Andrew J. Weissberger

The antinatriuretic action of biosynthetic human growth hormone in man involves activation of the renin-angiotensin system

Previous studies using human pituitary extracts have not resolved whether the sodium retaining effects of human growth hormone (hGH) are mediated in part by increased aldosterone secretion. We have studied the effects of an authentic biosynthetic GH (bio-hGH) preparation on sodium metabolism and on the activity of the renin-angiotensin system. Six young men were administered this preparation at 0.2 U/kg/d subcutaneously for five consecutive days. Twenty-four-hour urine collections were obtained for measurement of sodium excretion and osmolality and blood collected for quantitating changes in sodium, osmolality, plasma renin activity (PRA), aldosterone, and arginine vasopressin (AVP) concentrations. Bio-hGH administration resulted in a fall in 24-hour urinary sodium excretion (197 +/- 38 to 42 +/- 20 mmol, mean +/- SD, P less than .005), a reduction in urine volume (1,652 +/- 182 to 848 +/- 348 mL, P less than .05) but not osmolality. PRA increased significantly from 1,118 +/- 73 to 3,608 +/- 1,841 fmol angiotensin 1 L/s (P less than .005), which was associated with a sevenfold increase in plasma aldosterone concentration (52 +/- 12 to 402 +/- 99 pg/mL, P less than .001). Plasma osmolality and AVP concentrations did not change significantly. The results show that Bio-GH-induced retention of sodium involves the activation of the renin-angiotensin system. This mechanism may explain in part the occurrence of plasma volume expansion and hypertension in acromegaly and suggests a risk of fluid retention and possibly hypertension in subjects receiving supraphysiological doses of bio-hGH for treatment of short stature.

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 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.

Sex Steroid Regulation of Growth Hormone Secretion and Action

Evidence that oestrogen is involved in the regulation of the somatotrophic axis in adult humans is provided by the observations that mean growth hormone (GH) levels are higher in women than men, that the fall in GH and insulin-like growth factor-1 (IGF-1) with aging are correlated to oestradiol levels and that oestrogen increases the GH responses to provocative stimuli. To investigate whether oestrogen modulates GH secretion and action in adult life, we studied the impact of oestrogen replacement on circulating GH and IGF-1 levels in postmenopausal women. Since the liver is the major source of circulating IGF-1 and the oral route of oestrogen delivery causes nonphysiologic effects on hepatic proteins, we compared the effects of oral and transdermal routes of delivery. Oral ethinyl oestradiol administration resulted in a significant fall in mean IGF-1 levels and a threefold increase in mean 24-hour GH. Transdermal administration of 17 beta-oestradiol resulted in a slight increase in serum IGF-1 but no change in mean 24-hour GH levels. To determine whether differences in oestrogen type rather than in the route of delivery caused the different effects on the GH/IGF-1 axis, we compared the effects of three oral oestrogen formulations. Ethinyl oestradiol, conjugated equine oestrogen and oestradiol valerate each induced a fall in IGF-1 and a rise in mean 24-hour GH levels in postmenopausal women. To determine the significance of oestrogen-induced changes on IGF-1, we studied effects on markers of connective and bone tissue activity. We found that propeptide concentrations of type III and type I collagen, and osteocalcin rose and fell in parallel with IGF-1 during oral or transdermal oestrogen therapy. Oestrogen causes distinct, route-dependent effects on the somatotrophic axis. The dissociation of the GH/IGF-1 axis by the oral route is likely to arise from impaired hepatic IGF-1 production which causes increased GH secretion through reduced feedback inhibition. Oestrogen treatment may have longer-term metabolic effects on hypogonadal women exerted through effects on the somatotrophic axis.

Secretory Patterns of Growth Hormone According to Sex and Age

Gender and age have distinct and interrelated effects on GH secretion in adults. GH secretion falls significantly with aging, particularly in women. The fall in GH release is amplitude- rather than frequency-modulated and appears to be related to estrogen status. Oral estrogen administration is unphysiological and causes a marked perturbation of the GH/insulin-like growth factor I axis. A nonparenteral route of administration is required for further investigations of the physiological role of estrogen in GH secretion.

QUANTIFICATION OF URINARY GROWTH HORMONE (GH) EXCRETION BY CENTRIFUGAL ULTRAFILTRATION AND RADIOIMMUNOASSAY: APPRAISAL OF THE RELATIONSHIP BETWEEN 24 H URINARY GH AND MEAN 24 H SERUM GH LEVELS IN NORMAL AND ABNORMAL STATES OF GH SECRETION

We have applied a simple method for the quantification of 24 h urinary GH excretion (24 h UGH), combining centrifugal ultrafiltration and radio‐immunoassay (RIA), to an appraisal of the relationship between 24 h UGH and mean 24 h serum GH levels in normal and abnormal states of GH secretion. Forty‐four subjects, comprising 13 normal adults, 12 short‐statured subjects and 19 subjects with active acromegaly, underwent blood sampling at 20‐min intervals and concurrent urine collection for 24 h. Mean 24 h serum GH and 24 h UGH were also determined in four post‐menopausal women before and during cyclical oestrogen replacement therapy, and 24 h UGH was measured in six normal men prior to and following the subcutaneous administration of biosynthetic GH (0.2 IU/kg).

Resolution of Apparent Growth Hormone-Dependent Growth Failure during Puberty: A Case Report

A prepubertal boy with apparent growth hormone (GH)-dependent growth failure displayed a marked increase in growth velocity, normal GH responses to arginine/insulin infusion and a fourfold increase in spontaneous 24-hour GH secretion following the onset of normal puberty. The case supports earlier observations of a transient form of GH insufficiency in some short prepubertal children, but represents the first evidence that puberty restores spontaneous as well as stimulated GH secretion in such patients.

Growth Hormone Economy in Hypogonadism: Effects of Sex Steroids

The adolescent growth spurt is accompanied by a progressive rise in serum concentrations of gonadal steroids that occurs contemporaneously with an increase in spontaneous growth hormone (GH) release (1, 2). This observation suggests that gonadal steroids play an important role in determining GH secretion and in regulating body growth and composition. Evidence for androgens as a positive regulator of GH secretion is provided by the finding that testosterone is positively correlated with plasma IGF-I and 24-h mean GH concentration in males during puberty (3). There is evidence that estrogen may also be an important regulator of GH secretion in women, although this has been less well studied. Significant correlations have been reported between serum estradiol levels and GH secretion in pubertal girls (4). GH secretion varies during the menstrual cycle, with mean concentrations highest during the late follicular phase when estrogen concentration is highest (5). Mean 24-h GH and IGF-I levels are lower in postmenopausal women than in premenopausal women, suggesting that reduced activity of the somatotrophic axis in the menopause may be secondary to estrogen deficiency (6). The collective observations suggest that gonadal steroid deficiency may be associated with a reduction in GH secretion, which can be restored by sex steroid replacement.