M. J. Watson

The short Synacthen and insulin stress tests in the assessment of the hypothalamic–pituitary–adrenal axis

OBJECTIVE The best dynamic test for the assessment of the hypothalamic–pituitary–adrenal axis and the interpretation of the cortisol levels, remain a matter of controversy. We aimed to establish normal ranges with current assays, for both the short Synacthen (SST) and insulin stress tests (IST) and then to use these data to examine whether the SST can satisfactorily substitute for the IST in assessment of the hypothalamic–pituitary–adrenal axis.

Hyperprolactinemia: Long-term effects of bromocriptine

Patients with hyperprolactinemia may be managed by pituitary surgery or irradiation, bromocriptine treatment, or a combination of these methods, and some patients remain untreated. Little is known of the long-term consequences of some of these therapeutic regimens. Forty-six hyperprolactinemic patients (40 female and six male) managed solely with bromocriptine or no treatment over a period of 12 months to six years were therefore evaluated in this study. Nine patients with radiologically normal pituitary fossae were untreated and 10 received bromocriptine, 7.5 to 10 mg daily, while 20 patients with radiologic evidence of a pituitary tumor were treated with bromocriptine, generally 10 to 20 mg daily. Patients were assessed clinically, biochemically, and radiologically before treatment and at least six weeks after discontinuation of therapy. A further seven patients were similarly assessed before and after eight bromocriptine-induced pregnancies. Symptoms persisted in the untreated group of nine patients, although menstruation returned in four of the females with previous amenorrhea; serum prolactin levels remained elevated, other pituitary function did not change, and pituitary fossae remained normal radiologically. In all patients treated with bromocriptine, symptoms improved irrespective of radiologic findings on the pituitary, and were abolished in 67 percent during treatment associated with a decrease in serum prolactin levels in all, and a return of levels to within normal limits in 80 percent of patients. Persistent side effects were usually dose-related, but remained troublesome in 13 percent. Bromocriptine-induced tumor regression was evident radiologically in all patients with suprasellar tumor tissue and in some with purely intrasellar adenomas. This effect occurred rapidly and persisted or increased throughout follow-up. On discontinuation of treatment, prolactin levels remained significantly lower than before therapy (mean 2,934 versus 5,052 mU/liter, p less than 0.05) but were within the normal range in only two patients. Other pituitary function was unaltered, or improved in some patients with definite tumors. Bromocriptine-induced pregnancy produced no permanent change in clinical, biochemical, or radiologic status. Long-term bromocriptine treatment for hyperprolactinemia is thus highly effective in alleviating symptoms and suppressing prolactin secretion, and induces persistent tumor regression on treatment without deterioration of other pituitary function in patients with macroadenomas. On discontinuation of therapy, however, hyperprolactinemia usually recurs, and treatment may therefore need to be continued for years.

VARIATION IN OSMOREGULATION OF ARGININE VASOPRESSIN DURING THE HUMAN MENSTRUAL CYCLE

Osmoregulation of vasopressin secretion was studied in eight healthy women in the follicular and luteal phases of the menstrual cycle. Basal plasma osmolality in the luteal phase was significantly lower than in the follicular period (282·4±0·6, 285·6 ± 1·1 mmol/kg, respectively, P<0·05). Plasma AVP (pAVP) and plasma osmolality (pOsm) were measured during the infusion of 850 mmol/1 saline in both phases of the cycle, and linear regression analyses of these data gave the following regression equations (i) follicular, pAVP = 0·43 (pOsm‐284), r=+0·93, (ii) luteal, pAVP = 0·31 (pOsm‐279), r=+0·95. Both the slope and abscissal intercept were significantly different (P<0·01). Osmotic threshold for thirst sensation in the luteal phase was lower than the follicular (293±2, 297±1 mmol/kg, P<0·005). We conclude that, in the luteal phase, the threshold for AVP release and the gain or sensitivity of the osmostat are reduced together with lowering of the thirst threshold, which account for the lower basal luteal plasma osmolality.

EFFECTS OF SOMATOSTATIN ANALOGUE SMS 201–995 IN NORMAL MAN

Long‐acting somatostatin analogues may be of benefit in certain hypersecretory endocrine and gastrointestinal disorders. The 24 h hormonal and metabolic profiles of six normal male subjects receiving a twice daily subcutaneous injection of one such analogue SMS 201–995, 50 μg, has been compared to that obtained following placebo injection. Spontaneous daytime peaks of GH secretion were delayed until 1400 h following SMS 201–995 but nocturnal and total 24 h GH secretion were unaffected. The nocturnal rise in thyrotrophin was abolished by SMS 201–995 but thyroid function was unaffected. Insulin levels were suppressed following SMS 201–995 and the response to meals was inhibited. Glucose intolerance followed main meals. Glucagon levels were suppressed for up to 6 h. Circulating alanine levels were raised between 1200 h and 0600 h and there were intermittent elevations in lactate, pyruvate, glycerol and 3‐hydroxybutyrate. Amino acid levels, including branched chain amino acids, were also increased. All six subjects suffered gastrointestinal side‐effects. SMS 201–995, 50 μg, given twice daily shortly before meals does not suppress 24 h GH secretion, but demonstrates significant effects on metabolism and causes side effects in normal subjects.

REDUCED‘GONADOTROPHS RESPONSE TO RELEASING HORMONE’AFTER CHRONIC ADMINISTRATION TO IMPOTENT MEN

Ten endocrinologically normal men with secondary sexual impotence were given 500 μg LHRH subcutaneously every 8 h. After 4 weeks treatment the LH response to 500 μg LHRH was reduced from a peak of 35.7 ± 5.2 to 16.8 ± 3.5 mu/ml (P< 0.01) and the FSH response from 4.2 ± 0.93 to 2.39 ± 0.4 mu/ml (P< 0.01). Circulating total testosterone, oestradiol, prolactin and sex hormone binding globulin showed no significant changes. Whether this inability of the pituitary to maintain its response to LHRH is peculiar to impotent men requires further study.

A double blind cross over trial of gonadotrophin releasing hormone (LHRH) in sexually impotent men.

A double blind cross over trial of 500 μg of gonadotrophin releasing hormone or placebo subcutaneously every 8 h for 4 weeks in ten men with secondary sexual impotence is reported. No obvious clinical improvement occurred but statistical analysis of a libido score showed some overall improvement, especially the spontaneous occurrence of erections during the treatment period (P < 0.05).

PITUITARY FUNCTION FOLLOWING MEGAVOLTAGE THERAPY FOR CUSHING'S DISEASE: LONG TERM FOLLOW UP

Eight patients who had received megavoltage therapy for Cushings disease 5–12 years previously have been reviewed. The long term response to this therapy was assessed with respect to efficacy of treatment in inducing continued remission and disturbance of hypothalamic‐pituitary function. One patient showed clear evidence of relapse of Cushings disease. One patient had unequivocal hypopituitarism. Basal levels of growth hormone (GH), TSH, LH, and FSH were not statistically different from controls, but provocative testing revealed significant abnormalities of response of cortisol/ACTH, GH, prolactin and LH. Six out of eight patients had absent diurnal cortisol variation and five patients had elevated serum prolactin levels. Thus, in this group of patients normal pituitary‐adrenal function has not been satisfactorily restored. It is clear that significant disturbances of hypothalamic‐pituitary function follow mega‐voltage therapy and these may progress to overt hypopituitarism.

THE EFFECT OF KETANSERIN, A SPECIFIC SEROTONIN ANTAGONIST ON THE PRL, GH, ACTH AND CORTISOL RESPONSES TO HYPOGLYCAEMIA IN NORMAL SUBJECTS

The role of serotonin in the prolactin, growth hormone, ACTH and cortisol responses to hypoglycaemia has been investigated in normal subjects using a selective serotonin (5HT2) receptor antagonist, ketanserin. Circulating concentrations of these hormones were measured after administration of insulin (0·1 units/kg body weight iv) to eight normal male subjects with and without simultaneous iv ketanserin (10 mg). Plasma glucose fell to less than 2·0 mmol/l in all subjects and was unaffected by ketanserin. Ketanserin induced a 50% decrease in the serum prolactin response to hypoglycaemia, 45 and 60 min after administration of insulin (increase in serum prolactin at 60 min: 1145 ± 295 mU/l without ketanserin; 558 ± 176 mU/l with ketanserin, P < 0·05). The peak ACTH response was reduced by 30% (95·3 ± 33·6 ng/l without ketanserin; 60·0 ± 22·9 ng/l with ketanserin, P < 0‐05) but the plasma cortisol response was not significantly altered. The serum growth hormone response was unaffected by serotonin blockade. These findings suggest that serotonin, probably acting through 5HT2 receptors, is involved in the stimulation of prolactin and ACTH release but not in the release of growth hormone, during insulin induced hypoglycaemia.

THE LONG‐TERM EFFECTS OF MEGAVOLTAGE RADIOTHERAPY AS SOLE OR COMBINED THERAPY FOR LARGE PROLACTINOMAS: STUDIES WITH HIGH DEFINITION COMPUTERIZED TOMOGRAPHY

The long‐term sequelae of external pituitary irradiation alone or in combination with surgery and/or bromocriptine therapy have been studied in 14 patients with large prolactinomas over an observation period of 6–22 years (mean 13 years). Galactorrhoea was abolished in four of the five females with this symptom, but menstrual disturbance persisted in five of six patients. Sexual function was normal without sex hormone replacement in only one of the eight males after treatment. Neurological deficits were abolished or improved by treatment in all 9 patients with this presentation. Serum prolactin levels declined after treatment (P > 0·001) and fell to within the normal range off bromocriptine therapy in six of the 14 patients at a mean of 9 years (range 5–17 years) after radiotherapy. All patients had anterior pituitary deficiency of some degree at reassessment, and 13 required replacement treatment. Serial skull radiographs revealed remineralization of the fossa floor in five patients and a decrease in fossa size in three. All five patients who did not also have surgery had evidence of tumour shrinkage without bromocriptine treatment (on CT scan or metrizamide cisternography). Fourth generation CT scans on completion of the study revealed a decrease in tumour mass in all patients, with varying degrees of empty sella in 13 and a cystic intrasellar tumour in the remaining one. Residual tumour was demonstrated in 10 patients, three of whom had normal serum prolactin levels, while one patient without visible tumour had persistent hyperprolactinaemia. Radiotherapy, alone or in combination with surgery and bromocriptine, effectively decreases prolactin secretion and tumour size in patients with large prolactinomas at the expense of other anterior pituitary function. Circulating prolactin levels are a poor marker of residual tumour volume.

Effects of somatostatin analogue SMS 201-995 In non-insulin-dependent diabetes

The 24‐h hormonal and metabolic profiles obtained in five non‐insulin‐dependent diabetics receiving twice daily s.c. injections of the long‐acting somatostatin analogue SMS 201–995 (50 μg) have been compared with those obtained following placebo injection. Injections were given 30 min before breakfast and the evening meal. GH secretion was not suppressed by the analogue administered in this manner. Despite suppression of serum insulin levels following breakfast and the evening meal, blood glucose levels were similar during the two study periods with no evidence of worsening in diabetic control. Prolonged suppression of plasma glucagon levels was observed and the nocturnal elevation in serum TSH levels was abolished. Free T4 levels fell significantly following the analogue but total T3 levels were unaffected. Blood alanine levels were elevated throughout the study period following SMS 201–995 but changes in lactate, pyruvate, glycerol and 3‐hydroxybutyrate were minor. All five subjects suffered gastrointestinal side‐effects. SMS 201–995 (50 μg) given twice daily before meals does not cause a deterioration in metabolic control, does not suppress 24‐h GH secretion and causes significant side‐effects in patients with non‐insulin‐dependent diabetes mellitus.