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.     

The effects of growth hormone replacement therapy on overnight metabolic fuels in hypopituitary patients

OBJECTIVE: Hypopituitary adults on conventional replacement have low concentrations of metabolic fuels throughout the night, possibly related to GH deficiency or to decreased cortisol levels overnight. We investigated whether GH replacement corrects the overnight fuel deficiency. DESIGN: We measured circulating levels of metabolic fuels: glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate (3-OHB) and insulin concentrations over 24 h (from 0730 h to 0700 h) in hypopituitary adults before and after GH treatment in a randomized double-blind placebo-controlled trial of 3 months' duration. PATIENTS: Thirteen hypopituitary patients, 8 women and 5 men, were studied. RESULTS: Six patients (4 women and 2 men) received GH and 7 patients (4 women and 3 men) were allocated to receive placebo. There was no difference in fasting (0730 h), area under the curve (AUC) between 2400 h and 0700 h (overnight) and AUC over 24 h for plasma glucose, 3-OHB, glycerol and insulin concentrations as a result of GH treatment. Fasting and overnight AUC for NEFA were significantly higher on GH treatment ((mean +/- SEM) 243 +/- 29 vs. 446 +/- 90 micromol/l, P = 0.03, 1522 +/- 208 vs. 2167 +/- 123 micromol/l H, P = 0.046, respectively), but AUC over 24 h was not affected significantly. No significant changes in any fuel were seen in the placebo group. The changes in fasting, overnight and 24 h AUC for glucose, 3-OHB, glycerol and insulin levels with GH and with placebo for 3 months were similar. The changes in fasting and overnight AUC for NEFA before and after 3 months were significantly different in the group treated with GH vs. the group treated with placebo (median (lower-upper quartile) 104 (90-276) vs. -89 (-98 to 26) micromol/l, P = 0.002; 633 (263-967) vs. -895 (-1379 to -494) micromol/l h, P = 0.002, respectively), but the changes in 24-h AUC for NEFA were not significant between the two groups. CONCLUSIONS: GH replacement in hypopituitary adults increases fasting and overnight (between 2400 h and 0700 h) non-esterified fatty acid concentrations, consistent with the known lipolytic effect of GH. GH did not influence the concentrations of other metabolic fuels or insulin.     

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.     

The effects of five-year growth hormone replacement therapy on muscle strength in elderly hypopituitary patients

OBJECTIVE: Little is known of the long-term effects of GH replacement therapy on muscle strength in elderly adults with adult onset GH deficiency (GHD). In this study, the effects of 5 years of GH replacement therapy on muscle function were determined in adults over 60 years of age with adult onset GHD. DESIGN: A prospective, open-label, single-centre study. Patients Twenty-six (12 male and 14 female) consecutive hypopituitary adults with adult onset GHD, mean age 65.0 (range 61-74) years. MEASUREMENTS: Upper leg muscle strength was measured using a Kin-Com dynamometer. Right and left handgrip strength were measured using an electronic grip force instrument. RESULTS: The mean insulin-like growth factor-I (IGF-I) SD score increased from -1.10 at baseline to 1.21 at end of the study. Body weight was unchanged during the 5-year study. A sustained increase in lean body mass and a sustained reduction of body fat was observed as measured using dual-energy X-ray absorptiometry (DEXA). The GH replacement therapy induced a sustained increase in isometric (60 degrees ) knee flexor strength. After statistical correction for age and sex variables using observed/predicted value ratios, a sustained increase was also observed in concentric knee flexor strength at an angular velocity of 60 degrees /s, concentric knee extensor strength at 60 degrees /s and 180 degrees /s, and peak right handgrip strength. At baseline, knee flexor strength was 90-96% of predicted, knee extensor strength was 85-87% of predicted, and hand-grip strength was 74-80% of predicted values. At study end, knee flexor strength was 98-106% of predicted, knee extensor strength was 90-100% of predicted, and hand-grip strength was 80-87% of predicted values. CONCLUSION: Elderly patients with adult onset GH deficiency had decreased baseline muscle strength also after correction for age and sex. The 5-year GH replacement therapy normalized knee flexor strength and improved, but did not fully normalize, knee extensor strength and handgrip strength.     

Dehydroepiandrosterone (DHEA) replacement reduces growth hormone (GH) dose requirement in female hypopituitary patients on GH replacement

OBJECTIVE: GH dose requirement is lower in ACTH replete compared with ACTH deficient hypopituitary patients suggesting that adrenal androgens may augment IGF-I generation for a given GH dose. This study aimed to determine the effect of dehydroepiandrosterone (DHEA) administration on GH dose requirements in hypopituitary adults. DESIGN: A double blind placebo controlled trial was conducted adding 50 mg DHEA to the standard replacement of hypopituitary patients, including GH, over an initial 6 months, followed by an open phase study of 6 months DHEA replacement and a final 2 month washout phase after DHEA withdrawal. The dose of GH was adjusted to achieve a constant serum IGF-I. PATIENTS: Thirty female and 21 male hypopituitary patients were enrolled. Data from 26 women and 18 men were analysed after patient withdrawal. MEASUREMENTS: The primary outcome objective was the GH dose required to achieve a stable serum IGF-I. Secondary outcome measures were lipoprotein profiles, insulin, insulin sensitivity, IGFBP-3, waist/hip ratio and indices of bone remodelling. RESULTS: DHEA replacement in female patients lead to a 14.6 +/- 20% reduction in the dose of GH for a constant serum IGF-I (P < 0.05, 95% CI: 1.8, 32.7). This was maintained for 12 months and there was a significant fall in serum IGF-I two months after withdrawal of DHEA. There was no change in the male group. CONCLUSIONS: DHEA replacement may reduce GH dose requirements in female hypopituitary patients.     

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.     

Comparison of measures of body composition in a trial of low dose growth hormone replacement therapy

OBJECTIVE: We assessed the effects of the administration of low dose growth hormone in growth hormone deficient adults on body composition and physical performance. We compared the validity of different measures of body composition in GH treated adults. DESIGN: An uncontrolled longitudinal study of eight patients with GH deficiency who were treated with 4 units of biosynthetic growth hormone (Norditropin), three times a week. Subjects were studied for 8 weeks. PATIENTS: Eight patients with acquired growth hormone deficiency as defined by < 5 mU/l GH following standard provocative investigations in whom other hormone replacement was optimized. MEASUREMENTS: IGF-I was measured on day 1 and after 4 and 8 weeks of treatment with recombinant human growth hormone. Body composition was estimated by dual energy X-ray absorptiometry, bioelectrical impedance, skinfold anthropometry, total body potassium measurement and by computerized tomography of a representative cross-sectional area of thigh on day 1 and following 8 weeks of treatment. Exercise capacity was measured on an electromechanical bicycle and palmar grip strength was measured using a Jamar dynamometer on day 1 and after 8 weeks. RESULTS: IGF-I increased significantly. Exercise capacity and maximum heart rate achieved on the electromechanical bicycle increased significantly. Grip strength did not change. There was a significant increase in fat-free mass and a decline in fat mass as shown by dual energy X-ray absorptiometry and bioelectrical impedance. However, this was not confirmed by other methods. No side-effects were noted. CONCLUSIONS: This study shows that a low dose of biosynthetic growth hormone can elevate IGF-I levels and have a pronounced physical impact in the growth hormone deficient adult without the side-effects seen at higher dosage schedules. Over a 2 month period the increase in fat-free mass may be due to an increase in total body water; however, the decline in fat mass is a genuine effect.     

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.     

Modulation of cortisol metabolism by low-dose growth hormone replacement in elderly hypopituitary patients

11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) functions as a net reductase converting cortisone to cortisol. GH inhibits 11beta-HSD1, resulting in a shift in cortisol metabolism favoring cortisone, an observation that may have significance in patients with ACTH deficiency who are unable to compensate for such changes. We have studied the effect of three doses of GH replacement (0.17, 0.33, and 0.5 mg each given for 12 weeks in ascending order) on cortisol metabolism in nine patients, aged 62-70 yr, with hypopituitarism who were receiving fixed doses of oral hydrocortisone. Serum insulin-like growth factor I levels rose in a dose-dependent manner over the course of the study. Fat mass decreased significantly at 24 weeks (P = 0.02), a change that was maintained at 36 weeks. Fasting serum insulin levels did not change significantly over the course of the study. The ratio of urine cortisol to cortisone metabolites (Fm/Em) fell significantly at 12 weeks (GH dose, 0.17 mg/day) from 1.32 (0.91-2.20) at baseline to 1.08 (0.89-2.11) (P < 0.05). Although it did not fall further as the dose of GH was increased, the reduction in the Fm/Em ratio persisted at 24 weeks (GH dose, 0.33 mg/day), 1.09 (0.8-2.11) (P < 0.05 vs. baseline), and 36 weeks (GH dose, 0.5 mg/day), 1.19 (0.82-2.31) (P < 0.05 vs. baseline). The Fm/Em ratio did not correlate with serum insulin-like growth factor I, fat mass, or fasting insulin levels at any time during the study. This study confirms the inhibitory effect of GH on 11beta-HSD1 but has shown that the effect occurs maximally at very low GH doses and is not mediated indirectly by change in circulating insulin. Patients with partial or total ACTH deficiency, in whom cortisol replacement is suboptimal, may be at risk of the clinical manifestations of cortisol deficiency when they are commenced on GH therapy.     

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.     

Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy

A retrospective comparison was performed between 1411 hypopituitary adults without GH replacement [mean age, 56.9 (sd 18.6) yr] and the normal population in terms of fatal and nonfatal morbidity. A similar prospective comparison was then made in 289 hypopituitary patients on long-term GH replacement [mean age, 47.6 (sd 14.8) yr; mean duration of GH treatment, 60 months].In the 1411 hypopituitary patients without GH replacement, overall mortality (P < 0.001), and the rates of myocardial infarctions (P < 0.01), cerebrovascular events (P < 0.001), and malignancies (P < 0.001) were increased compared with the normal population. Colorectal cancer was the most common malignancy in this cohort (P < 0.001 vs. the background population). In the 289 hypopituitary patients on GH replacement, overall mortality and the rate of malignancies were similar to the normal population. In the hypopituitary adults on GH therapy, the rate of myocardial infarctions was lower than that in the background population (P < 0.05), and there was a tendency toward an increased rate of cerebrovascular events.In conclusion, overall mortality and the rate of myocardial infarctions were increased in hypopituitary patients without GH replacement. An increased rate of malignancies was observed in the hypopituitary adults without GH therapy, with a predominance of colorectal cancer. GH replacement appeared to provide protection from myocardial infarctions. The rate of cerebrovascular events tended to be increased also in hypopituitary adults on GH therapy.     

Effects of growth hormone replacement therapy on levels of cortisol and cortisol-binding globulin in hypopituitary adults

OBJECTIVE: To determine if human growth hormone (hGH) replacement therapy alters pharmacokinetics of hydrocortisone (CS) substitution in hypopituitary adults. DESIGN: To this aim, we analysed serum and salivary CS profiles 270 min after oral CS administration at baseline and 6 and 12 months after initiation of hGH replacement therapy. METHODS: Serum IGF-I, cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG) and sex hormone-binding hormone (SHBG) were measured using commercially available radioimmunoassays. In-house immunofluorometric assays were employed for measurements of CS and hGH. RESULTS: hGH replacement did not change total serum CS bioavailability (area under the serum cortisol profile curve). Interference of orally administered CS with salivary measurement of free CS (fCS) caused significant bias. Therefore, fCS levels were calculated from their total CS and cortisol-binding globulin (CBG) levels. CBG decreased by approximately 30% after both 6 and 12 months of hGH replacement therapy (n=20, P<0.01). A significant negative correlation between deltaCBG (CBG6months-CBGbaseline) and deltaIGF-I (IGF-I6months-IGF-Ibaseline) was observed (P=0.04). The calculated values of free CS tended to increase with physiological hGH replacement, but this effect was marginal and did not reach statistical significance. In contrast to the CBG concentrations, plasma levels of sex hormone-binding globulin and thyroxine-binding globulin were essentially stable. CONCLUSION: Given that no clinically relevant alterations in pharmacokinetics of CS were evoked by initiation of hGH replacement in hypopituitary adults, we conclude that CS substitution does not require dose adjustment after initiation of hGH replacement.     

The effect of growth hormone replacement therapy in hypopituitary adults on calcium and bone metabolism*

OBJECTIVE The importance of growth hormone (GH) for normal skeletal growth in childhood and adolescence is well established but much less is known about its action on the adult skeleton. We therefore wished to investigate the effects of replacement treatment with blosynthetic human GH in hypopituitary adults on aspects of calcium homeostatis, bone metabolism and bone mineral mass. PATIENTS Forty hypopituitary adults (21 females and 19 males; aged 19–67 years). DESIGN A prospective randomized double-blind placebo-controlled trial lasting for 6 months. PROTOCOL Following baseline assessments, GH was given in a daily dose of 0·02–0·05 IU/kg body weight subcutaneously (or a placebo (P)) at bedtime. Patients were reviewed at 1, 3 and 6 months. MEASUREMENTS Plasma calcium, phosphate and total plasma alkaline phosphatase were measured at 0, 1, 3 and 6 months. Serum insulin like growth factor I (IGF-I), osteocalcin, procollagen 1 carboxyterminal peptide (P1CP) and intact parathyroid hormone (PTH) level, 24-hour urinary calcium and creatinine excretion were all measured at 0 and 6 months. Bone mineral density of total body and lumbar spine was also measured by dual energy X-ray absorptiometry at 0 and 6 months in 12 patients on GH and 14 on placebo. RESULTS Thirty-eight patients completed the study (18 on GH, 20 on placebo). Serum IGF-I Increased significantly on GH treatment (mean ± SD) (GH: 276 ± 197 vs P: 88 ± 50 μg/l, P < 0 0001 at 6 months). Plasma calcium increased slightly but significantly in the GH-treated group (2·23 ± 0·11–2·29 ± 0·11 mmol/l, P<0·05). At the end of the study, plasma calcium was however similar on GH and placebo (GH, 2·29 ± 0·11; P, 2·26 ± 0·09 mmol/l). Plasma phosphate increased on GH (GH: 1·02±0·23–1·32±0·19; P: 0·99±0·16–0·96±0·12 mmol/l over the 6 months of treatment, P<0·001). There was no significant change in the urinary calcium excretion on GH therapy. Plasma total alkaline phosphatase, osteocalcin and P1CP were significantly higher on GH than P at 6 months (alkaline phosphatase: GH: 104±32 vs P: 69±32 U/I, P<0·01, osteocalcin: GH: 17·2±8·0 vs P: 5·3±3·2 μg/l, P<0·001 and P1CP: GH: 207 ± 152 vs P: 93±31 μg/l, P<0·01). There was no difference in the intact parathyroid hormone level (GH: 31 ± 14 vs P:31 ± 15 ng/l, NS). No significant change was observed in bone mass after 6 months of GH treatment, either in total body bone mineral content or in the lumbar spine. CONCLUSION In this large study, GH replacement in hypopituitary adults for 6 months increased bone turnover but did not affect bone mineral content. Longer-term studies are required to assess further any effect on bone mass.     

Dehydroepiandrosterone improves psychological well-being in male and female hypopituitary patients on maintenance growth hormone replacement

CONTEXT: Patients with panhypopituitarism have impaired quality of life (QoL) despite GH replacement. They are profoundly androgen deficient, and dehydroepiandrosterone (DHEA) has been shown to have a beneficial effect on well-being and mood in patients with adrenal failure and possibly in hypopituitarism. OBJECTIVE: Our objective was to determine the effect of DHEA administration on mood in hypopituitary adults on established GH replacement with a constant serum IGF-I. DESIGN: A double-blind, placebo-controlled trial was conducted over an initial 6 months followed by an open phase of 6 months of DHEA. SETTING: The study was conducted at a tertiary referral endocrinology unit. PATIENTS: Thirty female and 21 male hypopituitary patients enrolled. Data from 26 females and 18 males were analyzed after patient withdrawal. INTERVENTIONS: DHEA (50 mg) was added to maintenance replacement including GH. MAIN OUTCOME MEASURES: The primary outcome objective was the effect on QoL and libido assessed by QoL assessment in GH deficiency in adults, Short Form 36, General Health Questionnaire, EuroQol, and sexual self-efficacy scale. RESULTS: Patients had impaired QoL at baseline compared with the age-matched British population. Females showed improvement in QoL assessment in GH deficiency in adults score (-2.9 +/- 2.8 DHEA vs.-0.53 +/- 3 placebo; P < 0.05), in Short Form 36 social functioning (14.6 +/- 23.1 DHEA vs.-4.7 +/- 25 placebo; P = 0.047), and general health perception (9.6 +/- 14.2 DHEA vs.-1.2 +/- 11.6 placebo; P = 0.036) after 6 months of DHEA. Men showed improvement in self-esteem (-1.3 +/- 1.7 DHEA vs. 0.5 +/- 1.5 placebo; P = 0.03) and depression (-1.6 +/- 2.2 DHEA vs. 1.2 +/- 2.4 placebo, P = 0.02) domains of the General Health Questionnaire after 6 months of DHEA. CONCLUSIONS: DHEA replacement leads to modest improvement in psychological well-being in female and minor psychological improvement in male hypopituitary patients on GH replacement.     

The effect of growth hormone replacement on serum lipids, lipoproteins, apolipoproteins and cholesterol precursors in adult growth hormone deficient patients

OBJECTIVE Adult patients with growth hormone deflciency are thought to be at higher risk of mortallty from cardiovascular disease. We therefore investlgated the effect of recombinant human growth hormone (rhGH) replacement therapy on fasting serum concentrations of IIplds, lipoproteins and cholesterol precursors in adult growth hormone deficient patients. DESIGN Double-blind placebo controlled trial. Patients were randomly allocated to placebo or rhGH replacement therapy (0·018 Ulkglday for 1 month followed by 0·036 Ufkglday for 1 month). PATIENTS Eighteen patients with severe growth hormone deficiency. MEASUREMENTS Fasting lipid, lipoprotein and cholesterol precursors (lathosterol and mevalonic acid) were measured at baseline and after 2 months. RESULTS In the rhGH treated group there was a significant fall in serum cholesterol (P < 0·01) (6·44 ±0·49 to 5·71 ± 0·48 mmol/l), LDL cholesterol (P < 0·02) (4·29 ± 0·49 to 3·62 ± 0·44 mmol/l), LDL cholesterollHDL cholesterol ratio (P < 0·02) (3·99 · 0·62 to 3·26 ± 0·39), apollpo-protein B (P>0·01 (1·30 ± 0·11 to 1·15 ± 0·11 g/l) and mevalonic acid (P<0·05) (13·4 ±10·96 to 6·21 ± 1·91 μg/l). There were no significant changes In triglycerides, HDL cholesterol, apolipoprotein A1, lipoprotein (a) or lathosterol concentrations. In the GH treated group the rise in serum insulln was inversely correlated wlth the fall in cholesterol (P < 0·05), LDL cholesterol (P < 0·01) and apolipoproteln B (P < 0·01). There were no significant changes in any of the measured variables in the placebo group. CONCLUSION We conclude that GH may be involved in the regulation of lipid and lipoprotein metabolism and that rhGH replacement therapy of adult GHD patients is associated with beneficial changes in lipid and lipoprotein profiles. The reduction in mevalonic acid is consistent with up-regulation of hepatic LDL receptors caused by GH and this may explain the fall in LDL cholesterol and apolipoprotein B concentrations.