Showing papers in "European Journal of Endocrinology in 1995"

Thyroid hormones and brain development.

Abstract: Thyroid hormone is a major physiological regulator of mammalian brain development. Cell differentiation, migration and gene expression are altered as a consequence of thyroid hormone deficiency or excess. The physiological role of thyroid hormone can perhaps be defined so as to ensure the timed coordination of different developmental events through specific effects on the rate of cell differentiation and gene expression. All triiodothyronine (T 3 ) receptor isoforms are expressed in the brain and their spatial and temporal patterns of expression suggest unique and complementary functions for the different isoforms. Cell biology studies suggest a role for T 3 and its receptors in oligodendroglial and neuronal differentiation and the control of cell death. Some of the effects on neuronal differentiation might be due to an action of thyroid hormone on the production of neurotropins and their receptors. In recent years a number of T 3 -dependent genes have been identified in the rat brain, such as myelin protein-encoding genes or specific neuronal genes, and thyroid hormone-responsive elements have been demonstrated in some of these genes. The identification of the gene network regulated by thyroid hormone during brain development, the elucidation of the mechanism of regulation and the clarification of the physiological roles of the regulated genes remain major goals for future studies.

Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a.

Abstract: The occurrence of thyroid abnormalities and the appearance of organ- and non-organ-specific autoantibodies during long-term recombinant interferon alpha-2a (IFN-alpha) therapy were studied in 86 and 51 consecutive outpatients with hepatitis C and B virus-related chronic active hepatitis (CAH-HCV and CAH-HBV), respectively. Most patients had longstanding community-acquired hepatitis. At baseline, 9.3% of CAH-HCV and 3.9% of CAH-HBV patients showed clinical and/or biochemical signs of thyroid dysfunction. The remaining patients were euthyroid, although anti-thyroid autoantibodies were found in 33/78 (42.3%) of CAH-HCV and in 5/49 (10.2%) of CAH-HBV patients. During IFN-alpha treatment, increased anti-thyroid autoantibody levels were seen in 40% of CAH-HCV initially negative patients, while they became detectable in no more than 10% of CAH-HBV patients. Interferon-alpha-induced hypo- or hyperthyroidism was recorded in 12 of 35 CAH-HCV patients treated for 12 months (34.3%). Only one CAH-HBV patient developed hyperthyroidism. High titers of anti-nuclear autoantibodies (ANA) were recorded at enrollment in 5/36 (13.8%) of CAH-HCV and in 3/16 (18.7%) of CAH-HBV patients. Only one CAH-HCV patient displayed anti-parietal cell antibodies (PCA). After IFN-alpha treatment, ANA were found in 10/28 (35.7%) and PCA in 2/28 (7.1%) of CAH-HCV patients, while an additional CAH-HBV patient developed PCA, but not ANA. However, no signs of systemic autoimmune disease were recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroendocrine regulation of growth hormone

Abstract: This short review is focused on the neuroendocrine regulation of growth hormone (GH) pulsatile secretory pattern and GH gene expression. The neuronal network involved in the central control of GH includes extrahypothalamic neurons such as the noradrenergic and cholinergic systems, which regulate the two antagonistic neurohormonal systems: somatostatin (SRIH) and GH-releasing hormone (GHRH). Intrahypothalamic Proopiomelanocortin- and Galanin-containing interneurons also participate in the regulation of SRIH and GHRH neuronal activity, which also is dependent on sex steroids and GH and/or insulin-like growth factor I (IGF-I) feedback. cAMP (controlled mainly by GHRH and SRIH), thyroid and glucocorticoid hormones. IGF-I and activin are among the factors that regulate GH gene expression at the transcriptional level and may play a role in somatotroph differentiation and proliferation during ontogeny as well as physiological and pathological states such as acromegaly.

Calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin: homologous peptides, separate receptors and overlapping biological actions

Abstract: Calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin are structurally related peptides with N-terminal 6-7 amino acid ring structures linked by a disulfide bridge and with amidated C-termini. Among the related bioactive peptides, the structures of the calcitonin receptor and subtypes thereof have been identified so far through molecular cloning. Cross-reaction between receptors of calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin, as well as overlapping biological actions, anticipate that the respective receptors belong to a family of G-protein-coupled receptors that include those of parathyroid hormone, secretin and vasointestinal peptide.

Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy

Abstract: This review stresses changes in osmoregulation as well as the secretion and metabolism of arginine vasopressin during pregnancy, focusing on human gestation. Pregnant women experience a decrease in body tonicity, plasma osmolality decreasing immediately after conception to a nadir approximately 10 mosmol/kg below non-pregnant levels early in pregnancy, after which a new steady state is maintained until term. Data from both human and rodent gestation have led to a formation of how these changes occur. The osmotic thresholds for thirst and antidiuretic hormone release decrease in parallel. Lowering the threshold to drink stimulates increased water intake and dilution of body fluids. Because arginine vasopressin (AVP) release is not suppressed at the usual level of body tonicity, the hormone continues to circulate and the ingested water is retained. Plasma osmolality declines until it is below the osmotic thirst threshold, and a new steady state with little change in water turnover is established. Pregnancy is characterized by increments in intravascular volume, but volume-sensing AVP release mechanisms appear to adjust as gestation progresses so that each new volume status is "sensed" as normal. The metabolic clearance of AVP increases fourfold, the rise paralleling that of circulating cystine aminopeptidase (vasopressinase), and enzyme produced by the placenta. Furthermore, the disposal rate of 1-deamino-8-D-AVP, and AVP analogue resistant to inactivation by vasopressinase, is unaltered in pregnancy. Thus, the increase in AVP's metabolism and the high circulating aminopeptidase levels have been implicated in certain forms of transient diabetes insipidus that occur in late pregnancy. Finally, mechanisms responsible for the altered osmoregulation in pregnancy are obscure, but chorionic gonadotropin and relaxin may be implicated in the changes.

Cigarette smoking and the thyroid

Abstract: The effects of smoking on the function of endocrine glands have been investigated extensively but still are to be elucidated fully. It is widely recognized that the most important component of the smoke produced from the burning of tobacco, in terms of endocrine effects, is nicotine. Nicotine acts through the interaction with acetylcholine receptors, but it seems likely that others among the numerous smoke products may somehow influence endocrine homeostasis. The present paper will focus on the relationship between smoking and variations in thyroid economy or the occurrence of thyroid dysfunction.

Effects of growth hormone and insulin-like growth factor I on the immune system

Abstract: Growth hormone-releasing hormone (GHRH), growth hormone (GH), prolactin (PRL) and insulin-like growth factor I (IGF-I) are synthesized and secreted by various immunocompetent cells. In addition, GHRH, GH, PRL and IGF-I receptors are expressed on immune cells. Growth hormone, PRL and IGF-I stimulate the proliferation of immunocompetent cells and modulate humoral and cellular immune functions, i.e. immunoglobuline secretion of B cells, thymulin secretion of thymic epithelial cells, natural killer cell activity, phagocytosis, oxidative burst and killing capacity of neutrophils and macrophages. No clinically significant cellular or humoral immunodeficiency has been found in GH-deficient patients. However, several immunological parameters and functions are altered in GH-deficient patients when compared to normal controls. The data available to date indicate that endocrine and pleiotropic para- and autocrine mechanisms of action are involved in a neuropeptide immune network, including GH, PRL and IGF-I as modulators of immune function.

Abnormalities of endocrine function in patients with clinically "silent" adrenal masses.

Abstract: Because, in recent years, patients with incidentally discovered adrenal masses have been encountered increasingly, their endocrine function was investigated in basal conditions and after dynamic tests. Thirty-two patients (23 women and 9 men, aged 28-74 years) were studied. Lesion diameter, as documented by computed tomography and/or nuclear magnetic resonance imaging, ranged between 5 and 65 mm; the tumors were localized on the right in 22 patients, on the left in 5 and bilaterally in 5 cases. In basal conditions, urinary free cortisol (UFC) excretion, plasma adrenocorticotropin (ACTH) and cortisol levels were normal, except for 4 patients who showed high UFC and ACTH levels in the low-normal range. Ovine corticotropin-releasing hormone (CRH, 1 microgram/kg iv) was given to 18 patients, inducing normal ACTH and cortisol responses in 12, blunted responses in 4 and no response in 2 cases. No reduction in ACTH and cortisol levels after suppression tests was observed in 4 of 29 patients after dexamethasone (1 mg overnight) or in 6 of 29 after loperamide. The 4 patients who were unresponsive to both tests did not show any further inhibition after high-dose dexamethasone administration, had low plasma ACTH levels and showed impaired or absent responses to the CRH test: they were diagnosed as affected with preclinical Cushing's syndrome. An exogenous ACTH test performed in 30 patients caused a normal cortisol rise. Basal mean 17-hydroxy-progesterone (17-OHP) levels were not different from those in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of age and gender on pituitary-adrenocortical responsiveness in humans

Abstract: This study compared plasma concentrations of adrenocorticotropin (ACTH) and cortisol in young men (N = 10, mean age 244 years), young women (N = 10, mean age 254 years), old men (N = 8, mean age 816 years) and old women (N = 8, mean age 835 years) under basal resting conditions and after stimulation with either human corticotropin-releasing hormone (hCRH, 100 micrograms iv) or a combined injection of hCRH (100 micrograms) and arginine vasopressin (VP, 05 IU iv) Basal secretion of cortisol did not differ among groups, but basal concentrations of ACTH were diminished in young women (p < 001), indicating an enhanced adrenal sensitivity to ACTH in these subjects Pituitary responses to hCRH did not differ between young men and women However, responses to hCRH/VP were stronger in the young females (p < 001), suggesting an enhanced pituitary responsiveness to the augmenting effect of VP on ACTH release in this group Pituitary-adrenal secretory responses were greater in old than in young men after sole injection of hCRH (p < 005) and even more so after combined injection of hCRH/VP (p < 001) In old women, pituitary-adrenal secretory responses were also greater than in young women (p < 005) But, in particular for responses to hCRH/VP, these effects were less distinct than within the men Results indicate an enhancing effect of age on pituitary responsiveness to the hypothalamic secretagogues hCRH and VP, modulated by the subject's gender

Test of growth hormone secretion in adults: poor reproducibility of the insulin tolerance test

Abstract: The insulin tolerance test (ITT) is regarded as the most reliable provocative test in the diagnosis of growth hormone (GH) deficiency in adults. In the present study the test was evaluated by investigating the range of GH responses in normal adult males and females and the intra-individual reproducibility of the test. Sixteen healthy non-obese adults, eight males (median age 31.5 years) and eight females (median age 31.8 years) were tested twice with the ITT, with a minimum of 72 h between each test. The females were tested between day 3 and day 10 of their menstrual cycles. Adequate hypoglycemia was achieved in all cases with a median nadir blood glucose of 1.3 mmol/l (range 0.8-2.0). Growth hormone in serum was measured by immunoradiometric assay and low values were confirmed by a different assay. Median peak GH concentration responses to the ITT were : in males 27.9 μg/l, range 5.0-71.1 (test 1) and 30.5 μg/l, range 7.9-69.5 (test 2) ; and in females 9.0 μg/l, range 4.1-17.9 (test 1) and 8.4 μg/l, range 0.09-42.4 (test 2). The rise in GH concentration during the ITT was higher in males than in females. In the males, all stimulated GH values were ≥ 5.0 μg/l. In the females, four out of 16 tests gave values below 5.0 μg/l and in one test the GH value was around the detection limit of the assays. There was poor reproducibility during repeated testing, with no correlation between the results of the two tests. The results did not correlate to the magnitude of the hypoglycemia. The results of this study illustrate the complexity of the regulation of GH secretion and indicate that the ITT is less useful for diagnosing GH deficiency in adults than previously anticipated. The diagnosis of GH deficiency in adults and especially in adult females should not be based on the results of a single ITT alone.

Plasma brain natriuretic peptide concentrations in healthy children from birth to adolescence: marked and rapid increase after birth.

Abstract: The aim of the present study is to establish the normal range and to determine the developmental changes of plasma brain natriuretic peptide (BNP) concentrations in children. We measured plasma BNP concentrations as well as atrial natriuretic peptide (ANP) concentrations in 58 healthy children from birth to adolescence and in the umbilical vein of 20 healthy neonates using highly sensitive immunoradiometric assays. The plasma BNP concentration was the highest at 0 days of age and descended through maturation to be almost constant and to be at the adult level at 3 months of age. The plasma BNP concentration at 0 days of age (56.7 +/- 49.6 fmol/ml; mean +/- SD) was 25 to 30 times higher than the adult level and 21 times higher than that in the umbilical vein (2.7 +/- 1.4 fmol/ml). The plasma ANP concentration at 0 days of age was not significantly different from that in the umbilical vein. The ratio of BNP to ANP was also the highest at 0 days of age (1.39 +/- 0.72) and decreased through maturation to be at the adult level at 3 months of age. Thus, the plasma BNP concentration in healthy subjects showed a marked, rapid and preferential increase immediately after birth, suggesting that BNP has a physiological role distinct from that of ANP in the perinatal circulatory changes from fetus to neonate.

Reduced bone mineral density in adults with growth hormone (GH) deficiency: increased bone turnover during 12 months of GH substitution therapy.

Abstract: To evaluate the consequences of growth hormone (GH) deficiency on bone mineral density and to evaluate the effects of GH substitution therapy 68 adults (25 females and 43 males) aged 22-61 (mean 442 ± 12) years with GH deficiency (GHD) were studied Fifty-eight patients had panhypopituitarism, three had isolated GHD and in seven patients at least one additional pituitary function was affected Twenty-one patients had childhood onset GHD The patients were randomized to receive either GH in daily injections (0125 IUkg -1 week -1 for the first 4 weeks and subsequently 025 IU kg -1 weeek -1 ) or placebo for 6 months The trial continued as an open study with GH treatment for 6 or 12 months, with data presented as compiled data of 12 months of GH treatment in 64 patients Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry and bone turnover was assessed by serum markers of bone metabolism (osteocalcin, procollagen I peptide, crosslinked telopeptide of type I collagen and alkaline phosphatase activity) In women with adult onset GHD (N = 19) and in men with childhood onset GHD (N = 15), total body, spine and hip BMD was significantly reduced at baseline compared to Swedish age- and sex-matched control material In men with adult onset of GHD (N = 28), BMD did not differ from male controls During the placebo-controlled period GH induced decreased total body and spine BMD, probably due to an expansion of the remodelling space, whereas all serum markers of bone turnover increased Compiled GH data showed similar results after 6 months of treatment After 12 months of GH treatment, BMD did not differ from basal values except for total body BMD, which was lower, whereas the serum markers of bone metabolism were still increased as compared to basal values Two-thirds of the patients experienced fluid retention with peripheral oedema and arthralgias on the higher GH dosage One obese patient developed non-insulin-dependent diabetes mellitus and was withdrawn from the study These results demonstrate that GHD has negative effects on BMD and that GH substitution induces increased bone turnover Continued long-term observations will reveal if there is a positive effect of GH substitution on bone mass in the adult GHD patient

Decrease of incidence of toxic nodular goitre in a region of Switzerland after full correction of mild iodine deficiency

Abstract: In 1980 the iodide content of salt was increased in Switzerland from 7.5 to 15 mg/kg. This raised the mean urinary iodine excretion from 90 (indicating mild iodine deficiency) to 150 micrograms/g creatinine. We examined whether this public health measure was followed by a change of the incidence of hyperthyroidism in a defined catchment area of 109,000 persons. Except for a 27% rise in the first year of the new salt, the total incidence of hyperthyroidism declined steadily to reach 44% of the control level in 1988/89. This was due to a decrease mostly of toxic nodular goitre (minus 73%), less so of Graves' disease (minus 33%). We conclude that correction of mild iodine deficiency has beneficial effects on the incidence of hyperthyroidism, contrary to what is seen initially after correction of severe deficiency.

Effects of selenium deficiency on thyroid necrosis, fibrosis and proliferation: a possible role in myxoedematous cretinism

Abstract: It has been suggested that selenium deficiency is a co-factor to iodine deficiency in the pathogenesis of myxoedematous cretinism. The mechanism proposed is that the generation of hydrogen peroxide is greatly increased in iodine-deficient thyroid glands, and that selenium is involved in the control of hydrogen peroxide and its derived free radicals. This study was carried out to investigate the effect of the possibly impaired cellular defence mechanism associated with selenium deficiency on thyroid necrosis and tissue repair. For this purpose, we studied thyroid tissue from selenium- (SE-) and/or iodine-deficient (I-) rats before and after an acute toxic iodine overload. In I- thyroids, necrotic cells were numerous. Acute iodine administration increased this effect. Necrosis was associated with transient infiltration of inflammatory cells. In I-SE+ thyroids the tissue resumed its normal appearance. In I-SE- thyroid glands, the iodide toxicity was stronger, with greater necrosis and inflammatory reaction. The inflammation resolved but was replaced by fibrotic tissue. Fifteen days after the toxic overload, the connective tissue volume was twice the control value. Before iodide overload, the proportion of dividing cells was equal in I-SE+ and I-SE- thyroids. Three days after the iodide overload, this proportion was increased in I-SE+ thyroids but reduced in the I-SE- thyroids. Overall, the I-SE- thyroids had four times fewer dividing cells than the I-SE+ thyroids. In summary, selenium deficiency coupled to iodine deficiency increased necrosis, induced fibrosis and impeded compensatory epithelial cell proliferation. These results are compatible with histological and functional description of thyroid tissue from myxoedematous cretins.

In vivo responsiveness of morphological variants of growth hormone-producing pituitary adenomas to octreotide

Abstract: The somatostatin analog, octreotide, is an inhibitor of growth hormone (GH) secretion that has been used to treat patients with GH-producing pituitary tumors. In this study we investigated the in vivo responsiveness to treatment with this analog in patients harboring different morphological types of GH-producing pituitary adenomas. Both GH and insulin-like growth factor I (IGF-I) plasma levels in 30 patients treated with octreotide (300 micrograms/day) for 4 months preoperatively were compared with those from 30 patients who did not receive treatment preoperatively. Tissue samples were studied using ultrastructural and immunohistochemical techniques. Amongst patients harboring densely granulated (DG) adenomas, mean GH levels were reduced to 32 +/- 9% by octreotide, to 30 +/- 7% by surgery and to 26 +/- 9% of baseline by both interventions. Surgery was equally as effective in lowering GH levels in patients with sparsely granulated (SG) adenomas as it was in those with DG adenomas; in patients with SG adenomas, GH levels were reduced by surgery alone to 37 +/- 16% and to 24 +/- 15% when performed following octreotide pretreatment. In contrast, treatment with octreotide alone in patients harbouring SG adenomas reduced GH levels to only 70 +/- 13% of baseline (p < 0.02 compared to surgery alone, or surgery and octreotide). We conclude that the GH inhibitory effects of octreotide are significantly better in patients harboring DG somatotroph adenomas compared with those harboring SG adenomas.

Changes in systemic gonadal and adrenal steroids in asymptomatic human immunodeficiency virus-infected men : relationship with the CD4 cell counts

Abstract: Serum sex hormone-binding globulin (SHBG), testosterone, non-SHBG-bound testosterone, androstenedione, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and cortisol were measured in 58 homosexual men seropositive for human immunodeficiency virus (HIV), all clinically asymptomatic (Centers for Disease Control 1993 classification stage A). The HIV patients were divided into four groups according to the CD4 lymphocyte count-group 1 (more than 500/μl, N = 14), group 2 (between 350 and 500/μl, N = 16), group 3 (between 200 and 349/μl, N = 22) and group 4 (less than 200/μl, N = 6)-and compared with 11 antibody-negative men as controls. The SHBG levels were significantly increased in groups 1, 2, 3 (p < 0.01) and 4 (p < 0.05) compared with controls, with no differences between groups of patients. Compared with controls, testosterone concentrations were significantly lower in group 4 (p < 0.05) and non-SHBG-bound testosterone levels were significantly lower in groups 1 (p < 0.05), 2 (p < 0.01), 3 (p < 0.001) and group 4 (p < 0.001) ; DHT and androstenedione levels were significantly lower in group 4 (p < 0.05) and DHEA levels were significantly lower in group 2, group 3 (p < 0.01) and group 4 (p < 0.05) than in controls. Cortisol levels were significantly increased in groups 1 and 4 (p < 0.05) and FSH and LH concentrations were not significantly higher in HIV-infected men than in controls. Also, the DHEA, androstenedione, non-SHBG-bound testosterone and DHT levels were correlated with CD4 cell counts, showing that hypogonadism occurs as the CD4 lymphocytes decrease. A strong reverse correlation between CD4 cell counts and cortisol/DHEA ratios (p < 0.001) confirms the alterations in adrenal steroid secretion, with a shift from androgen to glucocorticoid production as the disease progresses. These data show that in asymptomatic HIV-infected patients serum SHBG levels increase independently of CD4 cells counts, even in patients with undiminished CD4 cell counts ; an alteration in serum androgen occurs as the CD4 cell counts decrease ; and the cortisol/DHEA ratios increase as the CD4 cell counts decrease, resulting from alterations in adrenal secretion with both a decrease in serum DHEA levels correlated with CD4 cell counts and a slight increase in cortisol levels.

Retrospective evaluation of subtotal and total thyroidectomy in Graves' disease with and without endocrine ophthalmopathy

Abstract: A retrospective analysis was performed in 173 consecutive patients with Graves' disease (GD) with the principal aim of evaluating the influences of subtotal (N = 157) and total (N = 19) thyroidectomy on postoperative recurrence rates, endocrine ophthalmopathy (EO) and thyrotropin receptor antibody (TSH-R-ab) titres. Postoperatively recurrent disease, identified by increased thyroid hormone levels, occurred in 32 patients (20%) who underwent subtotal resection. These recurrences were associated with over-representation of preoperative EO (p < 0.001) as well as high TSH-R-ab levels postoperatively (p < 0.05-0.01). Subtotal and total resections were followed by an aggravation of preoperative EO in nine (16%) and one (6%), and by a development of EO in two and none of the patients, respectively. Persistently elevated TSH-R-ab titers during thyrostatic therapy became close to normalized in seven (32%) and 15 (88%) of the patients undergoing subtotal or total thyroidectomies, respectively, which illustrates a thyroid tissue dependency of the autoantibody production. Among the total material of 173 patients, altogether 75 cases exhibited persistent or progressive EO and/or TSH-R-ab elevation after more than 1 year of preoperative thyrostatic treatment. In this group, recurrent GD or aggravated EO occurred in 23 (39%) of those operated with subtotal resection and in one (6%) of those undergoing total thyroidectomy (p < 0.05). The results thus indicate that EO, particularly at the time of surgery, and prevailing TSH-R-ab titers are associated with an increased risk of recurrent GD and suggest that patients exhibiting these characteristics should benefit from total rather than subtotal thyroidectomy.

Influence of thyroid hormones on the regulation of growth hormone secretion

Abstract: The effects of thyroid hormones on GH secretion and the mechanisms underlying their action are very similar in man and the laboratory animal. We feel that it is possible to organize the available data into a unique pathophysiological model explaining these complex interactions (Table 1). In summary, physiological levels of circulating thyroid hormones are necessary to maintain normal pituitary GH secretion owing to their direct stimulatory actions. When the serum concentrations of thyroid hormone increase above the normal range there is an increase in hypothalamic somatostatin tone, which in turn suppresses pituitary GH secretion and overrides any stimulatory effects. The suppression of GH secretion by thyroid hormones may be mediated at the hypothalamic level also by a decrease in GHRH release.

Evidence for a role for the neurosteroid allopregnanolone in the modulation of reproductive function in female rats.

Abstract: The present study investigated the effect of allopregnanolone (5 alpha-pregnan-3 alpha-ol-20-one) or of passive immunoneutralization of brain allopregnanolone, the most potent steroid produced by neurons, on ovulation rate and sexual behavior in female rats. Allopregnanolone was injected intracerebroventricularly in rats on diestrus and proestrus and tests were done on estrus. The intracerebroventricular injection of allopregnanolone significantly decreased the number of oocytes collected on estrus (p < 0.01). To support a physiological involvement, antiserum to allopregnanolone was injected centrally to block the activity of the endogenous neurosteroid. When administered on diestrus and proestrus or only on proestrus, the antiserum was shown to be correlated with a significant increase (p < 0.01) in oocytes retrieved on estrus. In female rats treated with antiserum to allopregnanolone, the lordosis intensity was augmented significantly as compared to controls. Finally, the possible changes of medial basal hypothalamus concentration of allopregnanolone throughout the estrous cycle and at the time of ovulation were investigated. Hypothalamic extracts were eluted on high-pressure liquid chromatography and allopregnanolone concentration was measured by radioimmunoassay. Brain cortex was used as control tissue. Hypothalamic allopregnanolone concentration on proestrus morning and afternoon was found to be significantly lower than in the remaining phases of the estrous cycle (p < 0.01), while no significant changes were observed in brain cortex concentration of allopregnanolone. The present results suggest that hypothalamic allopregnanolone may be involved in the mechanism of ovulation, affecting hormonal and behavioral events.

Effects of treatment with octreotide in acromegalic patients - a multicenter Italian study

Abstract: Treatment of acromegaly is effective in reversing the reduced life-span of patients only when serum growth hormone (GH) concentrations are lowered to less than 2.5 μg/l. Usual treatments achieve this goal in no more than 50-60% of patients. The effects of octreotide were studied in a prospective, open label study with 68 acromegalic patients enrolled in 10 Italian centers. Octreotide was administered sc at a dose of 100 μg t.i.d. for 1 year. After 3 months of therapy, octreotide was effective in decreasing serum GH levels below 2.5 μ/l in 16 out of 64 acromegalic patients (25%). Fifteen of them had pretreatment GH levels below 25 μg/l. Insulin-like growth factor I (IGF-I) levels normalized in about 40% of patients. No further GH reduction was observed after 1 year of treatment. The presence of abnormal GH responses to thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone was reduced from 54 to 24% and from 16 to 12%, respectively. Tumor shrinkage was observed in 50% of 26 non-irradiated patients after 12 months of treatment. Both basal and TRH-stimulated serum prolactin levels significantly decreased in the 11 hyperprolactinemic patients. Although serum thyrotropin, free triiodothyronine and free thyroxine concentrations were not modified, a significant reduction of thyrotropin response to TRH was observed in the 9th month of therapy. In non-diabetic patients, an increase of mean blood glucose levels without modifications of fasting morning concentrations was found. About one-quarter of the patients with overt diabetes mellitus had an impairment of their metabolic control. Main clinical symptoms of acromegaly improved in 70-80% of patients. An 18% decrease of low-density-lipoprotein cholesterol and unchanged high-density-lipoprotein cholesterol levels were observed in 35 patients studied. Triglyceride levels decreased in patients with hypertriglyceridemia pretreatment. Regarding side effects, gallstones were newly diagnosed in five patients, three patients dropped out because of severe diarrhea and two diabetic patients dropped out due to worsening of their metabolic control. In conclusion, octreotide is an effective treatment of acromegaly, mainly in patients with moderate elevation of serum GH levels. The drug has also been proved to positively affect dyslipidemia.

Treatment of central precocious puberty with depot leuprorelin

Abstract: We evaluated the pituitary and gonadal suppression in 40 girls and nine boys treated with depot leuprorelin (3.75 mg sc if body weight > or = 20 kg, 1.87 mg if body weight < 20 kg) every 28 days for central precocious puberty. Gonadal suppression was obtained in most of the children with this dose: 3 months after initiation of the treatment, 85% of children had a peak plasma luteinizing hormone response to gonadotropin-releasing hormone < 3 IU/l and the gonadal axis remained suppressed throughout the duration of the study (up to 24 months). Four patients required higher doses of leuprorelin to achieve suppression. In two girls, a cutaneous reaction to the drug was associated with incomplete suppression and the treatment had to be interrupted. Plasma leuprorelin levels tended to increase from day 3 to day 28 after injection. Residual leuprorelin levels measured 28 days after injection were stable during the first year of the study. We conclude that an initial dose of depot leuprorelin of 3.75 mg sc every 28 days is efficient in most children with central precocious puberty.

Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate

Abstract: Testosterone preparations producing constant physiological testosterone serum levels are desirable for long-term treatment of androgen deficiency. However, all injectable testosterone esters used clinically for substitution of male hypogonadism are characterized by unfavourable pharmacokinetics. We therefore tested two groups of five long-term orchidectomized cynomolgus monkeys (Macaca fascicularis), which received a single intramuscular injection of 10 mg/kg body weight of an injectable testosterone undecanoate (TU) preparation or testosterone enanthate (TE) in a preclinical study to assess the pharmacokinetic and pharmacodynamic characteristics of TU in comparison to TE. The dose was equivalent to 6.3 and 7.2 mg of pure testosterone per kilogram body weight in the TU and TE group, respectively. Following injection of TU, mean serum testosterone rose to 58 +/- 18 nmol/l on day 1 and remained at moderately supraphysiological levels of 40-68 nmol/l for 45 days. Thereafter, testosterone levels were maintained in the normal range of intact monkeys for another 56 days. The TE injection resulted in highly supraphysiological levels of 100-177 nmol/l from immediately after the injection to day 5. A rapid decline followed and testosterone levels reached the lower limit of normal after 31 days. Serum testosterone levels were significantly higher in the TE-than in the TU-treated animals on days 0.5-7 (p < 0.05). Significantly lower testosterone levels were seen in the TE than in the TU group on days 16, 22, 25 and 31 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)