Effects of adult growth hormone deficiency and growth hormone replacement on circadian rhythmicity

In health, growth hormone (GH) is secreted in a circadian rhythm with superimposed pulsatility. Temporal fluctuations of hormone concentrations are essential for physiological action, and loss of diurnal rhythm is important in the development of disease. GH feedback occurs through the hypothalamus and involves neuropeptides such as somatostatin, GH-releasing hormone, GH-releasing peptides and neuropeptide Y. In addition, the same neuropeptides are involved in the regulation of other hormone axes and biological systems, thus, establishing a link through which regulation by GH may occur. Clinical features of adult growth hormone deficiency (AGHD) include abnormal body composition, reduction in quality of life, osteoporosis and increased risk of cardiovascular mortality. In health, many of the factors which regulate these features demonstrate circadian rhythmicity and pulsatility. Furthermore, AGHD is associated with abnormalities in the periodic variation of such controlling factors. GH replacement therapy, administered in the form of timed, intermittent subcutaneous injections, results in improvement of many of the clinical effects of AGHD, and is associated with normalization of the temporal fluctuations. Currently, there remains scope for further investigation of the effects of AGHD and subsequent GHR on the circadian rhythmicity of many hormones and systems; and additional studies are required to understand the physiological significance of the changes observed to date.     

Growth hormone replacement is important for the restoration of parathyroid hormone sensitivity and improvement in bone metabolism in older adult growth hormone-deficient patients

Alterations in PTH circadian rhythm and PTH target-organ sensitivity exist in adult GH-deficient (AGHD) patients and may underlie the pathogenesis of AGHD-related osteoporosis. GH replacement (GHR) results in increased bone mineral density, but its benefit in AGHD patients over 60 yr old has been debated. To examine the effect of age on changes in PTH circadian rhythm and target-organ sensitivity after GHR, we recruited 22 AGHD patients (12 were <60 yr of age, and 10 were >60 yr of age). Half-hourly blood samples were collected for PTH, calcium, phosphate, nephrogenous cAMP (marker of renal PTH activity), type-I collagenbeta C-telopeptide (bone resorption marker), and procollagen type-I amino-terminal propeptide (bone formation marker) before and after 1, 3, 6, and 12 months of treatment with GHR. Significant PTH circadian rhythms were present in both age groups throughout the study. After GHR, PTH decreased and nephrogenous cAMP, adjusted calcium, and bone turnover markers increased in both groups, suggesting increased PTH target-organ sensitivity. In younger patients, the changes were significant after 1 month of GHR, but, in older patients, the changes were delayed until 3 months, with maximal changes at 12 months. Older AGHD patients derive benefit from GHR in terms of improvement in PTH sensitivity and bone metabolism. Their response appears delayed and may explain why previous studies have not shown a positive effect of GHR on bone mineral density in older AGHD patients.     

Gender variation in leptin circadian rhythm and pulsatility in adult growth hormone deficiency: effects of growth hormone replacement

OBJECTIVES: Adult growth hormone deficiency (AGHD) is characterized by obesity and associated with increased leptin concentration and decreased leptin pulsatility. Growth hormone replacement (GHR) results in a decrease in leptin concentration and increase in leptin pulsatility, followed by reduction in body fat mass (BFM). In both health and AGHD, women exhibit relatively higher leptin concentrations compared to men. The effect of gender on leptin rhythm and pulse parameters in AGHD is yet to be defined and the gender difference in the response of leptin secretory pattern to GHR has not been determined. Therefore the aim of this study was to evaluate the effect of gender on circadian and pulse parameters of leptin secretion in AGHD, and examine the gender variation in response of these parameters to GHR. STUDY DESIGN: A prospective, open treatment design study to determine the effect of gender on leptin rhythm and pulse parameters in untreated and treated AGHD. GH was commenced at a daily dose of 0.5 IU, and titrated up by increments of 0.25 IU at 2-weekly intervals to achieve and maintain IGF-I SDs between the median and upper end of the age-related reference range. PATIENTS: Twelve patients (six men, six women) with severe AGHD following pituitary surgery, defined as peak GH response < 9 mU/l to provocative testing were studied. All patients required additional pituitary replacement hormones following pituitary surgery and were on optimal doses at recruitment. MEASUREMENTS: Plasma leptin was measured at half-hourly intervals for 24 h, before and 1 month after initiation of GHR. Cosinor analysis was used to determine the circadian rhythm parameters: MESOR (rhythm-adjusted mean), acrophase and amplitude; and ULTRA algorithm used for pulse analysis. Body composition was measured using bioelectrical impedance. RESULTS: BFM was higher in women than men at both visits (P < 0.05), but there was no significant change in BFM in either gender following 1 month of GHR. Women had a higher mean 24-h leptin concentration, MESOR, circadian amplitude and pulse amplitude, both before and after GHR (P < 0.05). Following treatment, mean leptin concentration and MESOR decreased significantly in both men and women (P < 0.05), with no significant difference in percentage change between the genders. Pulse frequency increased and duration decreased significantly after GHR in both groups, without any significant gender difference. IGF-I and IGF SDs were similar in both genders at baseline (P = 0.93). However, after 1 month GHR, the increase in both measurements was greater in men than women (P = 0.005) and men had significantly higher IGF-I and IGF SDs than women (P = 0.01). CONCLUSIONS: As in healthy individuals, leptin levels were higher in women with AGHD than men, both prior to and after GHR. Decline in leptin concentrations and increase in leptin pulsatility following 1 month of GH treatment were similar in both genders. Changes in leptin secretory parameters appeared to occur without any significant decrease in BFM, suggesting a regulatory role for GH. Additionally, the action of GH on leptin secretory pattern does not appear to be mediated by IGF-I. Our data suggest that changes in leptin concentration and rhythm parameters following GHR are independent of gender.     

Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients

BACKGROUND: The effect of GH replacement on thyroid function in hypopituitary patients has hitherto been studied in small groups of children and adults with conflicting results. OBJECTIVE: We aimed to define the effect and clinical significance of adult GH replacement on thyroid status in a large cohort of GH-deficient patients. PATIENTS AND METHOD: We studied 243 patients with severe GH deficiency due to various hypothalamo-pituitary disorders. Before GH treatment, 159 patients had treated central hypothyroidism (treated group) while 84 patients were considered euthyroid (untreated group). GH dose was titrated over 3 months to achieve serum IGF-1 concentration in the upper half of the age-adjusted normal range. Serial measurements of serum T4, T3, TSH and quality of life were made at baseline and at 3 and 6 months after commencing GH replacement. RESULTS: In the untreated group, we observed a significant reduction in serum T4 concentration without a significant increase in serum T3 or TSH concentration; 30/84 patients (36%) became hypothyroid and needed initiation of T4 therapy. Similar but lesser changes were seen in the treated group, 25 of whom (16%) required an increase in T4 dose. Patients who became hypothyroid after GH replacement had lower baseline serum T4 concentration, were more likely to have multiple pituitary hormone deficiencies and showed less improvement in quality of life compared with patients who remained euthyroid. CONCLUSION: GH deficiency masks central hypothyroidism in a significant proportion of hypopituitary patients and this is exposed after GH replacement. We recommend that hypopituitary patients with GH deficiency and low normal serum T4 concentration should be considered for T4 replacement prior to commencement of GH in order to provide a robust baseline from which to judge the clinical effects of GH replacement.     

Serum resistin concentrations in growth hormone-deficient children during growth hormone replacement therapy

We performed this study to examine whether the serum resistin concentrations in growth hormone (GH)-deficient (GHD) children are influenced by administration of GH and to assess the relationship between serum resistin and free fatty acid levels during GH replacement therapy. The study included 20 prepubertal GHD children (16 boys and 4 girls) who were treated with recombinant human GH (hGH). The serum levels of resistin, insulin-like growth factor I, free fatty acid (FFA), triglyceride, cholesterol and glucose levels, leukocyte counts, and hemoglobin A(1c) were measured at baseline and after 1 month of hGH treatment. The serum resistin levels after hGH therapy were significantly higher than the basal resistin levels (median [range], 6.2 [4.9-11.8] vs 5.6 [4.4-8.3] ng/mL; P < .05), whereas the serum FFA levels were unchanged before and after treatment (0.51 [0.34-0.76] vs 0.37 [0.24-0.60] mEq/L). No significant relationship was found between serum resistin and FFA levels after hGH therapy. Body mass index, serum triglyceride, cholesterol and glucose levels, leukocyte counts, and hemoglobin A(1c) showed no significant differences before and after hGH treatment. Our results suggest that elevated serum resistin levels after 1-month hGH therapy in GHD children are not associated with the GH-induced lipolysis as found in GHD adults during short-time hGH therapy.     

Growth hormone therapy and fracture risk in the growth hormone-deficient adult

Adults with childhood-onset growth hormone deficiency (GHD) and younger adults with adult-onset GHD have a reduced bone mineral content (BMC). Recent trials with prolonged GH replacement therapy have demonstrated increased BMC in such patients. GH treatment in animals increases the amount of bone and the total strength while the density (BMC per unit volume) and the quality of the bone is not increased. A sensitive non-invasive parameter for the detection of effects of GH on bone in clinical studies is therefore to use the BMC from dual-energy X-ray absorption (DEXA) analysis. Bone density is strongly related to fracture risk in women. A number of other risk factors for fractures can be identified in adult GHD patients which, collectively, might explain the increased fracture frequency observed in these patients. The increase in BMC in response to long-term GH replacement therapy is promising. Whether more prolonged treatment will result in a normalization of the bone mass and reduced fracture frequency remains to be established.     

Insulin sensitivity in growth hormone-deficient children: influence of replacement treatment

OBJECTIVE: In adults, excessive GH secretion may lead to secondary diabetes mellitus, while prolonged GH treatment may accelerate the onset of type 2 diabetes mellitus in predisposed children. The aim of the study was to evaluate insulin sensitivity (IS) and glucose tolerance (GT) in a group of GH-deficient children treated with GH for a period of 6 years. PATIENTS AND DESIGN: One hundred and twenty-eight children (40 females, 88 males) were included in the study. At the beginning of treatment chronological age was 8.9 +/- 3.2 years, height standard deviation score (SDS) -2.43 +/- 0.90 and body mass index (BMI) SDS 0.18 +/- 1.60. At the end of the study chronological age was 13.0 +/- 2.9 years, height SDS -1.24 +/- 1.27 and BMI SDS 0.23 +/- 1.54. GH was administered at a mean weekly dosage of 0.3 mg/kg, injected subcutaneously over 6-7 days. GT was assessed according to the criteria of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. IS was evaluated with the quantitative insulin sensitivity check index (QUICKI). RESULTS: No cases of impaired GT or diabetes were recorded during the follow-up period. IS, already lower than in controls before starting treatment with GH, decreased significantly during the first year of therapy (QUICKI: 0.346 +/- 0.033 vs. 0.355 +/- 0.044, P < 0.05), with no further decrease in the following years. No correlation was found between QUICKI, BMI, years of treatment and onset of puberty. CONCLUSIONS: GH treatment in GH-deficient children does not lead to an impaired GT or type 2 diabetes mellitus, although it does significantly decrease IS.     

A monocentric experience of growth hormone replacement therapy in adult patients

Objectives

To describe the results of growth hormone (GH) therapy in adult GH-deficient patients treated in a tertiary referral center, with a focus on quality of life and adherence.

Patients and methods

Retrospective study of patients followed over a total period of 11 years. Quality of life (QOL) was assessed by the QOL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) score and adherence to treatment was measured by a specific questionnaire. Clinical, biological, body composition and bone mineralization parameters were also analyzed.

Results

Data from 81 patients were analyzed. After a median treatment duration of 7 years, 2/3 of patients reported improved QOL (mean decrease of AGHDA score of 3.0 points, P < 0.001). A trend towards more frequent improvement was observed in middle-aged patients, women, childhood-onset GHD, and in patients with initially more impaired QOL. More than 60% of the patients reported continuing treatment without interruption. Seventy percent declared good adherence (≤ 2 missed injections/month). A majority reported enhanced well-being. Additionally, we observed a mean weight increase of 2 kg, while fat mass, waist/hip circumference ratio and lipids were unchanged. Bone mineral density was significantly increased at lumbar spine and femoral neck.

Conclusion

Our study confirmed a sustained improvement in quality of life and showed that majority of patients were still on GH treatment after a median duration of 7 years.     

Long-term effects of growth hormone replacement therapy on liver function in adult patients with growth hormone deficiency

ObjectiveNonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are frequently observed in patients with adult growth hormone deficiency (AGHD) and short-term GH replacement therapy (GHRT) has reportedly been efficacious in NAFLD and NASH. The aim of this study was to investigate whether long-term GHRT is an effective treatment for the hepatic comorbidities in AGHD.DesignThis is a retrospective observational study. We recruited 54 consecutive hypopituitary patients with AGHD. Among them, 31 patients who had received GHRT for more than 24 months were compared with 19 age- and sex-matched patients without GHRT. We also analyzed the long term effect of GHRT on 14 patients diagnosed with NASH by liver biopsy. In addition, we subdivided the GHRT group into GH-responder and GH-non-responder groups and analyzed the factors associated with the efficacy of the treatment.ResultsFor a period of 24 months, the significant reduction of serum liver enzyme levels and a fibrotic marker was observed in patients receiving GHRT compared with the control group. Furthermore, GHRT also improved liver enzyme levels in AGHD patients with NASH. The GH-non-responder group showed a higher proportion of patients who gained weight during the study period.ConclusionsThese results indicate that GHRT is efficacious for improving serum liver enzyme levels for at least 24 months in patients with AGHD. To optimize this effect, it is important to avoid body weight gain during the treatment.     

Long-term monitoring of insulin sensitivity in growth hormone-deficient adults on substitutive recombinant human growth hormone therapy

Since the effects of recombinant human growth hormone (rhGH) replacement therapy on glucose metabolism are still a matter of debate, the aim of the present study was to evaluate the impact of long-term rhGH treatment on insulin sensitivity. Simple indices of insulin resistance (IR) and insulin sensitivity (IS), based on fasting glucose and insulin, such as the homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin check index (QUICKI), were used to estimate the degree of IR and IS in 20 normoglycemic patients (11 men and 9 women; mean age, 44 +/- 14 years) with severe adult-onset GH deficiency (GHD). Measurements were determined at baseline and after 1 and 5 years of continuous rhGH therapy. Basal values were compared to those obtained in 20 healthy sex- and age-matched controls. Starting rhGH dose ranged from 3 to 8 microg/kg/d in keeping with sex and age, then doses were titrated according to insulin-like growth factor-I (IGF-I) levels. At baseline all patients had low IGF-I levels (10 +/- 5.4 nmol/L), high body mas index (BMI; 27.5 +/- 4 kg/m(2)), and elevated body fat percentage (BF%; 31.8 +/- 9.6). Fasting glucose and insulin levels, as well as HOMA-IR and QUICKI, did not differ significantly from those recorded in the control group. After 1 year of rhGH replacement therapy, normalization in IGF-I levels and a significant reduction in BF% were observed (P <.001), and these effects were maintained after 5 years of treatment. Fasting glucose increased from 79 +/- 10 to 87 +/- 13, and 87 +/- 12 mg/dL (P <.05) after 1 and 5 years of therapy, respectively. Fasting insulin significantly increased after 1 year, without further modifications in the long-term follow-up. HOMA-IR significantly increased from 2.1 +/- 1.7 to 2.5 +/- 1.7 (P <.05) after 1 year, then decreased to 2.3 +/- 1.5 (P = not significant [NS] v basal) after 5 years. A specular decrease in QUICKI from 0.37 +/- 0.05 to 0.34 +/- 0.03 (P <.01) occurred after 1 year, with a trend to increase (0.35 +/- 0.04; P = NS v basal) after 5 years. No patient developed impaired fasting glucose. In conclusion, rhGH therapy determined an increase in fasting glucose and insulin levels, causing in the short-term period a worsening of IS. The sustained reduction in BF%, without further deterioration of IS, suggests that long-term beneficial effects on body composition may overcome the negative influence of GH on glucose metabolism.     

Impact of 5 years of growth hormone replacement therapy on cardiovascular risk factors in growth hormone-deficient adults

The benefits of long-term effects of growth hormone (GH) substitution on carbohydrate and lipid metabolism in GH-deficient (GHD) adults are still controversial. The purpose of this study was to evaluate the effects of 5 years of GH substitution on body composition, glucose and lipid metabolism, and carotid artery intima-media thickness (IMT) in GHD adults. Fourteen patients were clinically assessed every 3 months for 5 years. Serum insulin-like growth factor 1 levels, lipid profile, oral glucose tolerance test, and ultrasonography of the carotid arteries were performed at baseline, 6 months, and every year during replacement. Visceral fat was measured by computed tomographic scan at baseline and at 6, 12, 24, and 60 months. The waist circumference was reduced after 6 months but increased during the next months toward baseline values. Visceral fat decreased during the study. Fasting glucose and insulin levels did not change, as well as the homeostasis model assessment of insulin resistance index. Despite an initial increase in frequency of abnormal glucose tolerance, mean 2-hour oral glucose tolerance test glucose levels decreased during the last 2 years. There was an increase in apolipoprotein A-1 levels during the treatment. Apolipoprotein B levels were reduced after 6 months and remained stable thereafter. A reduction in carotid artery IMT was observed during replacement. We concluded that 5 years of GH replacement therapy promoted positive effects on visceral fat, lipid profile, and carotid artery IMT in GHD adults. Long-term therapy improves insulin sensitivity through a reduction in visceral fat, and continuing monitoring is mandatory in terms of glucose metabolism.     

Did growth hormone-deficient children grow up to normal adult height by growth hormone treatment?]

One of the important aims of growth hormone (GH) treatment in GH deficient children is to allow them to grow to their full genetic potential. Usually, however, the final height of GH deficient children does not reach normal adult height and is below their target height. Furthermore, isolated GHD with spontaneous puberty is known to lead to a shorter adult height than that obtained in GHD associated with gonadotropin deficiency. The height at the start of puberty is reported to be well correlated with final height in GHD. Therefore, when isolated GHD subjects treated with GH reached puberty while they were still shorter than normal, they ended up by being shorter than normal as adults. The trial to increase the GH dose during puberty did not seem to increase the final height. The gonadal suppression therapy combined with GH treatment significantly increased the final height in isolated GHD. It is now the consensus that insufficient height at the onset of puberty leads to short final height and that early diagnosis of GHD is thus important to allow catch-up growth to optimal height before puberty. It may also be beneficial to treat GHD with higher doses to overcome the waning phenomenon with GH treatment.     

Growth hormone dosing variables in growth hormone-deficient adults

The use of growth hormone (GH) replacement for GH-deficient adults is now in its 10th year of FDA-approved use in the United States; it has been used for a longer period of time in some European countries. Despite widespread experience, there is still lack of consensus regarding the best approach to GH initiation and titration in adults with growth hormone deficiency. Several factors must be considered prior to dose selection, including patient age, gender, symptoms, and the use and route of estrogen replacement therapy.We retrospectively examined GH dosing practices within our institution over a 5-year period to define GH dose requirements during the initial titration and maintenance phases, the frequency of dose adjustments, and the reasons behind the dose adjustments in young and older adults. Based on this review, we offer practical recommendations for endocrinologists in the management of adults with hypopituitarism and long-term GH treatment.     

HDL-cholesterol reductions associated with adult growth hormone replacement

OBJECTIVE: To study the effects of human growth hormone (hGH) replacement on serum lipids and lipoprotein (a) (Lp(a)) concentrations. DESIGN: A randomized double blind placebo controlled trial for 6 months followed by an open trial where all patients were treated with hGH for a further 6 months. Treatment was with recombinant hGH given in a dose of 0.125U/kg/wk increasing to 0.25U/Kg/wk. PATIENTS: Thirty two patients with growth hormone deficiency were recruited, but two withdrew because of side effects. Of the thirty patients (age 35.1 +/- 11.8 year; mean +/- SD) completing the study 13 of were assigned to the placebo group for six months and 17 to active treatment from the start. MEASUREMENTS: Fasting serum samples were analysed for total cholesterol, High density lipoprotein (HDL)-cholesterol, HDL-subfractions, triglycerides, lipoprotein (a) (Lp(a)) and IGF-1. LDL-cholesterol was calculated using the Friedewald formula. RESULTS: Compared to placebo, 6 months treatment with hGH therapy resulted in increased IGF-1 (37.6 +/- 4.1 vs. 14.0 +/- 2.2 nmol/l, P < 0.01), but there was no significant difference in any of the lipid parameters measured between placebo and active treatment groups at 6 months. hGH was associated with a decrease in HDL-cholesterol concentration from baseline to 6 months (0.97 +/- 0.08 to 0.76 +/- 0.10 mmol/l P < 0.01), especially within the HDL2 subfraction. This reduction was maintained at 12 months. There was no change in Lp(a) concentrations from 0 to 6 months (placebo -26 (-340 to 82), median and range, active -4 (-586 to 212) mg/l). There was no change in total cholesterol, LDL-cholesterol, triglycerides or proportion of HDL subfractions. CONCLUSIONS: Treatment with hGH can reduce serum HDL-cholesterol concentrations. Further investigation of this is required.     

Apo E phenotype and changes in serum lipids in adult patients during growth hormone replacement

OBJECTIVE: To determine whether apo E phenotype influences changes in lipid profiles induced by growth hormone replacement in growth hormone (GH)-deficient adults. DESIGNS: Patients were treated for 6 months with recombinant human GH (hGH), given in a dose of 0.125 U/kg per week for 4 weeks followed by 0.25 U/kg per week thereafter. The effects on serum lipids and the influence of apo E phenotype were examined. METHODS: Thirty patients (aged 35.1+/-11.8 years: mean +/- S.D.) with adult growth hormone deficiency with included in the study. Fasting serum samples were analysed for apo E phenotype total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, lipoprotein (a) (Lp(a)) and IGF-I. Low-density lipoprotein (LDL)-cholesterol was calculated using the Friedwald formula. RESULTS: Six months of replacement treatment with hGH resulted in a reduction in HDL-cholesterol from 0.90+/-0.10 to 0.68+/-0.08 mmol/l (P<0.01), and a small, non-significant reduction in total cholesterol from 6.14+/-0.40 to 5.99+/-0.35 mmol/l (P = 0.06). There was no significant change in the other lipid parameters. The decrease in HDL-cholesterol concentration was greater in patients carrying the apo E2 allele (0.40+/-0.07 mmol/l, P<0.05) than in patients homozygous for the apo E3 allele (0.23+/-0.04 mmol/l) and patients carrying the apo E4 allele (0.15+/-0.36 mmol/l). Patients with the apo E4 allele had lower baseline cholesterol concentrations than patients lacking the apo E4 allele, and this persisted after treatment with hGH (P<0.05). CONCLUSIONS: Apo E phenotype may be a determining factor in the response of HDL-cholesterol to hGH in GH-deficient adults.     

Nitrogen metabolism in growth hormone-deficient children receiving oxandrolone and human growth hormone

Five prepubertal growth hormone-deficient children were treated with oxandrolone (0.1 mg/kg/day) and human growth hormone (HGH) 2 mg three times weekly alone and in combination. Average nitrogen retained (mg/kg/day) was calculated from 9-day balance data obtained at the beginning and end of each 6-mo treatment period. Oxandrolone increased the range of nitrogen retention from control values of 2.5–50 to 20.4–107.1, which was statistically significant. Persistently increased nitrogen retention was demonstrable at the end of 6 mo of oxandrolone therapy. Addition of HGH further enhanced the anabolic effect (67.7–139.3), which also was statistically significant and persistent to the end of 6 mo of combination therapy (57.4–114.3). Despite continued HGH treatment with-drawal of oxandrolone was associated with a drop to pretreatment values by the end of 6 mo (0.8–38.4). Oxandrolone and HGH have synergistic anabolic effects which probably involve different mechanisms. During some balance periods, nitrogen retention was calculated by determination of ¹⁵N excretion after oral administration of labeled glycine. Results were similar but lacked statistical significance. The smallest increment in height for 1-yr advancement in bone age while receiving oxandrolone was 2.17 inches.