Showing papers in "European Journal of Endocrinology in 1993"

Cardiovascular risk factors in adult patients with growth hormone deficiency

Abstract: Patients with adult onset growth hormone deficiency have a decreased life expectancy owing to an increased mortality from cardiovascular disease. In the present study, 104 subjects (66 men and 38 women, aged 22-74 years) with growth hormone deficiency and with adequate replacement therapy with glucocorticoids, thyroid hormones and gonadal steroids were studied with respect to known risk factors for cardiovascular disease. For comparison, data from a population study, "the MONICA study", were obtained. The patients had a significantly higher body mass index compared to controls (p < 0.001). Serum triglyceride concentration was higher (p < 0.001) but there was no difference in serum total cholesterol concentration. Serum high-density lipoprotein cholesterol concentration was lower (p < 0.001) in the patients. There was no difference in the prevalence of diabetes mellitus. The prevalence of treated hypertension was higher (p < 0.05) in the patients but the prevalence of smoking was lower (p < 0.001). Even after taking the increased body mass index into consideration, the changes in the prevalence of treated hypertension (p < 0.05) and in the serum concentrations of triglycerides (p < 0.05) and high-density lipoprotein concentrations (p < 0.001) remained. These results indicate that growth hormone deficiency alters lipoprotein metabolism and increases the risk for development of hypertension, which in turn might contribute to the increased risk for cardiovascular disease.

Reduced bone mineral content in adult patients with growth hormone deficiency

Abstract: Bone mineral content was measured in a follow-up study of adult patients with hypopituitarism and growth hormone deficiency. There were 95 patients (59 males, mean age 54.0 years, range 21-74 years; 36 females, mean age 53.5 years, range 31-73 years). Routine replacement therapy with cortisone acetate and L-thyroxine was given. All males that were gonadal deficient were on proper testosterone therapy, except in four patients who were treated separately. Bone mineral content (g/cm) was measured using dual-photon absorptiometry in the third lumbar vertebra. Bone mineral content in the patients was compared with a control population (N = 413, 25-74 years of age). Bone mineral content was significantly lower in males (N = 55, p < 0.05) compared with controls. In females, bone mineral content was significantly lower both among the subjects with untreated gonadal deficiency (p < 0.001) and among those with treated gonadal deficiency and normal premenopausal gonadal function (p < 0.005) compared with controls. To summarize, patients with hypopituitarism on routine replacement therapy but not growth hormone have a lower bone mineral content than the controls. The reduced bone mineral content might be a result of untreated growth hormone deficiency.

Effect of growth hormone treatment on hormonal parameters, body composition and strength in athletes

Abstract: The effect of recombinant GH on strength, body composition and endocrine parameters in power athletes was investigated in a controlled study. Twenty-two healthy, non-obese males (age 23.4 +/- 0.5 years; ideal body weight 122 +/- 3.1%, body fat 10.1 +/- 1.0%; mean +/- SEM) were included. Probands were assigned in a double-blind manner to either GH treatment (0.09U (kg BW)-1 day-1 sc) or placebo for a period of six weeks. To exclude concurrent treatment with androgenic-anabolic steroids urine specimens were tested at regular intervals for these substances. Serum was assayed for GH, IGF-I, IGF-binding proteins, insulin and thyroxine before the onset of the study and at two-weekly intervals thereafter. Maximal voluntary strength of the biceps and quadriceps muscles was measured on a strength training apparatus. Fat mass and lean body mass were derived from measurements of skinfolds at ten sites with a caliper. For final evaluation only data of those 8 and 10 subjects in the two groups who completed the study were analyzed. GH, IGF-I and IGF-binding protein were in the normal range before therapy and increased significantly in the GH-treated group. Fasting insulin concentrations increased insignificantly and thyroxine levels decreased significantly in the GH-treated probands. There was no effect of GH treatment on maximal strength during concentric contraction of the biceps and quadriceps muscles. Body weight and body fat were not changed significantly during treatment. We conclude that the anabolic, lipolytic effect of GH therapy in adults depends on the degree of fat mass and GH deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone metabolism in obesity: changes related to severe overweight and dietary weight reduction.

Abstract: A non-invasive evaluation of bone metabolism was performed in 44 morbidly obese patients before and after a mean weight loss of 22.4 kg (range 7.9-43.4 kg) after 2 months and a further weight loss of 7.3 kg after 8 months (0.8-20.0 kg). This weight reduction was obtained by a nutritionally adequate very-low-calorie diet. Before treatment the bone mineral content of the distal forearm was increased compared to normals (51.9 U vs. 43.7 U, p < 0.001). Bone formation was evaluated by serum alkaline phosphatase and serum osteocalcin. Serum alkaline phosphatase was increased (187.8 U/l vs 147.4 U/l, p < 0.001) while serum osteocalcin was lower than in the controls (0.67 nmol/l vs 0.98 nmol/l, p < 0.01). Bone resorption, as measured by the urinary hydroxyproline/creatinine ratio, was not increased in the obese patients (19.2 molar ratio x 10(-3) vs 16.7 molar ratio x 10(-3), NS). After 2 months, the bone mineral content had declined by 3.3%. Serum alkaline phosphatase remained unchanged (187.8 U/l vs 186.9 U/l, NS) but serum osteocalcin demonstrated a significant rise (3.94 nmol/l vs 10.53 nmol/l, p < 0.001), parallel to changes in the hydroxyproline/creatinine ratio (19.2 molar ratio x 10(-3) vs 25.2 molar ratio x 10(-3), p < 0.001). At 8 months, no further change in the bone mineral content was seen. The hydroxyproline/creatinine ratio did still increase (from 25.8 molar ratio x 10(-3) to 30.1 molar ratio x 10(-3), p < 0.05), while serum alkaline phosphatase and serum osteocalcin remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreas and gut hormone responses to oral glucose and intravenous glucagon in cystic fibrosis patients with normal, impaired, and diabetic glucose tolerance

Abstract: Pancreatic and gut hormone responses to oral glucose, and insulin sensitivity were studied in cystic fibrosis patients with normal (N = 14), impaired (N = 4), and diabetic (N = 12) glucose tolerance, and in 10 control subjects, and beta cell responses to oral glucose and intravenous glucagon were compared. Compared to control subjects, initial insulin and C-peptide responses to oral glucose were lower in all patient groups, and decreased with decreasing glucose tolerance. Insulin sensitivity in patients with impaired and diabetic glucose tolerance was lower than in control subjects. The 6 min post-glucagon C-peptide concentration was positively correlated with the initial insulin response to oral glucose. Fasting levels of pancreatic polypeptide, pancreatic glucagon, total glucagon, glucagon-like peptide-1 7-36 amide, and gastric inhibitory polypeptide were normal in all patient groups. Following oral glucose, pancreatic polypeptide responses were absent in all patients, suppressibility of pancreatic glucagon secretion was increasingly impaired with decreasing glucose tolerance, and gut hormone levels were normal. In conclusion, at cystic fibrosis (a) insulin secretion is impaired even when glucose tolerance and insulin sensitivity are within the normal range, (b) the glucagon test gives valid estimates of residual beta cell function, (c) pancreatic polypeptide response to oral glucose is absent, (d) glucagon suppressibility decreases with decreasing glucose tolerance, and (e) the enteroinsular axis is intact.

Plasma levels of several androgens and estrogens from birth to puberty in male domestic pigs.

Abstract: Plasma concentrations for several androgens and estrogens were determined in male domestic pigs from birth to eight months of age. Samples (N = 6) of blood were collected from Yorkshire males at weekly intervals from birth to four weeks, and thereafter at monthly intervals to eight months. Radioimmunoassays were done without extraction from plasma for dehydroepiandrosterone sulphate, androstenedione and estrone sulphate. Other steroids were measured after solid-phase extraction, separate elution of unconjugated and conjugated fractions, and solvolysis of sulpho-conjugated steroids (testosterone, 5 alpha-androstane-3 beta, 17 beta-diol, epiandrosterone, 19-nortestosterone and estradiol-17 beta). All steroids showed a peak in plasma levels at 2-4 weeks after birth. Concentrations remained low from 2-5 months and rose markedly thereafter. Most steroids were present in much greater quantities as sulpho-conjugated compounds. Concentrations of testosterone sulphate and testosterone were similar (9.4 mumol/l) at three weeks but the sulphated form predominated after six months of age. This study shows that during postnatal development the testes of the domestic pig are remarkably active in steroidogenesis with a peak at 2-4 weeks after birth. Also, the range of steroid products seen at this stage is comparable to that shown by the mature boar.

Microsomal antibodies during gestation in relation to postpartum thyroid dysfunction and depression

Abstract: Rationale Microsomal antibodies have been related to postpartum thyroid dysfunction and postpartum depression. Objectives To detect the value of microsomal antibodies during gestation in a random population, as a risk factor for thyroid dysfunction and depression during the postpartum period. Main findings The presence of microsomal antibodies was investigated in a random population of 293 women at 32 weeks' gestation. At the same time, postpartum thyroid function was assessed repeatedly in all women every six weeks up to 34 weeks' postpartum. Postpartum thyroid dysfunction, defined as the presence of abnormal TSH, in combination with abnormal fT4 and/or fT3 values, occurred in 21 women (7.2%) during the postpartum period. Depression was assessed using the Research Diagnostic Criteria without knowing the results of biochemical thyroid function tests. At 32 weeks' gestation there were 27 (9.2%) women with elevated microsomal antibody titres. Compared with microsomal-antibody negative women at 32 weeks' gestation, these women had an RR of 20 for developing postpartum thyroid dysfunction and an RR of 1.7 for developing postpartum depression. Conclusions Women with elevated microsomal antibody titres during gestation are particularly at risk for postpartum thyroid dysfunction, but only have a slightly increased risk for postpartum depression.

Life events in the pathogenesis of Graves' disease. A controlled study.

Abstract: Contradictory findings have been reported about a possible causal relationship of life stress to Graves' disease. We evaluated this issue by investigating the occurrence of stressful life events in the year before the first signs of disease onset, using methods that have been found to be valid and reliable in psychosomatic research. Seventy consecutive patients with Graves' disease and a control group of 70 healthy subjects, matched for sociodemographic variables, were studied. Paykel's Interview for Recent Life Events (a semistructured research interview covering 64 life events) was administered to patients, not during the acute phase of illness but while on remission, by antithyroid drug treatment. Patients with Graves' disease reported significantly more life events compared to controls (p < 0.001). They also had more independent events (p < 0.001) and events that had an objective negative impact (p < 0.001) according to an independent rater, unaware whether the events had occurred in patients or controls. All categories of events were found to be significantly more frequent in patients suffering from Graves' disease than in controls. By rigorous methods (inclusion of patients with Graves' disease only, careful dating of the onset of symptoms, accurate event definition, delay of the interview upon disease remission, use of a blind rater for judging independence and objective negative impact), our results support the concept of an excess of life events in Graves' disease. Stressful life events may affect the regulatory mechanisms of immune function in a number of ways. Within the extreme complexity of the phenomena implicated in the pathogenesis of autoimmune thyroid hyperfunction, our findings emphasize the role of emotional stress.

Plasma corticotropin-releasing hormone, β-endorphin and cortisol inter-relationships during human pregnancy

Abstract: To investigate the dynamic relationships among corticotropin-releasing hormone (CRH), beta-endorphin (beta EP), cortisol and obstetric events during pregnancy, blood samples were collected from 193 women at 28 weeks, 38 weeks, during labour and on the second postnatal day. Cord blood at delivery was also obtained. We found that: (1) Maternal plasma CRH, beta EP and cortisol rose from 28 to 38 weeks. (2) During the third trimester maternal plasma CRH and beta EP were correlated (r = 0.30, p < 0.001). (3) During labour, no correlations were found among maternal plasma CRH, beta EP and cortisol. (4) Maternal CRH at labour and the duration of labour were not correlated. (5) Maternal plasma CRH tended to be higher in women who delivered early (more than seven days prior to estimated date of confinement [EDC]) relative to those who were on time (within seven days' EDC) or late (greater than seven days after EDC). (6) CRH in maternal plasma at labour and cord blood were correlated (r = 0.29, p < 0.05) as were maternal and fetal beta EP (r = 0.43, p < 0.001). (7) Fetal obstetric difficulty was correlated with fetal beta EP (r = 0.54, p < 0.001). Our findings support the hypothesis that maternal plasma CRH regulates maternal beta EP during the third trimester, but other factors are involved during labour and in response to maternal obstetric stress.

Cortisol increases plasma insulin-like growth factor binding protein-1 in humans.

Abstract: Insulin-like growth factor binding protein-1 (IGFBP-1) modulates the metabolic and mitogenic actions of the IGF peptides. Previous studies have established insulin as the major regulator of plasma IGFBP-1 in humans, acting to suppress hepatic IGFBP-1 synthesis. In this study, we investigated the regulation of plasma IGFBP-1 by cortisol in humans, independent of insulin. Following an overnight fast, six healthy adult volunteers received a euglycemic pancreatic clamp (somatostatin, 0.12 microgram.kg-1.min-1; GH, 3 ng.kg-1.min-1; insulin, 0.05 mU.kg-1.min-1) to block endogenous insulin secretion and to control glucose and plasma hormone concentrations at desired levels. Three hours after the initiation of the pancreatic clamp, each subject received an additional 360 min infusion of either cortisol (2 micrograms.kg-1.min-1) or saline on separate occasions and in random order. Plasma cortisol concentrations increased from 220 to 970 nmol/l during the cortisol infusion. Insulin concentrations were maintained at approximately 30 pmol/l throughout saline and cortisol infusions. Plasma IGFBP-1 concentrations increased threefold in response to hypoinsulinemia, reaching plateau values of approximately 140 micrograms/l with saline infusion. During cortisol infusion, IGFBP-1 levels increased to approximately 300 micrograms/l. Over the 360 min study period, the integrated response of plasma IGFBP-1 to cortisol infusion was 314% greater than to saline infusion (p < 0.01). Our data confirm that, under conditions of hypoinsulinemia, cortisol is a significant modulator of plasma IGFBP-1 in humans.

Mortality in patients treated for hyperthyroidism with iodine-131

Abstract: Causes of death were studied in 10,552 Swedish hyperthyroid patients treated with 131I diagnosed between 1950 and 1975. The patients were followed for an average of 15 years (range 0-35 years) and were matched with the Swedish Cause of Death Register. A total of 5,400 deaths were observed and the overall standardized mortality ratio was 1.47 (95% confidence interval (CI) 1.43-1.51). The standardized mortality ratio for females was 1.50 (95% CI 1.46-1.55) compared to 1.31 (95% CI 1.23-1.39) in males. The most common cause of death (61%) was from cardiovascular diseases (standardized mortality ratio 1.65; 95% CI 1.59-1.71). Significantly elevated risks were also seen for tumours, diseases of the endocrine system, respiratory system, gastro-intestinal system, and congenital malformations. In all causes of death, except tumours and trauma, decreasing standardized mortality ratios over time were seen. Patients followed for more than 10 years had significantly elevated risks for tumours, diseases of the endocrine, respiratory, and cardiovascular systems. Patients given higher 131I activity and younger patients had higher standardized mortality ratios than those given lower activity and older patients. The hyperthyroidism per se, rather than the 131I treatment, appeared to be the major explanation for the elevated mortality.

Graves' disease, endocrine ophthalmopathy and smoking

Abstract: We have evaluated the association between smoking, Graves' disease and endocrine ophthalmopathy in a case-control study of 208 patients with newly diagnosed Graves' disease and carried out a retrospective survey of 72 patients treated for Graves' disease and admitted to our ward because of endocrine ophthalmopathy. In the prospective study, patients with Graves' disease smoked significantly more than their healthy controls (41% vs 30%, p < 0.01 for current smokers, odds ratio 1.6, 95% confidence interval 1.1-2.3, and p < 0.05 for patients with a history of smoking, odds ratio: 1.4, 95% confidence interval 1.0-1.9). Among the patients with endocrine ophthalmopathy at diagnosis, there were slightly more patients with a history of smoking (p < 0.05, odds ratio 2.1, 95% confidence interval 1.1-3.9), but not more current smokers when compared with the remaining group. The patients with eye problems tended to have a more active disease with higher levels of thyroxine and TSH-receptor antibodies, but no difference was seen in thyrogastric autoantibodies. No effect of smoking on thyroid hormone and autoantibody levels could be detected. In the retrospective survey we found 64%, 71% and 87% smokers among patients with moderate, severe and malignant eye disease, respectively. In summary, the results show that smoking is associated with an increased risk of contracting Graves' disease and that it enhances the severity of the eye disease in cases that develop endocrine ophthalmopathy during the course of treatment.

Long-term follow-up in patients with autonomous thyroid adenoma.

Abstract: A group of 375 untreated euthyroid patients with solitary autonomous adenoma of the thyroid were studied in a long-term follow-up (observation period 52.8 (mean)/46 (median), range 3-204 months). During the period of observation, 133 (34.2%) of all initially untreated patients underwent treatment (surgery, radioiodine, antithyroid medication) because of hyperthyroidism, mechanical problems, or at the patient's request. Sixty-seven patients developed hyperthyroidism resulting in a mean incidence of 4.1% per year. The incidence of hyperthyroidism increased during follow-up (3% in the first seven years, 10% in the following years). Age, sex, nodule size, initial scintigraphic appearance and the TRH test were of no individual prognostic value in predicting hyperthyroidism. Eleven of 14 patients with untreated hyperthyroidism became euthyroid without treatment during the time of follow-up. After iodine excess (by history or elevated iodine levels in urine, N = 45), 14 patients (31%) developed hyperthyroidism. In conclusion, we recommend a definitive treatment of autonomous adenoma at least in patients with advanced age, concomitant diseases and a higher probability of iodine exposure.

Thyroxine administration to infants of less than 30 weeks gestational age decreases plasma tri-iodothyronine concentrations

Abstract: Objective: To investigate the effect on thyroid hormone metabolism of the administration of thyroxine to very preterm infants. Design and methods: Two hundred infants of less than 30 weeks gestation were enrolled into a randomized, double-blind, placebo-controlled trial. Thyroxine (T4) (at a fixed daily dose of 8 mg/kg birthweight) or placebo was started 12‐24 h after birth and discontinued 6 weeks later. Plasma concentrations of T4, tri-idothyronine (T3), reverse T3 (rT3), TSH, and thyroxine-binding globulin were measured weekly during trial medication and 2 weeks thereafter. Results: The T4 and the placebo group each comprised 100 infants. Antenatal, perinatal, and postnatal clinical characteristics were comparable in both groups. T4 and rT3 were significantly increased in the T4 group. TSH concentrations were depressed in the T4 group and T3 was significantly decreased, probably as a result of TSH depression. The T4/T3 and T4/rT3 ratios differed significantly between the two study groups. Conclusions: Daily T4 administration during the first 6 weeks after birth to infants of less than 30 weeks gestation prevents hypothyroxinemia, but decreases plasma T3 concentrations. Our finding possibly implies that very preterm infants should receive supplements of both T4 and T3.

Long-term treatment of Laron type dwarfs with insulin-like growth factor-1 increases serum insulin-like growth factor-binding protein-3 in the absence of growth hormone activity

Abstract: Insulin-like growth factor binding protein-3 (IGFBP-3) is the major carrier of insulin-like growth factor I (IGF-I) in serum, and its production is growth hormone (GH) dependent. It is unclear whether in humans IGFBP-3 production is directly regulated by GH or mediated via IGF-I. We addressed this question in six patients with Laron-type dwarfism, a syndrome characterized by the absence of GH receptor activity (LTD), who were chronically treated with recombinant IGF-I. Analysis of the electrophoretic profiles of serum IGFBPs in these patients by Western ligand blotting revealed an extremely low IGFBP-3 level. A striking progressive increase in serum IGFBP-3 was observed with continuous treatment, despite the absence of GH action. In LTD children, serum IGFBP-3 increased up to 19-fold after six months of therapy and equalled levels observed in controls, whereas in adult LTD patients the increase was smaller. A rise in serum levels of 34, 30 and 24 kDa BPs (presumably IGFBP-2, -1 and -4, respectively was also noted with chronic IGF-I therapy. This proof of GH-independent induction of IGFBP-3 by IGF-I may be a major advantage in the therapeutic use of biosynthetic IGF-I in several types of short stature children.

Efficacy of insulin-like growth factor binding protein 3 in predicting the growth hormone response to provocative testing in children treated with cranial irradiation.

Abstract: Recent data suggest that the plasma concentration of insulin-like growth factor binding protein 3 (IGFBP-3) is useful as a screening test for growth hormone (GH) deficiency. In this study, we measured by radioimmunoassay the levels of IGFBP-3 in a group of 20 subjects (12 males) of 5 years and 7 months to 16 years of age undergoing standard GH testing following cranial irradiation. The patients had received 1800 to > 6000 cGY of radiation to the hypothalamic-pituitary region, a median of 2.7 years (range 2-7 years) prior to testing. The IGFBP-3 concentrations were discordant with the results of GH testing 60% (12/20) of the time. Although IGFBP-3 levels were below the mean for age in 14 of 15 GH-deficient (peak GH < 10 micrograms/l) patients, only three of 15 GH-deficient patients had IGFBP-3 concentrations that fell below age-adjusted norms. In contrast, the IGFBP-3 levels were within the normal range in all five patients with normal GH responses. The low sensitivity (20%) of IGFBP-3 in predicting the subjects with abnormal responses was not improved by adjusting the values for bone age or stage of puberty. We concluded that a single plasma determination of IGFBP-3 is not a useful screening test for GH deficiency among patients previously treated with cranial irradiation.

Insulin-like growth factors and their binding proteins in plasma and milk after growth hormone-stimulated galactopoiesis in normally lactating women.

Abstract: We performed a double-blind randomized placebo-controlled trial of recombinant human growth hormone (hGH) in normally lactating women (N = 8 per group) to investigate the endocrine mode of action of the galactopoietic effect of this hormone. Insulin-like growth factors I (IGF-I) and II (IGF-II) and their binding proteins (IGFBP-1, IGFBP-2 and IGFBP-3) were measured by radioimmunoassay in plasma and milk samples collected throughout the study. All assays were validated for human plasma and milk. Human GH treatment (0.1 IU.kg-1 body wt.day-1 for 7 days) increased plasma concentrations of IGF-I from 22.1 +/- 1.3 nmol/l (mean +/- SEM) to 59.7 +/- 2.5 nmol/l (p < 0.01). At the end of the study the increase in plasma IGF-I correlated significantly with the increase in milk volume (r = 0.67, p < 0.005, N = 16). The IGF-I levels were considerably lower in milk, with 0.14 +/- 0.03 nmol/l before and 0.31 +/- 0.04 nmol/l after hGH treatment. The increase in milk IGF-I levels (134.0 +/- 14.5%) with hGH treatment was significant (p < 0.01) and plasma and milk IGF-I concentrations correlated significantly when considering all samples of the study (r = 0.45, p < 0.001, N = 56). The concentrations of IGF-II were not changed significantly with hGH treatment in plasma (52.5 +/- 2.5 nmol/l before and 42.6 +/- 3.9 nmol/l after treatment) or milk (2.1 +/- 0.29 nmol/l before and 2.3 +/- 0.49 nmol/l after hGH treatment).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of tibolone on serum concentrations of lipoprotein(a) in postmenopausal women.

Abstract: OBJECTIVE To evaluate the effects of tibolone (Org OD14), a synthetic steroid used for the relief of postmenopausal symptoms, on serum concentrations of lipoprotein(a) (Lp(a)), an independent risk marker for coronary heart disease. DESIGN Subset of women participating in a non-randomized prospective trial of tibolone therapy. Twenty-seven women requesting relief of menopausal symptoms were treated with tibolone 2.5 mg/day for six months; 27 women who did not request treatment acted as controls. RESULTS Tibolone induced a substantial fall (p < 0.001) in serum Lp(a) levels (median change -48%, range -100% to +3%). CONCLUSIONS In terms of cardiovascular risk, the ability of tibolone to lower serum concentrations of Lp(a) may be advantageous in view of the unwanted reduction in high density lipoprotein concentrations which has previously been demonstrated in users of this steroid.

Endocrine function following single fraction and fractionated total body irradiation for bone marrow transplantation in childhood

Abstract: Forty-nine children who had undergone treatment with cyclophosphamide and total body irradiation before bone marrow transplantation were investigated for impaired endocrine function. Twenty-six patients received single fraction total body irradiation as a dose of 9-10 Gy, whereas 23 patients received fractionated total body irradiation as a total dose of either 12 Gy divided into six fractions or 14.4 Gy divided into eight fractions, administered over 3 or 4 days. Half of the patients in the single fraction group and nine in the fractionated group had received cranial irradiation prior to total body irradiation. Pathological changes in thyroid function were observed in 19 patients (73%) of the single fraction group (elevated thyrotrophin (58%) and decreased thyroxine levels (15%)), whereas in the fractionated group only six patients (25%) developed transient raised thyrotrophin levels: the mean observation period was 3.2 years in the single fraction group and 2.7 years in the fractionated group. The stimulated growth hormone peak concentration was influenced significantly by previous cranial irradiation and was independent of the type of total body irradiation administered. In the patients who had received cranial irradiation, the mean growth hormone peak levels were 8.4 mU/l (single fraction group) and 13.9 mU/l (fractionated group), whereas in those who received only total body irradiation they were 24.9 mU/l(single fraction group) and 28.1 mU/l (fractionated group). The basal gonadotrophin concentration in children older than 9 years showed elevated levels in nine patients (50%) of the single fraction group and in only three patients (30%) of the fractionated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Infant feeding, fetal growth and adult thyroid function

Abstract: Prolonged breast-feeding in humans is associated with increased low-density lipoprotein cholesterol and higher death rates from ischaemic heart disease in adult life. The reasons for this link are unclear. A possible explanation is that thyroid hormones present in breast milk and absorbed by the suckling infant could, by the process of hormonal imprinting, permanently down-regulate the set point of thyroid homeostasis. Thyroid hormones influence cholesterol metabolism, and could explain the link between infant feeding and the regulation of cholesterol levels in the adult. We therefore investigated whether infant feeding was related to adult thyroid function in 303 women aged 60-71 years who were born in the county of Hertfordshire, UK, where birthweight, the weight at 1 year and the method of infant feeding had been recorded routinely. Free thyroxine (FT4) concentrations but not free triiodothyronine (FT3) or thyrotrophin (TSH) were increased in the women who, as infants, had been breast-fed beyond 1 year of age (p < 0.01). In women who were bottle-fed, with or without breast-feeding, serum TSH rose and FT4 fell with increasing birthweight (p = 0.01 and p = 0.04, respectively). Although the metabolic significance of these findings is unclear, they suggest that the set point of thyroid function in the adult is determined by fetal growth and infant feeding.

The expression of insulin-like growth factors and their binding proteins in normal human lymphocytes

Abstract: The expression of insulin-like growth factors and their binding proteins in normal human peripheral lymphocytes was studied using the reverse transcriptase polymerase chain reaction method and Western ligand blotting A quantitation of RT-PCR products was used to study the differences between normal and PHA stimulated lymphocytes Normal freshly collected lymphocytes expressed mRNAs for both IGF-I receptor and IGF-II receptor but no expression of the corresponding growth factors was detectable After stimulation with phytohemagglutinin the lymphocytes, however, expressed both IGF-I and IGF-II Of the five IGFBPs examined, unstimulated lymphocytes expressed only IGFBP-2 and -3 Stimulated lymphocytes expressed IGFBP-4 and -5, in addition to IGFBP-2 and -3, whereas IGFBP-1 mRNA remained undetectable The ligand blotting of lymphocyte conditioned media revealed production of 34K, 43K and 49K IGFBPs The addition of estrogen, progesterone, IGF-I or growth hormone did not affect secretion of IGFBPs by lymphocytes

Effect of growth-hormone and insulin-like growth factor-i on urinary albumin excretion - studies in acromegaly and growth-hormone deficiency

Abstract: Glomerular hyperfiltration is a characteristic feature of acromegaly but it is uncertain whether albuminuria is elevated in this disease. To investigate the role of abnormal growth hormone (GH) and insulin-like growth factor I (IGF-I) levels on urinary protein excretion, we measured the overnight urinary albumin excretion rate (UalbV) and creatinine clearance in 14 acromegalic patients with metabolically active disease (fasting GH > 5 ug/l and IGF-I > 2.2 kU/l), 8 GH-deficient patients and 20 control subjects. The UalbV was higher in the acromegalic patients (median 8.4 (range 4.2-68.2) mug/min) than in the GH-deficient patients (2.0 (0.9-5.9) mug/min, p <0.001) and control subjects (3.3 (1.0-7.8) mug/min, p <0.0 1). Five acromegalic patients had UalbV levels above the normal upper normal limit of 10 mug/min. Only one patient with concomitant untreated hypertension had persistent microalbuminuria. Creatinine clearance also was higher in the acromegalic patients (p <0.0 5) and lower in the GH-deficient patients (p <0.0 5) than in the control subjects. In 11 of these acromegalic cases, the lowering of GH by 63% and of IGF-I by 48%, following treatment with the somatostatin analogue (N = 10) or spontaneous pituitary infarction (N = 1), reduced the UalbV by 2 9% to 4.9 (3.1-4 5.2) mug/min (p <0.01). Among the acromegalic patients (25 observations), the UalbV was related to GH (r = 0. 6 1. p <0.01), IGF-I (r = 0.57, p

Impairment of neuromotor and cognitive development in iodine-deficient schoolchildren with normal physical growth

Abstract: In order to detect somatic and psychomotor disturbances in children and adolescents residing in areas of iodine deficiency, schoolchildren from three areas with different degrees of iodine deficiency were studied. In Randan, the prevalence of severe endemic goiter was accompanied by alteration in thyroid function, increased thyrotropin levels and retardation of both bone and psychomotor age and decreased intellectual quotient. In Tehran, where iodine deficiency is mild, visible goiter was present in 15% of schoolchildren but no alterations in thyroid function, serum thyrotropin, somatic or psychomotor development could be detected. In Zagoon, where the prevalence and severity of goiter was less than Randan but more than Tehran, thyroid function was normal but slightly decreased as compared to Tehran; somatic development was unaltered, but retardation in psychomotor development was evident and the mean intellectual quotient was less than that of Tehranian schoolchildren. These findings indicate the occurrence of physical and psychomotor disturbances in apparently normal schoolchildren from areas of iodine deficiency. Alteration in psychomotor development may occur in children with normal physical growth, due to iodine deficiency.

Effects of chronic heroin abuse on bone and mineral metabolism

Abstract: Though the chronic use of opiates can modify several body functions, only a few data are available on the effects of opioid drugs on mineral metabolism. We have examined the possible consequences of chronic opiate abuse on bone mass, bone turnover and calcium metabolism in 13 male chronic heroin users, examined 1-2 days after the last administration of the drug (group A), 14 former male heroin addicts, examined 4-24 months after drug discontinuation (group B), and 22 healthy, age- and sex-matched control subjects. In group A, the vertebral bone mineral density (measured by Dual-Photon Absorptiometry) was significantly lower (p < 0.05) than in the control subjects, despite similar values of total body bone mineral, lean body and fat mass. Blood-ionised calcium and urinary calcium and hydroxyproline were significantly increased (p < 0.01), whereas parathyroid hormone was lower than in controls (p < 0.01). Bone alkaline phosphatase and osteocalcin, however, were not significantly different from the control values. LH and testosterone levels were low (p < 0.01 vs controls). In contrast, group B subjects did not show significant differences from the control group. The chronic abuse of opioid drugs may be associated with altered bone metabolism and reduced trabecular bone mass, attributable, at least in part, to gonadal deficiency. These alterations seem reversible after drug discontinuation.

Epidemiology and pathogenesis of pituitary adenomas.

Abstract: Pituitary tumorigenesis is characterized by initiation, implying spontaneous or acquired mutations and promotion, implying that tumour expansion is sustained by intrinsic or extrinsic promoting factors. Pituitary tumours have a doubling time of 100 to 700 days. Seventy per cent of cases occur in 30 to 50-year-old patients, but tumours with highest growth rate (prolactin and ACTH-secreting adenomas) are also encountered in patients < 20 years. Pituitary adenomas occur at a greater frequency in females but there is no vivo evidence for a direct role of sex hormones. Oestrogen can amplify tumour growth factors in pituitary cell lines. One-third of GH-secreting adenomas have elevated cAMP resting levels which appear to be caused by a somatic mutation in the Gs protein associated with the GHRH receptor. This maintains the adenylate cyclase system in a turned-on state. Patients with mutant Gs protein have higher GH levels, reduced GHRH response, elevated TRH response, good suppressibility by SRIH and smaller tumour size compared to other acromegalic patients. Hypothalamic releasing hormones may be able to sustain pituitary tumour development since some acromegalic patients with GHRH-secreting tumours may harbour a pituitary GH-secreting adenoma. A lack of inhibitory factors may also have a promoting role in tumour progression.

Subclinical hypothyroidism and hyperlipoproteinaemia: indiscriminate L-thyroxine treatment not justified.

Abstract: It is still under discussion whether subclinical hypothyroidism is a biochemical syndrome or a disease associated with an increased risk for development of vascular diseases due to lipid elevation. Therefore, we investigated lipid values in 40 patients with subclinical hypothyroidism, which is defined in terms of normal (N = 26) or slightly increased (N = 14) basal TSH values and/or an exaggerated TSH response (N = 34) to TRH (> 25 mU/l). Patients with increased lipid values were treated with L-thyroxine and reanalysed three months later. Mean levels of total cholesterol. LDL- and HDL-cholesterol and triglycerides in patients with subclinical hypothyroidism were comparable with those in normal subjects. Individual analysis, however, revealed hyperlipoproteinaemia (HL) in 22.5% of the patients investigated (HL type IIa in seven, type IV in two patients). Thyroid function was the same in affected patients as in those with normal lipid values, whereas higher age was significantly more often associated with this syndrome (p < 0.01). Treatment with L-thyroxine resulted in a significant decrease in total and LDL-cholesterol (p < 0.05), although a normalization of their lipid values could be obtained only in half of the patients. None of the subjects with hyperlipoproteinaemia had a history or clinical signs of actual vascular disease. Although the incidence of hyperlipoproteinaemia in our study group of patients with mild subclinical hypothyroidism (22.5%) is comparable to that of the normal population (21.5%), it is more severe in the former group (LDL-cholesterol in patients 5.26 +/- 0.58 vs 4.8 +/- 0.56 mmol/l in controls; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal responses to the new potent GnRH antagonist Cetrorelix

Abstract: GnRH antagonists, unlike the GnRH agonists, immediately suppress gonadotropins and testosterone secretion without initial stimulatory effect. We report here on a single-dose study with the new GnRH antagonist Cetrorelix (Ac-D-Nal(2)1, D-Phe(4C1)2, D-Pal3, D-Cit6, D-Alal0) in 25 normal men. The study involved five different dose groups (0.25, 0.5, 1.0, 1.5 or 3.0 mg) and subjects were observed over a 40 h period. Five men served as controls. Serum levels of LH, FSH and testosterone decreased rapidly with a dose-related decline for testosterone of 25%, 24%, 41%, 53% and 72%, respectively, for testosterone within the first 8 h of antagonist administration. All effects were reversible and no serious side effects were observed. Thus, this GnRH antagonist is active in men even in small doses and could become a new therapeutic tool for sex hormone-dependent diseases. Cetrorelix seems to have the highest suppressive rate per mg peptide of all other antagonists from the literature, such as Nal-Glu (Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal3, Arg5, D-Glu6(AA), D-Alal0), Detirelix (Ac-D-Nal(2)1, D-pCl-Phe2, D-Trp3, D-hArg(Et2)6, D-Alal0) or 4F (Ac-delta 3Prol, 4F-D-Phe2, D-Trp3,6). During the time of suppression after a dose of 3 mg there was an LH and testosterone peak in the early morning coinciding with the testosterone peak in untreated men. The GnRH antagonist seems to unmask the circadian rhythm of LH secretion.

Recovery from lymphocytic hypophysitis associated with painless thyroiditis: clinical implications of circulating antipituitary antibodies

Abstract: Lymphocytic hypophysitis usually occurs in the antepartum or postpartum period and recovery of pituitary dysfunction has not been documented in most cases reported previously. We present a 50-year-old woman with lymphocytic hypophysitis who spontaneously recovered from panhypopituitarism over 18 months with the disappearance of an intrasellar mass. Although lymphocytic hypophysitis is thought to be an autoimmune disease, the clinical and pathogenetic significance of circulating antipituitary autoantibodies has not been clarified. Antipituitary antibodies were studied by immunofluorescence in blood samples obtained during the whole clinical course in this particular patient. Antibodies against rat pituitary cytosol were positive during the period of hypopituitarism and became negative when pituitary function recovered. Antibodies reacting with intact prolactin-secreting rat GH3 and corticotropin-secreting mouse AtT-20 cells were also positive during her period of hypopituitarism. They remained positive for several years after the recovery of pituitary function. We conclude that circulating antibodies against rat pituitary cytosol are good markers of pituitary inflammation in this patient. The other point to be emphasized in this case is the simultaneous development of painless thyroiditis and lymphocytic hypophysitis. We have discussed the pathogenic relationship of these two diseases on the basis of similar cases reported previously.

Effect of different types of stressors on peptide messenger ribonucleic acids in the hypothalamic paraventricular nucleus

Abstract: Using in situ hybridization we have studied the effects of different types of stressors, such as ether, immobilization, cold and swimming, on the expression of several peptide messenger ribonucleic acids (mRNAs) in the hypothalamic paraventricular nucleus of adult male rats. Paraventricular nucleus sections were hybridized using synthetic oligonucleotide probes complementary to mRNA for corticotropin-releasing hormone, neurotensin, enkephalin and thyrotropin-releasing hormone. A clear upregulation of neurotensin mRNA was seen after ether and, to a lesser extent, after immobilization stress, whereas after the two other stressors neurotensin mRNA was undetectable, as in control rats. An increase in enkephalin mRNA was observed in a selective region of the dorsal part of the medioparvocellular subdivision of the paraventricular nucleus only after ether and immobilization stress. No significant changes were seen in corticotropin-releasing hormone and thyrotropin-releasing hormone mRNA levels in any of the experimental paradigms. The present results show selective changes for various peptide mRNAs in the paraventricular nucleus after various types of stress. Significant effects could be demonstrated only on neurotensin and enkephalin mRNA after ether and immobilization stress. This suggests that adaptive changes in the rate of synthesis, processing and transport of the peptide may develop over a longer period of time.