Adult growth hormone deficiency (GHD): an established diagnosis?

The adult GH deficiency (GHD) indication is now an established clinical therapy worldwide. However, as the number of patients being replaced with GH increases, some aspects in the management of adult GHD patients emerge which are not yet fully defined. These aspects relate primarily to the diagnosis of adult GHD which had initially been based on criteria developed for patients with typical forms of adult pituitary disease (pituitary tumor); the expanding spectrum of the adult GHD indication has disclosed the full variability of the clinical presentation of the adult GHD syndrome indicating the limitations of some existing diagnostic criteria. Other aspects affected by the expanding spectrum of the adult GHD diagnosis are the separation of adult from childhood onset patients and the assessment of long-term outcomes after GH replacement. However, such a situation is by no means surprising as also the use of GH in pediatric endocrinology has been currently improved over decades, based on accumulating clinical experience. Thus it can be anticipated that the adult GHD indication will follow a similar pattern, and more and more optimisation steps will be introduced over time as experience with GH treatment in adults accumulates.

Bone status and fracture prevalence in Russian adults with childhood-onset growth hormone deficiency.

The consequences of lifelong untreated childhood-onset GH deficiency (COGHD) on adult bone and especially fracture prevalence are largely unknown due to the lack of data on long-term outcome of untreated patients. Therefore, we studied adult Russian patients (n = 66; 28 females and 38 males) with idiopathic GH-untreated COGHD. Patients had isolated GH deficiency (IGHD; n = 18, age 23 +/- 10 yr) or multiple pituitary hormone deficiency (MPHD) with open (OMPHD; n = 27, age 23 +/- 5 yr) or closed growth plates (CMPHD; n = 21, age 55 +/- 12 yr). Bone mineral content (BMC) and bone mineral density (BMD) values were compared with 821 normal Russian controls. Fracture prevalence was ascertained from medical history and compared with similar data from 333 normal controls. Height sd score was -4.6 (range, -1.8 to -8.1). This represents 82% of the height of normal Russian adults. BMC of the lumbar spine, femoral neck, and total body of patients with IGHD was 54, 71, and 59%, respectively, of that of age- and sex-matched controls (all P < 0 0.001). A similarly decreased BMC (42-69% of expected values) was found for all bone regions of patients with both OMPHD and CMPHD. Mean areal BMD measurements (g/cm(2)) varied (Z scores between -1.8 and -3.0), but the calculated true bone density (g/cm(3)) was normal in patients with IGHD or CMPHD and only slightly decreased (Z score, -0.8) in patients with OMPHD. Lifetime low-energy fracture prevalence was normal in patients with IGHD but substantially exceeded the expected prevalence in OMPHD (odds ratio of fracture = 3.0; 0.6 fractures per patient; P < 0.0001) or CMPHD patients (odds ratio for fracture = 7.4; 2.2 fractures per patient; P < 0.0001). In conclusion, IGHD and MPHD of childhood onset very substantially impair adult height and BMC. Although areal BMD is frankly decreased, volumetric bone density is unaffected, but nevertheless, the fracture prevalence in patients with MPHD is markedly increased. These observations demonstrate that not only volumetric density but also bone mass and shape are major determinants of bone strength.

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.

Use of human GH in elderly patients with accidental hip fracture.

OBJECTIVE: To investigate whether early intervention with recombinant human growth hormone (hGH) after hip fracture improves functional recovery and long-term outcome. SUBJECTS AND METHODS: Functional recovery after hip fracture is often incomplete. The catabolic situation that develops after the hip fracture accident, and a state of malnutrition either pre-existing or developing after surgery, are main contributing factors for the poor clinical outcome. hGH has been used to promote anabolism in a variety of clinical catabolic situations. The study design was randomized, double-blind and placebo-controlled. A total of 111 patients older than 60 years with an accidental hip fracture (mean age 78.5+/-9.1 (s.d.) years) were randomized to receive either hGH (20 microg/kg per day) or placebo for a period of 6 weeks, starting within 24 h after the hip fracture accident. Thereafter patients were followed up for an additional period of 18 weeks. Efficacy was assessed by comparing the changes in the Barthel Index score of activities of daily living and in a patient's living situation between the hGH- and the placebo-treated subjects. RESULTS: Eighty-five (78.5%) patients completed the first 8 weeks of the study and 76 (68.5%) the entire study period of 24 weeks. When split according to age, a trend was found that for patients older than 75 years the changes in Barthel Index score from baseline were less in the hGH group than in the placebo group (-18.6+/-18 vs -28.1+/-26) at 6 weeks after surgery (P<0.075). There was an overall trend to a higher rate of return to the pre-fracture independent living situation in the hGH group than in the placebo group. Analysis by age revealed a significantly higher proportion of hGH- than placebo-treated patients returning to the pre-fracture living situation for subjects older than 75 years (93.8 vs 75.0%, P=0.034). hGH treatment increased IGF-I values to levels in the range of those of normal subjects of 50-60 years of age. CONCLUSIONS: A 6 week treatment with hGH (20 microg/kg per day) of otherwise healthy patients after an accidental hip fracture may be of benefit if given to subjects older than 75 years of age. The rate of return to the pre-fracture living situation in subjects of this age treated with hGH was significantly increased when compared with the placebo-treated group. The treatment intervention was well tolerated and no safety issues were recorded.

The safety profile of GH replacement therapy in adults.

OBJECTIVE: The benefits of GH replacement in GH-deficient adult patients are becoming accepted but the safety profile continues to be defined. The GH deficiency in adults may have arisen i either childhood or during adult life and these two groups differ with regard to history of disease. The aid of the present report was to study differences in safety profile between these two groups during long-term replacement therapy with recombinant human GH (hGH). Possible factors which placed a patient at risk of experiencing an adverse event were also examined. PATIENTS AND DESIGN: GH-deficient adult patients were randomized into two study protocols, differing only in age of onset of the GH deficiency syndrome. There were 98 patients with adult-onset and 67 patients with childhood-onset GH deficiency. Each study consisted of a 6-month double-blind placebo-controlled phase followed by an open-label hGH treatment phase. Glucose tolerance, incidence of treatment-emergent adverse events and relationship to IGF status were studied throughout the 36 months of treatment. RESULTS: Human growth hormone-related adverse events were reported less commonly in childhood-onset patients compared with adult-onset patients. Adult-onset patients who continued into the open-label therapy phase reported an increased incidence of arthralgia, myalgia and paraesthesia. There were significant increases in fasting glucose with hGH therapy but values remained within the normal range. Hypertension was reported in 7.7% of adult-onset patients at 18 months of hGH, which was within the expected prevalence for the number of patients, but was not reported for any childhood-onset patients. Only in adult-onset patients were sufficient adverse events reported to enable analysis of risk factors. Patients reporting hGH-related adverse events were significantly heavier and, therefore, received more hGH. There was a significantly greater increase in IGF-I and IGFBP-3 in the first month in patients who experienced hGH-related adverse events compared with those who did not. CONCLUSION: The risks of replacement therapy with hGH in GH-deficient adults varied with pathogenesis of disease; hGH-related adverse events occurred more frequently in patients with adult-onset compared with those childhood-onset GH deficiency. In the adult-onset patients there was an increased risk of adverse events in heavier patients and those who had the greatest increases in IGF-I and IGFBP-3 at 1 month of therapy.

Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. Adult Growth Hormone Deficiency Study Group.

The onset of adult GH deficiency may be during either adulthood (AO) or childhood (CO), but potential differences have not previously been examined. In this study the baseline and GH therapy (12.5 micrograms/kg per day) data from CO (n = 74; mean age 29 yr) and AO (n = 99; mean age 44 yr) GH-deficient adult patients have been compared. The first 6 months comprised randomized, double-blind treatment with GH or placebo, then all patients were GH-treated for a further 12 months. At baseline the height, body weight, body mass index, lean body mass, and waist/hip ratio of AO patients were significantly (P < 0.001) greater than in CO patients. Serum insulin-like growth factor-I (IGF-I) levels were below normal but were lower in CO than AO patients (P < 0.001), and the correlation with IGF binding protein-3 was stronger in CO than in AO patients. Osteocalcin concentration in CO patients was above the normal range and significantly greater than in AO patients. Both groups had significant psychosocial distress, but the deviation from normality was greater in AO patients. Throughout GH therapy there was a significant increase in lean body mass and significant decrease in percent body fat and sum of skinfolds in each group. Wais/hip ratio was decreased by long-term therapy in AO but not CO patients. Total and low density lipoprotein cholesterol levels were decreased from baseline at 6 months in AO but not CO patients and high density lipoprotein cholesterol was increased in both groups throughout therapy. IGF-I and IGF binding protein-3 were increased into the normal range by GH therapy in both groups. Mean osteocalcin level in AO patients was increased at 6 months with no further change with GH therapy, whereas in CO patients there was a steep increase up to 12 months but then a sharp decrease. Nottingham Health Profile scores showed significant improvements in physical mobility and energy at 18 months of therapy in AO patients but no consistent effects in CO patients. GH-induced side effects were mainly reported by AO patients; very few CO patients reported treatment-emergent adverse events. These results demonstrate significant differences in clinical and biochemical presentation and responses to therapy of the adult GH deficiency syndrome. This is consistent with the existence of two entities, developmental (CO) and metabolic (AO), and the different functions of GH at different periods of life.