C.R.W. Edwards

HORMONAL AND METABOLIC RESPONSES TO AN ENKEPHALIN ANALOGUE IN NORMAL MAN

An enkephalin analogue [D-Ala2, MePhe4, Met(o)-ol] enkephalin (DAMME), given intravenously to normal subjects raised serum prolactin and growth-hormone levels but lowered serum levels of luteinising hormone, follicle-stimulating hormone, cortisol, and corticotrophin. There was also a small fall in total glucagon and gastric inhibitory peptide (G.I.P.) and a rise in thyrotrophin. beta-Lipotrophin, motilin, vasoactive intestinal peptide, insulin, gastrin, and pancreatic glucagon were unchanged. Blood-glycerol increased, and blood lactate, alanine, and glucose fell. Prior administration of the opiate antagonist, naloxone, attenuated the hormonal responses to DAMME. This enkephalin analogue produces endocrine and metabolic changes in man which may be mediated through opiate-binding receptors both within and outside the brain. The enkephalins and related substances may provide an important link between perception, behaviour, and neuroendocrine regulation of hormone secretion and metabolism.

Cyclical combination chemotherapy and gonadal function. Retrospective study in males.

The effect of cyclical chemotherapy on fertility and gonadal function was investigated in seventy-four male patients who had been treated for advanced Hodgkins disease. All patients were azoospermic after therapy, and, with a median follow-up period of 27 months (range 1--62 months), only four patients have regained spermatogenesis. Testicular biopsy showed an absence of germinal epithelium without other gross architectural changes. Despite this high degree of infertility, 60% of patients were practising contraception. A decline in libido and sexual performance with frequent long periods of sexual inactivity was noted by most men during therapy. Although some recovery was apparent once therapy was stopped, this was incomplete in approximately half of the patients. Follicle-stimulating-hormone levels were consistently raised after therapy at all periods of study. Median luteinising-hormone levels were at, or just above, the upper limit of normal, and median testosterone levels were normal. Increased prolactin levels were noted in 42% of patients, of whom about a half had an identifiable cause for hyperprolactinaemia. Return of spermatogenesis could not be predicted by serial hormone assessment. Because of the guaranteed infertility and the low frequency and unpredictability of recovery of spermatogenesis, sperm storage should be available for male patients undergoing cytotoxic therapy, since most of these patients may enjoy prolonged survival. Hormone-replacement therapy will usually be unnecessary. However, the probability of major changes in libido and sexual performance should be discussed with patients so that additional stress can be avoided. Contraceptive advice should be available to those who require it.

INHIBITION OF THE PLASMA-ALDOSTERONE RESPONSE TO FRUSEMIDE BY BROMOCRIPTINE

The administration of the long-acting dopaminergic agonist bromocriptine to five healthy volunteers inhibited the rise in plasma-aldosterone that normally follows the administration of frusemide. This inhibition was not due to a lowering of plasma-renin activity. It is suggested that dopamine may modulate the normal secretion of aldosterone either directly, or indirectly, possible by inhibition of prolactin secretion.

ENDOCRINE FUNCTION IN THE PRADER‐WILLI SYNDROME

Hypothalamic, pituitary and gonadal function was studied in five male and three female patients with the Prader‐Willi syndrome. All were clinically hypogonadal: all males had low circulating testosterone levels, although in two females basal plasma oestradiol was within the normal range for the early follicular phase of the menstrual cycle. Basal gonadotrophin levels were low and the response to the intravenous administration of LHRH was subnormal in seven. Repeat administration of LHRH after 10 days and 6 weeks treatment with oral clomiphene (200 mg daily) was followed by a normal rise in luteinizing hormone (LH) and follicle stimulating hormone (FSH) in four out of five patients tested. All five males were tested with human chorionic gonadotrophin (hCG) and the rise in plasma testosterone was subnormal in four. Treatment with hCG was continued for 6 weeks in these four patients, but in only one did testosterone levels rise (transiently) to the normal adult male range. In one female patient studied no rise in plasma oestradiol was detected in response to human menopausal gonadotrophin (hMG). These results suggest that the hypogonadism in the Prader‐Willi syndrome is due to combined hypothalamic and primary gonadal abnormalities.

Pro-opiocortin related peptides in human pituitary and ectopic ACTH secreting tumours.

Basal and stimulated secretion of N‐terminal pro‐opiocortin (Pro‐γ‐MSH), ACTH and LPH from seven pituitary and three ectopic ACTH secreting tumours have been studied in vitro using a perfused isolated cell system. The peptides were shown to be released concomitantly and in equimolar amounts. The pituitary tumours responded to stimulation with rat stalk median eminence extracts (SME) and synthetic AVP. However, peptide release from the ectopic tumours, although pulsatile, remained autonomous. Prior to surgery, gel‐chro‐matographic profiles of plasma immunoreactive ACTH showed only one peak, which eluted in the position of 1–39 ACTH, in patients with the pituitary tumours, but there was a second peak of large molecular weight ACTH present in the plasma from those with the ectopic ACTH syndrome. This second form of ACTH could not be detected in any of the tumour cell column effluents. An eighth pituitary tumour was atypical, in its unusually large size, clinically aggressive nature and spectrum of peptide release. Although peptide release in response to stimulation with SME was similar to that observed with the other pituitary tumours, the chromatography of the plasma ACTH resembled the ectopic plasma pattern, showing two peaks of immunoreactivity.

Relationship between plasma testosterone and dihydrotestosterone concentrations and male facial hair growth

Linear facial hair growth and the density of facial hair were measured by a photographic method and their relationship to plasma testosterone (T) and dihydrotestosterone (DHT) concentra tions was examined in twelve healthy men. In addition, we investigated eight men with coeliac disease in whom we had previously demonstrated reversible androgen resistance. The divergence of plasma T (increased) and DHT (decreased) concentrations in this condition enabled examination of possible independent actions of these androgens on facial hair growth.

REVERSIBLE INSENSITIVITY TO ANDROGENS IN MEN WITH UNTREATED GLUTEN ENTEROPATHY

Plasma androgen and gonadotrophin concentrations have been measured before and during treatment of 23 men with gluten enteropathy. Before treatment, there was marked rise in total plasma-testosterone, free testosterone concentration (as assessed by the free testosterone index), and plasma-luteinising-hormone concentration. In contrast, 5 alpha-dihydrotestosterone concentrations were lower than normal. All these abnormalities reverted towards normal with successful treatment of the jejunal mucosal lesion. These data are consistent with a reversible tissue resistance to circulating plasma-testosterone in men with gluten enteropathy and subtotal villous atrophy.

THE ENDOCRINE AND METABOLIC EFFECTS OF CIMETIDINE

Serial blood sampling in nine patients treated with cimetidine (1 g/day) showed that PRL values were within the normal range apart from a stress‐induced initial rise. Hormonal and metabolic profiles from 08.30 to 18.30 h were performed in six patients before and after 1 months treatment with cimetidine (1 g/day). Circulating PRL, LH, FSH, GH, TSH T3, T4 and testosterone were similar before and after treatment. The mean blood glucose fell from 5·4 ± 0·3 mmol/l to 4·8 ± 0·2 mmol/l on cimetidine (P<0·02). Small changes were also observed in blood pyruvate, lactate, 3‐hydroxybutyrate and the (lactate)/(pyruvate) ratio. The effects of oral or i.v. cimetidine on the circulating concentrations of insulin, glucose and intermediary metabolites were investigated in normal subjects. Intravenous cimetidine (100 mg/h for 4 h) given to fasting subjects decreased blood glucose and serum insulin by 15 and 34% respectively at 150 min. During an oral GTT, i.v. cimetidine caused a striking decline in blood glucose, lactate and pyruvate responses compared with control studies, although the serum insulin was similar to control values. When given for 48 h before the study, oral cimetidine did not alter basal serum insulin and blood glucose, lactate, pyruvate, alanine, glycerol and 3‐hydroxybutyrate levels. However, 150 min after an oral GTT the serum insulin was increased by 47% by oral cimetidine although the blood glucose was not significantly changed compared with the control day. Oral cimetidine had no effect on the blood glucose or serum insulin during an i.v. GTT. These results show that oral cimetidine given at therapeutic doses to patients with peptic ulcers does not produce consistent changes in circulating anterior pituitary hormones. Oral cimetidine given to patients for 1 month and i.v. cimetidine given to normal subjects have mild hypoglycaemic effects. Oral cimetidine administered over 48 h to normal subjects has little effect on blood glucose concentration.

CLINICAL EXPERIENCE WITH 75Se SELENOMETHYLCHOLESTEROL ADRENAL IMAGING

The results of quantitative adrenal imaging using 75Se selenomethylcholesterol in sixty‐two subjects are analysed. The adrenal area was localized by a renal scan, lateral views of which enabled adrenal depth to be estimated. The first nineteen cases were scanned with a rectilinear scanner and the remaining forty‐three cases imaged with a gamma camera. Quantitation of adrenal uptake was performed on computer‐stored static images obtained 7 and 14 days post‐injection of 75Se selenomethylcholesterol (3 and 6 days in the first ten cases studied). Normal uptake was found to be 0·07–0·30% of the administered dose. Overall predictive accuracy of the type of adrenal disorder of thirty‐two patients with Cushings syndrome was 90·6%, this included twelve cases of Cushings disease (mean uptake 0·58%), seven ectopic ACTH syndromes (mean uptake 0·69%), five unilateral adenomata (mean uptake 0·93%), three post adrenalectomy regrowths (mean uptake 1·37%), three adrenal carcinomas (mean uptake 0·01%), one congenital hyperplasia (mean uptake 3·4%) and one unilateral nodular hyperplasia. Overall predictive accuracy of the cause of Conns syndrome in twenty‐two cases was 86·4%; this included thirteen cases of bilateral hyperplasia (mean uptake 0·34%), eight unilateral adenomata (mean uptake 0·47%) and one patient with mineralocorticoid excess in whom the cause has not been confirmed. The mean uptake in the normal adrenal in cases of unilateral adenoma was 0·19% (range 0·07–0·30%). Causes of unsatisfactory adrenal imaging are examined. The procedure is recommended as the localizing and lateralizing technique of choice in Cushings syndrome except where due to adrenal carcinoma, and as an important non‐invasive technique in Conns syndrome for the lateralization of adenoma.

THE EFFECT OF CYPROTERONE ACETATE ON SERUM TESTOSTERONE, LH, FSH, AND PROLACTIN IN MALE SEXUAL OFFENDERS

The anti‐androgen, cyproterone acetate, was administered in a dose of 100 mg/day to eight adult male sexual offenders for 21–31 days. Serum testosterone fell to subnormal levels within 7 days and remained low for 6–28 days after treatment was stopped. The fall in testosterone was accompanied by a fall in serum luteinizing hormone (LH) and follicle stimulating hormone (FSH), and a rise in serum prolactin. All subjects experienced a decrease in libido and in frequency of masturbation. The probable mechanisms of action of cyproterone acetate are discussed, as is its potential role in the management of sexual offenders. These studies suggest that measurement of serum testosterone could be used as an index of compliance in sexual offenders treated with cyproterone acetate who are released on parole.