Effects of 7 years of growth hormone replacement therapy in hypopituitary adults

Short-term studies of GH replacement in adult hypopituitarism have usually demonstrated beneficial effects on body composition and circulating lipids, with neutral or occasionally adverse effects on glucose tolerance. Fasting hyperinsulinemia has been reported. GH effects on cardiac function have been variable. The effects of long-term GH therapy, taking into account the consequences of increasing age, are not fully known. Thirty-three hypopituitary, initially middle-aged adults were studied over a 7-yr period; 12 patients took GH therapy (mean, 0.7 mg daily) continuously (group A); 11 took GH for only 6-18 months, a minimum of 5 yr previously (group B); and 10 patients never received GH therapy (group C). Other pituitary replacement was maintained. Effects on anthropometry, body composition (by bioimpedance analysis, total body potassium, and dual energy x-ray absorptiometry), circulating lipids, glucose and insulin concentrations, cardiac 2-dimensional and Doppler echocardiography, and exercise tolerance were assessed before and after the treatment period. Continuous GH therapy had no significant effect on body weight, but it prevented the increase in waist circumference and waist to hip ratio that occurred in the patients without GH substitution (waist to hip ratio, group A, 0.87+/-0.08 at baseline, 0.85+/-0.09 at 7 yr; group B, 0.89+/-0.11 at baseline, 0.94+/-0.11 at 7 yr; P < 0.005 for GH effect; group C, 0.87+/-0.10 at baseline, 0.92+/-0.10 at 7 yr; P < 0.005 for GH effect). A GH-induced decrease in subscapular skinfold thickness was also observed. By bioimpedance analysis, GH therapy caused an increase in total body water and fat-free mass, and a decrease in the percent body fat. Although changes occurred with time in all groups, no significant additional GH therapy effects were observed on glucose tolerance, insulin concentrations, lipid levels, cardiac dimensions, echocardiographic diastolic function, or exercise tolerance. In conclusion, prolonged GH substitution in middle-aged hypopituitary adults causes a sustained improvement in body composition. Other benefits, e.g. on lipid levels and exercise tolerance, were not apparent at 7 yr when comparisons were made with GH-untreated hypopituitary controls. Potentially adverse effects on glucose tolerance and insulinemia did not develop with prolonged GH therapy.     

Growth hormone deficiency and replacement in hypopituitary patients previously treated for acromegaly or Cushing's disease.

OBJECTIVE: To compare baseline characteristics in adult patients with growth hormone (GH) deficiency (GHD) who had previously been treated for Cushing's disease or acromegaly with data from patients with GHD of other aetiologies. To study the effects of GH therapy in those patients who had completed at least 6 months of GH replacement. DESIGN: Data from a large outcomes research database (KIMS (Pharmacia International Metabolic Database)). METHODS: 135 patients were identified with previous Cushing's disease, 40 had had acromegaly, and 1392 had GHD of other aetiologies. The number of additional hormone deficiencies, and the mean age of the patients were similar in the three groups. Similar proportions of patients in each group were treated using surgery, but radiotherapy was used more often in patients with acromegaly than those with other diagnoses. RESULTS: At baseline, the prevalence of diabetes mellitus and hypertension were significantly higher in the group treated for Cushing's disease, and the prevalence of stroke was significantly higher in the group treated for acromegaly. The incidence of coronary heart disease and claudication were similar in all three groups. Patients treated for Cushing's disease had lower bone mineral density and suffered fractures more often than other GHD adults. Body mass index, waist-hip ratio, serum concentrations of lipids and standard deviation scores of serum concentrations of insulin-like-growth factor-I were similar in the three groups. The dose of GH administered was comparable in the three groups and the effects of GH replacement on waist circumference, blood pressure and quality of life were also similar across the groups. The numbers and types of adverse events reported were not different between the groups. CONCLUSIONS: These data suggest that the characteristics of patients in these diagnostic groups depend on the primary disease which resulted in GHD, and that the clinical expression of GHD does not differ between the groups. Patients with previous hypercortisolism showed more long-term effects of their disease, such as diabetes mellitus, hypertension and fractures. A benefit from GH replacement was evident in patients previously treated for acromegaly and Cushing's disease particularly in relation to quality of life.     

Growth hormone treatment in hypopituitary GH deficient adults reduces circulating cortisol levels during hydrocortisone replacement therapy

OBJECTIVES Patients with GH deficiency frequently have multiple hormone deficiencies and require hydrocortisone replacement. We have investigated whether GH treatment alters circulating cortisol levels in hypopituitary patients receiving stable replacement therapy. DESIGN Subjects were studied during 6 or 12 months of S.C. GH at a dose of 0.25 IU/kg/week (0.125 IU/kg/week for the first 4 weeks), and after a wash-out period of at least 2 months off GH (range 2–5 months). PATIENTS Fourteen hypopituitary patients (2F:12M) receiving stable hydrocortisone replacement and thyroxine, gonadal steroids and bromocriptine therapy as required. MEASUREMENTS Serum cortisol values were measured throughout the day over 10.5 hours. Thyroid hormones and cortisol binding globulin (CBG) were measured in the baseline sample. Comparisons of the serum cortisol peak after receiving the first dose of hydrocortisone, the time when the serum cortisol peak was obtained, the area under the curve (AUC) for the cortisol values and the levels of unbound cortisol on and off OH therapy were made. The results are expressed as mean ± SEM. Comparisons were carried out within Individuals, using the Wilcoxon signed rank test. A P-value less than 0.05 was considered statistically significant. RESULTS During OH therapy, there was a significant reduction in the mean cortisol peak (662.2 ± 61.1 vs 848.0 ± 58.6 nmol/l; P= 0.001), and In the AUC for cortisol (185.3 ± 18.3 vs 230 ± 17.9 nmol/l/10.5h; P= 0.03), but there was no significant change in the time of the cortisol peak (55.7 ± 7.6 vs 57.8 ± 4.9 minutes; P= NS). During GH therapy there was a significant reduction In CBG levels (33.64 ± 1.16 vs 40.86 ± 1.34mg/l; P= 0.001); however, no changes were found In the levels of calculated unbound cortisol on and off GH (2.87 ± 0.38 vs 2.90 ± 0.30 nmol/l; P= NS). During OH therapy, there was a significant increase In serum trilodothyronine (T3) (1.88 ± 0.15 vs 1.44 ± 0.11 nmol/l; P= 0.01), and a significant decrease in thyroxine (T4) levels (74.9 ± 11.1 vs 97.6 ± 10.9 nmol/l; P= 0.02) but levels remained within the normal range. No change was observed in serum TSH levels (0.29 ± 0.13 vs 0.83 ± 0.71 mU/I; P = NS). CONCLUSIONS These results suggest that OH therapy In GH deficient adults produces an alteration in the measured serum cortisol profile, with a reduction in concentration of total cortisol in blood after erally administered hydrocortisone. These changes in circulating cortisol probably depend primarily on the fall in CBG levels, as no changes were found in the levels of calculated unbound cortisol on and off GH. Our data show that when measuring circulating cortisol levels, the results should be interpreted with caution in OH deficient patients on GH replacement, and different criteria may have to be applied to the circulating cortlsol profile of these patients. The results highlight the importance of ensuring adequate corticosteroid replacement in patients starting GH therapy.     

Transdermal estrogen replacement does not increase calcitonin secretory reserve in postmenopausal women

The effect of transdermal estrogen replacement on ionized calcium and calcitonin levels was examined in 15 postmenopausal women. Following baseline measurement of calcitonin and ionized calcium in the fasting state, the effect of calcium infusion on calcitonin levels was studied. Estrogen replacement resulted in a fall in baseline ionized calcium, however, the rate of rise of calcium was the same before and after estrogen administration. Thus the time at which a particular calcium concentration was attained was later after the commencement of the calcium infusion following estrogen replacement. Although there was no detectable difference in baseline calcitonin concentrations (pre-estrogen, 2.4 +/- 0.4; post-estrogen, 2.1 +/- 0.4 pmol/l), following estrogen replacement the time at which a particular calcitonin concentration was attained was later after the commencement of the calcium infusion, reflecting the slower attainment of a particular calcium concentration (p = 0.014 by ANOVA). Analysis of total calcitonin production by area under the curve, however, did not show a significant difference before and after estrogen replacement (643 +/- 184 and 407 +/- 115 pmol.l-1.100 min-1, respectively). When the calcitonin response to calcium infusion was compared at the same calcium concentration, estrogen status had no effect on the relationship. We conclude that transdermal estrogen replacement has no effect on calcitonin secretory reserve in postmenopausal women and does not alter the relationship between elevated calcium and calcitonin levels. We cannot exclude an effect of estrogen on baseline calcitonin levels as the calcium concentration was lower but the calcitonin levels not different.     

GH replacement does not increase the risk of recurrence in patients with craniopharyngioma

BACKGROUND: A significant number of patients with craniopharyngioma are GH deficient. The safety of GH replacement in these subjects has not been established. OBJECTIVE: To assess the effect of GH replacement upon recurrence in patients with craniopharyngioma. PATIENTS AND METHODS: All the patients with craniopharyngioma followed-up at the Departments of Endocrinology or Paediatrics in Oxford and treated or not with GH were studied retrospectively. These were recruited from the databases of the departments consisting of subjects diagnosed between January 1964 and July 2005. The impact of GH replacement upon recurrence was evaluated after adjusting for possible confounding factors. RESULTS: Forty-one subjects received GH replacement. Nine of them did not have follow-up imaging during GH therapy and were not included in the statistical analyses. The remaining 32 (22 males/10 females) received GH for a mean period of 6.3 +/- 4.6 years (median 5.1, range 0.8-22); 21 started during childhood (13 of them continued after the achievement of final height with an adult dose) and 11 during adult life. The mean duration of their follow-up (from surgery until last assessment) was 10.8 +/- 9.2 years (range 1.9-40). Fifty-three subjects had not received GH therapy (30 men/23 women). The mean duration of their follow-up (from surgery until last assessment) was 8.3 +/- 8.8 years (range 0.5-36). During the observation period, 4 patients treated with GH and 22 non-GH treated ones developed tumour recurrence. After adjusting for sex, age at tumour diagnosis and type of tumour therapy (gross total removal, partial removal, surgery + irradiation), GH treatment was not a significant independent predictor of recurrence (P = 0.06; hazard ratio = 0.309). Similar results were obtained when the impact of GH replacement was assessed according to its duration (P = 0.18; hazard ratio = 0.991/month of treatment). None of the nine patients with insufficient imaging data for inclusion in the statistical analyses [5 men/4 women, 3 treated with GH during childhood/6 during adult life, mean duration of GH therapy 2.9 +/- 2.4 years (median 1.8, range 0.4-7)] showed clinical features suggestive of recurrence during the period of GH replacement. CONCLUSION Based on the data of the craniopharyngiomas database in Oxford, there is no evidence that GH replacement is associated with an increased risk of tumour recurrence.     

Growth hormone replacement reduces C-reactive protein and large-artery stiffness but does not alter endothelial function in patients with adult growth hormone deficiency

Hypopituitary patients have an increased risk of vascular mortality that may relate to growth hormone deficiency (GHD). We investigated the effects of 6 months of GH therapy on large- and small-artery function and high-sensitivity C-reactive protein (hsCRP) in a cohort of GH-deficient patients. Sixteen hypopituitary patients were randomized to 6 months of GH therapy or no treatment, then vice versa. hsCRP, 24-h blood pressure (BP) and pulse wave velocity (PWV) were measured and resistance arteries were used to construct concentration-response curves to endothelium-dependent and -independent agents. GH therapy increased IGF-1 from 60 +/- 7.2 to 167 +/- 16.2 microg/l [confidence interval (CI) 94.9, 138.8, P < 0.001]. hsCRP declined after 6 months of GH from 3.8 +/- 0.88 to 2.0 +/- 0.49 mg/l (CI 0.73, 3.57, P = 0.006). Mean arterial BP fell from 91.7 +/- 1.5 to 89.3 +/- 1.2 mmHg (CI 0.81, 4.07, P = 0.005), as did PWV (8.1 +/- 0.4 to 6.7 +/- 0.5 m/s). The decline in PWV correlated with the decline in hsCRP (r = 0.68, P = 0.01). Resistance artery function was unchanged after GH therapy. GH replacement may lead to differentially altered production of vasorelaxant agents from the endothelium of large and small arteries. Reduction in vascular inflammation may be associated with reduced vascular risk.     

Growth hormone (GH) replacement decreases serum total and LDL-cholesterol in hypopituitary patients on maintenance HMG CoA reductase inhibitor (statin) therapy

Objective Adult onset GH deficiency (GHD) is characterized by abnormalities of serum lipoprotein profiles and GH replacement results in favourable alterations in serum total and low density lipoprotein (LDL)‐cholesterol. Preliminary evidence has indicated that the effect of GH replacement in this respect may be additive to that of HMG CoA reductase inhibitor (statin) therapy. We have examined this possibility during prospective follow‐up of adult onset hypopituitary patients enrolled in KIMS (Pfizer International Metabolic Database), a pharmacoepidemiological study of GH replacement in adult hypopituitary patients. Design Lipoprotein profiles were measured centrally at baseline and after 12 months GH replacement therapy. Patients Sixty‐one hypopituitary patients (30 male, 31 female) on maintenance statin therapy (mean 2·5 ± 2·7 SD years before GH) (statin group – SG) and 1247 (608 male, 639 female) patients not on hypolipidaemic therapy (nonstatin group – NSG) were studied. All patients were naïve or had not received GH replacement during the 6 months prior to study. Patients who developed diabetes mellitus during the first year of GH therapy or in the subsequent year and those with childhood onset GHD were excluded from this analysis. An established diagnosis of diabetes mellitus was present in 18% SG and 4·4% NSG at baseline. Measurements Serum concentrations of total, high density lipoprotein (HDL)‐cholesterol, triglycerides and IGF‐I were measured centrally in all patients and LDL‐cholesterol was estimated using Friedewald's formula. Results The relative frequency of various statin use was simvastatin 52% (15·8 ± 8·1 mg, mean ± SD), atorvastatin 30% (14·4 ± 7·8 mg), pravastatin 9·8% (31·6 mg ± 13·9 mg), lovastatin 6·6% (17·5 ± 5 mg) and fluvastatin 1·6% (40 mg). Baseline serum total and LDL‐cholesterol (mean ± SD) were 5·2 ± 1·4 and 3·1 ± 1·3 mmol/l in SG and 5·8 ± 1·2 and 3·7 ± 1·0 mmol/l in NSG, respectively (P < 0·0001, SG vs. NSG). After 12 months GH replacement (SG: 0·32 ± 0·17 mg/day; NSG: 0·38 ± 0·1 mg/day) serum total and LDL‐cholesterol decreased by a mean (±SD) of 0·48 (± 1·25) mmol/l (P < 0·0004) and 0·53 (± 1·08) mmol/l (P < 0·0001) in SG and by 0·30 (± 0·89) mmol/l (P < 0·0001) and 0·28 (± 0·80) mmol/l (P < 0·0001) in NSG, respectively. There were no significant changes in HDL‐cholesterol or triglycerides in either group (SG vs. NSG: NS). A relationship between LDL‐cholesterol at baseline and the decrease in LDL‐cholesterol after 12 months GH was evident in both groups (SG: R = –0·54, P < 0·001; NSG: R = –0·4, P < 0·001) and a similar relationship for cholesterol was observed. Conclusions These data indicate that GH replacement exerts additional beneficial effects on lipoprotein profiles in patients on maintenance statin therapy, confirming that the effects of these interventions are complementary rather than exclusive.     

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.     

Parathyroid hormone does not increase nephrogenous cyclic AMP excretion by the dog

The renal excretion of nephrogenous cyclic AMP (NcAMP) increases in response to parathyroid hormone (PTH) in man, and thereby serves as a test of parathyroid function. However, during studies of calcium-PTH (PTH) in man, and thereby serves as a test of parathyroid function. However, during studies of calcium-PTH interrelationships in dogs we observed no change in total urinary cAMP (UcAMP) excretion when endogenous plasma PTH levels were increased up to 10-fold. This study was designed to investigate the effects of physiologic and pharmacologic levels of PTH on NcAMP and UcAMP excretion in the dog. Maintaining plasma Ca 2 mg/dl below normal for 40 minutes caused an 8-fold increase in plasma PTH concentration, a 50% increase in the urinary fractional excretion of phosphate (FEP) but no changes in plasma cAMP levels or in UcAMP or NcAMP excretion. Infusion of a pharmacologic amount of parathyroid extract (15 U/min for 20 min) increased plasma cAMP 5-fold, UcAMP excretion 3-fold and FEP by 50% but was without effect on NcAMP excretion. We conclude that NcAMP excretion is not stimulated by PTH in the dog and thus cannot be used as an index of PTH action in vivo. The increase in UcAMP excretion by pharmacologic amounts of PTH results from glomerular filtration of increased plasma cAMP, which may be generated in bone.     

Growth hormone replacement therapy is not associated with retinal changes

GH and/or growth factors are thought to play a role in the pathogenesis of diabetic retinopathy. In addition, the occurence of retinal changes mimicking diabetic retinopathy in two GH-deficient (GHD) patients receiving GH replacement therapy (GHRT) has recently been reported. The present study was performed to evaluate whether this was a coincidence or whether GHRT might regularly induce retinal changes. Sixty-one GHD patients on GHRT with a mean age of 42.5 +/-17.3 yr were examined by one ophthalmologist (AR). The mean duration of GHRT was 8.4 +/- 3.7 yr in childhood onset and 3.5 +/- 2.1yr in adult onset patients. Plasma insulin-like growth factor I concentrations were 76.4 +/- 49.6 ng/mL before GHRT and 244.3 +/- 119.2 ng/mL while receiving GHRT with a dose of 1.7 +/- 0.7 IU/day. After pupil dilatation with tropicamide, fundus examinations of both eyes were performed using a Volk 90 diopter fundus lens with a slit lamp (Haag Streit, Bern, Switzerland). In none of the patients were vascular or retinal changes like macular edema, microaneurysms, hemorrhages, hard exsudates, cotton wool spots, preproliferative signs, or proliferations found. The optic discs were also normal in all patients. We conclude, therefore, that long-term GHRT can be administered safely in GHD patients without an increased risk of retinal changes.