Growth Hormone References

J Clin Invest. 1981; 67(5):1361-9 (ISSN: 0021-9738)

Rudman D; Kutner MH; Rogers CM; Lubin MF; Fleming GA; Bain RP

Growth hormone (GH) release was studied in adults of normal stature, ages 21-86 yr. The subjects were 85-115% of ideal body weight, between the 5th and 95th percentiles in height, and free of active or progressive disease. 9 to 12 individuals in each decade from thirds to ninth were evaluated. The following criteria of GH status were measured: serum GH concentration, analyzed by radioimmunoassay at half-hour intervals for 4 h after onset of sleep, and at 1-h intervals from 8 a.m. to 4 p.m. in 52 subjects; daily retention of N, P, and K in response to 0.168 U human (h)GH/kg body wt3/4/day in 18 subjects; and plasma somatomedin C (SmC) level before and during exogenous hGH treatment in 18 subjects. All 10 individuals, 20-29 yr old, released substantial amounts of endogenous GH during both day and night (average peak serum GH obtained during day and night was 7.3 and 20.3 ng/ml, respectively); average plasma SmC was 1.43 U/ml (95% tolerance limits, 0.64-2.22 U/ml).

There was no significant effect of exogenous hGH on elemental balances or on plasma SmC. In contrast, 6 of 12 individuals 60-79 yr old showed the following evidences of impaired GH release; peak waking and sleeping serum GH less than 4 ng/ml; plasma SmC less than 0.38 U/ml; a significant retention in N, P, and K; and a significant rise in plasma SmC, in response to exogenous hGH. Plasma SmC, serum GH during sleep, serum GH during the day, retentions of N, P, and K in response to exogenous hGH, and rise in plasma SmC in response to hGH were all intercorrelated (P less than 0.05). Plasma SmC less than 0.38 U/ml corresponded to peak nocturnal serum GH less than 4 ng/ml. The prevalence of plasma SmC less than 0.38 U/ml increased progressively from age 20 to 90: third decade, 0%; fourth, 11%; fifth, 20%; sixth, 22%; seventh, 42%; eight, 55%; and ninth, 55%. Within each decade, plasma SmC was inversely related to adiposity.

Metabolism. 1987; 36(12):1115-7 (ISSN: 0026-0495)

Crist DM; Peake GT; Mackinnon LT; Sibbitt WL; Kraner JC
Department of Medicine, University of New Mexico School of Medicine, Albuquerque 87131.

In order to assess the potential relationship between human growth hormone (GH) and body composition (BC) and natural immunity (NI), we measured the effects of exogenous GH on fat weight (FW), fat-free weight (FFW), and the cytotoxic activity of natural killer (NK) cells in women with impaired GH secretion. Mean peak serum concentrations of GH in response to L-dopa/arginine stimulation were 6.2 +/- 1.1 (SEM) ng/mL in 6 untreated subjects (US) and 5.4 +/- 1.5 ng/mL in 6 GH-treated subjects (TS). Moreover, the pretreatment circulating levels of IGF-I were low in both groups (US 684 +/- 121 mU/mL and TS 583 +/- 83 mU/mL), and they correlated with pretest levels of NK cell activity (r = .59, P less than .05) when both groups were combined. The TS were given 700 micrograms of human GH IM for an average of 14 days while the US were studied in parallel without GH treatment.

As measured by hydrodensitometry or skinfold anthropometry, FW decreased (26.1 +/- 6.8 kg to 23.8 +/- 6.3 kg, P less than .05) and FFW increased (44.9 +/- 3.3 kg to 46.2 +/- 3.8 kg, P less than .05) in the TS. In the US, there were no significant (P less than .05) changes in either FW or FFW. Using a standard 51Cr release assay to measure the specific lytic (SL) activity of NK cells, mean SL activity increased from 24.4 +/- 7.0% to 44.1 +/- 8.9% (P less than .05) in the TS, whereas levels in the US were not altered significantly (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Clin Endocrinol (Oxf). 2002; 57(3):363-70 (ISSN: 0300-0664)

Gilchrist FJ; Murray RD; Shalet SM
Department of Endocrinology, Christie Hospital, Manchester, UK.

BACKGROUND: Quality of life (QoL) is reduced in GH-deficient adults compared with the normal population. Further support for the role of GH in the maintenance of QoL is derived from short-term studies of GH replacement in severely GH-deficient adults; these have predominantly reported beneficial effects, although the degree of improvement has often been modest. To date, however, there are few data to demonstrate whether this beneficial effect on QoL is maintained in the long term.

PATIENTS AND METHODS: This study consisted of the follow-up of 85 GH-deficient adults who completed the Nottingham Health Profile (NHP) and the Psychological General Well-Being Schedule (PGWB) self-rating questionnaires in 1992, as part of a 12-month double-blind randomized study of GH replacement. In 2001 we attempted to contact all 85 patients and asked them to complete the two questionnaires again. Follow-up data were obtained in 61 patients. The findings were analysed according to whether the individual had received GH continuously since completion of the initial study, received no further GH replacement, or received GH replacement for only part of the intervening time. Both the NHP and the PGWB give a total score and subsection scores for six specific areas of QoL. A high score correlates with increased morbidity in the NHP, and with reduced morbidity in the PGWB.

RESULTS: Fifty-nine patients completed the NHP at both time points. The patients who continued GH (n = 17) had significantly greater morbidity at baseline than patients who opted to discontinue therapy (n = 27), as reflected by the higher scores overall (5.7 +/- 4.0 vs. 2.8 +/- 3.5; P = 0.01) and in the energy subsection (47.0 +/- 34.7 vs. 13.2 +/- 28.6; P < 0.001). Over the study period energy levels improved in the patients who remained on GH therapy (47.0 +/- 34.7 vs. 25.7 +/- 31.0; P = 0.04). By contrast, a deterioration in the physical mobility subsection (2.4 +/- 5.4 vs. 8.2 +/- 16.7; P = 0.04) occurred in the patients who did not continue GH therapy, and no change occurred in the energy subsection. In the 36 patients who completed the PGWB significant differences were observed at baseline between patients who received GH replacement continuously (n = 10) and those who discontinued therapy (n = 21) in the overall score (67.2 +/- 14.1 vs. 86.8 +/- 14.7; P = 0.001); and in the subsections for anxiety (P = 0.04), depression (P = 0.04), well-being (P = 0.001), self-control (P = 0.04) and vitality (P < 0.001); the greater morbidity at baseline being observed in the patients who continued GH replacement. In the patients receiving GH continuously for 9 years the vitality subsection score improved significantly (7.7 +/- 2.4 vs. 12.5 +/- 3.2; P = 0.003), whereas no change in vitality score occurred in patients who did not continue GH therapy. The change in the energy subsection of the NHP and vitality subsection of the PGWB over the 9 years of the study were significantly different between the patients who opted to continue GH replacement and those who discontinued therapy (P = 0.008 and P < 0.001, respectively).

CONCLUSION: During this 9-year study, small but significant declines in health were observed in GH-deficient adults who remained untreated. By contrast, the patients who received GH continuously experienced improvements in energy levels while all other areas of QoL were maintained. The beneficial effects of GH on QoL are therefore maintained with long-term GH replacement and obviate the reduction in QoL seen over time in untreated GH-deficient adults.

Clin Endocrinol (Oxf). 2000; 52(3):295-303 (ISSN: 0300-0664)

Davies JS; Obuobie K; Smith J; Rees DA; Furlong A; Davies N; Evans LM; Scanlon MF
Department of Medicine, University of Wales College of Medicine, Cardiff, UK.

OBJECTIVES: Adult GH deficiency (GHD) is associated with profound alterations in body composition, lipid profiles and quality of life which frequently improve after GH therapy. However, the beneficial effects of treatment are not derived by all and consequently some scepticism persists with regard to the use of GH therapy in adults. We assessed whether a 3-month therapeutic assessment with GH therapy could be used to determine which GHD adults should be treated over the longer term. We also assessed the continued prescription of GH by general practitioners (GPs) following the initial therapeutic assessment.

DESIGN: A three month open therapeutic trial of GH in GHD adults. Patients were treated with GH at an initial dose of 0.01 iU/kg/d, increased after 1 month to 0.015 iU/kg/d for males and 0.02 iU/kg/d for females. After completion of the three months the continued prescription of GH by the GPs was assessed. PATIENTS: All adult GHD patients were considered for GH therapy.Thirty-nine GHD adults wanted GH therapy (group 1) and their baseline characteristics such as age, duration of GHD, and IGF-1 concentration were compared with 24 subjects who declined to receive GH (group 2).

MEASUREMENTS: Measurements of body composition using bioelectrical impedance analysis, lipids and quality of life measured using a dedicated questionnaire were made before and after GH therapy. The response of the general practitioners to continued GH therapy after the initial therapeutic assessment was also noted.

RESULTS: Compared with subjects who declined GH therapy (group 2), subjects of group 1 were younger (46.4 +/- 14.4 vs. 54.2 +/- 15.7 years, P < 0.05) and had lower peak GH responses to provocative testing (1.4 +/- 2.1 vs. 2.9 +/- 2.7 mU/l, P < 0.001), though there were no differences between IGF-1 concentration (11.7 +/- 6.2 vs. 14. 2 +/- 7.9 nmol/l). Following three months of GH therapy, there were significant improvements in all measured parameters including increased free fat mass (50.2 vs. 52.4 kg, P < 0.005) and total body water (37 vs. 38.7 l, P < 0.005), reduced fat mass (31.6 vs. 29.8 kg, P < 0.005), reduced AGHDA score (7 vs. 4, P < 0.001) and reduced cholesterol (6.3 vs. 5.8 mmol/l, P < 0.001), LDL (4 vs. 3.33 mmol/l, P < 0.001) and cholesterol/HDL ratio (5.57 vs. 4.67, P < 0.001).IGF-1 concentrations were significantly increased following treatment (12 vs. 32.4 nmol/l). Six subjects decided to discontinue GH therapy, 2 before the end of the study due to potential drug-related side-effects and 4 subjects derived no benefit from treatment. Despite the demonstrable benefits of treatment for the remaining 33 GHD adults, 6 GPs refused to continue to prescribe GH therapy for reasons of lack of familiarity with the drug or advice from their health authority.

CONCLUSION: Patients who wanted GH therapy were usually younger and more severely GHD than counterparts who elect not to be treated. However, a therapeutic trial of GH therapy is required to distinguish those subjects who derive benefit from treatment. We have shown that three months of low dose GH therapy is a sufficient period to elicit significant beneficial responses in quality of life, body composition parameters and lipids for the majority of patients and appears to be a sufficient period for patients to decide whether they want longer term therapy. The initial therapeutic trial also provides the objective evidence for the general practitioners to decide upon the continued prescription of therapy. Despite the positive evidence provided by this study, a small minority of general practitioners still refuse to prescribe GH therapy.

Clin Endocrinol (Oxf). 2000; 53(1):99-106 (ISSN: 0300-0664)

Moorkens G; Berwaerts J; Wynants H; Abs R
Departments of Internal Medicine; Endocrinology, University Hospital Antwerp, Belgium.

OBJECTIVE: Previous studies have revealed that hormonal disturbances may accompany the chronic fatigue syndrome (CFS). Changes in the secretion of the pituitary-adrenal axis have been demonstrated, as well as abnormalities in the GH-IGF-I axis. However, data have not always been well characterized and were sometimes conflicting. The small number of CFS patients investigated in earlier studies may have played a role in the interpretation of the results.

SUBJECTS AND DESIGN: Hormonal testing was performed in 73 nonobese CFS patients and nonobese 21 age-and gender-matched healthy controls.We investigated GH, ACTH and cortisol responses to insulin-induced hypoglycaemia. In a subgroup of patients arginine and clonidine stimulation for GH was also performed. Nocturnal secretion of GH, ACTH and cortisol were determined. Serum levels of IGF-I, prolactin, TSH, and free thyroxine were also measured. Visceral fat mass was assessed by CT scanning.

RESULTS: GH response to insulin induced hypoglycaemia assessed by peak value (17.0 +/- 13.1 microg/l vs. 22. 1 +/- 9.8 microg/l; P = 0.01) and by AUC (450.0 +/- 361.3 microg/l vs. 672.3 +/- 393.0 microg/l; P = 0.002) was significantly decreased in CFS patients vs. controls. Nocturnal GH secretion assessed by GH peak value (5.4 +/- 3.7 vs. 9.0 +/- 5.1 microg/l; P = 0.44) and by AUC (34.4 +/- 20.2 vs. 67.4 +/- 43.1; P = 0.045) was also significantly impaired in CFS patients. Arginine and clonidine administration showed no differences in GH secretion between CFS patients and controls. In the CFS group, GH peak values were significantly higher after ITT than after arginine (P = 0.017) or clonidine (P = 0.001). No differences in serum IGF-I levels were found between CFS patients and controls. Except for a significantly lower nocturnal cortisol peak value, no differences were found in ACTH and cortisol secretion between CFS patients and controls. Significantly higher serum prolactin levels (7.4 +/- 4.7 microg/l vs. 4.4 +/- 1.3 microg/l; P = 0.004) and significantly higher serum TSH levels (1.6 +/- 1.0 mU/l vs. 1.0 +/- 0.4 mU/l; P = 0.011) were found in CFS patients. Serum free thyroxine was comparable in both groups. Visceral fat mass was significantly higher in CFS patients (86.6 +/- 34.9 cm2 vs. 51.5 +/- 15.7 cm2; P < 0.001).

CONCLUSIONS: We observed a significant impairment of GH response during insulin-induced hypoglycaemia and a low nocturnal GH secretion in CFS patients. These changes did, however, not lead to different concentrations in serum IGF-I. The clinical expression of this inadequate GH secretion can thus be questioned, although the alteration in body composition may be related to this relative GH deficiency. Significantly increased prolactin and TSH levels were found when compared to controls. These findings give support to the hypothesis of a decreased dopaminergic tone in CFS. Further investigations are required in order to identify specific adaptations within the neurotransmitter system in CFS and to determine the clinical importance of the impaired GH homeostasis.

Horm Res. 2001; 56 Suppl 1:55-8 (ISSN: 0301-0163)

Stabler B
Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, N.C. 27599-7160, USA. pedpsych@med.unc.edu

The relationship between growth hormone (GH) deficiency (GHD) and quality of life (QOL) is coming into sharper focus. Psychological studies of short GHD children referred for GH treatment sometimes show that they have a poor QOL, often due to their feelings of anxiety, depression, social isolation and difficulties maintaining attention. These difficulties may lead to low academic achievement and impoverished interpersonal skills, both of which impact on life satisfaction and productivity. Recent observations suggest that short children who are not referred for medical diagnosis do not experience the same problems. We have observed that after patients are started on GH therapy the incidence of behavioral problems declines to within normal limits on standardized psychometric tests.

Pediatric GHD patients are not generally followed closely after growth targets are achieved. Over the past 25 years, several observers have noted that many patients treated with GH in childhood report poor QOL during young adulthood despite achievement of acceptable height and replacement of necessary hormones. They appear, as a group, to be underemployed, often unmarried, and sometimes unhappy. Some have suggested that this may be due to their overprotected early childhood. We have examined a cohort of young adults treated with GH during childhood and found they exhibit symptoms of previously undetected psychiatric disorder. Anxiety, depression, panic disorder and obsessive compulsive disorder were found. Strikingly, the incidence of a particularly disabling anxiety disorder, social phobia, was detected in 38% of one of our groups. This disorder occurs in approximately 13% of the general population. Similar QOL outcomes have been reported in adults who became GHD in later life. We conclude that the spectrum of potential disabilities tied to GHD is broader than previously thought. Management of these patients should include consideration of QOL issues throughout their lifespan. Potential treatment strategies may include continuation of GH therapy as indicated, psychotropic medication, or psychosocial support and rehabilitation.

Clin Endocrinol (Oxf). 1997; 47(4):439-46 (ISSN: 0300-0664)

Wallymahmed ME; Foy P; Shaw D; Hutcheon R; Edwards RH; MacFarlane IA
Neuroendocrine Clinic, Walton Hospital, Liverpool, UK.

OBJECTIVE: Adults with GH deficiency complain frequently of low energy levels, emotional lability and mental fatigue resulting in a low perceived quality of life (QOL). Body composition is altered with increased fat mass and decreased lean body mass and muscle strength is reduced. The aims of this study were to determine the effects of replacement GH treatment on: (a) body composition and muscle strength and (b) QOL, using specifically selected and adapted measures.

DESIGN: A 12-month study (double-blind placebo-controlled for the first 6 months and open for the second 6 months) of GH replacement injections (0.125 iu/kg/week for the first month and 0.25 iu/kg/week for the following 5 months of each study period) in GH deficient adults on QOL, body composition and muscle strength. This was followed by an open study of a further 12 months' GH treatment assessing QOL and muscle strength. Finally, QOL was assessed after up to 3 years of GH replacement treatment.

PATIENTS: Thirty of the 32 adult patients with GH deficiency enrolled completed the initial 12-month study (10 male, mean age 33.5 years, mean (SD) stimulated serum GH response 3.0 mU/l (2.86)).Nineteen patients then opted to continue GH treatment. Of these, 13 patients were available for assessment after a further 12 months' and 24 months' treatment.

MEASUREMENTS: Health-related QOL was assessed using 2 specifically adapted scales for adults with GH deficiency: the Life Fulfillment Scale and the Impact Scale. In addition 4 other self-rating questionnaires were used: Nottingham Health Profile, Hospital Anxiety and Depression Scale, Self Esteem Scale and Mental Fatigue Scale. Body composition was assessed by DEXA and quadriceps muscle strength by measuring maximum voluntary contractions. RESULTS: In the initial 12 months' placebo-controlled study perceived energy levels increased after 6 and 12 months of GH treatment (P < 0.01 compared with baseline) in the patients receiving GH for the full 12-month period. There were no changes in energy levels throughout the study in the group receiving placebo for the first 6 months. Also small improvements in impact scores were found after 6 months of GH treatment (P < 0.05) but this was not sustained at 12 months. In both GH and placebo groups life fulfillment worsened after 6 months, but then improved to baseline values after 12 months. In the patients who persisted with GH replacement, energy levels continued to improve (at 2 years, P < 0.01 compared with baseline) but then fell (at 3 years, P = NS compared with baseline). A similar pattern was observed in emotional reaction scores. However, improvements in self-esteem were maintained (at 3 years, P < 0.05 compared with baseline). Body composition altered favourably over the initial 12-month study period with a significant increase in lean mass and decrease in fat mass in both groups after 6-12 months of GH. There were no changes in muscle strength in either group during the initial 12-month study. However, in the patients who were available for assessment after a further 12 months of GH treatment, muscle strength increased significantly (P < 0.02 compared with baseline).

CONCLUSION: GH replacement treatment for 6-12 months leads to significant improvements in body composition (DEXA) but longer-term treatment may be needed to increase muscle strength. Self-esteem scores improve and are maintained after 3 years of treatment. Energy levels and emotional reaction improve during treatment for up to 2 years but decline thereafter.

Arch Gen Psychiatry. 1990; 47(2):113-8 (ISSN: 0003-990X)

Jarrett DB; Miewald JM; Kupfer DJ
Department of Psychiatry, University of Pittsburgh, School of Medicine, Western Psychiatric Institute and Clinic, PA 15213.

Sleep onset is a powerful physiologic stimulus for growth hormone secretion. Difficulty falling asleep and poor sleep maintenance are prominent symptoms in patients with a major depressive disorder. Much of the disturbance in the sleep electroencephalograms of depressed patients occurs within the first half of the night, the time when growth hormone is usually secreted. Growth hormone secretion was measured during electroencephalographically monitored sleep in 38 patients with a recurrent major depressive disorder and 35 healthy control subjects. Before treatment, depressed patients had a statistically significant reduction in growth hormone secretion during sleep. This reduction, which persisted through treatment and recovery into the drug-free remitted state, may be a trait marker in patients with a recurrent depressive disorder.

Eur J Endocrinol. 2004; 151(3):325-32 (ISSN: 0804-4643)

Mahajan T; Crown A; Checkley S; Farmer A; Lightman S
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK.

OBJECTIVE: Some growth hormone deficient adults (GHDAs) have an impaired quality of life, which may improve with growth hormone (GH) treatment. The objective of our study was to make an in-depth psychiatric evaluation of patients with adult-onset (AO) and childhood-onset (CO) GH deficiency (GHD), and to assess the time course of changes in their quality of life and symptoms of depression in response to GH treatment.

DESIGN: The study design was a 4-month, double-blind, cross-over, placebo-controlled trial of GH therapy.

METHODS:We used a detailed psychiatric interview to characterise 25 patients with proven GHD at baseline. They were reassessed at monthly intervals during treatment with GH or placebo, using the Nottingham Health Profile and two well-recognised depression rating scales.

RESULTS: 11/18 (61%) of the patients with AO-GHD, but 0/7 of the patients with CO-GHD, were found to have atypical depression at baseline. There were significant improvements in the depression rating scale scores after 2 months of GH therapy, with significant improvements in emotional reaction and social isolation scores from 1 month, and in energy levels and sleep disturbance from 2 and 3 months respectively.

CONCLUSIONS: The results of our study confirm that a large proportion of GHDAs have unequivocal psychiatric morbidity, and suggest that a response to treatment can be seen after a short trial of GH therapy. We hypothesise that this rapid improvement of symptoms of atypical depression represents a direct central effect of GH therapy.

Psychoneuroendocrinology. 1996; 21(3):313-22 (ISSN: 0306-4530)

Deijen JB; de Boer H; Blok GJ; van der Veen EA
Department of Psychophysiology, Vrije Universiteit, Amsterdam, The Netherlands. jbd@psy.vu.nl

In order to establish whether reported psychological complaints in hypopituitary adults are related to growth hormone (GH) deficiency or other pituitary hormone deficiencies, emotional well-being and cognitive performance were evaluated in 31 men with multiple pituitary hormone deficiencies (MPHD) and in 17 men with isolated growth hormone deficiency (IGHD). Assessments included evaluation of somatic and psychological complaints, depression, fatigue, vigor, tension, state and trait anxiety, iconic memory, short-term memory, long-term memory and perceptual-motor skill. The control group consisted of 41 healthy men, matched for age. Growth hormone secretion was more severely impaired in MPHD than in IGHD patients. Despite oral replacement therapy, MPHD patients also had lower serum testosterone levels than IGHD subjects. The MPHD patients were found to have lower vigor scores, higher state anxiety scores, worse perceptual-motor skill and worse memory performance than controls.

In contrast, IGHD patients only showed subnormal memory performance. It was concluded, therefore, that the cognitive impairment in both MPHD and IGHD was related to GH deficiency. The subnormal vigor scores in MPHD patients were attributed to the reduced testosterone levels. The worse perceptual-motor skill in MPHD patients might be related specifically to ACTH deficiency. Finally, the higher state anxiety in MPHD was attributed to a low self-esteem, which may be the psychological consequence of the hypogonadal appearance these patients have. We conclude that, from a psychological point of view, MPHD and IGHD adult patients are quite distinct groups.

Psychoneuroendocrinology. 1998; 23(1):45-55 (ISSN: 0306-4530)

Deijen JB; de Boer H; van der Veen EA Department of Psychophysiology, Free University, Amsterdam, The Netherlands. jb.deijen@psy.vu.nl

The present study evaluates the effects of 2 years of growth hormone (GH) replacement therapy on psychological well-being and cognitive performance in adults with childhood-onset growth hormone deficiency (CO-GHD). A total of 48 GHD adult men (mean age: 27 years) were randomly assigned to one of four treatment groups: placebo treatment, or GH replacement in a dose of 1, 2, or 3 IU/m2, respectively. Placebo treatment was given for 6 months. Psychological assessments were made every 6 months. Assessments included somatic and psychological complaints, depression, fatigue, vigor, tension, state/trait anxiety, iconic memory, short-term memory, long-term memory and perceptual-motor skill. GH treatment was considered physiological if the observed insulin-like growth factor-I (IGF-I) levels were within the normal range. It was considered supraphysiological if serum IGF-I rose to a value exceeding the upper normal limit. During the placebo-controlled phase of the study the changes in memory performance were positively correlated to the GH induced changes in serum IGF-I concentration and, more weakly, to the daily GH substitution dose.

At 6 months memory only had improved in the group receiving supraphysiological GH treatment, but not in the group of patients who had a normalization of serum IGF-I. However, after 1 year of treatment a normalization of memory functioning was found in both groups of patients and this was preserved during the 2nd year of treatment. No changes were observed in psychological well-being and perceptual-motor skill. We conclude that GH replacement improves memory function in adults with CO-GHD. It has no effect on psychological well-being or perceptual-motor skill. Supraphysiological treatment accelerates the recovery of memory performance. However, the long-term effects are not different from those achieved with physiological GH replacement.

Clin Endocrinol (Oxf). 1990; 33(4):495-500 (ISSN: 0300-0664)

Aström C; Pedersen SA; Lindholm J
Department of Clinical Neurophysiology, University Hospital, Copenhagen, Denmark.

Eight patients with isolated growth hormone deficiency (IGHD), 20-30 years old were studied with polysomnography before and after 6 months of treatment with growth hormone (GH). During GH treatment total sleep time decreased and REM sleep time increased significantly. Delta sleep time (stage 3 + 4) did not change significantly. All patients reported improved well-being and none wished to discontinue the treatment with growth hormone. These findings suggest that GH has an effect on sleep. The effect of increased REM sleep in humans is incompletely understood, but sleep recordings may be one way of directly monitoring the effect of GH on the central nervous system.

J Urol. 2000; 164(6):2138-42 (ISSN: 0022-5347)

Becker AJ; Uckert S; Stief CG; Truss MC; Machtens S; Scheller F; Knapp WH; Hartmann U; Jonas U
Department of Urology, Hannover Medical School, Hannover, Germany.

PURPOSE: Treatment with recombinant human growth hormone in adult patients with growth hormone deficiency increases nitric oxide and cyclic guanosine monophosphate (cGMP). We examined the functional in vitro effects of recombinant human growth hormone on tissue tension and cyclic nucleotide levels of human corpus cavernosum and detected changes in growth hormone in the cavernous and peripheral blood during different phases of penile erection.

MATERIALS AND METHODS: Relaxant responses of human corpus cavernosum were investigated using the organ bath technique. Tissue levels of cGMP were determined by a specific radioimmunoassay after dose dependent exposition of isolated human corpus cavernosum strips to recombinant human growth hormone. In 35 healthy potent volunteers blood samples were obtained simultaneously from the corpus cavernosum and cubital vein during different functional conditions of the penis, including flaccidity, tumescence, rigidity and detumescence.Penile erection was induced by audiovisual and tactile stimulation. Serum growth hormone was determined by an immunoradiometric assay.

RESULTS: Recombinant human growth hormone elicited dose dependent relaxation of human corpus cavernosum strips in vitro. The relaxing potency of recombinant human growth hormone was paralleled by its ability to elevate intracellular levels of cGMP. In vivo the peripheral growth hormone serum profile of the respective penile conditions did not significantly differ from those of cavernous serum. The main increase in growth hormone to greater than 90% was determined during developing penile tumescence, followed by a transient decrease afterward.

CONCLUSIONS: These results suggest that penile erection may probably be induced by growth hormone through its cGMP stimulating activity on human corpus cavernosum smooth muscle.

J Clin Endocrinol Metab. 1999; 84(1):279-84 (ISSN: 0021-972X)

Janssen YJ; Doornbos J; Roelfsema F
Department of Endocrinology, Leiden University Medical Center, The Netherlands.

Adults with GH deficiency (GHD) suffer from muscle weakness, which can be caused by the frequently reported decrease in muscle mass. However, measurements of both muscle strength and mass of muscle tested are scarce in adults with GHD. The aim of the present study was, therefore, to investigate intrinsic muscle strength (strength expressed per muscle volume unit) in adults with GHD at baseline and after 52 weeks of recombinant human GH (rhGH) therapy given in low, more physiological doses. A second objective was to investigate the influence of GH on muscle bioenergetics in the resting muscle. Isometric and isokinetic quadriceps strengths were measured in 28 males with GHD and in healthy controls matched for age and height. Quadriceps mass, determined by magnetic resonance imaging, and muscle bioenergetics, determined by phosphorus nuclear magnetic resonance spectroscopy, were measured in 20 of 28 patients with GHD and in controls matched for age and height. All patients were treated with doses of rhGH ranging from 0.6-1.8 IU/day, given for 52 weeks. Measurements of muscle mass, strength, and bioenergetics were repeated after 52 weeks of treatment with rhGH.

The mean GH dose at 52 weeks of rhGH treatment was 1.3 +/- 0.8 IU/day. The mean serum insulin-like growth factor I level at baseline was 9.4 +/- 0.7 nmol/L and significantly increased to 26.4 +/- 1.2 nmol/L after 52 weeks of rhGH treatment. Adults with GHD had significantly reduced quadriceps muscle mass (P = 0.034) and reduced isometric muscle strength (P = 0.002) and tended to have low isokinetic muscle strength (P = 0.06), which all improved after rhGH therapy. Intrinsic muscle strength was not significantly different in adults with GHD compared with that in healthy controls and did not change during rhGH therapy. No bioenergetic abnormalities at baseline or after rhGH therapy were found in males with GHD. In conclusion, quadriceps muscle mass is decreased in adults with GHD and increased with rhGH therapy. These changes in muscle mass account for the changes in muscle strength found in these patients, as no changes in intrinsic muscle strength were found.

Clin Endocrinol (Oxf). 2004; 61(1):113-22 (ISSN: 0300-0664)

Elgzyri T; Castenfors J; Hägg E; Backman C; Thorén M; Bramnert M Department of Endocrinology, University Hospital, Malmo, Sweden. targ.elgzyri@skane.se

OBJECTIVES: To assess effects of GH replacement therapy on cardiac structure and function, exercise capacity as well as serum lipids in elderly patients with GH deficiency (GHD).

PATIENTS AND METHODS: Thirty-one patients (six females, 25 males), aged 60-79 years (mean 68 years) with GHD on stable cortisone and thyroxine substitution were studied. All men with gonadotropin deficiency had testosterone and one woman had oestrogen replacement. They were randomized in a double-blind manner to GH or placebo treatment for 6 months, followed by another 12 months GH (Humatrope, Eli Lilly & Co, Uppsala, Sweden). GH dose was 0.017 mg/kg/week for 1 month and then 0.033 mg/kg/week divided into daily subcutaneous injections at bedtime. Echocardiography, exercise capacity tests and serum lipid measurements were performed at 0, 6, 12 and 18 months.

RESULTS: During the 6-month placebo-controlled period there were no significant changes in the placebo group, but in the GH-treated group there was a significant increase in IGF-I to normal levels for age, with median IGF-I from 6.9 to 18.5 nmol/l, increase in resting heart rate and maximal working capacity. During the open GH study, IGF-I increased from 8.7 to 19.2 nmol/l at 6 months and 18.8 nmol/l at 12 months (P < months 12 after cholesterol HDL serum and ratio LDL of improvement significant by accompanied reduction with improved profiles Lipid parameters. noninvasive functional structural cardiac on effects negative without safe was therapy the Thus, improved. transiently capacity working Maximal changes no were there end At rate. heart in increase transient a only caused GHD patients elderly to substitution GH

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Vnitr Lek. 2005; 51(12):1356-64 (ISSN: 0042-773X)

Olsovská V; Siprová H; Bernek M; Soska V
II. interní - klinika Lékarské fakulty MU a FN u sv. Anny, Brno. vera.olsovska@fnusa.cz

A syndrome of growth hormone deficiency in adults (GHDA) is a syndrome characterised by metabolic deviations, body composition abnormalities, fatigue, decreased quality of life and some cardiovascular changes. The aim of the study was to assess the influence of the growth hormone (GH) replacement therapy on body composition, bone changes, serum lipids levels and some parameters of sugar metabolism in the course of 7-year monitoring. We followed 34 individuals of mean age of 41.73 +/- 2.49 years (mean +/- SE). Severe deficiency of GH was demonstrated by performing stimulation insulin tolerance test. Duration of treatment was 4.13 +/- 0.36 years (mean +/- SE). Patients were examined before the initiation of replacement therapy, after 6 months and further in yearly visits.

To determine a statistical level of significance in individual parameters we compared initial baseline status (before drug administration) with the status in individual time intervals. The body composition was examined by anthropometric methods, bioelectric impedance and by densitometry, bone changes were examined by means of DEXA. There were no statistically significant changes of weight, but the waist circumference significantly decreased (p < 0.05), as well as the sum of skinfold thickness (p < 0.05) within the whole treatment period. The percentage of body fat mass measured by the BIA method was significantly changed after the period of 3 years (p < 0.05). Upon the densitometrical measurement of the body composition a significant decrease in kilograms of body fat mass (FM) occurred in the first year of the treatment (p < 0.05) and an increase in lean body mass (LBM) in kilograms during our complete monitoring (p < 0.05).

A statistically significant increase in bone density was found in the whole-body BMD and BMC after the first year of the treatment. In the examination of peripheral bone changes a statistically significant increase in BMD occurred (expressed as a Z score) in the area of proximal femur after the first year and collum femoris after three years (p < 0.05), there was a significant increase in BMD of the lumbar spine already after one year of the treatment (p < 0.05) and changes were significant also in further four years. There were found no statistically significant changes related to the sugar metabolism. In the field of lipid metabolism a decrease of total and LDL cholesterol occurred already after a half of the year of the treatment (p < 0.05), changes were significant also in further four years. HDL cholesterol levels have had a progressive tendency, but they were not statistically significant. Positive changes of body composition, an increase in bone density and a decrease of total and LDL cholesterol were demonstrated in the course of the growth hormone replacement therapy.

J Clin Endocrinol Metab. 1999; 84(2):453-7 (ISSN: 0021-972X)

Pfeifer M; Verhovec R; Zizek B; Prezelj J; Poredos P; Clayton RN
Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center, Ljubljana, Slovenia.

Hypopituitary patients have increased mortality from vascular disease, and in these patients, early markers of atherosclerosis [increased carotid artery intima-media thickness (IMT) and reduced distensibility] are more prevalent. As GH replacement can reverse some risk factors of atherosclerosis, the present study examined the effect of GH treatment on morphological and functional changes in the carotid and brachial arteries of GH-deficient (GHD) adults. Eleven GHD hypopituitary men (24-49 yr old) were treated with recombinant human GH (0.018 U/kg BW x day) for 18 months.

IMT of the common carotid artery (CCA) and the carotid bifurcation (CB), and flow-mediated endothelium-dependent dilation (EDD) of the brachial artery were measured by B mode ultrasound before and at 3, 6, 12, and 18 months of treatment, and values were compared with those in 12 age-matched control men. Serum concentrations of lipids, lipoprotein(a), insulin-like growth factor I (IGF-I), and IGF-binding protein-3 (IGFBP-3) were also measured. In GHD men before treatment the IMTs of the CCA [mean(SD), 0.67(0.05) mm] and CB [0.75(0.04) mm] were significantly greater (P < 0.001) than those in control men [0.52(0.07) and 0.65(0.07) mm, respectively]. GH treatment normalized the IMT of the CCA by 6 months [0.53(0.04) mm] and that of the CB by 3 months [0.68(0.05) mm].

The IMT of the carotid artery (CCA and CB) was negatively correlated with serum IGF-I (r = -0.53; P < 0.0001). There was a significant improvement in flow-mediated EDD of the brachial artery at 3 months, which was sustained at 6 and 18 months of GH treatment (P < 0.05). GH treatment increased high density lipoprotein cholesterol at 3 and 6 months, but did not reduce total or low density lipoprotein cholesterol and was without effect on lipoprotein(a). There was no correlation between plasma lipids and changes in IMT or EDD of the arteries examined. In conclusion, GH treatment of hypopituitary GHD men reverses early morphological and functional atherosclerotic changes in major arteries and, if maintained, may reduce vascular morbidity and mortality. GH seems to act via IGF-I, which is known to have important effects on endothelial cell function.

J Clin Endocrinol Metab. 2002; 87(5):2121-7 (ISSN: 0021-972X)

Svensson J; Fowelin J; Landin K; Bengtsson BA; Johansson JO
Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. johan.svensson@medic.gu.se

The few trials in GH-deficient (GHD) adults that have investigated the long-term effects of GH-replacement therapy on insulin sensitivity have shown conflicting results. In this study, insulin sensitivity was determined using the hyperinsulinemic, euglycemic clamp technique in 11 GHD adults at baseline and after 6 months, 1 yr, 2 yr, and 7 yr of GH-replacement therapy. Furthermore, insulin sensitivity in the GHD patients was compared with that in 11 matched control subjects at baseline and with that in 11 other matched controls at study end. The mean initial GH dose was 1.10 mg/d. The dose was gradually lowered; and after 7 yr, the mean dose was 0.61 mg/d. A sustained reduction in body fat and a sustained increase in fat-free mass were observed.

Serum high-density lipoprotein-cholesterol (HDL-C) increased, and serum low-density lipoprotein-cholesterol (LDL-C) decreased, after 7 yr of treatment. Fasting blood glucose was transiently increased during the first year of GH replacement. The glucose infusion rate/body weight (GIR/BW), as measured using the hyperinsulinemic, euglycemic clamp technique, was unaltered during GH-replacement therapy. The comparisons with the control subjects revealed that GIR/BW in the GHD patients was 45% of that in the control subjects at baseline; whereas, at study end, the GIR/BW was 71% of that in the control subjects (P = 0.06 vs. baseline). This could suggest that GH-replacement therapy may prevent the age-related decline in insulin sensitivity in GHD patients.

Clin Exp Rheumatol. 2001; 19(1):81-4 (ISSN: 0392-856X)

Neidel J
Klinik für Orthopädie, Charité University Hospital, Schumannstrasse 20, D-10117 Berlin, Germany. jasper.neidel@charite.de

OBJECTIVE: To determine whether circulating levels of insulin-like growth factors and their binding proteins are altered in patients with adult onset rheumatoid arthritis.

METHODS: Plasma-levels of insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding-protein 2 (IGFBP-2), and IGFBP-3 were measured by radioimmunoassay in 53 patients with clinically active rheumatoid arthritis (RA) and in 51 control subjects.

RESULTS: In RA patients plasma levels of IGF-II were lower (601 +/- 34 vs. 731 +/- 32 micrograms/L (mean +/- SEM); p = 0.005; Mann-Whitney rank sum test) than in age- and sex-matched controls (n = 30 per group). In contrast, plasma levels of IGFBP-2 (412 +/- 40 vs. 254 +/- 20 micrograms/L; p = 0.003) and IGFBP-3 were elevated in RA patients (3.34 +/- 0.19 vs. 2.87 +/- 0.21 mg/L; p = 0.019) as compared with the matched controls. The molar ratio of IGF-I to IGFBP-3 was significantly reduced in subjects with RA (0.18 +/- 0.01 vs. 0.24 +/- 0.02; p = 0.008). Furthermore, in RA patients plasma levels of IGFBP-2 were positively (r = 0.45), and levels of IGF-2 negatively (r = -0.45) correlated with circulating levels of C-reactive protein (p < 0.01 in both cases; Spearman rank correlation).

CONCLUSION: Increased levels of IGFBPs in RA may result in the reduced availability of free IGFs that can bind to IGF receptors. The observed changes in the IGF system may thus participate in the catabolic processes in rheumatoid arthritis.

Int J Obes Relat Metab Disord. 2001; 25(8):1101-7 (ISSN: 0307-0565)

Nam SY; Kim KR; Cha BS; Song YD; Lim SK; Lee HC; Huh KB Division of Endocrinology, Department of Internal Medicine, YongDong Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. namsy16@yumc.yonsei.ac.kr

OBJECTIVE: To evaluate the effects of low-dose growth hormone (GH) therapy combined with diet restriction on changes in body composition and the consequent change in insulin resistance in newly-diagnosed obese type 2 diabetic patients. DESIGN: Double-blind and placebo-controlled trial of 25-kcal/kg IBW diet daily with GH (n=9; rhGH, 0.15 IU/kg body weight/week) or placebo (n=9) for 12 weeks.

SUBJECTS: Eighteen newly-diagnosed obese type 2 diabetic patients (age 42--56 y, body mass index 28.1+/-2.7 kg/m(2)).

MEASUREMENTS: Body composition and fat distribution parameters (by bioelectrical impedance analyzer and CT scans), serum IGF-1; serum glucose, insulin and free fatty acid (FFA) during oral glucose tolerance test (OGTT); HbA(1c); serum lipid profiles; and glucose disposal rate (GDR) by euglycemic hyperinsulinemic clamp at baseline and after treatment.

RESULTS: The fraction of body weight lost as fat lost was significantly greater (0.98+/-0.39 vs 0.52+/-0.32 kg/kg, P<0.05) and visceral fat area was decreased more in the GH-treated group compared to the placebo-treated group (27.9 vs 21.6%, P<0.05). Lean body mass and muscle area were reduced in the placebo-treated group, whereas an increase in both was observed in the GH-treated group. GDR the was significantly increased in only the GH-treated group (4.67+/-1.05 vs 6.95+/-0.91 mg/kg/min, P<0.05). The GH-induced increase in GDR was positively correlated with the decrease in the ratio of visceral fat area/muscle area (r=0.588, P=0.001). Serum glucose levels and insulin- and FFA-area under the curve during OGTT and HbA(1c) were significantly decreased after GH treatment. LDL-cholesterol level was decreased in only the GH-treated group.

CONCLUSION: Low-dose GH treatment combined with dietary restriction resulted not only in a decrease of visceral fat but also in an increase of muscle mass with a consequent improvement of the insulin resistance observed in obese type 2 diabetic patients.

Horm Metab Res. 2000; 32(2):66-70 (ISSN: 0018-5043)

Gómez JM; Gómez N; Fiter J; Soler J
Department of Endocrinology, Ciutat Sanitària i Universitària de Bellvitge, Barcelona, Spain.

BACKGROUND: Only few previous studies have assessed the effects of long-term growth hormone (GH) replacement therapy on bone mineral density (BMD) in adult patients with GH deficiency. The aim of this study was to investigate the effects of long-term GH therapy on bone metabolism and BMD.

MATERIAL AND METHODS: At the start of the study, 20 adults with GH deficiency were randomized to receive either GH, 0.25 IU x kg per week, or placebo. After 6 months, patients in the placebo group were switched to GH therapy, and they received GH for a further 18 months. Of the 20 patients, 14 were male and 6 female with GH deficiency of adult-onset. The mean age of the patients at the start of the study was 40.3+/-10.9 years and the duration of GH deficiency was 10.6+/-6.4 years. Patients deficient in pituitary hormones other than GH had been receiving stable replacement doses of appropriate hormones for at least 6 months before the start of the study. Rates of bone metabolism were assessed by measuring calcium, phosphate, alkaline phosphatase, calciuria, phosphaturia and osteocalcin. BMD was measured by dual X-ray absorptiometry. Body composition was calculated from measurements of bioelectrical impedance.

RESULTS: Before GH treatment, BMD in the femoral neck was lower in patients than in controls. The rate of bone resorption markers increased significantly after 6 months and remained stable during the whole treatment period. BMD significantly increased in L2-L4 after 12 months of treatment with an increase of Z-score. The total BMD increase was 4.5+/-6.5%. BMD in the femoral neck increased after 12 months with an increase of Z-score after 18 months. The total increase was 10.4+/-18%. The total BMD increase was not different among patients with or without basal osteopenia. In both groups BMD in L2-L4 and in the femoral neck remained stable after 12 months without GH treatment. Sex, age, BMI and the time in which GH deficiency started, before or after the end of the peak of BMD, did not correlate with BMD. The BMD values and their response to GH treatment did not correlate with other associated deficiencies, and we did not find differences among BMD increase and GH dose, levels of insulin-growth factor-I, insulin growth factor binding protein-3, and parameters of body composition.

CONCLUSIONS: The results of the study support previous ones that BMD is subnormal in adults with GH deficiency; that GH replacement therapy stimulates bone turnover with initial biochemical changes; and that in the long term, this stimulation results in a significant augmentation in BMD that continues to increase after 2 years and remains stable after 12 months of GH withdrawal.

Tech Urol. 2000; 6(3):236-9 (ISSN: 1079-3259)

Baffa R; Reiss K; El-Gabry EA; Sedor J; Moy ML; Shupp-Byrne D; Strup SE; Hauck WW; Baserga R; Gomella LG
Department of Urology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania 19107, USA.

PURPOSE: Insulin-like growth factor 1 (IGF-1) is an important mitogenic and antiapoptotic peptide that affects the proliferation of normal and malignant cells. Contradictory reports on the association between serum IGF-1 level and prostate cancer have been highlighted in the recent literature. The purpose of this study was to investigate the relation between serum levels of IGF-1 and prostate cancer.

MATERIALS AND METHODS: We analyzed a population of 57 patients who underwent radical prostatectomy (RP) for adenocarcinoma. Serum samples were collected before RP (T0), 6 months after RP (T6), and from 39 age-matched controls. IGF-1 levels were determined by the active IGF-1 Elisa kit (Diagnostic Systems Laboratories, Inc.). Parallel samples were evaluated for prostate-specific antigen (PSA) levels. Data between groups were analyzed using Welch's t-test and levels before RP and after 6 months were compared by paired t-test.

RESULTS: The normal mean serum IGF-1 for case patients at T0 (124.6+/-58.2 ng/mL) was significantly lower than the control subjects (157.5+/-70.8 ng/mL; p = .0192). The normal mean serum IGF-1 for case patients at T0 (124.91+/-58.6 ng/mL) also was significantly lower when it was compared with the T6 group (148.49+/-57.2 ng/mL; p = .0056). No association was found between IGF-1 and PSA blood levels, or IGF-1 and patient weight (p = 0.2434). An inverse relation between IGF-1 levels and age in the normal controls (p = .0041) was observed.

CONCLUSION: Findings of this study indicate a significant association between low serum levels of IGF-1 and prostate cancer.

Am J Physiol. 1992; 262(3 Pt 2):R426-31 (ISSN: 0002-9513)

Ng EH; Rock CS; Lazarus DD; Stiaino-Coico L; Moldawer LL; Lowry SF
Department of Surgery, New York Hospital-Cornell Medical Center, New York 10021.

Insulin-like growth factor I (IGF-I) has been implicated in the regulation and maintenance of skeletal muscle protein balance and thus may be of potential benefit in attenuating the cancer-cachectic process. To examine this hypothesis, 47 sham or tumor-implanted Fischer 344 rats were randomized to receive either continuous subcutaneous IGF-I (220 or 400 micrograms/day) or saline as control. In the tumor-bearing (TB) population, IGF-I-treated groups showed a dose-dependent increase in host weight gain (P less than 0.05), final carcass weight (P less than 0.05), and gastrocnemius muscle weights (P less than 0.05) and protein contents (0.50 +/- 0.02, 0.40 +/- 0.01, and 0.52 +/- 0.03 g/100 g host wt, for non-TB saline, TB saline, and TB 400 mg IGF-I groups, respectively; P less than 0.01, IGF-I vs. saline).

Similar increases in muscle RNA and DNA contents (P less than 0.01) were induced by IGF-I treatment (P less than 0.05). IGF-I treatment in this rat sarcoma model significantly reduced the proportion of aneuploid cells in the tumor (aneuploid-to-diploid ratio: TB saline 1.1 +/- 0.2 vs. TB IGF-I 0.5 +/- 0.1; P less than 0.05). IGF-I treatment attenuated host muscle protein and lean tissue depletion without stimulation of tumor growth. The tumor aneuploid population was reduced in response to IGF-I treatment. Thus IGF-I may be a potential therapeutic agent in cancer-induced cachexia.

J Clin Endocrinol Metab. 2003; 88(8):3664-7 (ISSN: 0021-972X)

Besson A; Salemi S; Gallati S; Jenal A; Horn R; Mullis PS; Mullis PE

Department of Paediatrics, University Children's Hospital, Inselspital, CH-3010 Bern, Switzerland.

Increased longevity of hypopituitary dwarf mice and GH- resistant knockout mice appears to be in contrast with observations made in clinical practice. In humans, on one hand hypopituitarism and GH deficiency (GHD) are believed to constitute risk factors for cardiovascular disease and, therefore, early death. But on the other hand, patients with a PROP-1 gene mutation, presenting with a combined pituitary-derived hormonal deficiency, can survive to a very advanced age, apparently longer than normal individuals in the same population. The aim of this study was to analyze the impact of untreated GHD on life span. Hereditary dwarfism was recognized in 11 subjects. Genetic analysis revealed an underlying 6.7-kb spanning deletion of genomic DNA encompassing the GH-1 gene causing isolated GHD. These patients (five males and six females) were never treated for their hormonal deficiency and thus provide a unique opportunity to compare their life span and cause of death directly with their unaffected brothers and sisters (11 males and 14 females) as well as with the normal population (100 males and females). Although the cause of death did not vary between the two groups, median life span in the GH-deficient group was significantly shorter than that of unaffected brothers and sisters [males, 56 vs. 75 yr (P < 0.0001); females, 46 vs. 80 yr (P < 0.0001)]. Therefore, with the wealth of information regarding the beneficial effects of GH replacement and the dramatic findings of this study, GH treatment in adult patients suffering from either childhood- or adult-onset GHD is crucially important.

J Clin Endocrinol Metab. 1988; 66(6):1119-23 (ISSN: 0021-972X)

Sukegawa I; Hizuka N; Takano K; Asakawa K; Horikawa R; Hashida S; Ishikawa E; Mohri Z; Murakami Y; Shizume K

Department of Medicine, Tokyo Women's Medical College, Japan.

Daily (24-h) urinary GH excretion was measured using a highly sensitive sandwich enzyme immunoassay in 10 normal adults, 6 patients with hypopituitarism, 25 normal but short children who had normal plasma GH responses (peak plasma GH level, greater than 10 micrograms/L) to provocative tests, and 8 patients with acromegaly. The mean urinary GH values in the normal adults, patients with acromegaly, and patients with hypopituitarism were 13.8 +/- 4.0 (+/- SE) and 431.1 +/- 149.1 ng/g creatinine (Cr) (1.56 +/- 0.45 and 48.77 +/- 16.87 ng/mmol Cr) and undetectable, respectively; these mean values were significantly different from each other. In the normal but short children the urinary values ranged from undetectable to 55.8 ng/g Cr (6.31 ng/mmol Cr). All of the normal but short children and 4 patients with hypopituitarism participated in a 24-h endogenous GH secretion study. The urinary GH values correlated significantly with the mean 24-h plasma GH concentrations as an index of endogenous GH secretion (r = 0.81; P less than 0.001) and plasma somatomedin-C levels (r = 0.67; P less than 0.001), respectively. In 6 patients with acromegaly whose plasma GH levels were constant throughout a 4-h period, the urinary GH values also significantly correlated with the mean plasma GH levels (r = 0.95; P less than 0.01). These data indicate that urinary GH measurements reflect endogenous GH secretion and that measurement of urinary GH excretion is a useful, simple, and practical method for evaluating endogenous GH secretion.

Eur J Endocrinol. 2003; 148 Suppl 2:S9-14 (ISSN: 0804-4643)

Monson JP

Department of Endocrinology, Division of General and Developmental Medicine, St Bartholomew's Hospital, West Smithfield, London ECIA 7BE, UK. J.P.Monson@qmul.ac.uk

Demonstration of the long-term efficacy of GH replacement in GH-deficient adults has depended on a combination of single-centre studies and data from large multinational databases, which, by virtue of their size, are likely to detect rare adverse events and also permit analysis of mortality rates. The Pharmacia International Metabolic Surveillance (KIMS) study (a pharmacoepidemiological survey of the safety and efficacy of GH replacement in adults, sponsored by Pharmacia) is currently the largest database, with information on over 8000 patients from a total of 27 countries. Abundant epidemiological evidence confirms that hypopituitarism is associated with premature mortality, with an increase in cardiovascular and cerebrovascular disease as a primary underlying cause. Central adiposity, hyperlipidaemia, insulin resistance, and diabetes mellitus are common in adults with hypopituitarism. GH replacement is associated with improvements in central fat mass and mean reductions in serum total and low-density lipoprotein cholesterol which may be additive to those achieved with hydroxymethylglutaryl-coenzyme A reductase inhibitors.

These beneficial effects are maintained for at least 2 Years after initiation of therapy, as are reductions in central adiposity, with similar benefits seen in men and women when the GH dose is titrated to achieve a serum IGF-I between the median and the upper end of the age-related reference range. Fasting plasma glucose and glycated haemoglobin increase, usually within the reference range, during prolonged GH replacement, but do not tend to rise further above baseline in subjects with pre-existing impaired glucose tolerance. Bone remodelling increases during GH replacement therapy, but indices tend to return to baseline within 5 Years of commencing treatment. Bone mineral density increases in men whereas, in women, improvement is limited to stabilisation of bone density.

Data from the KIMS study demonstrate that prolonged GH replacement is associated with a reduction in the number of patients requiring assistance with daily living and a significant reduction in sick leave and hospital admissions. GH replacement therapy improves psychological well-being, particularly in those patients with the greatest deficit prior to treatment, with improvement maintained beyond 6 Months of therapy and sustained during long-term follow-up. Data from the KIMS population show that there is no increase in the overall occurrence of de novo neoplasia or the rate of regrowth of primary pituitary tumours. There is an apparent increase in intracranial neoplasia, which may be an artefact of comparing a surveillance population with general population data. Unlike mortality in untreated hypopituitary GH-deficient patients, mortality in the KIMS study is currently similar to that predicted for the normal population.

Clin Endocrinol (Oxf). 1993; 39(4):417-25 (ISSN: 0300-0664)

Cohn L; Feller AG; Draper MW; Rudman IW; Rudman D

Department of Medicine, Medical College of Wisconsin, Milwaukee.

OBJECTIVE: We studied the relationship between plasma level of insulin-like growth hormone I (IGF-I), changes in lean body mass and in adipose mass, and adverse side-effects during human growth hormone (hGH) treatment of elderly men who had low IGF-I levels.

DESIGN: The first six months was a period of baseline observation. The subjects were then randomized into two groups so that during months 7-18, men in group I received hGH, and men in group II served as untreated controls.

SUBJECTS: Eighty-three overtly healthy elderly men, who were selected because their plasma IGF-I level was less than 0.35 units/ml. The men were randomly assigned in a ratio of three to one into group I (n = 62) or into group II (n = 21).

MEASUREMENTS: Plasma IGF-I level was measured monthly. Lean body mass and adipose mass were measured every six months.

RESULTS: Fifteen men left the study during the baseline period because of personal reasons or intercurrent medical events. In those who received drug (group I), there were a number of adverse reactions which could have been related to the hGH therapy: carpal tunnel syndrome 10, gynaecomastia 4, and hyperglycaemia 3. In total there were 27 dropouts from group I and two dropouts from group II after the six-month point, for a variety of medical and non-medical reasons, the majority probably not related to hGH therapy. During the hGH treatment of group I, plasma IGF-I increased from the range 0.10-0.35 units/ml into the range 0.5-2.2 units/ml. Among the 18 men who completed 12 months of hGH treatment without experiencing one of the three above-noted presumed hGH side-effects, mean and peak plasma IGF-I during treatment were significantly lower than among the 13 men who experienced carpal tunnel syndrome or gynaecomastia (one subject had both) while on hGH. With one exception, neither carpal tunnel syndrome nor gynaecomastia occurred in any individual with a mean IGF-I level less than 1.0 units/ml during hGH treatment. Twelve months of hGH treatment (group I) caused an increase in lean body mass to 106% of the initial baseline (month one of the protocol), and a reduction in adipose mass to 84% of the baseline. Meanwhile, the lean body mass of the untreated men in group II declined to 97% of the initial baseline. The body composition responses after 12 months of treatment in group I were larger in the men whose mean intra-treatment IGF-I level was 0.5-1.0 units/ml, than in the men whose mean intra-treatment IGF-I level was 1.0-1.5 units/ml.

CONCLUSIONS: These observations show that when elderly men with low circulating IGF-I concentrations are treated continuously with hGH, elevation of plasma IGF-I above 1.0 units/ml is associated with a substantial frequency of carpal tunnel syndrome or gynaecomastia. It may be that the effects of the hormone in expanding lean body mass and reducing adipose mass can be achieved, and the side-effects avoided, by maintaining the mean IGF-I level in the range 0.5-1.0 units/ml.

J Clin Endocrinol Metab. 2004; 89(7):3306-12 (ISSN: 0021-972X)

Svensson J; Bengtsson BA; Rosén T; Odén A; Johannsson G

Research Centre for Endocrinology and Metabolism, Gröna Straket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. Johan.Svensson@medic.gu.se

A retrospective comparison was performed between 1411 hypopituitary adults without GH replacement [mean age, 56.9 (sd 18.6) yr] and the normal population in terms of fatal and nonfatal morbidity. A similar prospective comparison was then made in 289 hypopituitary patients on long-term GH replacement [mean age, 47.6 (sd 14.8) yr; mean duration of GH treatment, 60 months].In the 1411 hypopituitary patients without GH replacement, overall mortality (P < 0.001), and the rates of myocardial infarctions (P < 0.01), cerebrovascular events (P < 0.001), and malignancies (P < 0.001) were increased compared with the normal population. Colorectal cancer was the most common malignancy in this cohort (P < 0.001 vs. the background population).

In the 289 hypopituitary patients on GH replacement, overall mortality and the rate of malignancies were similar to the normal population. In the hypopituitary adults on GH therapy, the rate of myocardial infarctions was lower than that in the background population (P < 0.05), and there was a tendency toward an increased rate of cerebrovascular events.In conclusion, overall mortality and the rate of myocardial infarctions were increased in hypopituitary patients without GH replacement. An increased rate of malignancies was observed in the hypopituitary adults without GH therapy, with a predominance of colorectal cancer. GH replacement appeared to provide protection from myocardial infarctions. The rate of cerebrovascular events tended to be increased also in hypopituitary adults on GH therapy.