D. G. Johnston

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.

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.

ORAL GLUCOSE INHIBITS GROWTH HORMONE SECRETION INDUCED BY HUMAN PANCREATIC GROWTH HORMONE RELEASING FACTOR 1–44 IN NORMAL MAN

The interaction between the inhibitory effect on growth hormone secretion of a 75 g oral glucose load and the stimulatory effect of human pancreatic growth hormone releasing factor 1–44 (hpGRF 1–44, 10 μg i.v.) has been studied in six normal subjects. hpGRF 1–44 alone induced a rise in growth hormone concentrations (maximum mean ± SEM, 16–5 ± 1.7 mU/1 15 min after injection) while growth hormone levels were suppressed by oral glucose alone (& < 1 ‐5 mU/1 from 45 to 135 min after glucose ingestion). When hpGRF 1–44 was injected 60 min after oral glucose, the growth hormone response was attenuated (maximum, 6.7±1.4 mU/1 at 15 min, P<005). Increments of blood glucose within the physiological range diminish the growth hormone response to hpGRF 1‐44 in normal man.

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.

THE RESPONSE OF OBESE SUBJECTS TO CONTINUOUS INFUSION OF HUMAN PANCREATIC GROWTH HORMONE‐RELEASING FACTOR 1–44

The growth hormone (GH) response of seven obese subjects to a 4 h continuous infusion of human pancreatic GH‐releasing factor, 0·3 μg/kg/h, has been compared with that obtained in seven sex and age matched controls. The pattern of response was normal in the obese but peak GH levels (mean ± SEM: 13·8 ± 1·9 compared to 30·9 ± 4·7 mU/l, P < 0·01) and integrated GH levels (mean ± SEM: 27·1 ± 3·6 compared to 62·0 ± 9·7 mU/l/h, P < 0·01) were reduced in obese subjects. There was a negative correlation between the integrated GH response and the percentage ideal body weight (r=−0·80, P < 0·05), but no significant correlation with somatomedin‐C levels (r=+ 0·72; P= 0·07). Obese subjects have an impaired GH response to infusion of GH‐releasing factor which is not related to negative feedback by somatomedins.

EVIDENCE THAT THYROID HORMONES REGULATE GLUCONEOGENESIS FROM GLYCEROL IN MAN

We have previously reported that glucose production assessed using radioiso‐topic methods is 50% increased in hyperthyroidism but 30% decreased in hypothyroidism. These studies, however, do not distinguish between glycogenolysis and gluconeogenesis. In fasting man more than 80% of circulating glycerol is cleared by the liver and enters the gluconeogenic pathway. We have therefore measured glycerol clearance following bolus intravenous glycerol administration as an indirect assessment of gluconeogenic capacity. Hyperthyroid and hypothyroid subjects were compared with separate matched controls after an overnight fast. In hyperthyroid subjects blood glucose and blood glycerol were increased but lactate, pyruvate, and alanine concentrations were normal. Glycerol clearance was increased in hyperthyroidism and followed a double exponential decay with a shortened second component half‐time. Endogenous glycerol production was increased three‐fold. In hypothyroidism fasting circulating levels of glucose, lactate, pyruvate, alanine, and glycerol were normal but glycerol clearance was diminished. Both first and second component half‐times were prolonged in hypothyroidism and endogenous glycerol production was decreased by 50%. Thus in hyperthyroidism glycerol clearance is greatly enhanced whilst in hypothyroidism glycerol clearance is diminished. The magnitude of the changes suggests that alterations in gluconeogenesis are probably the major factors concerned in the reported increase and decrease in glucose production in hyperthyroidism and hypothyroidism respectively.

THE INTERACTION OF HUMAN PANCREATIC GROWTH HORMONE RELEASING FACTOR 1–44 WITH SOMATOSTATIN IN VIVO IN NORMAL MAN

The interaction between the stimulatory effects of hpGRF 1–44 and the inhibitory effects of somatostatin on GH release have been investigated in six normal male subjects receiving continuous 4 h infusions of these peptides alone and in combination. hpGRF 1–44 0·3 μg/kg/h alone produced a peak GH response of 27·0 ± 7·6 mU/1 (mean ± SEM). Somatostatin 1·0 μg/kg/h markedly inhibited the GH response to hpGRF 1–44 with mean levels > 4·0 mU/1 during the infusion, though a rebound rise in GH levels to 26·1 ± 9·0 mU/1 was observed at the end of the infusion period. Somatostatin 0·2 μg/kg/h inhibited the GH response to hpGRF 1–44 to a lesser degree (peak GH during the infusion 11·7 ± 2·5 mU/1) and the rebound rise in GH levels (maximum 13·2 ± 4·3 mU/1) was less than that observed with high dose somatostatin. During somatostatin 1·0 μg/kg/h alone GH levels were suppressed > 1·0 mU/1 followed by a rebound at the end of the infusion in only two subjects. These data demonstrate a dose‐dependent inhibition of hpGRF 1–44 by somatostatin in vivo in man.

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.

The metabolic effects of dopamine in man

SummaryThe metabolic effects of dopamine have been investigated by its infusion in normal man with and without simultaneous somatostatin administration. Dopamine was infused into overnight fasted men at 1.5 µg/kg/min (n=6) and 3.0 µg/kg/min (n=5) for 120 min. Plasma dopamine concentrations at 120 min were 78±9 nmol/l and 117±17 nmol/l respectively, associated with a marginal rise in plasma noradrenaline. Dopamine (1.5 µg/kg/min) induced an early and sustained rise in plasma glucagon (48±9 pg/ml versus 19±6 pg/ml in saline controls at 10 min, p<0.01)and a transient elevation in serum growth hormone which peaked to 17.7 (range 4.5–71.8)mU/l at 60 min (7.2 (range 0.6–37.7) mU/l with saline, p<0.05), but did not alter serum insulin, blood glucose or other metabolite levels. At 3.0 µg/kg/min, dopamine in addition provoked mild and transient elevations in blood glucose and serum insulin. Somatostatin (250 µg/h) suppressed circulating insulin, glucagon, and growth hormone levels and abolished the small hyperglycaemic effect seen with the higher dopamine dose. Somatostatin alone induced a progressive rise in circulating non-esterified fatty acid and 3-hydroxybutyrate levels reflecting insulin deficiency. This rise in NEFA and 3-hydroxybutyrate was increased by dopamine particularly at the higher dosage (plasma NEFA; somatostatin alone, 1.08±0.13 mmol/l; somatostatin plus dopamine 3 µg/kg/min, 1.44±0.17 mmol/l at 120 min, p<0.01: blood 3-hydroxybutyrate; somatostatin alone, 0.32±0.04 mmol/l; somatostatin plus dopamine 3 µg/kg/min, 0.56±0.12 mmol/l at 120 min, p<0.05). Thus: 1) dopamine at pharmacological dosage has minor effects when other endocrine mechanisms are intact, 2) it enhances lipolysis and ketogenesis during somatostatin-induced insulin deficiency, 3) the hyperglycaemic effect of the higher dopamine dose is probably mediated through stimulated glucagon secretion.

Coeliac disease in monozygotic twins

A case of concordance for coeliac disease in monozygous twins is reported. One presented with failure to enter puberty and responded to the exclusion of gluten from her diet. The other twin was asymptomatic. They represent a well documented example of monozygous twins with concordance for coeliac disease.