclonal antibodies. With some modifications all tests are suitable for a clinical study of the usefulness of the thyrotropin assay as a primary test for thyroid function.

The renal concentrating ability (RCA) was studied in 30 obese subjects before and after modified fasting (MF) and T3 supplementation, and during hypocaloric-carbohydrate refeeding. We also studied the effect of sodium supplementation on the RCA during MF. Modified fasting induced a low T3-high rT3 state ("sick euthyroid"). During T3-supplementation plasma T3 levels increased but were in the normal range for normal weight controls. Plasma sodium, potassium, and calcium remained within the normal range during all study periods. After MF (14 days) the mean maximal urinary osmolality was significantly lower compared to prefast values both after dehydration alone (706 +/- 12 mosm/kg H2O v 975 +/- 14, P less than 0.001) and after dehydration plus sc vasopressin administration (676 +/- 19 v 899 +/- 17, P less than 0.001). After 14 days MF followed by 14 days MF + T3-supplementation plasma urea, urinary urea excretion, and the creatinine clearance were significantly greater than after MF alone as was the RCA (764 +/- 15 v 652 +/- 25, P less than 0.002). Sodium chloride supplementation increased RCA (P less than 0.02) but no additive effect of T3 and sodium chloride supplementation was observed. Severe dietary salt restriction induced a significant decline in RCA (P less than 0.005). Refeeding with carbohydrate increased plasma T3 from 79.9 +/- 7.7 to 97 +/- 7.5 ng/100 mL (NS) and decreased plasma rT3 from 0.33 +/- 0.02 to 0.27 +/- 0.02 ng/mL, (P less than 0.02); no significant change in RCA was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of a low-calorie diet (200 kcal) composed of about 50 per cent glucose and 50 per cent protein on body weight, thyroid hormone levels and pituitary thyrotrophin response was studied in 18 grossly obese subjects (relative weight 131-205 per cent) for 28 d; during the last 14 d eight subjects (Gp B) served as controls, while in the other ten subjects (Gp A) the low T3-high rT3 state was treated by T3 supplementation (150 micrograms daily). During the first 14 d (period 1) weight loss (corrected for the sodium diuresis) appeared to be constant and to be equal for both groups. The thyroid hormone concentration and the basal and TRH stimulated TSH concentrations were similar to the results from previous total starvation studies. Despite marked changes in serum T3 levels a normal pituitary TSH response was maintained and no delayed response of TSH to TRH occurred. During T3 supplementation the serum T3 levels increased to high values, the rT3 concentration declined to below initial values, the T4 and TSH concentrations were depressed and the response of the TSH concentration to TRH disappeared; apparently these 'high normal' levels of serum T3 must be considered inappropriate for this condition of severe calorie restriction. In the controls the serum T3 levels remained constant after the end of the first period; the serum rT3 concentration declined from day 14 to day 28, but remained above the initial values. The serum T4 concentration remained almost constant during the whole study; basal and TRH stimulated TSH concentrations did not change during the whole study. During period 2 weight loss diminished in the control group, but remained constant in Gp A (T3 supplemented); the correlation between the weight loss and the increase of the serum T3 concentration during triiodothyronine supplementation was significantly negative (r = -0.64; P less than 0.05). The well-being of the subjects did not change during T3 administration and no signs of hyperthyroidism developed. One could speculate this reflects a decrease in number or sensitivity of intracellular receptor sites. It is concluded that at the peripheral level no complete resistance develops against T3 administration; in the low T3 state the hypothalamic-pituitary axis reacts as if euthyroidism exists.

Cushing's disease may originate from either the anterior pituitary lobe or the neurointermediate lobe, a major characteristic of the latter group being bromocriptine responsiveness. This study of two patients with Cushing's disease demonstrates that bromocriptine responsiveness also may be associated with anterior pituitary corticotroph hyperplasia or a normal pituitary gland. The two patients were a 14-yr-old boy (patient 1) and a 29-yr-old woman (patient 2); their cortisol production rates were 121 and 234 mumol/24 h (normal values, less than 80 mumol/24 h), respectively. A single oral dose of 2.5 mg bromocriptine resulted in a gradual decrease in plasma cortisol from 680 to 130 nmol/L after 6 h in patient 1 and from 640 to 170 nmol/L after 4 h in patient 2. Both patients then received medical treatment for a period of 2 yr. Whereas sodium valproate was ineffective, bromocriptine (5 mg/day) abruptly decreased the cortisol production rate to 60 mumol/24 h in patient 1 and to 138 mumol/24 h in patient 2, and both patients had a partial clinical remission. Despite an increase in bromocriptine dosage to 30 mg daily and 24 mg/day cyproheptadine, the clinical and biochemical remission was not sustained in patient 1, and no further improvement occurred in patient 2. Total hypophysectomy then was performed in both patients. Sections of the pituitary from patient 1 showed diffuse anterior pituitary corticotroph hyperplasia, with early nodule formation in some areas. The sections from patient 2 showed normal numbers and distribution of corticotrophs. We conclude that the heterogeneous nature of Cushing's disease cannot be explained on the basis simply of anterior vs. intermediate lobe origin of the disease.

A patient with Cushing's disease was unsuccessfully treated by pituitary surgery and external pituitary irradiation. One year later sodium valproate treatment induced a remission and finally hypocorticism developed. After drug withdrawal hypercoticism recurred. Treatment with cyproheptadine again induced hypocorticism necessitating corticosteroid substitution therapy. Biochemical characteristics of this patient included responsiveness to bromocriptine and cyproheptadine in acute tests. The study demonstrates that sodium valproate and cyproheptadine may both be effective independently in the treatment of the same patient with Cushing's disease. It is proposed that the disease is due to an ACTH producing tumour of pituitary intermediate lobe origin.

To determine the role of vasoactive intestinal polypeptide (VIP) and prolactin (PRL) in digestion, plasma VIP and PRL levels were measured in healthy, non-obese and obese premenopausal women fed isocaloric breakfasts containing a high carbohydrate or a high fat-protein content. A significant increase in plasma VIP concentration occurred after a high fat-protein breakfast, the increase being independent of body mass index. Plasma PRL level was unaltered by breakfast. Results suggest that the release of VIP after a meal depends on a high fat concentration in the duodenum, which may then stimulate bicarbonate release and fat-stimulated release of cholecystokinin.

We designed a systematic study of patients with Cushing's disease to compare the results of acute experiments with cyproheptadine, sodium valproate and bromocriptine with the results of chronic treatment with sodium valproate. In 13 patients the plasma cortisol response to single doses of 2.5 mg bromocriptine, 6 mg cyproheptadine and 300 mg sodium valproate was assessed over 4-8 h. All patients were then treated with sodium valproate 200 mg three times a day for a period of 3 months. Subjects were classified as responders when there was a reduction in plasma cortisol by at least 50% below the basal level in two consecutive plasma samples during one of these tests, and/or clinical remission and normalization of cortisol production rate during sodium valproate treatment. Four patients responded significantly to at least one of the agents (group I) and 9 did not (group II). In group I three patients were bromocriptine responsive and one of these responded also to cyproheptadine; in this patient both sodium valproate and cyproheptadine were able to induce a remission during chronic treatment. In the one patient of the responder group who was bromocriptine insensitive, sodium valproate treatment also induced a remission. In two patients of the responder group sodium valproate treatment was ineffective. However, in both patients chronic treatment with bromocriptine induced a marked clinical improvement associated with a decrease of cortisol production rate. There was no difference between the groups in sex, age, clinical presentation, duration or severity of hypercortisolism. In one patient in group I a macroadenoma with suprasellar extension was present, while a microadenoma was detected in four patients in group II.(ABSTRACT TRUNCATED AT 250 WORDS)

We have measured GH and PRL changes following separate and combined administration of insulin and GH releasing factor (GRF) in six normal males. Peak GH responses to separate administration of insulin and GRF were comparable (71.4 +/- 10.2 vs 70.1 +/- 27.7 mU/l; mean +/- SEM). However, the peak GH response following combined administration was significantly higher (120.8 +/- 29.7, P less than 0.05) as was the total GH released as calculated by measuring the area under the curve (P less than 0.05). In contrast the PRL response to hypoglycaemia was not altered by the combined administration of insulin and GRF. This effect was not due to any direct action of hypoglycaemia or insulin at pituitary level since basal and 10(-8) M GRF stimulated GH release from rat anterior pituitary cells in vitro was not influenced by varying glucose and insulin levels. Our findings support the hypothesis that GRF and insulin-induced hypoglycaemia release GH via different pathways which are, at least in part, additive.

Since 1975, 10 families with the multiple endocrine neoplasia (MEN)-2A syndrome and five with the MEN-2B syndrome, making a total of 101 patients, have been identified in The Netherlands. Twenty-three of the MEN-2A patients died before the start of the screening program. The average age of the patients whose death was due to pheochromocytoma (n = 11) or medullary thyroid carcinoma (n = 12) was 34.9 and 49.2 years, respectively. Eighty-seven patients with the MEN-2A syndrome and eight with the MEN-2B syndrome underwent thyroidectomy for C-cell hyperplasia and/or medullary thyroid carcinoma. Eighteen patients had signs or symptoms caused by MEN-2A (group A), 60 were relatives of these patients who had been found to be affected at the first screening of the family (group B), and nine relatives had had negative screening results that later became positive (group C). Five patients had signs or symptoms due to MEN-2B (group A) and three were relatives of these patients who had been found to be affected at the initial screening (group B). To assess the effect of screening, we compared these groups with respect to the occurrence of metastatic medullary thyroid carcinoma at thyroidectomy and the results of the postoperative calcitonin tests. Among the MEN-2A families, 72 percent of group A, 33 percent of group B, and none of group C were found to have metastatic medullary thyroid carcinoma at surgery. In the MEN-2B families, all five patients in group A and one of the three patients in group B had metastatic disease. The "cure rates" in these three groups with MEN-2A, as determined by stimulated calcitonin assessment, were 11, 57, and 100 percent, respectively. One of the five patients with MEN-2B in group A and two of the three patients in group B showed normalization of the stimulated calcitonin value after surgery. From these results, it may be concluded that screening can lead to the detection of medullary thyroid carcinoma in an earlier stage, which in turn may permit curative treatment and improvement of both prognosis and life expectancy. The need for supervision of affected families by central registration to promote periodic examination and to guarantee the continuity of such screening is discussed.

Thyroid hormones, sympatho-adrenomedullary activity and metabolic responses have been studied in eight healthy obese subjects during modified fasting (0.8 MJ, 200 kcal/d) for 14 d, followed by hypocaloric-carbohydrate refeeding (2.4 MJ, 600 kcal/d) for 3 d. In the week preceding modified fasting, the subjects received a 7.2 MJ (1800 kcal) diet daily containing 20 mmol sodium, in order to distinguish the effects of salt depletion from those of energy restriction. Sodium (20 mmol/d) and potassium (80 mmol/d) were kept constant throughout the study. During modified fasting a low T3-high rT3 state developed; concomitantly a marked decrease in sympatho-adrenomedullary activity (assessed by 24-h urinary excretion of catecholamines) was observed. Upon refeeding plasma T3 increased and plasma rT3 decreased, but not completely to pre-fast values. Upon refeeding urinary catecholamine excretion markedly increased. A strong inverse relationship was found between the marked decrement of both thermogenic hormones and the catabolism of protein. No correlation between these parameters was found during brief refeeding. The observed decline of both thermogenic hormones may represent an adaptation to protect tissues from the catabolic effect of these substances during severe energy deficiency.

The case history is presented of a woman with secondary amenorrhoea, mild hyperprolactinaemia and pituitary enlargement with suprasellar extension, mimicking a pituitary adenoma. It appeared that she had primary hypothyroidism. After L-thyroxine treatment, all abnormalities disappeared. The literature on the combination of primary hypothyroidism, hyperprolactinaemia and pituitary enlargement is reviewed and the pathophysiology is discussed. It is concluded that determination of thyrotropin is essential in all patients with pituitary enlargement and hyperprolactinaemia.