Impaired GH Secretion Research Articles

Factors affecting growth hormone treatment in short stature children born small for gestational age in China: a single-centre, real-world study.

The study aimed to evaluate the factors influencing recombinant human growth hormone (rhGH) treatment in Chinese children with short stature born small for gestational age (SGA). A single-centre, real-world retrospective study was conducted in short stature children born SGA in China. Outcomes were observed at 6, 12, 18, 24, 30, and 36 months. Outcome measures included height standard deviation score (HTSDS), height, growth velocity (GV), and change of HTSDS (ΔHTSDS). The study used the generalized estimating equation (GEE) to identify potential influencing factors, such as rhGH treatment duration, age at rhGH initiation, sex, 11p15 hypomethylation, GH secretion, and birth weight. A subgroup analysis was conducted to investigate the impact of 11p15 hypomethylation related to SGA or impaired GH secretion. Of all 101 SGA patients included in the screening, 41 were eligible for inclusion in the study. The mean age at rhGH initiation was 5.6 ± 2.4 years. The results of the GEE analysis showed a significant association between time after rhGH initiation and HTSDS, height, GV, and ΔHTSDS. GV increased after treatment, with the highest increase observed in the first six months. Additionally, the study found negative correlations between 11p15 hypomethylation and GV, as well as between birth weight and both GV and ΔHTSDS. The study found a positive correlation between impairment in GH secretion and both GV and ΔHTSDS. No statistically significant difference was observed in the comparison of GV or ΔHTSDS between the initiation age of GH treatment and 11p15 hypomethylation. After 24 and 30 months of rhGH treatment, patients with impaired GH secretion had significantly higher ΔHTSDS scores. In short stature Chinese children born SGA, those without SGA-related 11p15 hypomethylation or with impaired GH secretion showed better response to rhGH treatment. These findings highlight the importance of pre-treatment evaluation, including genetic and endocrine assessments.

Effect of GH Deficiency Caused by Nonfunctioning Pituitary Masses on Serum C-reactive Protein Levels.

GH supplementation for GH deficiency (GHD) has been reported to decrease high-sensitivity C-reactive protein (hs-CRP), an inflammatory marker; however, the association between GHD and hs-CRP remains unclear. We aimed to clarify the impact of impaired GH secretion due to pituitary masses on hs-CRP levels. We retrospectively examined the association between GH secretion, assessed using GH-releasing peptide-2, and serum hs-CRP levels before and a year after the pituitary surgery in patients with nonfunctioning pituitary neuroendocrine tumor or Rathke cleft cyst. Among 171 patients, 55 (32%) presented with severe GHD (peak GH response to GH-releasing peptide-2 < 9 ng/mL). Serum hs-CRP levels were significantly higher in patients with severe GHD than in those without (P < .001) and significantly correlated with the peak GH (r = -0.50, P < .001). Multiple regression analyses showed that the peak GH significantly and negatively predicted hs-CRP levels (β = -0.345; 95% CI, -0.533 to -0.158) and the lowest quartile of the peak GH (<5.04 ng/mL) were significantly associated with increase in hs-CRP levels (exp [β] = 1.840; 95% CI, 1.209 to 2.801), after controlling for other anterior hormones and metabolic parameters. Postoperative change in the peak GH (N = 60) significantly predicted change in hs-CRP levels (β = -0.391; 95% CI, -0.675 to -0.108), independent of alterations in other anterior hormones and metabolic parameters. The inverse association between GH secretion and hs-CRP levels highlights the protective role of GH in the increase in hs-CRP.

Short and Long-Term Effects of Growth Hormone in Children and Adolescents With GH Deficiency.

The syndrome of impaired GH secretion (GH deficiency) in childhood and adolescence had been identified at the end of the 19th century. Its non-acquired variant (naGHD) is, at childhood onset, a rare syndrome of multiple etiologies, predominantly characterized by severe and permanent growth failure culminating in short stature. It is still difficult to diagnose GHD and, in particular, to ascertain impaired GH secretion in comparison to levels in normally-growing children. The debate on what constitutes an optimal diagnostic process continues. Treatment of the GH deficit via replacement with cadaveric pituitary human GH (pit-hGH) had first been demonstrated in 1958, and opened an era of therapeutic possibilities, albeit for a limited number of patients. In 1985, the era of recombinant hGH (r-hGH) began: unlimited supply meant that substantial long-term experience could be gained, with greater focus on efficacy, safety and costs. However, even today, the results of current treatment regimes indicate that there is still a substantial fraction of children who do not achieve adult height within the normal range. Renewed evaluation of height outcomes in childhood-onset naGHD is required for a better understanding of the underlying causes, whereby the role of various factors - diagnostics, treatment modalities, mode of treatment evaluation - during the important phases of child growth - infancy, childhood and puberty - are further explored.

Increased adiposity and insulin correlates with the progressive suppression of pulsatile GH secretion during weight gain

Pathological changes associated with obesity are thought to contribute to GH deficiency. However, recent observations suggest that impaired GH secretion relative to excess calorie consumption contributes to progressive weight gain and thus may contribute to the development of obesity. To clarify this association between adiposity and GH secretion, we investigated the relationship between pulsatile GH secretion and body weight; epididymal fat mass; and circulating levels of leptin, insulin, non-esterified free fatty acids (NEFAs), and glucose. Data were obtained from male mice maintained on a standard or high-fat diet. We confirm the suppression of pulsatile GH secretion following dietary-induced weight gain. Correlation analyses reveal an inverse relationship between measures of pulsatile GH secretion, body weight, and epididymal fat mass. Moreover, we demonstrate an inverse relationship between measures of pulsatile GH secretion and circulating levels of leptin and insulin. The secretion of GH did not change relative to circulating levels of NEFAs or glucose. We conclude that impaired pulsatile GH secretion in the mouse occurs alongside progressive weight gain and thus precedes the development of obesity. Moreover, data illustrate key interactions between GH secretion and circulating levels of insulin and reflect the potential physiological role of GH in modulation of insulin-induced lipogenesis throughout positive energy balance.

Deconvolution‐based assessment of pituitaryGHsecretion stimulated withGHRH+arginine inPrader‐Willi adults and obese controls

The assessment of GH deficiency in adult patients with Prader-Willi syndrome (PWS) has been previously assessed through the evaluation of quantitative parameters, such as the peak value of GH response to exogenous stimuli. A comprehensive description of the pattern of secretory response obtainable by deconvolution analysis is still lacking. The aim of our study was to characterize the time evolution of responses of PWS subjects compared with obese controls. GH responsiveness was measured following the combined administration of GHRH+arginine to 65 PWS adults (24 males, 41 females) aged 18-41·2years, and 17 age-, gender- and body mass index-matched obese controls. PWS subjects were analysed considering the stratification on different genotypes. GH response to GHRH+arginine was analysed in terms of peak values, standard area under the curves (AUCs), AUCs due to the stimulus, AUCs of the Instantaneous Secretion Rate signal and Secretion Response Analysis. In terms of both peak values and AUC, GH responses were statistically different between PWS UPD15 and PWS DEL15 subjects as well as between PWS UPD15 and obese controls. PWS subjects showed a lower and a more delayed GH response compared with obese controls. Moreover, PWS UPD15 subjects had the most delayed GH response. Our findings demonstrate that impaired GH secretion in PWS subjects compared with obese controls regards not only amplitude parameters such as peak value and AUC, but also the shape of the secretory response, which is more delayed, especially for UPD15 subjects.

Impaired GH Secretion in Patients with SHOX Deficiency and Efficacy of Recombinant Human GH Therapy

Background/Aims: Mutations of the short stature homeobox-containing (SHOX) gene on the pseudoautosomal region of the sex chromosomes cause short stature. GH treatment has been recently proposed to improve height in short patients with SHOX deficiency. The aim of this study was to evaluate GH secretion and analyze growth and safety of recombinant human GH (rhGH) therapy in short children and adolescents with SHOX deficiency. Patients and Design: We studied 16 patients (10 females; 9.7 ± 2.9 years old; height –2.46 ± 0.82 standard deviation score, SDS) with SHOX deficiency. All subjects underwent auxological evaluations, biochemical investigations, and were treated with rhGH (0.273 ± 0.053 mg/kg/week). Results: Impaired GH secretion was present in 37.5% of the studied subjects. Comparing baseline data with those at the last visit, we found that rhGH treatment improved growth velocity SDS (from –1.03 ± 1.44 to 2.77 ± 1.95; p = 0.001), height SDS (from –2.41 ± 0.71 to –1.81 ± 0.87; p < 0.001), and IGF-1 values (from –0.57 ± 1.23 to 0.63 ± 1.63 SDS, p = 0.010) without affecting body mass index SDS. Height SDS measured at the last visit was significantly correlated with chronological age (r = –0.618, p = 0.032), bone age (r = –0.582, p = 0.047) and height SDS (r = 0.938, p < 0.001) at the beginning of treatment. No adverse events were reported on rhGH therapy which was never discontinued. Conclusion: These data showed that impaired GH secretion is not uncommon in SHOX deficiency subjects, and that rhGH therapy may be effective in increasing height in most of these patients independent of their GH secretory status, without causing any adverse events of concern.

Growth Hormone Deficiency in 2 Siblings Associated with Combined GH1 Gene Polymorphisms

This study was performed to clarify the pathophysiology of familial short stature with moderate GH deficiency.The siblings showed moderate GH deficiency with short stature. Pedigree analysis revealed an accumulation of the history of short stature in father's relatives, although there was no consanguinity.We performed sequencing analysis of GH1 and GHSR gene in the siblings.We detected SNPs in the GH1 gene in the combination of the - 278G, - 57T, +1169T, and +2103C in one allele from the father and the - 278T, - 57G, +1169 A, and +2103T in the other allele from the mother in the siblings. In the previous report, the -278G and - 57T allele are associated with low serum IGF-I levels in patients with isolated GH deficiency and the haplotype of the - 278T, - 57G, +1169 A, and +2103T allele exhibited an impaired GH secretion in vitro.It is suggested that these haplotypes were responsible at least in part for the GH deficiency and short stature in these siblings.

Endocrine function in obesity

Obesity is associated to significant disturbances in endocrine function. Hyper insulinemia and insulin resistance are the best known changes in obesity, but their mechanisms and clinical significance are not clearly established. Adipose tissue is considered to be a hormone-secreting endocrine organ; and increased leptin secretion from the adipocyte, a satiety signal, is a well-established endocrine change in obesity. In obesity there is a decreased GH secretion. Impairment of somatotropic function in obesity is functional and may be reversed in certain circumstances. The pathophysiological mechanism responsible for low GH secretion in obesity is probably multifactorial. There are many data suggesting that a chronic state of somatostatin hypersecretion results in inhibition of GH release. Increased FFA levels, as well as a deficient ghrelin secretion, probably contribute to the impaired GH secretion. In women, abdominal obesity is associated to hyperandrogenism and low sex hormone-binding globulin levels. Obese men, particularly those with morbid obesity, have decreased testosterone and gonadotropin levels. Obesity is associated to an increased cortisol production rate, which is compensated for by a higher cortisol clearance, resulting in plasma free cortisol levels that do not change when body weight increases. Ghrelin is the only known circulating orexigenic factor, and has been found to be decreased in obese people. In obesity there is also a trend to increased TSH and free T3 levels.

Normal Sweat Secretion Despite Impaired Growth Hormone-Insulin-Like Growth Factor-I Axis in Obese Subjects

Adults with GH deficiency are known to exhibit reduced sweating. Whether sweating capacity is impacted in obese subjects with impaired GH secretion have not previously been investigated. The main objective was to investigate sweat secretion rate and the GH-IGF-I axis in obese subjects before and after weight loss. Sixteen severely obese women (BMI, 40.6 ± 1.1 kg/m2) were investigated before and after a diet-induced weight loss. Sixteen age-matched nonobese women served as controls. The obese subjects presented the characteristic decreased GH release, hyperinsulinaemia, increased FFA levels, and impaired insulin sensitivity, which all were normalised after diet-induced weight loss of 30 ± 5 kg. Sweat secretion rates were similar comparing obese and nonobese subjects (78 ± 10 versus 82 ± 9 mg/30 minutes) and sweat secretion did not change after a diet-induced weight loss in obese subjects. We conclude that although obese subjects have markedly reduced GH release and impaired IGF-I levels, sweat secretion rate is found to be normal.

Evaluation of GH-IGF-I Axis in Adult Patients with Coeliac Disease

The aim of this study was to evaluate GH/IGF-I axis and other pituitary functions in adult patients with coeliac disease. For this purpose, twenty-eight adult coeliac patients [20M, 8F:19-74 years; body mass index (BMI): 18.5-28 kg/m (2)] were recruited. Basal thyroid, adrenal and gonadal function, serum IGF-I and PRL, and routine parameters were evaluated. Dynamic GH secretion was carried out by GHRH plus arginine test. In 20 patients, antipituitary antibodies (APA) were also evaluated. Seven out of 28 patients, independently from disease onset and the gluten-free diet (GFD), showed an impaired GH secretion (25%). All were males, 2 with severe growth hormone deficiency (GHD) and 5 with partial GHD. In patients with GHD, as compared to coeliac patients with normal GH secretion, HOMA (2.1+/-1.2 vs. 0.9+/-0.4) and QUICKI (0.35+/-0.03 vs. 0.39+/-0.02) levels were significantly higher and lower, respectively, while IGF-I levels were slightly lower (17.7+/-3.7 vs. 24.7+/-6.3, p=NS). APA were negative in all 20 patients studied. In conclusion, a significant number of adult coeliac patients show an impaired GH secretion, this alteration being predominant in males and independent from disease onset and diet regimen. Given the absence of APAs, the cause of this pituitary dysfunction remains unclear even if a previous autoimmune involvement in some cases cannot be excluded.

Prevalence of the metabolic syndrome in moderately-severely obese subjects with and without growth hormone deficiency

There is a considerable heterogeneity in metabolic phenotype among equally obese subjects. Impaired GH secretion is frequent in obese patients, with GH secretion reduced up to levels that are comparable to those found in adult patients with organic GH deficiency (GHD). Low GH status exerts detrimental effects onmetabolic abnormalities in organic GHD patients. The aim of this observational, retrospective study was to investigate the prevalence of the metabolic syndrome (MetS) in moderately-severely obese subjects who met criteria for GDH (GHD) and in those with normal GH status (GH sufficient: GHS). One-hundred and ninety-five moderately-severely obese individuals partecipated, 149 women and 46 males [bodymass index (BMI) 43.0+/-4.4 kg/m2 aged 34.3+/-11.8 yr] . Main outcome measures were: GH peak after GHRH plus arginine test, IGF-I, MetS parameters according to National Cholesterol Education Program criteria. Fifty-five subjects (27.3%) were GHD (49 females and 6 males). The prevalence of MetS parameters was 70.9% in GHD subgroup vs 52.9% in GHS (chi2=5.281; p=0.02) and the likelihood of MetS was highest in GHD subgroup (odds ratio: 2.174; 95% confidence interval 1.113 to 4.248). At the multiple regression analysis either GH peak or IGF-I were the major determinants of waist circumference (beta=-0.380, t=-6.110 and beta=-0.326, t=-4.704, respectively; p<0.001), while age and IGFI were the major determinants of MetS (beta=0.255, t= 3.342, and beta=-0.282, t=-3.270; p=0.02, respectively). Among moderately-severely obese individuals the prevalence of the MetS was higher in GHD than in GHS subjects. Thus, in obese subjects, GH status investigation might be considered in the clinical evaluation of their metabolic risk profile.

Growth Hormone Treatment Prevents Loss of Lean Mass after Bariatric Surgery in Morbidly Obese Patients: Results of a Pilot, Open, Prospective, Randomized, Controlled Study

The loss of lean body mass (LBM) negatively influences the outcome in bariatric surgery. Impaired GH secretion is frequent in obese patients. Our objective was to investigate if GH treatment prevents LBM loss in the early postoperative period. This was an open, prospective, randomized, and controlled study. A total of 24 women (body mass index: 44.4 +/- 7.6 kg/m(2), aged 36.8 +/- 11.7 yr) undergoing laparoscopic-adjustable silicone gastric banding (LASGB) and with GH deficiency after LASGB was included in the study. Group A (n = 12) included a standardized diet regimen and exercise program plus recombinant human GH (0.5 +/- 0.13 mg every day), and group B (n = 12) included a standardized diet regimen and exercise program. The follow-up duration was 6 months. The excess of body weight loss did not differ between groups A and B after 3 and 6 months. At 3 months, LBM loss was lower (P < 0.0001) and fat mass (FM) loss was higher (P = 0.02) in group A than group B. At 3 and 6 months, appendicular skeletal muscle mass loss was lower (P = 0.000) in group A than group B. At 3 (P = 0.0003 and 0.0005, respectively) and 6 months (P < 0.0001 and 0.0002, respectively), the percent changes of FM and lean body mass were significantly higher in group A than group B. In both groups fasting and postglucose area under the plasma concentration-time curve insulin significantly reduced. The homeostasis model assessment of insulin and insulin sensitivity indexes and total to high-density lipoprotein cholesterol ratio improved only in group A. GH treatment for 6 months after LASGB reduces loss in LBM and appendicular skeletal muscle mass during a standardized program of low-calorie diet and physical exercise program, with improvement of lipid profile and without a deterioration of glucose tolerance.

Primary hyperparathyroidism is associated with marked impairment of GH response to acylated ghrelin

Impaired GH secretion is a common finding in patients with primary hyperparathyroidism (PHP). Ghrelin displays strong GH-releasing action, mainly at the hypothalamic level. To evaluate secretory response of GH to ghrelin in PHP patients. Fifteen patients [11 women/4 men, mean age 54 years, range 32-70 years, body mass index (BMI) 25.0 +/- 0.7 kg/m(2)] affected with PHP due to single parathyroid adenoma and 35 normal age-matched subjects (23 women/12 men, mean age 58 years, range 35-68 years, BMI 24.1 +/- 1.1 kg/m(2)). A measure of 1 microg/kg body weight i.v. acylated ghrelin or 1 microg/kg body weight i.v. GH releasing hormone (GHRH) followed by 0.5 g/kg body weight i.v. arginine (ARG) hydrochloride were administered to all subjects on alternate days in order to evaluate GH response. Mean serum GH peak after GHRH + ARG was 32.6 +/- 7.8 and 17.4 +/- 4.0 microg/l, in controls and PHP patients, respectively (P < 0.05). Mean serum GH peak after ghrelin was 70.4 +/- 31.5 and 16.8 +/- 1.9 microg/l, in controls and PHP patients, respectively, (P < 0.001). Using ROC curves, a serum GH peak > 22 microg/l after ghrelin stimulation might be considered as a cut-off value for identifying normal subjects. Ten (67%) PHP patients have impaired GH response to GHRH + ARG and 13 (87%) to ghrelin. Serum GH peak after ghrelin or GHRH + ARG was unrelated to serum IGF-1, PTH or ionized calcium concentrations. The present data confirm that GH secretion is impaired in PHP patients using the potent GH secretagogue ghrelin and suggest that impaired GH secretion is likely due to a deleterious effect of hypercalcaemia at the hypothalamic level in PHP patients.

Short-Term Treatment with Bromocriptine Improves Impaired Circadian Growth Hormone Secretion in Obese Premenopausal Women

A profound reduction of spontaneous as well as stimulated GH secretion has been consistently observed in obesity. Dopamine promotes GH release through activation of dopamine D2 receptors (D2Rs). Dopamine D2R availability in the brain is reduced in obese humans in proportion to body adiposity. We hypothesized that impaired dopamine D2R signaling is mechanistically involved in the deficient GH secretion associated with obesity. To test this hypothesis, we studied the effect of short-term bromocriptine (B) (a D2R agonist) treatment on spontaneous 24-h GH secretion in obese women, while body weight and caloric intake remained constant. This was a prospective, fixed order, cross-over study. The study was performed in the Clinical Research Center at Leiden University Medical Center. There were 18 healthy obese women (body mass index 33.2 +/- 0.6 kg/m2) studied twice in the early follicular phase of their menstrual cycle. Eight days of treatment with B and placebo (Pl) was performed. Blood was collected during 24 h at 10-min intervals for determination of GH concentrations. GH secretion parameters were calculated using deconvolution analysis. Short-term treatment with B significantly enhanced diurnal GH secretion (Pl 121.4 +/- 16.4 vs. B 155.4 +/- 15.2 microg/liter(volume of distribution).24 h; P = 0.01), whereas IGF-I concentrations remained constant (Pl 22.4 +/- 2.4 vs. B 21.8 +/- 1.6 nmol/liter; P = 0.928). Activation of dopamine D2Rs by B favorably affects impaired nyctohemeral GH secretion in obese women. Reduced dopaminergic neuronal signaling might be involved in the pathogenesis of obesity associated hyposomatotropism.

Significant GH deficiency after long-term cure by surgery in adult patients with Cushing’s disease

Impaired GH secretion usually accompanies Cushing's syndrome and a variable proportion of patients reportedly fail to recover normal GH secretion after successful treatment. This wide variability is most probably due to differences in the treatment (i.e. surgery and/or radiotherapy), timing of patient re-evaluation after surgery and dynamic tests employed to challenge GH secretion, and hinders a precise assessment of risk of GH deficiency after cure. The aim of the present study is to evaluate GH secretory status after long-term cure of Cushing's disease achieved by surgery alone. We studied 34 patients (27 females and 7 males, age range 21-68 years) formerly affected by Cushing's disease. Patients were studied 2-20 years (median 3.3 years) following remission of hypercortisolism; all patients underwent transsphenoidal surgery with the removal of an ACTH-secreting adenoma; repeat pituitary surgery for relapse was performed in two patients while bilateral adrenalectomy was necessary in two patients. In all subjects, the GH response to GHRH+arginine stimulation was evaluated. At the time of testing, 13 patients were still on steroid replacement therapy. In long-term surgical remission, 22 patients (65.0%) presented subnormal GH secretion; partial GH deficiency (GH peak <16.5 microg/l) was found in 11 patients and severe GH deficiency (GH peak <9 microg/l) in another 11. Male gender and length of hypercortisolism were risk factors for postsurgical GH deficiency. This study demonstrates the presence of GH deficiency in a high percentage of patients with Cushing's disease after long-term remission of hypercortisolism obtained by surgery alone. Male gender and length of hypercortisolism are the most significant predictors of postsurgical GH deficiency. This finding is significant as it highlights that even the most favourable therapeutical course, i.e. remission achieved by surgery alone, is accompanied by impaired GH secretion. Assessment of GH secretion is therefore recommended for all patients cured from Cushing's disease, even if not submitted to radiotherapy. Studies on the clinical impact of GH deficiency and the use of GH replacement therapy seem warranted in patients cured from Cushing's disease.

Impairment of GH responsiveness to combined GH‐releasing hormone and arginine administration in adult patients with Prader‐Willi syndrome

It is unclear if poor health outcomes of adult patients with Prader-Willi syndrome (PWS) are influenced by GH deficiency (GHD). Few studies have been focused on PWS adults, but further information on the concomitant role of obesity on GH/IGF-I axis function is needed. The aim of our study was to investigate the prevalence of GHD in a large group of adult subjects with genetically confirmed PWS. We studied the GH response to a combined administration of GHRH (1 microg/kg i.v. at 0 minutes) and arginine (ARG) (30 g i.v., infused from 0 to 30 minutes) as well as the baseline IGF-I levels, in a group of 44 PWS adults (18 males, 26 females) aged 18-41.1 years. The same protocol was carried out in a control group of 17 obese subjects (7 males, 10 females) aged 21.8-45.8 years. Blood samples were taken at -15 and 0 minutes and then 30, 45, 60, 90 and 120 minutes after GHRH administration. Serum GH and total IGF-I concentrations were measured by chemioluminescence. Statistical analysis was performed by Student's t-test for unpaired data, and using analysis of variance for parametric and nonparametric (Mann-Whitney test) data, where appropriate. The relationship between pairs of variables was assessed by Pearson's correlation. Independent variables influencing GH secretion were tested by multiple linear regression analysis. The GH response to GHRH + ARG was significantly lower in PWS patients (GH peak (mean +/- SE) 8.4 +/- 1.2 microg/l; AUC: 471.4 +/- 77.8 microg/l/h) than obese subjects (GH peak 15.7 +/- 2.9 microg/l, P < 0.02; AUC 956 +/- 182.9 microg/l/h, P < 0.005). When considered individually, 17 of 44 PWS individuals (38.6%) were severely GHD, according to the cut-off limit of 4.1 microg/l for obese individuals, and low IGF-I-values were present in 33 PWS patients. Moreover, impaired GH response was combined with subnormal IGF-I levels in all PWS patients with GHD. Adult subjects with PWS had a reduced responsiveness to GHRH + ARG administration associated with reduced IGF-I levels. In addition, a severe GHD for age was demonstrated in a significant percentage of PWS subjects. These findings are in agreement with the hypothesis that a complex derangement of hypothalamus-pituitary axis occurred in PWS, and suggested that impaired GH secretion is not an artefact of obesity.

Growth hormone secretion in primary and secondary hyperparathyroidism

Primary hyperparathyroidism (PHP) is associated with impaired GH secretion. Whether this effect is due to hypercalcemia or to increased serum PTH concentration is unclear. However, patients with familial hypocalciuric hypercalcemia (FHH), who have normal PTH and increased serum calcium concentrations, also have an impaired GH secretion, suggesting that calcium rather than PTH is responsable for this effect on GH secretion. To further investigate this issue, 10 consecutive patients with secondary hyperparathyroidism (SHP) due to vitamin D deficiency were evaluated by the GH response to GHRH+arginine (Arg) test. A group of 60 consecutive untreated PHP patients served as controls. Mean GH response to GHRH+Arg test was 15.8+/-14 microg/l and 37.5+/-16 microg/l (p<0.001) in PHP and in SHP patients, respectively. Forty-two out of 60 (70%) PHP patients had a suppressed or blunted GH response, whereas all SHP patients had normal GH response. The results of the present study confirm and extend our previous observations that PHP is associated with an impaired GH secretion in the majority of cases, and indicate that SHP patients have no abnormality of GH secretion. Thus, hypercalcemia rather than increased serum PTH is responsible for the abnormality of GH secretion.

Adults with partial growth hormone deficiency have an adverse body composition.

The current biochemical definition of severe GH deficiency (stimulated peak GH < 3 micro g/liter) provides good separation of GH-deficient (GHD) adults from normal subjects, although it may not account for all patients with impaired GH secretion. The vast majority of normal subjects display a peak GH level in excess of 7 micro g/liter in response to the insulin tolerance test. Using a peak GH response of 7 micro g/liter as an arbitrary upper limit, we investigated the effects of partial GH deficiency (GH insufficiency, GHI; peak GH response of 3-7 micro g/liter) on the body composition of hypopituitary adults. GHD adults (n = 30, peak GH < 3 micro g/liter) were of shorter stature than the controls. Body mass index was not significantly increased, but waist/hip ratio (0.885 vs. 0.818, P = 0.001) and skinfold thickness (78.2 vs. 59.6 mm, P = 0.003) were greater than control subjects. Bioimpedance analysis revealed these patients to have reduced lean body mass (LBM) (44.4 vs. 51.2 kg, P = 0.023) and increased fat mass (FM) (25.7 vs. 18.4 kg, P = 0.039). Dual-energy x-ray absorptiometry (DXA) analysis of body composition confirmed reduced LBM (43.6 vs. 50.6 kg, P = 0.010) and increased FM (26.0 vs. 19.2 kg, P = 0.015). The excess FM was observed to be primarily truncal in distribution. Similarly, GHI adults were of shorter stature but with increased waist/hip ratio (0.871 vs. 0.818, P = 0.006) and skinfold thickness (80.8 vs. 59.6 mm, P = 0.003), compared with controls. Bioimpedance analysis revealed a reduction in LBM (44.9 vs. 51.2 kg, P = 0.020). DXA studies confirmed the reduced LBM (45.0 vs. 50.6 kg, P = 0.041) and additionally noted an increase in percent FM (32.9 vs. 27.4%, P = 0.019). All measures of body composition in the GHI patients were intermediate between those of the controls and GHD patients. Serum leptin levels were significantly elevated in both the GHD (41.5 vs. 20.7 ng/ml, P = 0.009) and GHI (36.7 vs. 20.7 ng/ml, P = 0.022) adults, compared with healthy controls. The excess FM observed using DXA in the GHD and GHI adults equated to 6.5 kg (8%) and 3.5 kg (5.5%), respectively, relative to healthy controls. In summary, we have shown that adults with GHI have abnormalities of body composition characteristic of GHD. The degree of abnormality of body composition lies between that of healthy subjects and GHD adults and correlates with the IGF-I level. Any future trials of GH replacement in patients with GHI must await further studies to establish the exact impact of this relative deficiency on the broad spectrum of biological end points influenced by GH status.

Improvement of growth hormone deficiency in patients with primary hyperparathyroidism after parathyroidectomy: results of a prospective study.

GH secretion is impaired in most patients with primary hyperparathyroidism (PHP), although the secretion of the other anterior pituitary hormones is unaffected. However, whether restoration of euparathyroidism is associated with reversal of GH deficiency in PHP patients is not known. To address this issue, we studied 30 consecutive patients with PHP due to a single parathyroid adenoma before and after parathyroidectomy. GH secretion was evaluated by peak serum GH after the maximal GHRH + arginine (Arg) stimulation test. A group of 35 age- and sex-matched normal subjects served as controls. Serum IGF-I concentration was below the normal age- corrected values in six of 30 patients before surgery and in four of 30 patients after parathyroidectomy (P = not significant). Mean serum peak GH values after the GHRH + Arg test were 17.5 +/- 2.8 micro g/liter before surgery and 23.8 +/- 2.5 micro g /liter after surgery (P = 0.0008). The GH response to the GHRH + Arg test was reduced in 20 (67%) and normal in 10 (33%) of 30 PHP patients at baseline; after surgery, 22 of 30 (73%) PHP patients had a normal GH response to the GHRH + Arg test, and only eight (27%) had an impaired GH secretion (P < 0.02). In conclusion, this study confirms that GH secretion is impaired in PHP patients and indicates that it is reversed in many patients after parathyroidectomy. Accordingly, GH deficiency in PHP patients must be considered a functional phenomenon for which GH therapy is not recommended.

Assessment of GH reserve before and after successful treatment of adult patients with Cushing's syndrome.

Several studies have demonstrated impaired GH secretion in patients with active Cushing's syndrome (CS). It has been suggested that persistence of GH deficiency, despite treatment of cortisol excess, may delay the recovery of these patients and therefore temporary treatment with GH may have some benefit. However, the time course of restoration of GH secretion after successful treatment of CS has only been investigated in a limited number of mostly paediatric reports. The aim of the present study was the evaluation of GH reserve in adult patients with CS before and after correction of cortisol excess. Sixteen patients (12 females, four males) with CS aged 44.7 +/- 5.05 years were recruited. These included seven patients with Cushing's disease, four patients with ectopic ACTH secretion and five patients with adrenal adenoma. All patients were evaluated before any therapeutic intervention. Twelve patients were successfully treated following appropriate surgery and these were further studied. The combined pyridostigmine/GHRH test was used to assess GH reserve in these patients. In a proportion of cases an insulin tolerance test (ITT) was also used. Before any therapeutic intervention, an impaired GH response to PD/GHRH was noted in all patients. Restoration of GH response at 6 months was observed in six patients (50%); at 12 months in two; at 18 months in one patient. Two of the patients with no restoration of GH response at 12 months did not accept further investigation. Only one patient did not achieve an adequate GH response even when tested 30 months following cure of CS. Restoration of GH reserve was more commonly observed in those patients in whom there was recovery of the HPA axis. There was a good correlation between peak GH levels to PD + GHRH and ITT. No statistically significant difference was revealed in IGF-I levels between pre- and post-treatment evaluation. Adult patients with active Cushing's syndrome demonstrate a profound suppression of stimulated GH secretion. In the majority of these patients the disruption of GH secretion is normalized within a year after successful treatment of endogenous cortisol excess.