Gender difference in insulin-like growth factor I response to growth hormone (GH) treatment in GH-deficient adults: role of sex hormone replacement

GH production in healthy women is about thrice that in men. Yet insulin-like growth factor I (IGF-I) levels are similar, suggesting a lower responsivity to GH in women. In untreated GH-deficient adults, basal IGF-I levels are reportedly lower in females than in males, and the therapeutic recombinant human GH (rhGH) dose required to achieve optimal IGF-I levels is higher in the former, suggesting a pivotal role of estrogens on rhGH requirement in GH-deficient patients. We, therefore, analyzed our 2-yr data on the effect of rhGH on serum IGF-I in 77 GH-deficient patients (33 men, mean +/- SD age, 37.2 +/- 13.8 yr; 44 women, mean +/- SD age, 36.9 +/- 11.9 yr) with due attention to gender differences and to the effects of sex hormone replacement. Of the 44 women, 33 had estrogen substitution. Of the 33 men, 23 were on androgen replacement. Patients (11 premenopausal women and 10 men) not on hormonal replacement were eugonadal. Basal IGF-I levels in untreated GH-deficient women were significantly lower than in men (8.8 +/- 0.7 nmol/L vs. 12.2 +/- 0.9 nmol/L; P < 0.01), despite similar basal GH levels. The daily rhGH dose per kg body weight required to normalize IGF-I in women was higher than in men, the difference being statistically significant at all time points (P < 0.05-0.01). The IGF-I increase (delta) per IU GH/day x kg over the 24-month period was about twice higher in men than in women. Also calculated on a weight basis, rhGH responsivity (rhGH responsivity = (deltaIGF1(nmol/L)/dose (IU/day/kg)) was higher in men than in women at all time intervals (P < 0.05-0.01). Estrogen replacement in women significantly increased rhGH requirement. The rhGH dose per kg body weight required in estrogen-substituted women was significantly higher than in nonestrogen-substituted women (P < 0.01 at t = 18 and 24 months, respectively). In women on estrogen substitution, rhGH responsivity plateaued from 6 months on, whereas in eugonadal women without estrogen substitution the responsivity for rhGH increased over time. In men, the reverse was true; rhGH responsivity increased over time in men on androgen substitution, but plateaued in men without androgen substitution. The mechanisms underlying this gender difference are not known. Differential influences of estrogens and androgens on the expression of the GH receptor gene and IGF-I messenger RNA may be operative. The present study confirms short-term data published in the literature on a sex difference in rhGH dose requirement in GH-deficient patients. It furthers extends the data by demonstrating that this sex difference in GH responsivity persists and changes during the 24 months of the study. Moreover, it shows that estrogen replacement blunts the IGF-I response to rhGH in women, whereas in men with androgen substitution the responsivity increases over time, thus bearing a risk of undertreatment in women and overtreatment in men.     

Acromegalic features in growth hormone (GH)-deficient patients after long-term GH therapy

BACKGROUND: Craniofacial, hand, foot and somatic growth depend on normal GH secretion. Acromegalic features have been described in children with GH insensitivity after IGF-I treatment. We observed patients with acromegalic features such as increase of foot size, nose and jaw enlargement among our cases with GH deficiency, treated with standard recombinant (rh)GH doses. The aim of our study was to analyse the possible factors involved in the development of acromegalic features in these patients. PATIENTS: We evaluated 21 patients, 17 with combined pituitary hormone deficiency and four with isolated GH deficiency treated with rhGH (0.05-0.15 U/kg/day, sc, at night) for 2-12 years who achieved final height. IGF-I and IGFBP-3 were measured before and every 6 months during therapy and bone age was evaluated yearly. At the end of therapy, patients' hand and foot sizes and height were measured and plotted on nomograms for hand according to height and age, and foot size according to height. Lateral radiographs of the face were performed to obtain the linear measurement of the lower jaw length. RESULTS: Foot size was greater than 97th percentile in 8/21 patients and lower jaw length was greater than +2SD in 4/21 patients. Patients were classified in two groups: group 1 (with foot size greater than 97th percentile and/or lower jaw length greater than +2SD) consisted of 11 patients (six females); nine had combined pituitary hormone deficiency (six associated to hypogonadotrophic hypogonadism) and three had isolated GH deficiency; group 2 (with foot size smaller than 97th percentile and lower jaw length less than +2SD) consisted of 10 patients (seven boys); nine had combined pituitary hormone deficiency (six associated to hypogonadotrophic hypogonadism) and one with isolated GH deficiency. During treatment, IGF-I levels ranged from < or = 3 to +2SD and IGFBP-3 levels ranged from -3 to +2SD, in both groups. We observed no statistically significant differences between the two groups regarding chronological age, bone age, height at the beginning and at the end of therapy, pubertal development, duration of rhGH treatment and IGF-I and IGFBP-3 levels (P > 0.05). Foot size percentile exceeded final height percentile in 11/21 patients (seven girls). CONCLUSION: Long-term rhGH treatment with standard doses might be associated with acromegalic features (increased foot size and lower jaw measurements) in patients with GH deficiency who achieved final height, especially in girls. Neither the clinical nor the hormonal parameters, IGF-I and IGFBP-3 levels, were useful to predict the development of these features. Further studies are necessary to analyse the frequency of this side-effect and how to prevent it.     

Sex difference in human growth hormone (GH) response to intravenous human pancreatic GH-releasing hormone administration in young adults

Intravenous administration of a 100-micrograms dose of human pancreatic GH-releasing hormone (human pancreatic GHRH1-44, indicated by GHRH) disclosed a sex difference in GH responsiveness. The maximum GH increments [41 +/- 11 (SEM) vs. 15 +/- 4 ng/ml, P* less than 0.05] and the areas under the curves (419 +/- 105 vs. 148 +/- 53 area U, P* less than 0.05) were significantly higher in 12 men than in 10 women. No significant correlation was found in either group between the basal plasma estradiol or testosterone levels and the maximum or integrated GH response to GHRH. Serum PRL levels significantly increased in both groups within 5 min after GHRH injection (men, P less than 0.001 vs. t = 0; women, P less than 0.05 vs. t = 0). The areas under the curves of the PRL responses (355 +/- 184 vs. 189 +/- 73 area U) and the maximum PRL increments (58 +/- 18 vs. 36 +/- 6 mU/l, P* greater than 0.10) were similar. In conclusion, a sex difference in GH responsiveness to GHRH was found between young adult men and women. Recent in vivo and in vitro data reveal a similar sex difference in rodents and an enhancing effect of androgens, but not estrogens, on the GH response to GHRH. These findings support the theory that in humans testosterone also plays a key role in the genesis of this sex difference.     

Exercise training benefits growth hormone (GH)-deficient adults in the absence or presence of GH treatment

Reduced aerobic capacity is a prominent manifestation among patients with GH deficiency (GHD). Exercise training may improve the physiological capacity to undertake aerobic activity. The ability of patients with GHD to participate in and benefit from a structured program of aerobic exercise with or without replacement recombinant human GH (rhGH) was investigated. We examined the effect of aerobic training on cycle ergometers in a double-blind crossover trial. Ten patients with GHD trained for 3 months with rhGH (6 microg/kg.d) or placebo, stopped both exercise and drug for 2 months, and resumed training for another 3 months with the other agent. Peak oxygen uptake (VO(2)peak) and ventilation threshold (VeT) were measured during a progressive cycle ergometer test to fatigue or symptom-limited maximum. Serum IGF-I levels were monitored to assess compliance with GH treatment. VO(2)peak was low at the two baseline measures (B1, 19.3 +/- 5.5; B2, 19.9 +/- 6.9 ml/kg.min; normal, approximately 30 ml/kg.min) as was VeT (B1, 11.6 +/- 2.2 ml/kg.min; B2, 11.7 +/- 2.6 ml/kg.min; normal, approximately 16 ml/kg.min). Exercise training increased VeT with (8.6%) or without (9.4%) rhGH treatment. Similarly, exercise training resulted in significant reduction in submaximal heart rate in the presence (-5 +/- 4 beats per minute; P < 0.05) or absence of rhGH treatment (-4 +/- 4 beats per minute; P < 0.05). Peak oxygen uptake was not significantly affected by training with or without rhGH treatment. Our findings suggest that exercise training is a feasible intervention in GH-deficient adults that can measurably improve their submaximal responses to exercise. The beneficial effects of exercise can mimic and are not additive to the effects of GH treatment alone.     

Sleep apnoea and quality of life in growth hormone (GH)-deficient adults before and after 6 months of GH replacement therapy

OBJECTIVE: To investigate the sleep architecture and breathing as well as quality of life (QoL) in adults with GH deficiency (GHD) before and 6 months after GH replacement therapy. DESIGN: A prospective observational study. PATIENTS: Nineteen consecutive adults with GHD (11 men, eight women; mean age 53, range 21-73 years) were studied. MEASUREMENTS: An overnight sleep study was performed and the Minor Symptom Evaluation Profile (MSEP), Functional Outcome of Sleep Questionnaire (FOSQ), Short Form 36 (SF-36) and Epworth Sleepiness Scale (ESS) questionnaires were applied at baseline and after the treatment period. RESULTS: For the whole group, there were no significant changes in mean total sleep time (TST; 370 min vs. 374 min), proportion of slow-wave sleep (SWS; 17.8%vs. 18.4%) and rapid eye movement (REM) sleep (12.1%vs. 13.9%) on GH replacement. Mean apnoea-hypopnoea index (AHI) was high and remained unchanged (28.2/h before vs. 28.0/h following GH replacement). Twelve patients (63%) were found to have obstructive sleep apnoea (OSA; AHI >or= 10/h) at baseline. Compared with GH-deficient patients without OSA (AHI 3.9/h), the OSA patients (AHI 42.4/h) had less SWS (11.4%vs. 28.6%, P = 0.010) and REM sleep (10.1%vs. 15.5%, P = 0.036). A marginal increase was observed in REM sleep time (10.1% before vs. 12.7% after GH; P = 0.048) while SWS was unchanged in this group. Moreover, MSEP for General Well-being and Responsiveness, FOSQ scores for General Productivity, Activity Level and Vigilance as well as SF-36 domains for Vitality and Mental Health were improved. CONCLUSIONS: Contrary to some previous observations in a smaller group of patients, our data suggest that GH therapy does not induce or aggravate OSA in GH-deficient adults. Moreover, GH therapy may improve some of the QoL dimensions in these patients.     

The characteristics of quality of life impairment in adult growth hormone (GH)-deficient survivors of cancer and their response to GH replacement therapy

We studied 50 (27 women and 23 men) GH-deficient (GHD) cancer survivors and 47 (24 women and 23 men) GHD patients with pituitary pathologies. All GHD patients were considered for GH replacement on the basis of subjectively poor quality of life (QOL). Primary outcome measures were scores of QOL instruments psychological general well-being schedule (PGWB) and assessment of GH deficiency in adults (AGHDA) at baseline and early (6-13 months) and long-term (24-77 months) treatment follow-up. Of secondary interest were six PGWB domains. Linear mixed effect regression was used to model each QOL outcome. The groups differed with respect to three covariates: age, gender, and body mass index. These variables were included in all fitted models. Baseline scores for PGWB and AGHDA were not different between groups. Ranking of PGWB domains were similar between groups at baseline (lowest domain, vitality). The pattern of change in mean scores for all outcome measures from baseline did not differ between groups (P = 0.86). All QOL variables improved significantly with treatment [estimated mean change +/- se: PGWB, 16.2 +/- 1.7; AGHDA, -6.2 +/- 0.6; PGWB domains (transformed percentage scales): anxiety, 12.4 +/- 1.7; depression, 14.1 +/- 2.1; health, 12.4 +/- 1.7; self-control, 11.3 +/- 2.0; well-being, 15.2 +/- 1.7; vitality, 22.5 +/- 2.0 (vitality, greatest change)]. There was no evidence of group difference in early follow-up or long-term follow-up means for any outcome variable. The QOL in adult GHD cancer survivors was comparable to that in GHD adults with pituitary pathologies and improved with GH replacement in a similar manner. We conclude that QOL impairment in adult GHD cancer survivors appears mainly related to GHD rather than cancer diagnosis and treatment.     

Clinical implications of residual growth hormone (GH) response to provocative testing in adults with severe GH deficiency

CONTEXT: The diagnosis of GH deficiency (GHD) in adults is based on provocative tests of GH release, all influenced by clinical factors. It is unknown whether the amount of residual GH reserve under the cutoff value has any physiological implication. OBJECTIVES: We used a large pharmacoepidemiological database of adult GHD (KIMS) and tested the impact of confounding factors on GH release of no greater than 3 microg/liter after an insulin tolerance test (ITT) and evaluated its potential physiological role. DESIGN, SETTINGS, AND PATIENTS: A total of 1098 patients fulfilled the criteria of having a GH peak of no greater than 3 microg/liter during ITT as well as documented IGF-I levels. OUTCOMES: The impact of underlying hypothalamic-pituitary disease, age, gender, body weight, as well as treatment modalities such as irradiation on peak GH level to ITT was evaluated, and the correlations between GH peak and targets of GH action were analyzed. RESULTS: The GH response to ITT was regulated by gender, age, and the number of additional pituitary deficiencies. In a multivariate evaluation, the extent of hypothalamic-pituitary dysfunction was the most important single predictor of GH peak in ITT. GH peaks in ITT were positively related to IGF-I levels and high-density lipoprotein-cholesterol, as well as inversely to triglycerides. CONCLUSIONS: Even in adult severe GHD, GH release appears to be regulated by factors defined to play an important role in normal GH secretion. The impact of very low GH release on IGF-I and lipid parameters indicates a persistent physiological role of low GH concentrations in severely affected patients with GHD.     

Impaired growth hormone (GH) response to GH-releasing hormone in thalassemia major

The response of GH to acute administration of GH-releasing hormone (GHRH) was evaluated in 19 patients with thalassemia major and 8 normal children. In 13 of the 19 patients, GHRH induced a definite increase (greater than 5 ng/ml) in plasma GH levels, with peaks occurring 5-45 min postinjection. In 6 patients there was little or no GH rise after GHRH treatment. Overall, the mean GH response to GHRH of patients with thalassemia was lower than that of normal children. These data indicate that in thalassemia major, in addition to the described defect at the hepatic GH receptor or postreceptor level which impedes generation of somatomedins, there may be a marked impairment in somatotroph function. In one patient in whom the GH response to GHRH was superimposable on that of normal subjects, there was a blunted GH response to insulin hypoglycemia. This finding indicates that functional damage in hypothalamic structures for GH control can also occur in thalassemic patients.     

Calcitonin suppresses growth hormone (GH) response to growth hormone-releasing hormone (GHRH) in man

Calcitonin (CT) receptors have been found in the hypothalamus, suggesting a neuroendocrine role for this peptide. We have recently shown that, in the rat, central administration of salmon calcitonin (sCT) suppresses basal and GHRH-stimulated GH secretion. To further investigate how sCT alters GH secretion, we studied the effects of sCT (100U MRC, im) or placebo on basal and GHRH (50 micrograms, iv)-stimulated GH secretion in 6 normal men. GHRH was administered 1 h after sCT injection. Basal GH levels were not altered by sCT administration. However, GH response to GHRH was markedly suppressed by sCT (area under the curve - sCT: 574.6 +/- 69.7 vs placebo: 1057.2 +/- 284.8 micrograms. min/L; p less than 0.02). Cortisol levels were higher in sCT-treated subjects compared to controls, from 45 to 105 min after sCT injection (p less than 0.05). However, no correlation was found between GH response to GHRH and cortisol levels. No changes in glucose, calcium and PTH levels were seen. These results demonstrate that sCT inhibits GHRH-induced GH secretion in man by a mechanism apparently independent of changes in peripheral cortisol, glucose, calcium and PTH levels.     

Suppression of the growth hormone (GH) response to clonidine and GH-releasing hormone by exogenous GH

GH release in response to clonidine and human GH-releasing hormone-(1-44) (hGHRH-44) was assessed in 11 boys (aged 7-14 yr) with short stature, who had normal GH secretion. The response to these 2 provocative stimuli was repeated after, respectively, 2 and 3 days of treatment with human GH (0.1 U/kg, im). Exogenous GH significantly blunted the response to both clonidine [the mean 2-h integrated serum GH concentration falling from 1050 +/- 350 (+/- SEM) to 749 +/- 297 ng/ml X min; P = 0.03] and hGHRH-44, the 2-h integrated GH concentration falling from 1553 +/- 358 to 547 +/- 202 ng/ml X min; (P = 0.03). Plasma insulin-like growth factor (IGF-II) concentrations did not change after GH administration. In contrast, plasma IGF-I (somatomedin-C) concentrations increased from 97 +/- 16 ng/ml before administration of GH to 142 +/- 32 ng/ml (P = 0.05) after two days and 149 +/- 23 ng/ml (P less than 0.01) after the third treatment day. However, no correlation was found between the changes in response to clonidine or hGHRH-44 and changes in circulating levels of IGF-I. Our data confirm the existence of GH-dependent feedback inhibition of GH release during childhood and suggest that this inhibition operates, at least in part, at the level of the pituitary. While participation of the IGFs/somatomedins in this feedback loop cannot be excluded, the inhibitory effects of exogenous GH do not depend directly on circulating plasma IGF-I or IGF-II levels.     

Gender differences in the effects of long term growth hormone (GH) treatment on bone in adults with GH deficiency.

We recently observed that among patients with GH deficiency due to adult-onset hypopituitarism, men responded with a greater increase in serum levels of insulin-like growth factor I (IGF-I) and biochemical markers of bone metabolism than women when the same dose of recombinant human GH (rhGH) per body surface area was administered for 9 months. In the present study, 33 of the 36 patients in the previous trial (20 men and 13 women) continued therapy for up to 45 months. The dose of rhGH was adjusted according to side-effects and to maintain serum IGF-I within the physiological range. This resulted in a significant dose reduction in the men; consequently, the women received twice as much rhGH as the men (mean +/- SD, 1.9 +/- 1.1 vs. 1.0 +/- 0.6 U/day; P < 0.01). The increases in serum IGF-I levels and serum biochemical markers of bone metabolism were similar in men and women with these doses. The total bone mineral content (BMC) was increased after 33 and 45 months of treatment up to 5.1% (P = 0.004 and 0.0001). Bone mineral density (BMD), BMC, and the area of the femoral neck and the lumbar spine were also significantly increased after 33 and 45 months of treatment. When analyzed by gender, total body BMC, femoral neck BMD and BMC, and spinal BMC were significantly increased in males, but not in females (P < 0.05-0.01). In conclusion, rhGH treatment continued to have an effect on bone metabolism and bone mass for up to 45 months of therapy. The changes in bone mass were greater in the men, although they received lower doses of rhGH than the women. The results indicate that the sensitivity to GH in adult patients with GH deficiency is gender dependent.     

Effect of dexamethasone on growth hormone (GH) response to growth hormone releasing hormone in acromegaly

The effect of dexamethasone on the GH response to GH-releasing hormone (GHRH) was studied in vivo in six patients with acromegaly as well as in vitro in monolayer cultures of GH-secreting pituitary tumor cells obtained from three of these patients. Oral administration of 9 mg/day dexamethasone for 2 days decreased plasma GH responses to iv injection of 100 micrograms GHRH-(1-44 amide) in all six patients. Blood glucose levels were significantly increased, while plasma somatomedin-C levels were significantly decreased by this regimen of dexamethasone treatment. On the other hand, 2-day pretreatment with 50 nM dexamethasone of monolayer cultures of pituitary adenoma cells potentiated GH release basally and/or in response to 100 pM to 1 nM GHRH in vitro. These results indicate that the potentiating action of 2-day treatment of dexamethasone in vitro is overwhelmed in vivo by some extra-pituitary action, probably on the central nervous system, of glucocorticoids in patients with acromegaly.     

Amino acid profiles in adults with growth hormone (GH) deficiency before and during GH replacement therapy

ObjectiveGH replacement to growth hormone deficient (GHD) adults improves body composition. In a subset however, lean body mass (LBM) fails to increase despite normalization of IGF-I and amino acid availability could be of importance. We analyzed amino acid (AA) profiles in plasma and erythrocytes (RBC) and associations with LBM, serum IGF-I and IGFBP-1 before and during GH replacement.Design and methodsExaminations were performed in 15 GHD patients (six women), aged 34–61 yrs before and after 12 months of GH therapy and in a control group of 20 healthy males aged 31–68 yrs. LBM was measured by dual energy X-ray absorptiometry (DXA), free AAs in plasma and RBC by high performance liquid chromatography and serum IGF-I and IGFBP-1 by in-house RIAs.SettingTertiary care referral centre.ResultsAt baseline, female GHD patients tended to have lower concentrations of the essential branched – chain AAs isoleucine and leucine, total essential AAs, and of the non-essential AA glutamine than the male patients. Male GHD patients tended to have higher plasma and RBC glutamate than controls. At 12 months, IGF-I had normalized in all but one patient and mean LBM gain was 1.9 ± 0.4 kg. AA levels were unchanged. The change in LBM at 12 months was positively correlated to the ratio between the sum of isoleucine, leucine and valine and baseline LBM kg/m² (r = 0.76, p = 0.001, n = 15).ConclusionOur results suggest that the essential branched-chain amino acids in plasma are important for the LBM response to GH substitution. Our finding has to be confirmed in larger groups of GHD adults before making a proper selection of AAs to be measured in plasma and added as dietary supplement during GH therapy. GH administration did not change AA levels and measurements are not useful for monitoring of GH therapy at the time being.     

Insulin-like growth factor I levels during growth hormone (GH) replacement in GH-deficient adults: a gender difference

To evaluate the variation of serum IGF-1 levels during GH replacement and observe gender differences, 29 adults with GH deficiency (mean age 42.5 ± 10.1 year), were studied. Serum IGF-1 was assessed every 4 weeks during the titration period and afterwards every 3 months of GH therapy. At baseline 77.7% of women and 45.4% of men had serum baseline IGF-1 levels below the lower limit of normal age-related reference range. The time to reach the maintenance dose was lower in men than women (p < 0.05). There was an increase in IGF-1 levels after one year of GH therapy, significant only in men (p < 0.01). IGF-1 concentrations were higher in men than women (p < 0.05), at the 12th and 18th months of GH therapy. GH dose was reduced by 25% in men (p < 0.01). At the end of the study the mean GH dose was lower in men than in women (p < 0.05). The factor responsible for these findings is not known, however a possible role of androgens has been suggested.