Danièle Bosson

Serum levels of gonadotrophins and steroid hormones in the post-menopause and later life

Changes in the serum levels of gonadotrophins and steroid hormones with increasing age were studied in 449 women aged 40 and over to investigate the relationships between these hormones even very late in life. The levels of oestradiol (E2) and dehydroepiandrosterone sulphate (DHEA-S) fell after age 50 and remained low thereafter. However, while serum oestrone (E1), testosterone (T), delta-4-androstenedione (A) and prolactin (PRL) concentrations also decreased initially after age 50 they subsequently rose again progressively and this increase was in fact significant in the case of E1. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) rose after age 50, but whereas FSH remained elevated, LH decreased late in life. Cortisol (F) increased significantly after age 70. There was a significant correlation between androgens and E1 as well as between E2 and LH, even after age 60. Owing to the great heterogeneity of the population studied, it is not yet possible to speculate as to the physiopathological significance of these observations. It would seem, however, that the negative feedback effect of oestrogens on LH secretion remains operational very late in life.

Age, steroids and bone mineral content

The possible existence of correlations between bone mineral content (BMC), age and serum levels of steroid hormones was investigated. It was found that dehydroepiandrosterone sulphate (DHEA-S), oestradiol (E2) and delta-4-androstenedione (A) were correlated with BMC, whereas oestrone (E1) and testosterone (T) were not. Partial correlations after adjustment for age were significant (P less than 0.05) only between E2 and DHEA-S and BMC at the L2-L4 lumbar site (BMC-1) and between DHEA-S (P less than 0.01) and BMC at the midradius site (BMC-r). Stepwise multiple regression analysis showed that, apart from age, E2 was the only factor to fit (P less than 0.05) into the mathematical model with BMC-1 as the dependent variable, while DHEA-S was the only factor to fit (P less than 0.01) with BMC-r as the dependent variable. These data suggest that different hormonal influences are related to BMC at different sites, namely E2 to lumbar trabecular bone (L2-L4) and DHEA-S to cortical bone (midradius).

Familial adrenocorticotropin unresponsiveness associated with alacrima and achalasia: biochemical and molecular studies in two siblings with clinical heterogeneity.

The syndrome of familial adrenocorticotropin (ACTH) unresponsiveness is a rare form of primary adrenal insufficiency, usually without mineralocorticoid deficiency. It is characterized by elevated plasma ACTH concentration and undetectable plasma cortisol levels not responding to exogenous ACTH. Alacrima and achalasia have also been occasionally associated with adrenal insufficiency (triple A syndrome). Pathogenetic mutations have beein indentified in the ACTH receptor gene in families with isolated familial ACTH unresponsiveness. Whether the ACTH receptor represents the locus of the defect for the triple A syndrome is not known. Here we report two siblings with familial ACTH unresponsiveness who were discrenant for skin pigmentation and mineralocorticoid function. In addition, achalasia and alacrima wer documented only in the older sibling. The boy, studied at the age of 2 years, was hyperpigmented, in contrast to his normally pigmented siter, studied at the age of 9 years; basal plasma α-melanocyte stimulating hormone immunure-acitivity levels wer 79 and 38 pg/ml, respectively (normal <40 pg/ml). Furosemide-induced diuresis resulted in normal rises of plasma rein activity in both patients; however, plasma aldosterone levels increased only in the boy and not in his sister. Screening for abnormalities of the ACTH receptor gene by single strand conformation polymorphism analysis revealed no abnormality. Direct sequencing of the entire conding area of the ACTH receptor gene was also normal.ConclusionThe syndrome of familial ACTH unresponsiveness can vary clinically and biologically within the same family. In contrast to results from some families with isolated familial ACTH unresponsiveness, the ACTH receptor gene does not appear to be the locus of the defect in this pedigree, suggesting a different molecular aetiology for the triple A syndrome which assciates adrenal insuficiency alacrima and achalasia.

Dexamethasone Bovine Pharmacokinetics

SummaryDexamethasone phosphate (DXM-PHO) is an ester which is quickly hydrolysed by the bovine and the dexamethasone (DXM) plasma half-life was 5.16 h. It has been demonstrated that 54h after DXM-PHO injection, DXM concentrations were lower than 0.1 mg/ml.Tritiated dexamethasone was also administered twice to an another young bull for metabolite investigation. The elapsed time required to recover, in plasma, half of the radioactivity injected was 8.8h. Radioactivity recovery in the urine reached 36.4% and 22.6% for the first and the second injections respectively.

Osteocalcin and bone mineral content in rheumatoid arthritis

SummaryAbnormal bone metabolism was reported in rheumatoid arthritis (RA). In order to evaluate the interest of serum osteocalcin, also called bone GLA- protein (BGP), to assess bone metabolism in RA, we studied 20 postmenopausal RA out- patients and 20 matched controls. Nine patients were treated with low- dose corticosteroids (C+)for at least one year (< 10 mg/day, prednisolone equivalent), the remaining 11 (C−) received non-steroidal anti-inflammatory drugs (NSAID). The distal and proximal forearm bone mineral content (BMC) was measured by single photon absorptiometry, the vertebral BMC was measured by dual photon absorptiometry. A trend to low BGP was observed in the C+ group. The lowest values were observed in patients with vertebral fractures. Compared with controls, both RA groups had similar low significant BMC at the forearm sites. At the vertebral sites, the bone mineral content decrease observed in the two groups, was more marked in the C+ group. From our results, BGP did not appear as a useful index of osteoporosis in RA, except in some patients with vertebral fractures, treated with low-dose corticosteroids.

Enhanced ACTH and blunted cortisol responses to corticotropin-releasing factor in idiopathic panhypopituitarism

ADM IN 1STRATION of corticotropin-reteasing factor has been shown to stimulate the release of ACTH and cortisol in normal humans? -4 In one patient with hypothalamic anterior pituitary failure, Miiller et al? found a normal ACTH response without cortisol elevation. The purpose of our study was to assess the characteristics of the pituitaryadrenal responsiveness to CRF in a group of six patients with nontumoral idiopathic panhypopituitarism. METHODS Six patients (five males) with nontumoral idiopathic panhypopituitarism, aged 12 to 29 years, were examined, with informed consent. All patients had delayed growth and bone maturation. All were shown to have blunted responses of hGH and of cortisol to both insulin intravenously and glucagon intramuscularly 5 and absence of an increase of plasma l l-deoxycortisol or urinary 17hydroxysteroids after metyrapone. Serum dehydroepiandrosterone sulfate concentration ~was <100 ng/ml in all patients. All had tertiary hypothyroidism as assessed by TSH response to TRH, and gonadotropin deficiency as assessed by lowered LH and FSH responses to LH-RH and absence of spontaneous pubertal development. Skull radiographs were normal. All patients had been receiving hormonal substitutive therapy for several years. The two oldest patients (patients 4 and 5) were not receiving growth hormone treatment at the time of the study. Corticoid treatment had been stopped for 2 years in patient 4 and at

Specific determination of plasma dexamethasone by HPLC and RIA — application to standard dexamethasone suppression test in psychiatric patients

Three radioimmunoassays (RIA), with or without preparative HPLC, were applied to the monitoring of plasma dexamethasone (DXM) levels during standard dexamethasone suppression test (DST) in psychiatric patients. Due to the robotic ease of the fully automated HPLC process, precision of the chromatographic assay was equivalent to that of the direct assays, but prepurification improved both sensitivity and specificity. These improvements allowed the elucidation of the following features: (1) half (36) of the patients (68) displayed infranormal DXM levels (less than or equal to 0.40 ng/ml) whatever the cortisol response; (2) 22% (15) patients (68) with DXM levels in the low control range showed a strong inhibition of cortisol suppression. These observations raise some doubts on the validity of the DST test and introduce the following questions. (1) What is the dependence of cortisol suppression upon DXM absorption and catabolism? (2) Does plasma DXM measurement several hours after its physiological action still reflect its effect on the hypothalamo-hypophyseal axis? (3) What is the reliability of DXM direct assays when measuring low DXM levels in the presence of high cortisol?

Choice of parameter for expressing bone mineralization.

In this cross-sectional study, the relative importance of anthropometric factors and that of biological parameters on bone mineralization were evaluated and their practical implications inferred on the choice of the parameter to be used for the estimation of bone mineralization. A close relationship between anthropometric factors and bone mineral content (BMC) was observed and this relationship was shown to be independent of age. Furthermore, by regression analyses, anthropometric parameters appeared to explain a large part of the variance in BMC and preceded the hormonal parameters in the stepwise analysis of this model. Using bone mineral density (BMD) data, however, we observed a weaker relationship between anthropometric factors and bone mineralization and a relatively stronger relationship between steroid hormones and bone mineralization than those observed using the BMC data. Furthermore, by multiple regression analysis the hormonal factors preceded the anthropometric parameters in the stepwise analysis of the model. As strong epidemiological and clinical evidence exists on the relationship between steroid hormones and bone loss, these results constitute a supplementary argument for the use of BMD for the estimation of bone mineralization.

CONCOMITANT DETERMINATION OF AMNIOTIC FREE ALDOSTERONE (FAldo) AND ITS 18-OXO-GLUCURONIDE(GAldo) AND MATERNAL PLASMA ALDOSTERONE (PAldo) THROUGHOUT NORMAL PREGNANCY

Concentrations of FAldo and GAldo were simultaneously measured by specific RIA in 84 samples of human amniotic fluid (AF)collected between 15-34 weeks in normal pregnancies. PAldo was concomitantly determined by RIA on samples obtained at 14.00 hr, after two hours decubitus. PAldo showed a significant rise during pregnancy, its level averaging 134.5 ± 10.8 pg/ml (mean ± SEM) before 20 weeks (n = 62) and 288.2 ± 49.2 pg/ml between 20-34 weeks (n=22) {p < 0.01). In AF, the increase of GAldo during the second stage of pregnancy largely exceeded that of FAldo rising from 81.2 ± 5.7 pg/ml to 269.5 ±61.2 pg/ml and from 84.0 ±5.9 pg/ml to 118.8 ± 11.5 pg/ml for the latter between the 15-20 weeks and 20-34 weeks periods. A significant relationship between AF levels and age of pregnancy could only be detected for GAldo (r= 0.691, p<0.01). Our results agree with patterns of PAldo (Weir et al, 1974, Ledoux et al, 1975) and FAldo (Blankstein et al, 1980, Sippell et al, 1981) already reported. The increase of GAldo presently described disagrees with its high and stable level reported by Aderjan et al (1977) on poorly documented data. Simultaneous determination of F- and G-Aldo shows that the rate of increase of fetal aldosterone production is higher than could be expected from estimation of FAldo alone. Augmentation of GAldo in AF probably expresses both the increased contribution of urine to AF and the maturation of renal glycuronoconjugation process.

3 EFFECT OF GROWTH HORMONE RELEASING FACTOR (GRF) ON PLASMA GROWTH HORMONE (GH) AND PROLACTIN (PRL) LEVELS IN OBESE CHILDREN

Obese children have a blunted GH response to conventional pharmacological stimuli. To assess whether this blunted response has a hypothalamic or pituitary origin, the response of plasma GH to a glucagon stimulation test (0.1 mg/kg IM) and to a single IV bolus of 0.5 μg/kg of GRF was studied in 13 obese children [145 ± 7% (SEM) of ideal body weight (IBW)] and compared to that of 19 lean (93 ± 4% of IBW) short children with normal pituitary function (N). Peak GH response to glucagon was lower in obese than in N children (16.0 ± 2.0 vs 29.2 ± 4.5 ng/ml, p < 0.001) as was the GH response to GRF (12.4 ± 2.6 vs 39.2 ± 5.1 ng/ml, p < 0.001); the GH response to GRF tended to be more prolonged in obese than in N children. In neither group was there a correlation between peak GH after GRF and percentage of IBW or age. There were no acute changes in PRL levels after GRF in neither group : a normal decrease was observed between 9 and 11 AM (from 201 ± 48 and 211 ± 49 μU/ml to 146 ± 31 and 108 ± 27 μU/ml in the obese and N group, respectively).Conclusion: obese children have a blunted and prolonged GH response to GRF; this blunting is not correlated with age and is not associated with an acute increase in PRL levels, as seen in children with hypothalamic hypopituitarism (Ped Res 18 : 1216, 1984) and thus probably results from a different mechanism, perhaps at the pituitary level.