OBJECTIVE: We examined the relationship of adiposity to pituitary ± adrenal responses to corticotrophin-releasing hormone (CRH) in men and postmenopausal women, controlling for the in¯uence of depression. DESIGN: Studies of CRH responses, cortisol metabolite levels and depression scores in relation to adiposity in men and postmenopausal women. SUBJECTS: Thirteen men: age (median, interquartile range) 62 y (52 ± 63), body mass index (BMI) 29.0 kgam 2 (26.3 ± 33.1), waist circumference (waist) 105 cm (97 ± 111), waist : hip ratio (WHR) 1.03 (0.98 ± 1.07), subscapular to triceps skinfold thickness ratio (STR) 2.0 (1.2 ± 2.4), total body fat (TBF) 25.4 kg (19.8 ± 28.8); and eight women: age 54 y (53 ± 62), BMI 30 kgam 2 (23 ± 41), waist 86 cm (79 ± 117), WHR 0.94 (0.87 ± 1.10), STR 1.0 (0.85 ± 1.07), TBF 35.0 kg (18.7 ± 48.8). MEASUREMENTS: A standard CRH test was conducted with additional basal samples taken for leptin and interleukin 6 (IL-6). Total urine cortisol metabolites (TCM) and the ratio of urinary cortisol : cortisone (FmaEm) metabolites were measured. Depression scores were measured by the General Health Questionnaire (GHQ-30) and Hospital Anxiety and Depression Scale (HAD) questionnaire. All subjects completed an overnight dexamethasone suppression test. RESULTS: The basal to peak percentage increments (%inc.) in adrenocorticotrophic hormone (ACTH) and cortisol in men correlated directly with STR (ACTH %inc. r 0.70, P`0.01; cortisol %inc. r 0.55, P 0.05); this relationship was independent of depression scores. In women, the ACTH area under incremental curve (AUIC) correlated negatively with STR (r À0.81, P`0.05). In men, but not in women, there was a signi®cant correlation between GHQ-30 score and ACTH AUIC (r 0.62, P`0.05) and cortisol AUIC (r 0.72, P`0.01). Depression scores were consistently and directly related to indices of obesity and central obesity. There were no signi®cant relationships in either sex between urinary TCM or FmaEm ratio and BMI, waist, WHR, TBF, STR or CRH responses. The urinary FmaEm ratio was higher in men than in women (median 0.74 vs 0.66, P`0.05). In men, but not in women, GHQ-30 scores correlated positively with urinary TCM (r 0.57, P 0.05) and HAD-depression scores were inversely related to the urine FmaEm ratio (r À0.65, P`0.05). All subjects suppressed normally with dexamethasone. CONCLUSIONS: Cortisol metabolite levels were increased in depression in men, but were not related to adiposity in either sex. We demonstrate that central obesity in men, but not postmenopausal women, is associated with an enhanced pituitary ± adrenal response to CRH and that this relationship is independent of depression score.

A boy aged 4 with penoscrotal hypospadias and his brother aged 12 with micropenis had typical changes of homozygous Sa-reductase deficiency. After three injections of chorionic gonadotrophin there was a trivial rise in plasma dihydrotestosterone with a normal increase in plasma testosterone. Urine steroid chromatography showed abnormally high 513: Sa ratios and 5a-reductase activity was appreciably reduced in genital skin fibroblasts. The results indicate that 5a-reductase deficiency is not invariably associated with genital ambiguity. All previously reported males with 5a-reductase deficiency have had some degree of genital ambiguity with hypospadias. We describe two brothers with the conditic n, one of whom had micropenis without hypospadias while the other had penoscrotal hypospadias. Patients and methodsThe propositus and his older brother had consanguineous parents who come from Pakistan. At birth, the younger boy was found to have abnormal external genitalia with a small phallus and hypospadias. When he was 4 years old he was referred for evaluation of his genital anomaly. At that time he was noted to have a small penis (stretched length 1-9 cm) with noticeable chordee and penoscrotal hypospadias. The scrotum was normal but only the right testis was palpable.Initial investigations showed a 46XY karyotype. A sinogram showed a normal bladder; the proximal urethra had a male configuration with a prominent vermontarum and well developed utricle.After initial evaluation he was given one injection of depot testosterone (50 mg) to improve the size of his penis and hypospadias repair was carried out. A skin biopsy specimen for fibroblast culture was taken at that time.The older brother was noted to have a small penis at birth. He was seen at the age of 12 years, at the same time as his brother. His external genitalia were normal, apart from the size of his penis, which had a stretched length of 4 cm. There was no chordee and the urethra opened at the tip of the penis. Both testes were in the scrotum and were 6 ml in volume.Investigation showed a 46XY karyotype. After initial investigation a skin biopsy specimen was obtained from the scrotum.Plasma testosterone and dihydrotestosterone concentrations were measured by radioimmunoassay before and after three daily injections of 1000 units of human chorionic gonadotrophin. Urine steroid concentrations were measured by gas chromatography as previously described,4 and the results expressed in terms of SP: a ratios for different steroid metabolites.Fibroblasts were established in ciilture from genital skin to determine 5c-reduct..se activity and androgen receptor concentrations. The activity of 5a-reductase was measured after incubation of fibroblasts with serum free medium containing 2 nM of tritiated testosterone. The medium was extracted with ethyl acetate and analysed by single step thin layer chromatography. Areas corresponding to dihydrotestosterone, 5a-androstanedione, androsterone, epiandrosterone, and the 5a-androstanediols were cut out and counted for tr...

SUMMARY Serum and urine steroids were examined in two subjects with trophoblastic disease accompanied by large ovarian theca-lutein cysts and compared with those from 10 patients with trophoblastic disease but without palpable cysts. In the patients without cysts normal values were obtained for serum oestradiol, progesterone, 17a-hydroxyprogesterone and androstenedione, and for urinary total oestrogens, pregnanediol, pregnanetriol, and 17-oxosteroids. Nineteen urinary steroid metabolites, quantified by capillary gas-liquid chromatography, were either within reference limits or marginally raised. In several cases relatively minor increases in serum testosterone and cortisol and urinary free cortisol were observed. In contrast, the subjects with cysts showed pronounced excesses of androgen metabolites, 17a-hydroxypregnanolone, pregnanediol, and pregnanetriol, and both exhibited a similar pattern of unusual additional metabolites.The profiles superficially resembled those seen in 21-hydroxylase deficiency adrenogenital syndrome, but there were important discrepancies reflecting known differences in ovarian and adrenal steroid metabolism.Chemotherapy led to decline of human chorionic gonadotrophin concentrations, regression of the cysts, and return to normal of the steroid profile. Excess steroids in the patients with cysts may have originated in the ovary rather than in the trophoblastic tissue.Steroid excretion in subjects with trophoblastic disease has been little studied but has, in most cases, been reported as within normal limits. Urinary pregnanediol (Table 1) and oestrogens are seldom increased over non-pregnant concentrations,1 2 and trophoblastic tissue is limited in its capacity to synthesise steroids.3-5During routine follow up of subjects with gestational trophoblastic disease two patients had raised concentrations of human chorionic gonadotrophin (hCG) and large theca-lutein cysts of the ovary. In contrast to the other subjects with trophoblastic disease in whom ovarian cysts were not a feature, plasma and urinary steroids in these two patients were increased. Indeed, some steroids were present in very high quantities.To delineate further the nature and extent of the abnormality urinary steroid metabolites were examined by capillary gas-liquid chromatography and gas

There is a failure of growth in hypoxanthine guanine phosphoribosyltransferase deficiency; slow weight gain is marked after the second year of age but is apparent in the birth weights of all eight of our patients for whom we have data. However, head growth and bone development are less affected than weight. A partial defect in the adrenocortical 11 beta-hydroxylation of steroids was demonstrated after ACTH stimulation in all four patients studied. This hydroxylation takes place in mitochondria the function of which is modulated by purine nucleotide concentrations; this may be the link with the enzyme defect. Testicular atrophy at autopsy was found in two pubertal age boys and seven patients aged 12-17 years had no signs of puberty. All five boys aged 3-11 years showed less than the normal mean response of plasma testosterone concentration to human chorionic gonadotrophin despite the normal histological appearance of the testes of one 6-year-old-boy. Follicle stimulating hormone responses to gonadotrophin releasing hormone are probably less than in normal in at least three of the seven prepubertal boys. The absence of the normally high activities of hypoxanthine guanine phosphoribosyltransferase in testes appears to inhibit their ability to respond to gonadotrophin.

There is growing interest in the hydroxysteroid dehydrogenases (HSDs) as local modulators of hormone action. We have studied urinary steroid profiles from nine men and nine women with Major Depression to determine whether 11beta-HSD and 17beta-HSD activity are altered. Urinary steroid profiles were determined by high resolution gas chromatography. The ratio of 11-oxo over 11beta-hydroxy metabolites of cortisol was used as the index of 11beta-HSD activity and the ratio of dehydroepiandrosterone (DHA) over androstenediol-17beta was used as the index of 17beta-HSD activity. Symptom severity was assessed using the Hamilton Depression Rating Scale (HDRS). None of the measures of cortisol production, 9 AM plasma cortisol, 24 hour urinary free cortisol or 24 hour total urinary cortisol metabolites, correlated with HDRS in either men or women. 11Beta-HSD activity was altered and correlated with symptom severity in depressed women (r=0.688, p<0.05) but not men (r=0.132). In both depressed men and women, 17beta-HSD activity was altered and correlated with HDRS scores (r=-0.796, p<0.05 and r=0.688, p<0.05 respectively). However, although the ratio was changed in the same direction in depressed men and women. the correlation with symptom severity was positive in women but negative in men. We conclude that markers of subtle change such as these may prove more useful and informative than gross changes in plasma cortisol in depression.