Effect of growth hormone treatment on postprandial protein metabolism in growth hormone-deficient adults.

Growth hormone (GH) treatment of GH-deficient adults increases lean body mass. To investigate this anabolic effect of GH, body composition and postabsorptive and postprandial protein metabolism were measured in 12 GH-deficient adults randomized to placebo or GH treatment. Protein metabolism was measured after an infusion of [1-13C]leucine before and after a standard meal at 0 and 2 mo. After 2 mo, there was an increase in lean body mass in the GH group (P < 0. 05) but no change in the placebo group. In the postabsorptive state, there was increased nonoxidative leucine disappearance (NOLD; a measure of protein synthesis) and leucine metabolic clearance rate and decreased leucine oxidation in the GH group (P < 0.05) but no change in the placebo group. After the meal, there was an increase in NOLD and oxidation in all studies (P < 0.05), but the increase in NOLD, measured as area under the curve, was greater in the GH group (P < 0.05). This study clearly demonstrates for the first time that the increase in protein synthesis in the postabsorptive state after GH treatment of GH-deficient adults is maintained in the postprandial state.

The effects of two doses of replacement growth hormone on the biochemical, body composition and psychological profiles of growth hormone-deficient adults.

This study examined the effects of growth hormone (GH) replacement on the insulin-like growth factor-I (IGF-I), body composition and psychological profiles of GH-deficient adults. We assessed whether two doses of GH produced different effects on these variables and whether patients who, at the end of the study chose to remain on long-term GH replacement responded differently to those who chose to abandon therapy. Forty-two adults (aged 42.9 +/- 1.9 years (mean +/- S.E.M.)) with documented GH deficiency entered two studies (24 in study 1, 18 in study 2). Biochemical, body composition and psychological profiles were assessed at baseline, and after 6 months and 1 year. Psychological assessments were performed using well-established, independent, validated 'Quality of Life' questionnaires (Nottingham Health Profile (NHP) and the Psychological General Well-Being Schedule (PGWB)). The study protocols differed only in the doses of growth hormone (0.024 mg/kg per day and 0.012 mg/kg per day respectively). Comparison between studies and between patients eventually continuing and abandoning GH therapy was performed. GH replacement was associated with significant changes in IGF-I levels (P < 0.001), body composition (P < 0.01) and self-perceived well-being (NHP, P < 0.01; PGWB, P < 0.01). The higher dose of GH produced a greater IGF-I response than the lower dosage (44.6 +/- 7.3 vs 26.2 +/- 3.6 nmol/l, P < 0.05), but no better psychological response (NHP, P = 0.22; PGWB, P = 0.23). Those deciding to continue replacement therapy did not respond differently to those choosing to abandon therapy with respect to IGF-I (P = 0.72), body composition (P = 0.38) and psychological assessment (NHP, P = 0.29; PGWB, P = 0.24). GH replacement in GH-deficient adults was associated with significant improvements in self-perceived well-being as well as changes in body composition and other variables. This improvement was similar at two different doses of replacement GH. Those patients electing to continue on long-term replacement did not achieve a demonstrably different psychological, body composition or biochemical benefit to those patients deciding to discontinue replacement.

The role of growth hormone in the regulation of body composition in the adult.

Despite early evidence from studies performed soon after its discovery, the role of human growth hormone (GH) in metabolic processes during adulthood has, until recently, been largely ignored. The importance of GH in the regulation of body composition in the adult is clearly demonstrated by the abnormalities seen in "nature's experiments', i.e. acromegaly and GH deficiency. Body composition has been shown to change favourably following successful treatment of acromegaly. Formal replacement studies in adult GH-deficient patients, made possible by the recent advent of recombinant GH, have also shown dramatic changes in body composition, with increases in lean body mass and reductions in fat mass towards normality and associated improvements in physical performance. Thus, adult GH deficiency, like acromegaly, has become widely accepted as a distinct clinical entity warranting treatment.

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.

Characterization of 24-hour growth hormone secretion in acromegaly: implications for diagnosis and therapy.

OBJECTIVE: Early studies of acromegaly undertaken before the general availability of insulin-like growth factor I (IGF-I) assays have used arbitrary and varying growth hormone (GH) threshold levels for diagnosing and assessing outcome of treatment for this disease. We have undertaken a detailed study of GH secretion and its relationship to IGF-I levels to assess the usefulness of GH and IGF-I measurements in the assessment of acromegaly. PATIENTS: Thirty acromegalic subjects (12 untreated and 16 previously treated) and 30 age and sex-matched normal subjects were studied. MEASUREMENTS: Twenty-four-hour GH secretion was obtained from 20-minute sampling and serum IGF-I was measured. Comparisons were made of IGF-I, mean 24-hour GH concentration, and of the pulsatile and diurnal characteristics of GH secretion between the two groups. RESULTS: IGF-I levels in untreated acromegaly were elevated and clearly separated from the normal range. Mean 24-hour GH concentrations in untreated and treated acromegalic subjects with elevated IGF-I (> 40 nmol/l) were greater than (P < 0.01), and showed good separation from, those of normal subjects only after age-matching. From the 24-hour profiles, nadir GH levels in normal subjects fell below the level of detectability while those in untreated acromegalic subjects did not. Pulse amplitude (P < 0.01), ratio of pulsatile to non-pulsatile GH release and the night to daytime GH ratio (P < 0.05) were significantly reduced in acromegaly. In the six patients who attained normal IGF-I levels after surgery, pulsatile characteristics remained abnormal in four. Mean 24-hour GH was significant related (r = 0.57) to IGF-I. A random GH concentration > 2.5 micrograms/l (5 mIU/l) has a sensitivity of 77% and specificity of 95% in identifying acromegalic patients who have biochemically active disease (elevated IGF-I) after treatment. CONCLUSIONS: Patients with active acromegaly secrete more GH than age-matched normal controls. GH secretion in acromegaly is characterized by marked blunting of pulsatile secretion and, in contrast to normal subjects, the failure of GH to fall to undetectable levels at any time during the 24-hour day. IGF-I measurement is a more practical alternative in the diagnosis of acromegaly and in the assessment of therapeutic outcome. Since abnormalities of GH regulation may persist despite normalization of IGF-I, a distinction between remission and cure should be made. Detailed post-treatment evaluation of GH secretion is necessary to define the nature of underlying GH regulation and to evaluate the risk of disease recurrence.

Activation of the somatotropic axis by testosterone in adult males: evidence for the role of aromatization.

To determine whether testosterone modulates the somatotropic axis in adult males, we compared 24-h GH secretion (from 20-min sampling, using Cluster analysis) and insulin-like growth factor-I (IGF-I) levels of five hypogonadal men (aged 20-32 yr) with those of six normal men (aged 21-27 yr), and examined the effects of testosterone replacement (testosterone enanthate 250 mg im monthly). To elucidate whether the action of testosterone on the somatotropic axis is direct, or requires the aromatization of testosterone to estradiol, we also examined the effects of the nonsteroidal antiestrogen, tamoxifen (20 mg/day for 3 weeks), on 24-h GH secretion and IGF-I levels in the normal men and in four of the hypogonadal men during concurrent testosterone treatment. Compared to the normal men, the hypogonadal men had significantly reduced mean GH pulse amplitude (3.1 +/- 0.6 vs. 8.4 +/- 1.7 micrograms/L, P < 0.05), but not pulse frequency. Testosterone treatment resulted in a significant increase in 24-h mean serum GH (0.7 +/- 0.2 to 1.4 +/- 0.2 micrograms/L, P < 0.05), mean GH pulse amplitude (3.1 +/- 0.6 to 5.2 +/- 0.8 micrograms/L, P < 0.01) and serum IGF-I (0.9 +/- 0.1 to 1.1 +/- 0.1 U/mL, P < 0.05). In the normal men, tamoxifen significantly reduced 24-h mean serum GH (1.1 +/- 0.3 to 0.5 +/- 0.1 micrograms/L, P < 0.05), mean GH pulse amplitude (8.4 +/- 1.7 to 4.7 +/- 0.4 micrograms/L, P < 0.05), and serum IGF-I (1.0 +/- 0.1 to 0.7 +/- 0.1 U/mL, P < 0.001). In the hypogonadal men on testosterone replacement, tamoxifen lowered 24-h mean serum GH (1.3 +/- 0.2 to 0.6 +/- 0.2 micrograms/L, P < 0.01), mean GH pulse amplitude (5.5 +/- 1.0 to 2.4 +/- 0.8 micrograms/L, P < 0.01), and serum IGF-I (1.2 +/- 0.1 to 0.8 +/- 0.1 U/mL, P < 0.05). We conclude that testosterone plays an important role in the modulation of the male somatotropic axis in adulthood, as appears to be the case in puberty, and that this effect is partly dependent on the aromatization of testosterone to estradiol.

Protein metabolism in growth hormone deficiency, and effects of growth hormone replacement therapy.

The effects of growth hormone (GH) treatment on protein metabolism were studied in adults with GH deficiency (GHD). A double-blind, placebo-controlled trial of recombinant human GH, 0.018 IU/kg/day for 1 month followed by 0.036 IU/kg/day for 1 month, was performed with isotopic whole-body protein turnover studies at 0 and 2 months. In all, 18 adults with GHD (9 men, 9 women; mean age, 46.6 years; range, 30-56 years) were studied. Whole-body isotopic leucine turnover using L-[1-13C]leucine was assessed by measuring leucine Ra (a measure of protein degradation), non-oxidative leucine Rd (a measure of protein synthesis) and leucine oxidation rate. Lean body mass and circulating insulin-like growth factor I were significantly (p < 0.02) increased at 2 months in the GH-treated group, but not in the placebo group. There was no change in leucine Ra in either the placebo or GH-treated groups at 2 months. Leucine oxidation decreased (p < 0.01) and non-oxidative leucine Rd increased (p < 0.02) in the GH-treated group at 2 months. There was no significant change in either leucine oxidation or non-oxidative leucine Rd in the placebo group at 2 months. These results indicate that the increase in lean body mass resulting from GH treatment in adults with GHD is due to an increase in protein synthesis.

The effects of growth hormone on protein metabolism in adult growth hormone deficient patients.

OBJECTIVE: Growth hormone treatment given to adult growth hormone deficient patients leads to an increase in lean body mass by an unknown mechanism. The aim of this study was to investigate the actions of growth hormone treatment on protein metabolism in adult growth hormone deficient patients. DESIGN: Double-blind, placebo controlled trial of recombinant human growth hormone (0.018 U/kg/day for 1 month followed by 0.036 U/kg/day for 1 month) with isotopic whole body protein turnover studies at 0 and 2 months. PATIENTS: Eighteen adult growth hormone deficient patients (nine male, nine female of mean age 46.6 (range 30-56). MEASUREMENTS: Whole body isotopic leucine turnover using L-1-13C-leucine measuring leucine Ra (a measure of protein degradation), non-oxidative leucine Rd (a measure of protein synthesis) and leucine oxidation rate. RESULTS: Lean body mass (P < 0.02), circulating insulin-like growth factor I (P < 0.01) and insulin (P < 0.02) were significantly increased at 2 months in the treatment group but there was no change in the placebo group. When expressed in relation to body weight, leucine Ra and non-oxidative leucine Rd increased (P < 0.01) and leucine oxidation decreased (P < 0.02) after 2 months growth hormone treatment. When expressed in relation to lean body mass non-oxidative leucine Rd increased (P < 0.02) and leucine oxidation decreased (P < 0.02) but there was no significant change in leucine Ra after 2 months growth hormone treatment. In the placebo group there were no significant changes in leucine metabolism expressed as lean body mass or body weight after 2 months. changes in leucine metabolism expressed as lean body mass or body weight after 2 months. CONCLUSION: These results indicate that the increase in lean body mass resulting from growth hormone treatment in adult growth hormone deficient patients is due to an increase in protein synthesis.

Impact of short-term estrogen administration on growth hormone secretion and action: distinct route-dependent effects on connective and bone tissue metabolism.

We recently reported that estrogen exerts distinct effects on the GH/IGF-1 axis that are dependent on the route of delivery, probably reflecting a first-pass effect on hepatic IGF-1 production. Oral administration reduces IGF-1 and increases GH levels; transdermal administration elevates IGF-1 without changing GH concentrations. Since mesenchymal tissue is a target for GH and IGF-1 action, we studied changes in the GH/IGF-1 axis following oral (ethinyl estradiol, 20 micrograms/day) versus transdermal (Estraderm 100 TTS, Ciba Geigy, 100 micrograms 17 beta-estradiol per day) estrogen delivery and compared corresponding effects on connective and bone tissue metabolism. Mean 24 h GH levels, IGF-1, markers of fibroblast (procollagen III) and osteoblast (procollagen I, osteocalcin) function, and indices of bone turnover (fasting urinary hydroxyproline and calcium to creatinine ratios, UOHPr/Cr and UCa/Cr) were measured before and after 2 months of either oral or transdermal therapy in two groups of postmenopausal women. Transdermal estrogen administration significantly (p less than 0.05) increased IGF-1, procollagen III, procollagen I, osteocalcin, and UOHPr/Cr. In contrast, oral estrogen administration had a suppressive effect; the levels of IGF-1 (p = 0.001), procollagen III (p = 0.018), procollagen I (p = 0.002), osteocalcin (p = 0.015), and UOHPr/Cr (p = 0.004) were significantly different from those measured during transdermal administration. Both treatments significantly reduced UCa/Cr (p less than 0.015). IGF-1 changes during estrogen therapy were significantly related (p less than 0.05) to changes in procollagen III, procollagen I, osteocalcin, and UOHPr/Cr. Transdermally delivered estrogen stimulates IGF-1 production, increases osteoblastic function, and stimulates bone and nonbone collagen synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women.

Estrogen deficiency may account for lower circulating GH and insulin-like growth factor I (IGF-I) concentrations in the menopause. Since the liver is the major source of circulating IGF-I and oral estrogens have nonphysiological effects on hepatic function, we have compared GH secretion over 24 h from 20 min sampling and serum IGF-I levels in premenopausal women (n = 7, follicular phase) and postmenopausal women before and after 2 months of cyclical replacement therapy with either oral ethinyl estradiol (EE, 20 micrograms daily; n = 7) or transdermal 17 beta-estradiol (E2, 100 micrograms patches applied twice weekly; n = 7). The extent of GH binding to its serum binding protein was also examined by measuring the percent specific binding of [125I] GH in serum. Mean 24-h serum GH and serum IGF-I were significantly lower (P less than 0.05) in postmenopausal than in premenopausal women. Oral and transdermal estrogen therapy resulted in a comparable degree of gonadotropin suppression. Oral EE treatment increased mean 24-h serum GH (2.0 +/- 0.4 to 7.0 +/- 0.6 mIU/L, P less than 0.0005) and mean pulse amplitude (5.3 +/- 1.2 to 11.2 +/- 2.5 mIU/L, P less than 0.01) but significantly reduced circulating IGF-I (0.70 +/- 0.09 to 0.47 +/- 0.04 U/mL, P less than 0.02) levels. Oral EE increased the percent specific binding of [125I]GH (22.0 +/- 1.6 to 32.0 +/- 1.9%, P less than 0.0005), however the derived mean 24-h free serum GH concentrations were significantly higher (P less than 0.0005) after treatment. By contrast, transdermal E2 administration, which restored circulating E2 concentrations to the midfollicular range, increased circulating IGF-I (0.86 +/- 0.15 to 1.10 +/- 0.14 U/mL, P less than 0.005) to levels that were not significantly different from those of premenopausal women (1.41 +/- 0.21 U/mL). This was not accompanied by changes in 24-h GH secretion or the percent specific binding of [125I]GH in serum. The route of administration is a major determinant of the effects of exogenous estrogens on the GH/IGF-I axis. Oral estrogen administration inhibits hepatic IGF-I synthesis and increases GH secretion through reduced feedback inhibition. Reduced GH secretion in the menopause is not explained by estrogen deficiency since GH secretion is not restored by the attainment of physiological E2 concentrations using the transdermal route. The contrasting route dependent IGF-I responses have important implications for the long-term benefit of hormone replacement therapy in the menopause.

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.

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). Each subject's mean 24 h serum GH level was determined by assaying a 'pooled' sample, derived from equal aliquots of the 73 serum samples obtained during the 24 h study. The method for quantification of 24 h UGH employs centrifugal microconcentrators, and involves a 50-fold concentration of urine, followed by dialysis and RIA. Surface adsorptive hormone loss during sample collection and ultrafiltration is minimized by the prior addition of bovine serum albumin to the urine collection container. Immunoreactive GH in ultrafiltered urine dilutes in parallel with the RIA standard curve. GH is stable in urine stored at - 20 degrees C for at least 12 months. There was a highly significant correlation between 24 h UGH and mean 24 h serum GH values obtained from the combined population of normal adults (including the post-menopausal women during oestrogen therapy) and short-statured subjects (r = 0.69, P less than 0.0001). A significant correlation was also found in short-statured subjects alone (r = 0.63, P less than 0.05). In contrast, there was no significant correlation between 24 h UGH and mean 24 h serum GH in subjects with active acromegaly, and their 24 h UGH values were not distinguishable from those of the 'non-acromegalic' subjects. A significant increase in 24 h UGH occurred in the post-menopausal women given cyclical oestrogen replacement therapy (9.7 +/- 2.6 (mean +/- SE) to 24.6 +/- 1.0 muIU/mmol creatinine, P less than 0.02), reflecting the increase in their mean 24 h serum GH levels (0.8 +/- 0.3 to 5.3 +/- 0.7 mIU/l, P less than 0.01). Twenty-four hour UGH increased from 4.6 +/- 0.6 to 17.1 +/- 2.1 muIU/mmol creatinine (P less than 0.002) in the men given biosynthetic GH. Twenty-four hour UGH measurements reflect mean 24 h serum GH levels in normal adults and short-statured subjects. While the measurement of 24 h UGH shows promise as an investigative tool, our results cast doubt on its use in the diagnosis of acromegaly.

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/l 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 less than 0.01) which was associated with a marked reduction in urinary sodium excretion (196 +/- 38 to 45 +/- 20 mmol/day; P less than 0.025). Serum T3 increased during bio-hGH administration and was associated 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 (40 U/m2/week) or more in patients with GH responsive short stature.

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.