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André S. Meyer

It was reported previously (Meyer et al., 1955 a, Meyer, 1955 a) that incubation of dehydroepiandrosterone (I) and Δ4-androstene-3,17-dione (II) with bovine adrenal homogenate preparations produced a wide galaxy of conversion products. Of these, 11β-hydroxyandrostenedione (IV), 6β-hydroxyandrostenedione (V), 19-hydroxyandrostenedione (VI), and Δ4-androstene-3,11,17-trione (III) were isolated in crystalline form and identified. The presence of 6α-hydroxyandrostenedione (VII) and Δ4-androstene-3,6,17-trione (IX) was indicated by their mobilities in paper chromatographic systems and by spectroscopic data. For compound VIII, Rtol. 0.25 cm./h., the structure 6α, 1 1β-dihydroxyandrostenedione was tentatively postulated (as will be seen, erroneously) on the grounds of the rate of formation of a colour product in alkaline ethanolic solution and the infrared spectra of the compound and its acetate (VIII a).

A more definite proof of the structure of compound VIII was desirable. It could be anticipated that incubation of 6α-hydroxyandrostenedione (VII) with adrenal tissue would

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E. DÜKER, S. MEYER and B. WOLFF

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André S. Meyer, Orville G. Rodgers and Gregory Pincus

In vitro experiments with various adrenal preparations have lead to the recognition of some of the structural requirements of the steroid substrates necessary for their rapid hydroxylation at the positions 11β, 17α and 21. It has been demonstrated that the enzyme 1 1β-hydroxylase reacts more readily with C21-steroids with 20,21-ketol or dihydroxyacetone side chains than those with the 20-ketone (pregnane type), 20,17α-ketol, or 20,21-glycol structures (Hayano & Dorfman, 1953). It has also been shown that 17α-hydroxylation occurred with much greater ease on steroids with a 20-ketone than on those with a 20,21-ketol side chain (Hechter et al., 1951; Plager & Samuels, 1953; Zaffaroni, 1953). 21-hydroxylation appeared to proceed comparably with 20-ketones and 20,17-ketols (Hayano & Dorfman, 1952; Plager & Samuels, 1953). The perfusion of 21-desoxycortisone (Δ4-pregnen-1 7α-ol-3,1 1,20-trione) through surviving cow adrenal glands, described here, was undertaken to provide an answer to the question of whether

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S Schaefer, N Boegershausen, S Meyer, D Ivan, K Schepelmann and P H Kann

Objective

Hypothalamic–pituitary insufficiency may have diverse causes. The aim of this study was to determine the incidence of hypothalamic–pituitary insufficiency in patients with previous infectious diseases of the central nervous system (CNS) of different etiologies and mild-to-moderate clinical course.

Design

Patient series. Basal and stimulated (insulin tolerance test) pituitary function testing was performed in 19 patients with previous neuroborreliosis, encephalitis, or meningitis following an interval of between 10 and 56 months (mean 26.1±13.1 months) after the acute event.

Results

Four patients (21%; two males, two females) showed an isolated corticotropic insufficiency (peak cortisol <181.25 μg/l during the insulin tolerance test). Two patients (11%, males) showed borderline gonadotropic insufficiency (basal testosterone between 2.4 and 3.0 μg/l). No patient had somatotropic or thyrotropic insufficiency or evidence for diabetes insipidus; all had prolactin concentrations within the reference range.

Conclusions

Hypothalamic–pituitary dysfunction and especially isolated corticotropic insufficiency may develop in a relevant proportion of patients after infectious diseases of the CNS.

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E. SCHALLENBERGER, D. SCHAMS, H.H.D. MEYER, S.J. OSCHMANN and E. ABELE

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A. S. Meyer, Mika Hayano, Marjorie C. Lindberg, M. Gut and O. G. Rodgers

In the course of the continuation of studies on the in vitro metabolism of dehydroepiandrosterone (I) by adrenal tissue, it was noted in paper chromatographic analyses of the incubated material that several substances of a more polar nature than 1 1β-hydroxy-Δ4-androstene-3,17-dione (IV) were being formed. Compound IV had been isolated and identified earlier after perfusion of I through cow adrenals (Meyer et al., 1953 a). Initial experiments with various tissue preparations, whole glands, bovine adrenal whole homogenates, and washed homogenate residues (Hayano & Dorfman, 1953), all yielded crude extracts which produced a similar papergram pattern of products in that polar region. Further incubations with the washed residue preparations showed that the addition of adenosine triphosphate (ATP) plus diphosphopyridine nucleotide (DPN) increased the conversion appreciably. Thus, with this supplementation a large scale incubation was carried out for isolation purposes. Fractionation of the resultant steroidal material was accomplished by a

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Bálint Kacsóh, Judith S Opp (Meyers), William R Crowley and Clark E Grosvenor

Separation of neonatal rats from their mothers decreases, while a subsequent period of suckling (nursing) increases, serum growth hormone (GH) levels in neonatal rats. Milk-borne (humoral) factors and neural factors inherent in mother-offspring interaction have been implicated in these phenomena. Conflicting reports have demonstrated the α2-adrenergic agonist clonidine to increase and to decrease serum GH levels in 10-day-old rats. The present experiments were aimed at testing whether an interaction between the α2-adrenergic system and the nursing-induced changes in GH secretion could account for the discrepancy. Rat pups were treated with clonidine (150 μg/kg) or the α2-adrenergic antagonist yohimbine (10 mg/kg), and the drug treatment was combined with separation of the mothers and nursing. Yohimbine did not affect serum GH levels in separated two-day-old pups (i.e. basal levels of the hormone), but prevented the nursing-induced increase in serum GH concentration. In two-day-old pups, clonidine had no effect on basal GH levels but, like yohimbine, prevented the increase in serum GH normally associated with nursing. Both yohimbine and clonidine prevented active sucking behavior, i.e. the pups did not search for and/or attach to the nipples of their mothers. Moreover, the pups treated with yohimbine and clonidine were cooler to the touch than the littermate controls. In eight-day-old pups, yohimbine prevented the nursing-induced increase in serum GH and decreased GH levels below the saline-injected, separated control. As in two-day-old pups, clonidine prevented the suckling-induced release of GH and failed to induce GH-release above that of saline-injected, separated pups. By day 10 postpartum. clonidine became capable of stimulating GH release, but only in separated male pups. The effects of CLO and nursing in male pups were not additive: either treatment alone was as effective as the combined treatment. In female rats CLO prevented the increase in serum GH levels in response to nursing. It is concluded that (1) the α2-adrenergic agents yohimbine and clonidine inhibit nursing-induced GH secretion in an indirect (perhaps hypothermia-related) manner not involving the well-established α2-adrenergic-GH releasing hormone pathway; (2) the α2-adrenergic system becomes fully functional in terms of stimulation of GH secretion between days 8 and 10; (3) the GH-releasing effects of the α2-adrenergic system are sexually dimorphic in 10-day-old rats.

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S Schaefer, M Shipotko, S Meyer, D Ivan, K J Klose, J Waldmann, P Langer and P H Kann

Objective

Adrenal lesion is one of the features of multiple endocrine neoplasia type 1 (MEN1). This study aimed to assess prevalence, natural course and clinical relevance of small adrenal lesions without clinical symptoms, endocrine activity, or mechanical problems and thus without clear indication for surgical therapy by endoscopic ultrasound (EUS).

Design and methods

Forty-nine patients with familial MEN1 were studied. Twenty-seven of these with adrenal lesions were detected by EUS and at least two performed EUS examinations were included into a subgroup where changes in adrenal morphology were studied by measuring changes in the largest diameter of the dominant adrenal tumour.

Results

EUS detected adrenal lesions in 36 (73%) patients: 6 (12%) plump adrenals, 17 (35%) nodular hyperplasia, 12 (24%) adenomas and 1 (2%) cyst. Bilateral adrenal lesions were detected in 17 patients and unilateral in 19 patients. A change in the largest tumour diameter was found to be for nodular hyperplasia −0.02±1.41% per month (range −2.56 to 4.58%) and for adenomas −0.61±1.95% per month (range −6.25 to 1.15%). One patient had an adrenal cyst with significant growth. There was no evidence of carcinoma or metastatic disease during the study.

Conclusions

The prevalence of adrenal lesions in MEN1 is higher than that reported earlier. Except one cystic lesion, no significant change in the tumour size was observed over a mean observation period of more than 2 years. In a typical situation, small adrenal lesions in MEN1 seem to be constant in their morphology.

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M Quinkler, B Meyer, C Bumke-Vogt, C Grossmann, U Gruber, W Oelkers, S Diederich and V Bahr

OBJECTIVE: Progesterone binds to the human mineralocorticoid receptor (hMR) with nearly the same affinity as do aldosterone and cortisol, but confers only low agonistic activity. It is still unclear how aldosterone can act as a mineralocorticoid in situations with high progesterone concentrations, e.g. pregnancy. One mechanism could be conversion of progesterone to inactive compounds in hMR target tissues. DESIGN: We analyzed the agonist and antagonist activities of 16 progesterone metabolites by their binding characteristics for hMR as well as functional studies assessing transactivation. METHODS: We studied binding affinity using hMR expressed in a T7-coupled rabbit reticulocyte lysate system. We used co-transfection of an hMR expression vector together with a luciferase reporter gene in CV-1 cells to investigate agonistic and antagonistic properties. RESULTS: Progesterone and 11beta-OH-progesterone (11beta-OH-P) showed a slightly higher binding affinity than cortisol, deoxycorticosterone and aldosterone. 20alpha-dihydro(DH)-P, 5alpha-DH-P and 17alpha-OH-P had a 3- to 10-fold lower binding potency. All other progesterone metabolites showed a weak affinity for hMR. 20alpha-DH-P exhibited the strongest agonistic potency among the metabolites tested, reaching 11.5% of aldosterone transactivation. The agonistic activity of 11beta-OH-P, 11alpha-OH-P and 17alpha-OH-P was 9, 5.1 and 4.1% respectively. At a concentration of 100 nmol/l, progesterone, 17alpha-OH-P and 20alpha-DH-P inhibit nearly 75, 40 and 35% of the transactivation by aldosterone respectively. All other progesterone metabolites tested demonstrate weaker affinity, and agonistic and antagonistic potency. CONCLUSIONS: The binding affinity for hMR and the agonistic and antagonistic activity diminish with increasing reduction of the progesterone molecule at C20, C17 and at ring A. We assume that progesterone metabolism to these compounds is a possible protective mechanism for hMR. 17alpha-OH-P is a strong hMR antagonist and could exacerbate mineralocorticoid deficiency in patients with congenital adrenal hyperplasia.

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Rosalinda Y A Camargo, Eduardo K Tomimori, Solange C Neves, Ileana G S Rubio, Ana Luiza Galrão, Meyer Knobel and Geraldo Medeiros-Neto

Objective

To evaluate the prevalence of chronic autoimmune thyroiditis (CAT) and iodine-induced hypothyroidism, hyperthyroidism (overt and subclinical), and goiter in a population exposed to excessive iodine intake for 5 years (table salt iodine concentrations: 40–100 mg/kg salt).

Design

This was a population-based, cross-sectional study with 1085 participants randomly selected from a metropolitan area in São Paulo, Brazil, and conducted during the first semester of 2004.

Methods

Thyroid ultrasound examination was performed in all participants and samples of urine and blood were collected from each subject. Serum levels of thyroid-stimulating hormone, free thyroxine, and anti-thyroid peroxidase (TPO) antibodies, urinary iodine concentration, thyroid volume, and thyroid echogenicity were evaluated. We also analyzed table salt iodine concentrations.

Results

At the time the study was conducted, table salt iodine concentrations were within the new official limits (20–60 mg/kg salt). Nevertheless, in 45.6% of the participants, urinary iodine excretion was excessive (above 300 μg/l) and, in 14.1%, it was higher than 400 μg/l. The prevalence of CAT (including atrophic thyroiditis) was 16.9% (183/1085), women were more affected than men (21.5 vs 9.1% respectively, P=0.02). Hypothyroidism was detected in 8.0% (87/1085) of the population with CAT. Hyperthyroidism was diagnosed in 3.3% of the individuals (36/1085) and goiter was identified in 3.1% (34/1085).

Conclusions

Five years of excessive iodine intake by the Brazilian population may have increased the prevalence of CAT and hypothyroidism in subjects genetically predisposed to thyroid autoimmune diseases. Appropriate screening for early detection of thyroid dysfunction may be considered during excessive nutritional iodine intake.