L. Lazarus

Suppression of Human Growth Hormone Secretion by Melatonin and Cyproheptadine

Pituitary growth hormone (GH) release in the rat is stimulated via serotoninergic pathways and can be inhibited by treatment with compounds that act as serotonin antagonists, such as cyproheptadine or the pineal gland hormone, melatonin. To investigate a possible role for serotonin in the control of human GH release, the effects of cyproheptadine and melatonin administration on the GH responses of normal male subjects were examined. The oral administration of cyproheptadine (8-12 mg daily for 5 days) to normal subjects reduced their GH responses to both insulin-induced hypoglycemia and physical exercise to a highly significant extent. Similarly, the mean GH responses of 10 subjects to insulin-induced hypoglycemia were significantly reduced after the prior oral administration of melatonin (1 g). The data presented show that serotonin antagonism has a similar effect on GH secretion in man to that observed in the rat and provides further evidence for serotoninergic, and possibly pineal, involvement in the control of human GH secretion.

Peirs: A pathologist-maintained expert system for the interpretation of chemical pathology reports

Summary Provision of a comprehensive interpretative service is an important challenge facing chemical pathologists. Attempts to automate report interpretation using expert systems have been limited in the past by the difficulties of rule base maintenance. We have applied a novel knowledge acquisition technique, ripple down rules, in the development of PEIRS (Pathology Expert Interpretative Reporting System), a user‐maintained expert system for automating chemical pathology report interpretation. We created over 950 rules for thyroid function tests, arterial blood gases and other test sub‐groups in 9 mths of operation. A staff pathologist performed all maintenance tasks as part of his routine duties without any need for computer programming skills. No clerical staff involvement was required. Duplication of rule addition for reports requiring multiple comments was the only limitation to coverage of other high volume test groups. PEIRS is the first expert system for the automated interpretation of a range of chemical pathology reports which operates in routine use without extra staffing requirements. PEIRS does not require “knowledge engineering” expertise. Thus, the knowledge base is flexible and can be easily maintained and updated by the pathologist. Expert systems based on ripple down rules should enable pathologists to provide a comprehensive automated interpretative service within the context of the total testing process.

Growth Hormone Regulation by Melatonin and Serotonin

THERE is evidence to suggest the existence of a pineal gland substance which moderates growth both in man and the rat. In man, non-parenchymal tumours, such as gliomas or teratomas which result in destructive lesions of the pineal gland, are associated with precocious puberty1,2 and it has been hypothesized that such lesions prevent the pineal from secreting gonadal2 and growth3,4 inhibitory factors. It was recently reported5 that the ability of the pineal gland to influence both growth and gonadal development may be due to two distinct physiological mechanisms. Rats which are blinded or kept in constant darkness show reduced body weight4,5, reduced tibeal length4, and reduced accessory organ weights4 as well as retarded puberty2,5,6. Blinded rats were also found4 to have significantly reduced pituitary gland stores of growth hormone. The effects of blinding or constant darkness on growth and growth hormone stores were abolished by pinealectomy4,7—a procedure also found8 to increase the gain of body weight in otherwise normal rats. Pinealectomy has also been reported to result in increased growth of experimental tumours in rats9. The observation10 of a diurnal fluctuation in the secretion of growth hormone in the rat further suggests that the lighting regime can modify this release. When lighting is reduced, concentrations of the pineal hormone melatonin (N-acetyl-o-methylserotonin) are increased because it is synthesized within the pineal gland from serotonin (5-hydroxytryptamine) by the action of the enzymes serotonin-N-acetyltransferase and hydroxyindole-o-methyltransferase, both of which exhibit their highest activities in the absence of light11,12. The fact that the conditions favouring high melatonin production correlate with those which cause reduced growth (and the other way round) suggests that melatonin has an inhibitory role in growth hormone secretory mechanisms. Collu et al.13 demonstrated that intraventricular injections of serotonin stimulate secretion of growth hormone in the rat, and they proposed that in this animal secretion of growth hormone is controlled through serotoninergic pathways. Serotonin has also been implicated as the stimulus for secretion of growth hormone after the onset of slow-wave (non-rapid eye movement, NREM) sleep in normal humans14. It thus seems that serotonin and its pineal derivative, melatonin, may have opposing effects on the secretion of growth hormone. We describe here experiments which support this contention.

Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly. Effects of dose and frequency and long-term safety.

STUDY OBJECTIVE To determine the efficacy of stepwise incremental doses, to compare twice- with thrice-daily administration of the same total daily dosage of the long-acting somatostatin analog SMS 201-995 (octreotide, Sandoz Australia, Sydney, Australia), and to evaluate the risk for cholelithiasis after long-term therapy for acromegaly. DESIGN Nonrandomized, controlled trial. SETTING Tertiary care center at a medical research institute. PATIENTS Sequential sample of 19 patients with active acromegaly. Twenty-five age-matched normal subjects were also studied to establish the normal range for growth hormone (GH) and insulin-like growth factor 1 (IGF-1). INTERVENTIONS Eight patients (group 1) were treated with 100, 250, and 500 micrograms twice daily of octreotide, then switched to 333 micrograms three times daily, whereas 11 patients (group 2) were treated with 100, 200, 300, and 500 micrograms three times daily. Each treatment stage lasted 6 to 12 weeks. MEASUREMENTS AND MAIN RESULTS Octreotide, 100 micrograms administered twice or thrice daily, significantly reduced mean 12-hour and nadir GH (P less than 0.01), IGF-1 (P less than 0.05), and hand volume (P less than 0.05). Dose increment to 500 micrograms in both groups did not further reduce mean 12-hour GH, nadir GH, or hand volume. Switching from 500 micrograms twice daily to 333 micrograms thrice daily resulted in significant (P less than 0.05) reduction of mean 12-hour GH, IGF-1, and hand volume. Normalization of mean 12-hour GH and IGF-1 occurred in 8 of 19 patients; 7 of the 8 patients had pretherapy mean 12-hour GH below 20 mIU/L. The pretherapy mean blood glucose was a significant negative predictor (r = -0.89) of the change in mean blood glucose during therapy. Gallstones were present in 9 of 18 patients after therapy. CONCLUSION Thrice-daily was more effective than twice-daily administration of octreotide, and dose increments above 100 micrograms thrice daily did not confer additional benefit. Biochemical remission was achieved in 40% of patients and was dependent on the GH concentration at initiation of treatment. Cholelithiasis is a risk of octreotide therapy. Octreotide is effective and can be considered as a first-line therapy in patients with acromegaly with mean pretherapy GH concentrations below 20 mIU/L. In patients with mean GH over 20 mIU/L, octreotide may be used as an adjuvant to surgery or radiotherapy.

The gastrointestinal stimulus to insulin release. I. Secretin.

The gastrointestinal stimulus to the release of insulin has been investigated in man by the use of a radioimmunoassay for secretin. Serum secretin levels rose rapidly after the oral ingestion of glucose or protein and preceded the elevation of serum insulin. An intravenous infusion of highly purified secretin caused a release of insulin when the serum secretin levels were within the physiological range. Infusion of hydrochloric acid into the duodenum caused an elevation of serum secretin and serum insulin levels in normal subjects. A similar response of secretin and insulin was seen after intravenous infusion of pentagastrin even when the acid stimulus to the duodenum was prevented. The latter observation suggests that pentagastrin (and probably gastrin) releases secretin by a direct humoral effect which is later fortified by the arrival of gastric acid in the duodenum. These studies suggest that secretin participates in the augmentation of insulin release after oral stimuli, and that a rapid sequence of humoral events takes place, gastrin releasing secretin and secretin releasing insulin. Subsequently secretin release would be augmented by a local stimulus in the duodenum and insulin release by the rising level of blood glucose or amino acids. This humoral system, which could also involve other gastrointestinal hormones, would provide a mechanism for facilitating the release of insulin to coincide with the onset of metabolite absorption.

Treatment of Severe Diabetes Mellitus by Insulin Infusion

A new and simple form of insulin therapy for diabetic hyperglycaemia and ketoacidosis has been developed using a continuous intravenous infusion of insulin at a rate of 2·4 U/hr to maintain serum insulin concentration at physiological levels. This rate raises the mean serum insulin to 83 μU/ml and has a therapeutic effect which is not augmented by higher infusion rates. The response to such low doses of insulin indicates a need for a reappraisal of currently held theories about insulin resistance in diabetic ketoacidosis. In 11 diabetic patients with a mean plasma glucose of 514 mg/100 ml this therapy produced continuous falls in plasma glucose at a mean rate of 75 mg/100 ml/hr, and 10 out of 11 patients recovered within eight hours. This form of therapy is simple to institute, not complicated by hypoglycaemia, and avoids the confusion and empiricism of previously described forms of therapy.

Measurement of Norepinephrine and 3,4-Dihydroxyphenylglycol in Urine and Plasma for the Diagnosis of Pheochromocytoma

We compared the value of plasma samples with that of 24-hour urine samples in identifying patients with pheochromocytoma among those with hypertension. We employed specific gas chromatographic-mass spectrometric analysis of both urine and plasma for simultaneous assay of norepinephrine and its neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG). The study population consisted of 1086 patients with hypertension, among them 25 patients with proved pheochromocytoma. Reference ranges for free norepinephrine and DHPG in plasma and urine were established. Measurement of free norepinephrine in 24-hour urine samples provided the best index of a pheochromocytoma. This technique had 100 percent sensitivity and 98 percent specificity among 1192 urine samples, as compared with 82 percent sensitivity and 95 percent specificity among 358 plasma samples. Simultaneous measurement of norepinephrine and DHPG in urine further improved specificity (to 99 percent), but the use of the ratio of norepinephrine to DHPG reduced sensitivity (to 95 percent), since some patients with pheochromocytoma secrete large amounts of DHPG. We therefore recommend measurement of 24-hour urinary levels of free norepinephrine for the diagnosis of pheochromocytoma and suggest that simultaneous analysis for DHPG may sometimes prove useful in reducing the rate of false positive results.

THE PHARMACOKINETICS, SAFETY AND ENDOCRINE EFFECTS OF AUTHENTIC BIOSYNTHETIC HUMAN GROWTH HORMONE IN NORMAL SUBJECTS

The pharmacokinetics, safety and endocrine effects of an authentic human growth hormone (bio‐hGH), produced by the expression of genomic hGH in a mammalian cell line, were studied in six healthy young men who were administered 0.2 U/kg/day subcutaneously for five consecutive days. Changes in sodium balance and in thyroid function were studied during the week of bio‐hGH administration and safety parameters were monitored over a 3‐week period. Growth hormone levels reached a mean (±SD) peak of 106 ± 10 mIU/1 at 3.3 ± 0.5 h following the first dose and resulted in a significant rise of somatomedin C, free fatty acids, fasting blood glucose and insulin concentrations. Bio‐hGH administration resulted in a significant increase in body weight (80.0± 4.5 to 81.1 ± 4.3 kg; P<0.01) which was associated with a marked reduction in urinary sodium excretion (196 ± 38 to 45 ± 20 mmol/day; P<0.025). Serum T3 increased during bio‐hGH administration and was asssociated with reciprocal changes in free thyroxine and TSH concentrations. Cardiac, hepatic, renal, biochemical, haematological, endocrinological and immunological functions remained normal throughout the study. No antibodies to hGH or to host cell protein developed during the study. The results show that bio‐hGH is safe in the short term, well tolerated, possesses pharmacokinetic and biological properties similar to pituitary hGH, and has distinct effects on sodium balance and on thyroid function. This study stresses the need to monitor patients for effects on sodium retention, carbohydrate metabolism and thyroid function when using hGH doses of 1.0 U/kg/week (40U/m2/week) or more in patients with GH responsive short stature.

Growth Hormone Responses to Melatonin in Man

Oral administration of 1 gram of melatonin caused rapid and significant elevations of serum human growth hormone in eight out of nine normal male subjects. The mean (� standard error of the mean) of the peak response by growth hormone was 22.9 � 4.6 microunits per milliliter. The increased secretion of growth hormone may be due to interaction of melatonin with hypothalamic serotoninergic receptors.

Carrier solutions for low-level intravenous insulin infusion.

In the use of low-level intravenous insulin infusion for treating diabetic hyperglycaemia and ketoacidosis adsorption of insulin to containers or plastic infusion apparatus results in significant losses of 60-80% of insulin in dilute physiological saline solution (40 U/l). It is therefore necessary to add protein to the carrier solution to minimize losses and maintain a constant delivery rate. Recovery studies showed that 3.5% w/v polygeline solution (polymer of degraded gelatin) was a suitable medium for this purpose, offering some advantages over human serum albumin. A minimum concentration of 0.5% polygeline was required to ensure adequate delivery of insulin to the patient.