GH Replacement Therapy In Adults Research Articles

Long-term Effectiveness and Safety of GH Replacement Therapy in Adults ≥60 Years: Data From NordiNet® IOS and ANSWER.

Effectiveness and safety data on GH replacement therapy (GHRT) in older adults with adult GH deficiency (AGHD) are limited. To compare GHRT safety and clinical outcomes in older (≥60 years and, for some outcomes, ≥75 years) and middle-aged (35-<60 years) patients with AGHD. Ten-year follow-up, real-world data from 2 large noninterventional studies-NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program-were analyzed. GH-naïve and non-naïve patients with AGHD. Norditropin® (somatropin). Outcomes included GH exposure, IGF-I standard deviation scores (SDS), body mass index (BMI), glycated hemoglobin (HbA1c), serious and nonserious adverse reactions (SARs and NSARs, respectively), and serious adverse events (SAEs). Adverse reactions were events with possible/probable causal relationship to GHRT. The effectiveness analysis set comprised 545 middle-aged and 214 older patients (19 aged ≥75 years) from NordiNet® IOS. The full analysis set comprised 1696 middle-aged and 652 older patients (59 aged ≥75 years) from both studies. Mean GH doses were higher in middle-aged vs older patients. For both age groups and sexes, mean IGF-I SDS increased following GHRT, while BMI and HbA1c changes were similar and small.Incidence rate ratios (IRRs) did not differ statistically between older and middle-aged patients for NSARs [IRR (mean, 95% confidence interval) 1.05 (.60; 1.83)] or SARs [.40 (.12; 1.32)]. SAEs were more frequent in older than middle-aged patients [IRR 1.84 (1.29; 2.62)]. Clinical outcomes of GHRT in AGHD were similar in middle-aged and older patients, with no significantly increased risk of GHRT-related adverse reactions in older patients.

Treatment with Growth Hormone for Adults with Growth Hormone Deficiency Syndrome: Benefits and Risks.

Pharmacological treatment of growth hormone deficiency (GHD) in adults began in clinical practice more than 20 years ago. Since then, a great volume of experience has been accumulated on its effects on the symptoms and biochemical alterations that characterize this hormonal deficiency. The effects on body composition, muscle mass and strength, exercise capacity, glucose and lipid profile, bone metabolism, and quality of life have been fully demonstrated. The advance of knowledge has also taken place in the biological and molecular aspects of the action of this hormone in patients who have completed longitudinal growth. In recent years, several epidemiological studies have reported interesting information about the long-term effects of GH replacement therapy in regard to the possible induction of neoplasms and the potential development of diabetes. In addition, GH hormone receptor polymorphism could potentially influence GH therapy. Long-acting GH are under development to create a more convenient GH dosing profile, while retaining the excellent safety, efficacy, and tolerability of daily GH. In this article we compile the most recent data of GH replacement therapy in adults, as well as the molecular aspects that may condition a different sensitivity to this treatment.

Is insulin-like growth factor-I a good marker for treatment adherence in growth hormone deficiency in adulthood?

There is a paucity of studies on adherence to growth hormone treatment in growth hormone deficient (GHD) adults. Therefore, this study reports on adherence to GH-replacement therapy in adults with GHD, with a special focus on the course and potential predictors of nonadherence. Retrospective single-centre cohort study. From the local patient database, 179 suitable patients with GHD were identified. The primary outcome was adherence assessed by calculating the percentage of available prescription data in comparison with recommended GH dosages over a mean follow-up period of 92·4 months. Patients were categorized into five adherence categories ranging from <20% to >80%. Mean overall adherence was 74·0%, with 52·9% of patients falling into the adherence group of >80% and 8·8% of <20%. There was a significant drop in adherence (9·8%) between the first and second years of treatment (P < 0·001). Patients with childhood-onset GHD were significantly less adherent to GH treatment than patients with adult-onset GHD (62·0% vs 77·0%, P = 0·012); however, this finding was no longer significant after including age as a covariate. Frequency of IGF-1 levels lying outside the age- and sex-specific reference range was not a good indicator for adherence. Although overall adherence was relatively high in our study sample, there is a significant amount of patients who should be regarded as nonadherent. This applies in particular to younger patients. Treating physicians should be aware of the fact that IGF-1 levels do not seem to be a good indicator for adherence.

Clinical characteristics and effects of GH replacement therapy in adults with childhood-onset craniopharyngioma compared with those in adults with other causes of childhood-onset hypothalamic–pituitary dysfunction

Adults with childhood-onset (CO) craniopharyngioma (COCP) have poor quality of life (QoL) and clinical outcomes, but few studies have compared these patients with adults with other causes of CO hypothalamic-pituitary dysfunction. In this study, we compared baseline clinical characteristics and patient-reported outcomes before starting GH replacement therapy in adults with GH deficiency (GHD) due to COCP with those of adults either with CO idiopathic/congenital hypopituitarism (COH) or with CO extrasellar (COE) tumours, and evaluated the 1- and 5-year effects of GH replacement therapy. Retrospective analysis of the data recorded in KIMS (Pfizer International Metabolic Database) was carried out. Patients with COCP, COH and COE tumours were evaluated at baseline, and after 1 and 5 years of therapy. Compared with COH and COE patients, more COCP patients underwent surgery, had greater abnormalities of body composition and higher prevalence of pituitary hormone deficits (all P<0.001), but comparable fasting glucose, HbA1c, total cholesterol and LDL-cholesterol levels, marital status, parenthood, living arrangements, education, employment and annual sick-leave days. After 1 and 5 years of GH replacement therapy, similar changes were evident with regard to body composition, fasting glucose and HbA1c levels, QoL, and the level of and satisfaction with physical activity across the three groups. Adults with untreated COCP with GHD at baseline demonstrated more co-morbidities including greater abnormalities of body composition, pituitary hormone deficits and visual field defects. Overall, adults with COCP, COH and COE tumours responded comparably to short- and long-term GH replacement therapy, suggesting that patients with GHD due to COCP benefited from GH replacement therapy to a similar degree as those with other causes of CO hypothalamic-pituitary dysfunction did.

P01-47 Effects of 10 years of GH replacement therapy in adults with GH deficiency of childhood or adulthood onset

P01-47 Effects of 10 years of GH replacement therapy in adults with GH deficiency of childhood or adulthood onset

P-36 Using the candidate-gene approach to investigate the predictive impact of genetic polymorphisms on response to GH replacement therapy in adults

P-36 Using the candidate-gene approach to investigate the predictive impact of genetic polymorphisms on response to GH replacement therapy in adults

Baseline characteristics and response to GH replacement of hypopituitary patients previously irradiated for pituitary adenoma or craniopharyngioma: data from the Pfizer International Metabolic Database

To test the hypothesis whether the effects of GH replacement therapy in adults could be affected by prior pituitary irradiation, the baseline characteristics and response to GH were evaluated in adults with severe GH deficiency (GHD), who had received or not irradiation for the treatment of pituitary adenoma or craniopharyngioma. Data from 447 patients, who had received radiotherapy (427 in addition to surgery), and 630 patients, who were operated on but not irradiated for their tumour, were retrieved from Pfizer International Metabolic Database (KIMS) and compared at baseline and 1 and 2 years following the onset of GH replacement. Irradiated and non-irradiated patients exhibited the expected phenotype of GHD at baseline. However, irradiated patients had a greater impairment in the quality of life (QoL), a higher fat mass, lower high-density lipoprotein cholesterol levels and a lower bone mineral content (BMC) than non-irradiated patients. Treatment with GH induced similar changes in both groups. After 1 year of GH replacement, there was an increase in serum IGF-I and fat-free mass, a reduction in fat mass and an improvement in QoL, all changes being equivalent in irradiated and non-irradiated patients. The lipid profile also improved with the irradiated patients showing a better response. These beneficial effects were maintained and the BMC also increased in both groups by the second year of treatment. This analysis shows that prior irradiation for pituitary adenoma or craniopharyngioma does not compromise the beneficial effects of GH replacement therapy.

Effects of GH replacement therapy in adults on serum levels of leptin and ghrelin: the role of lipolysis

The regulation and function of systemic ghrelin levels appear to be associated with food intake and energy balance rather than GH. Since GH, in turn, acutely induces lipolysis and insulin resistance in skeletal muscle, we aimed to study the isolated and combined effects of GH, free fatty acids (FFAs) and insulin sensitivity on circulating ghrelin levels in human subjects. Seven GH-deficient patients (aged 37 +/- 4 years (mean +/- s.e.)) were studied on four occasions in a 2 x 2 factorial design with and without GH substitution and with and without administration of acipimox, which lowers FFA levels by inhibition of the hormone-sensitive lipase, in the basal state and during a hyperinsulinemic euglycemic clamp. Serum FFA levels decreased with acipimox administration irrespective of GH status. The GH-induced reduction in insulin sensitivity was countered by acipimox. Fasting ghrelin levels decreased insignificantly during GH administration alone, but were reduced by 33% during co-administration of GH and acipimox (Aci) (in ng/l): 860 +/- 120 (-GH - Aci), 711 +/- 130 (-GH + Aci), 806 +/- 130 (+GH - Aci), 574 +/- 129 (+GH + Aci), P < 0.01. The clamp was associated with a further, moderate lowering of ghrelin. GH and acipimox induced a reciprocal 25% increase in serum leptin levels (microg/l): 11.2 +/- 4.4 (-GH - Aci), 11.7 +/- 4.4 (-GH + Aci), 11.5 +/- 4.4 (+GH - Aci), 13.9 +/- 4.2 (+GH + Aci), P = 0.005. Our data suggest that antilipolysis via suppression of the hormone-sensitive lipase in combination with GH administration is associated with significant and reciprocal changes in ghrelin and leptin.

Long-term growth hormone replacement therapy in hypopituitary adults.

Growth hormone deficiency (GHD) in the adult has now been fully recognised as a clinical entity characterised by abnormal body composition, osteopenia, impaired quality of life, cardiac dysfunction and an adverse lipid profile. While short-term studies of GH replacement have demonstrated irrefutably a favourable effect on all if not most features of GHD, data on long-term administration spanning more than 2 years are still scarce. Experience of GH replacement up to 5 to 10 years indicate that the beneficial effects on body composition, predominantly a decrease in body fat and an increase in lean mass, is maintained during treatment. Long-term GH therapy also increases muscle strength and exercise performance. All data, with one exception, are consistent with a significant increase in bone mass during prolonged GH therapy. The most distinct effect on bone was observed in the worst affected individuals and in males. Improvement in quality of life is documented shortly after initiation of GH replacement and is maintained during long-term studies. This may explain the reduction in days of sick leave seen during GH therapy. The beneficial effect on cardiovascular risk factors is sustained over a prolonged period of time, revealing a reduction in intima wall thickness, and an improvement in serum lipid levels and clotting parameters. The increase in lipoprotein(a) levels with GH therapy in some studies may be disturbing, but difficulties in measuring this parameter and inconsistencies between the different studies makes it difficult to estimate its real impact. No data are yet available to show that GH replacement will normalise or even improve mortality rate and fracture rate. Adverse events associated with GH replacement therapy are mainly secondary to fluid retention as a result of excess dose administration. This can be adequately prevented by monitoring GH replacement according to serum insulin-like growth factor (IGF)-I levels. From what is currently known, GH replacement does not increase the prevalence of diabetes mellitus, and does not induce new neoplasms or recurrence of the primary brain tumour; however, longer follow-up studies are needed to provide definitive answers. In conclusion, it appears not only that long-term GH replacement therapy in adults with GHD is a procedure that can be safely used, but that GH replacement should be considered as a possible life-long therapy in order to maintain its benefits.

Baseline Characteristics and the Effects of Five Years of GH Replacement Therapy in Adults with GH Deficiency of Childhood or Adulthood Onset: A Comparative, Prospective Study

Baseline Characteristics and the Effects of Five Years of GH Replacement Therapy in Adults with GH Deficiency of Childhood or Adulthood Onset: A Comparative, Prospective Study

Coronary risk in growth hormone deficient hypopituitary adults: increased predicted risk is due largely to lipid profile abnormalities.

Hypopituitarism in adults is associated with increased vascular mortality, which has been attributed to GH deficiency. To compare the lipid profile and coronary risk predicted by the Framingham Heart Study equation in GH-deficient hypopituitary patients and healthy age and gender-matched controls. A cross-sectional observational study. We studied 50 adult-onset growth hormone deficient hypopituitary patients (23F, 27M), on appropriate conventional hormone replacement and 45 controls (22F, 23M) matched for age, gender and smoking habit. The subjects (age range 30-75 years) were free from diabetes, hypertension, ischaemic heart disease (IHD) and peripheral vascular disease. All hypogonadal male patients were on testosterone replacement therapy. A similar proportion of female patients (8/23) and controls (7/22) were on HRT. Body mass index (BMI), waist-hip ratio (WHR) and blood pressure were recorded. After an overnight fast blood glucose, total-cholesterol, triglycerides, HDL-cholesterol, apolipoproteins A-I, B and Lp (a) were measured. Coronary risk was calculated for each individual from age, gender, systolic blood pressure, total and HDL cholesterol, smoking habit and presence of diabetes and left ventricular hypertrophy using the Framingham equation. BMI and WHR were significantly increased in GHD hypopituitary adults of both sexes, but to a greater extent in females. Triglycerides were elevated in both sexes. Total and LDL-cholesterol were increased in both sexes (significantly only in males), and HDL cholesterol and apo A-I were lower (significantly only in females). The reduction in HDL cholesterol was correlated negatively with adiposity (BMI), particularly when centrally distributed (WHR) in patients and controls. LDL cholesterol did not correlate to adiposity but higher levels were present in GH-deficient subjects. The total to HDL cholesterol ratio was significantly increased in patients of both genders (P = 0.002). There were no differences in the apolipoproteins B and Lp(a) between patients and controls. Absolute risk (mean +/- SEM) of a fatal or non-fatal coronary event during the next 5 years was significantly greater in GHD hypopituitary patients than control subjects (4.82 +/- 0.73% vs. 2.94 +/- 0.53, P = 0.04). Cardiovascular risk relative to the local population (RR) was significantly higher in GHD hypopituitary adults (RR = 1.43 CL 1.06-1.80, P = 0.011) but not in the control group (1.08 CL 0.59-1.6). When divided by gender, RR for male patients was not increased (1.14 CL 0.83-1.45, P = 0.096). However, female patients had significantly higher RR (1.7 CL 1.05-2.5, P = 0.048). The RR for male and female controls was not different from the local population. Changes in lipid levels help to explain the results from risk factor modelling which show increased coronary risk in growth hormone deficient hypopituitary patients, particularly females. The abnormal lipid profile is characterized in both genders by an increase in the total to HDL ratio [corrected], an important parameter in the Framingham equation. The lipid abnormalities conferring increased risk is related to growth hormone deficiency either directly (LDL) or indirectly through increased central obesity (HDL) [corrected]. Adverse calculated coronary risk might provide a new objective indication for consideration of GH replacement therapy in adults.

The Treatment of Growth Hormone Deficiency in Adults

In analogy with other hormonal replacement therapy GH treatment should be commenced with a low starting dose, independent of body weight or body surface area. Hormonal replacement should mimic the normal physiology to minimize the risk of side effects in the life-long replacement of adults. We should, therefore, consider individual responsiveness and also be aware of the difference between pattern of GH under normal condition and during s.c. administration. The safety and monitoring of GH replacement therapy in adults have been addressed in the Growth Hormone Research Society Consensus Guidelines for Diagnosis and Treatment of Adults with GH Deficiency from the Port Stephens Workshop, April 1997. Besides finding better and more accurate biochemical markers for choosing correct GH replacement dose, future research should address the long-term benefits and safety with GH replacement in adults, with special emphasize on incipient risks in terms of cardiovascular disease and of neoplasia, in particular.

Treatment of Growth Hormone Deficiency in Adults

In analogy with other hormonal replacement therapy GH treatment should be commenced with a low starting dose, independent of body weight or body surface area. Hormonal replacement should mimic the normal physiology to minimize the risk of side effects in the life-long replacement of adults. We should, therefore, consider individual responsiveness and also be aware of the difference between pattern of GH under normal condition and during s.c. administration. The safety and monitoring of GH replacement therapy in adults have been addressed in the Growth Hormone Research Society Consensus Guidelines for Diagnosis and Treatment of Adults with GH Deficiency from the Port Stephens Workshop, April 1997. Besides finding better and more accurate biochemical markers for choosing correct GH replacement dose, future research should address the long-term benefits and safety with GH replacement in adults, with special emphasize on incipient risks in terms of cardiovascular disease and of neoplasia, in particular.

Guidelines for optimizing growth hormone replacement therapy in adults.

To minimize the rate of side-effects, a retrospective analysis of 28 studies of GH replacement therapy in adults indicates that the maintenance dose should usually not exceed 1.0 IU/m2/day (about 1.5-2.0 IU/day) in GHD patients 40-60 years old, or 1.5 IU/m2/day (about 2.5-3.0 IU/day) in GHD patients 20-40 years old. GHD women may tolerate, and in fact may need, higher replacement doses, though this issue requires further investigation. GH treatment should be started at a low dose, i.e. about 1.0 IU/day, and increased gradually, by about 0.5 IU per month, until the target dose is reached. In the absence of side-effects, the GH dose may be either too low, adequate, or too high. Measurement of GH-dependent serum markers provides the most promising approach to detect both GH depletion and excess, with serum IGF-I concentration the current method of choice. Clinical awareness of symptoms of GH excess remains important, however, particularly in patients with IGF-I levels in the high normal range.

The prevalence of severe growth hormone deficiency in adults who received growth hormone replacement in childhood

The few previous studies in which reassessment of GH status has been carried out in young adults treated with GH therapy for childhood GH deficiency concentrated on determining the incidence of 'transient GH deficiency'. As the benefits of GH replacement therapy in adults become increasingly appreciated, it is likely that GH therapy started in childhood for GH deficiency will be continued into adult life in many of those with severe GH deficiency. The aim of this study is to determine how many patients who received GH replacement therapy in childhood until completion of growth have GH deficiency severe enough to be considered for GH replacement therapy in adult life. Retrospective analysis of the peak GH responses to provocative stimuli performed at the time of diagnosis of GH deficiency in childhood and at the completion of growth after GH replacement therapy had been stopped. Eighty-eight adults (49 male, 39 female) who had received GH therapy in childhood for a diagnosis of GH deficiency. The aetiology of the GH deficiency included craniopharyngioma, radiation induced associated with either a cerebral tumour or acute lymphoblastic leukaemia, histiocytosis-X and idiopathic. In childhood the original diagnosis of GH deficiency was based biochemically on the failure of the peak GH response to reach 20 mU/l during two provocative tests in 59 of the 88 patients and to a single test in the remaining 29. A total of 147 tests were performed, the most common being an insulin tolerance test (ITT, n = 72) and an arginine stimulation test (AST, n = 53). At reassessment in young adult life 146 tests were performed (74 ITT, 64 AST). Severe GH deficiency was defined arbitrarily as a peak GH response of less than 9 mU/l to a single (n = 33) or to two (n = 55) pharmacological stimuli. By definition all patients were considered GH deficient at the time of initial diagnosis. A peak GH response of less than 9 mU/l was seen in 64.8% at initial assessment and 60.2% at reassessment. Analysis in aetiological terms, however, showed that between assessments the incidence of severe GH deficiency increased in the group of radiation induced (48.8 vs. 55.8%) but decreased in the idiopathic group (78.1 vs. 53.1%). Out of the 55 patients who underwent two tests at reassessment, 47.3% of those with a GH peak less than 9 mU/l at one test had a GH peak greater than 9 mU/l at the second test. Fifteen of the 55 patients had additional pituitary hormone deficiencies and all 15 had a GH peak below 9 mU/l in both tests. Our study suggests that all children who have received GH replacement therapy in childhood should undergo reassessment of GH status in young adult life. Between 40 and 60% of such patients merit consideration for GH therapy in adult life depending on the definition of severe GH deficiency in use. Patients with isolated GH deficiency should undergo two provocative tests of GH secretion, but those with additional anterior pituitary hormone deficiencies require only one test at reassessment.

The optimal growth hormone replacement dose in adults, derived from bioimpedance analysis.

The prevalence of clinical signs and symptoms related to fluid retention is high in most studies evaluating the efficacy of GH treatment in GH-deficient (GHD) adults. This may be a consequence of supraphysiological GH replacement. To examine whether fluid retention is a dose-related phenomenon, we evaluated the impact of various GH substitution doses on body fluid status in 46 GHD men participating in a 1-yr, double blind, and placebo-controlled study. The patients were randomized to receive either placebo (n = 13) or GH in a dose of 1 (n = 11), 2 (n = 10), or 3 (n = 12) IU/m2.day, respectively. Treatment was started at one third of the predetermined dose and was subsequently increased by another third every month until the maintenance dose was reached. Tissue hydration was assessed by means of electrical impedance measurements. Normal values were obtained from 128 age- and sex-matched controls. In the untreated GHD state, whole body resistance was abnormally high (observed, 642 +/- 82 omega; predicted, 550 +/- 31 omega; P < 0.001). This was mainly caused by an increase in specific resistance of the lean body as a consequence of a reduction in extracellular water (ECW). The first month of GH treatment was associated with a sharp decline in electrical resistance that was attributed to an increase in ECW. Whole body resistance reached its nadir after 3 months of treatment (517 +/- 72 omega, i.e. 19.6 +/- 6.5% lower than before treatment; P < 0.001) and did not change significantly thereafter. The GH-induced changes in body resistance were dose dependent. A significant decrease was observed with a dose as low as 0.33 IU/m2.day (P < 0.005). However, whole body resistance remained higher than normal in patients receiving less than 0.67 IU/m2.day (P = 0.05). Abnormally low resistance values, indicative of overhydration, were observed in patients receiving doses equal to or higher than 2 IU/m2.day (P < 0.005). Regression analysis of the pooled data showed that GH replacement in a dose of 1.10 IU/m2.day (95% confidence interval, 0.85-1.45 IU/m2.day) resulted in a normalization of whole body resistance. In conclusion, GH replacement therapy in adults rapidly corrects the preexisting deficit in ECW. This rehydration process is dose dependent and may result in a substantial weight gain.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth hormone deficiency in adults. Introduction to the problem

Growth hormone deficiency (GH) for a long time was recognized only in childhood. Compelling evidence has been obtained showing that HR replacement therapy effectively stimulates growth and, in many cases, achieves normal end-points of physical development. More recently, it was shown that the most effective in this regard was the appointment of regular evening injections of the drug, which mimic the physiological secretion of GH during sleep. Despite the fact that the acceleration of linear growth is the most objective criterion for the effectiveness of therapy for GH, it is known that GH has a significant effect on body structure, causing a decrease in fat mass and an increase in muscle mass.&#x0D; Until recently, GH was not considered an important hormonal regulator in adults, and therefore, there was no study of GH deficiency and treatment of children with GH deficiency when they reached adulthood, as well as patients with hypopituitarism who became ill in adulthood. However, in 1989, as a result of two double-blind trials using placebo in the control group, the effectiveness of GH replacement therapy in adults with an abnormally low level of GH, up to a severe degree of GH deficiency, was revealed. Further studies showed the presence of violations of both physical and mental status in adults in whom GH deficiency develops as a result of the tumor process in the pituitary gland or its therapy. Most of these disorders, but not all, can be corrected as a result of GH replacement therapy, which confirms the significant effect of GH throughout life.

Beneficial effects of GH replacement therapy in adults

Growth hormone deficiency in adults is associated with psychosocial maladjustment, reduced muscle strength, and reduced exercise capacity. Body composition is significantly altered, with increased fat and decreased muscle volume as compared with healthy subjects. Kidney function is subnormal. Epidemiological data suggest premature mortality owing to cardiovascular disease in hypopituitary patients. Short-term GH treatment trials have shown improved psychosocial performance, normalization of body composition, increased muscle strength, improved exercise capacity, increased cardiac performance, and normalization of kidney function. Thus GH replacement therapy in GH-deficient adults exhibits potential long-term beneficial effects. A number of important questions have to be addressed before long-term GH replacement therapy in GH-deficient adults can be considered on a routine basis.