Post-operative volumes following endoscopic surgery for non-functioning pituitary macroadenomas are predictive of further intervention, but not endocrine outcomes.

BACKGROUND: Transsphenoidal surgery (TSS) remains the treatment of choice for non-functioning pituitary macroadenomas (NFPMA). The value of measuring tumour volumes before and after surgery, and its influence on endocrine outcomes and further treatment of the residual or recurrent tumour are unknown. METHODS: Data from patients who underwent endoscopic TSS for a NFPMA (2009-2018) in a UK tertiary centre were analysed for pre- and post-operative endocrine and surgical outcomes. RESULTS: Of 173 patients with NFPMA, 159 (61% male) were treatment naïve. At presentation, 76.2% (77/101) had ≥1 pituitary axis deficit. Older age (p = 0.002) was an independent predictor for multiple hormonal deficiencies. Preoperative tumour volume did not correlate with degree of hypopituitarism. Postoperative tumour volume and extent of tumour resection were not predictive of new onset hypopituitarism. Hormonal recovery was observed in 16 patients (20.8%) with impaired pituitary function, with the greatest recovery in the hypothalamic-pituitary-adrenal axis (21.2%, 7/33). A larger residual tumour volume was predictive of adjuvant radiotherapy (3.40 vs. 1.24 cm3, p = 0.005) and likelihood for repeat surgery (5.40 vs. 1.67cm3, p = 0.004). CONCLUSION: Pre- and post-operative NFPMA volumes fail to predict the number of pituitary hormone deficits, however, greater post-operative residual volumes increase the likelihood of further intervention to control tumour growth.

High-dose oral colecalciferol loading in obesity: impact of body mass index and its utility prior to bariatric surgery to treat vitamin D deficiency.

Obesity is associated with lower vitamin D levels compared with normal weight subjects, and if levels are not replaced prior to bariatric surgery, this can increase fracture risk as bone density typically falls post-operatively. We analysed the effect of body mass index (BMI) on vitamin D levels in response to 300 000 IU of colecalciferol in patients with vitamin D deficiency (<30 nmol L-1 ). Patients were grouped according to their BMI as normal weight (20-24.9 kg m-2 ), overweight (25-29.9 kg m-2 ), obese class I (30-34.9 kg m-2 ) and obese class II and above (>35 kg m-2 ). The records were retrospectively analysed to investigate the effects of BMI on vitamin D (total 25-hydroxy vitamin D [25(OH)D]), serum Ca2+ and parathyroid hormone (PTH) levels at 6, 12, 26 and 52 weeks compared with baseline. Compared with normal weight subjects, overweight and obese patients achieved lower mean peak total 25(OH)D levels (6 weeks post-loading), which was most significant in the class II and above group (mean total 25(OH)D levels 96.5 ± 24.2 nmol L-1 and 72.42 ± 24.9 nmol L-1 , respectively; P = 0.003). By 26 weeks, total 25(OH)D levels fell in all groups; however, there was now a significant difference between the normal weight subjects and all other groups (mean total 25(OH)D levels 84.1 ± 23.7 nmol L-1 ; 58 ± 20 nmol L-1 , P = 0.0002; 62.65 ± 19.2 nmol L-1 , P = 0.005; 59.2 ± 21 nmol L-1 , P = 0.005, respectively). Far fewer patients in the overweight and obese groups maintained levels above the recommended level of 75 nmol L-1 52 weeks post-loading (93%; 20%, P = 0.0003; 23%, P = 0.01; and 14%, P = 0.001, respectively). Alternative regimes for the treatment of vitamin D deficiency are needed in overweight and obese patients, especially those in whom bariatric surgery is planned.

Thyroid dysfunction and fibrin network structure: a mechanism for increased thrombotic risk in hyperthyroid individuals.

CONTEXT: Hyperthyroidism is associated with increased thrombosis risk, and fibrin clot structure determines susceptibility to vascular thrombotic events. OBJECTIVE: Our objective was to investigate clot formation and lysis in hyperthyroidism using observational and interventional studies. DESIGN: Ex vivo fibrin clot structure/fibrinolysis and plasma levels of thrombotic/inflammatory markers were investigated in hyperthyroid individuals (n = 24) and matched controls (n = 19), using turbidimetric assays, ELISA, and confocal and electron microscopy. The effects of normalizing thyroid function were analyzed (n = 19) and the role of short-term exogenous hyperthyroidism in healthy volunteers studied (n = 16). RESULTS: Hyperthyroid subjects displayed higher clot maximum absorbance compared with controls (0.41 ± 0.03 and 0.27 ± 0.01 arbitrary units, respectively; P < 0.01), and longer clot lysis time (518 ± 23 and 461 ± 18 sec, respectively; P < 0.05), which correlated with free T(4) levels. Plasma levels of fibrinogen and plasminogen activator inhibitor-1 were significantly higher in patients compared with controls. Normalizing thyroid function in 19 subjects was associated with lower maximum absorbance and shorter lysis time, accompanied by reduction in fibrinogen, plasminogen activator inhibitor-1, and D-dimer levels. Complement C3, but not C-reactive protein, levels were higher in hyperthyroid subjects compared with controls (0.92 ± 0.05 and 0.64 ± 0.03 g/liter, respectively; P < 0.01), correlated with clot structure parameters, and decreased after intervention. Confocal and electron microscopy confirmed more compact clots and impaired fibrinolysis during hyperthyroidism. Exogenous hyperthyroidism in healthy volunteers had no effect on any of the clot structure parameters. CONCLUSIONS: Endogenous hyperthyroidism is associated with more compact clots and resistance to fibrinolysis ex vivo, related to the degree of hyperthyroidism and C3 plasma levels, and these changes are modulated by achieving euthyroidism. Altered clot structure/lysis may be one mechanism for increased thrombotic risk in hyperthyroidism.

A case of parathyroid carcinoma with severe hungry bone syndrome and review of literature.

We present a 45 year old female who was initially seen by Rheumatologist with long standing knee pain affecting her mobility. She was found to be severely hypercalcaemic and exhibited features suggestive of parathyroid carcinoma (palpable neck mass, extremely high parathyroid hormone, high alkaline phosphatase, concomitant presence of renal disease and skeletal involvement). Hence she was referred for parathyroidectomy. Postoperatively she developed profound hypocalcaemia with markedly raised serum alkaline phosphatase, requiring intensive intravenous calcium and oral vitamin D supplements, consistent with the development of hungry bone syndrome (HBS). HBS is a complication of parathyroid surgery where the correction of primary hyperparathyroidism is associated with rapid bone remineralisation, causing severe and prolonged hypocalcaemia. HBS is relatively rare but has to be considered in the differential diagnosis of postoperative hypocalcaemia particularly in severe cases. In the current report, we discuss pathogenesis, clinical course and management of HBS.

Utility of biochemical screening in the context of evaluating patients with a presumptive diagnosis of osteoporosis.

The ageing population is expected to increase the burden of osteoporosis on the health care system. Secondary causes of osteoporosis are found in a proportion of patients. There is much controversy regarding the best work-up for patients who have been diagnosed as having osteoporosis based on bone mineral density. It is difficult to decide where interventions should be targeted both from a patient's perspective and for cost effectiveness. We evaluated the utility of a standard panel (full blood count, plasma viscosity, plasma protein, electrophoresis, urine Bence Jones protein, thyroid function test, bone profile, fasting lipids and liver function test) of biochemical investigations in 327 consecutive patients (287 females, 40 males) referred to the new patient osteoporosis clinic from April 1999 to March 2000. Patients were characterised after measurement of spinal/femoral neck bone mineral density after a dual energy X-ray absorptiometry (DEXA) scan. There were 88 patients with osteoporosis, 91 with osteopenia, 130 had normal bone mineral density and 20 who did not have a bone scan. No case of multiple myeloma was found in this cohort of patients. There was no difference in the mean plasma viscosity of patients with and without osteoporosis (P=0.182). There was no significant difference in the abnormal urine calcium/creatinine (Ca/Cr ratio) in patients with osteoporosis and those without osteoporosis (P=0.316). There was no significant difference in the prevalence of hypothyroidism (P=0.213) or thyrotoxicosis (P=0.138) in patients with and without osteoporosis. There was no strong correlation between cholesterol concentrations and osteoporosis (r=0.069). We found no utility in performing a myeloma screen. A small proportion of patients had abnormalities of calcium homeostasis or thyroid disease. We recommend that a screening biochemical evaluation should be restricted to calcium/bone profile and thyroid function tests in patients with a presumptive diagnosis of osteoporosis.

Cognitive dysfunction in patients with pituitary tumour who have been treated with transfrontal or transsphenoidal surgery or medication.

OBJECTIVE: This study was carried out to examine the neuropsychological status of patients treated for pituitary tumour by transfrontal surgery, transphenoidal surgery or medical treatment only, with or without radiotherapy. DESIGN AND MEASUREMENTS: Three groups of 23 patients who had been treated for pituitary tumour were compared with 23 healthy controls on a range of neuropsychological measures. The surgical patients were also subdivided into two groups and compared. The neuropsychological measures were standardized psychological tests designed to assess aspects of attention, memory and executive function. PATIENTS: The patients were those who had been treated with transfrontal surgery (n = 23), transsphenoidal surgery (n = 23) and medication only (n = 23). The groups did not differ with respect to age, education or premorbid ability level as assessed by the National Adult Reading Test. All participants were free of known sources of cognitive impairment other than pituitary tumour. RESULTS: Comparison of the four groups revealed that nearly half of the transfrontal, one-third of the transsphenoidal and one-quarter of the non-surgical group had three or more neuropsychological tests scores below the 10th percentile compared to less than 5% of the controls. Impairments in memory and executive function were found in both surgical groups. The non-surgical patients appeared to have problems only on tasks requiring high levels of cognitive processing. Differences were found between the two surgical groups with respect to the severity of the cognitive impairment, the transfrontal patients having more severe impairment than the transsphenoidal. No significant negative effects on cognitive functioning were associated with radiotherapy; however, transfrontal surgery patients who had not been treated with radiotherapy were found to be more impaired than other patients. This was thought to be related to radical surgery. CONCLUSIONS: Many patients with treated pituitary tumour suffer significant cognitive impairment. The severity and nature of impairment differs between treatment groups, although the cause of this could not be addressed by this study. Recommendations are made for future research and clinical practice.

Bilateral sequential inferior petrosal sinus sampling with corticotrophin-releasing hormone stimulation in the diagnosis of Cushing's disease.

OBJECTIVE: The demonstration of a central to peripheral ACTH gradient in a hypercortisolaemic patient is diagnostic of Cushing's disease. We tried to determine whether single blood samples for ACTH obtained sequentially from each of the inferior petrosal sinuses following human corticotrophin-releasing hormone (hCRH) stimulation can reliably establish such a gradient. DESIGN: Prospective study. PATIENTS: Seventeen patients with clinical and biochemical features of Cushing's syndrome. METHODS: After the administration of hCRH, the patients underwent bilateral sequential inferior petrosal sinus sampling, with a single blood sample obtained from each of the inferior petrosal sinuses sequentially, along with a peripheral venous sample. The petrosal sinus catheter was withdrawn immediately after obtaining a blood sample. Patients did not require indwelling catheters in the petrosal sinuses, nor heparinisation. RESULTS: Bilateral sequential inferior petrosal sinus sampling correctly identified a pituitary source of ACTH, as shown by a central to peripheral ACTH ratio >2, in all patients in whom the procedure was successfully carried out. All patients underwent transsphenoidal pituitary surgery resulting in remission. CONCLUSIONS: The simplified method of inferior petrosal sinus sampling, using a single sequential sample from each of the inferior petrosal sinuses, following initial hCRH stimulation, is as accurate as the more complex test using multiple bilateral simultaneous inferior petrosal sinus samples. It avoids the use of indwelling cerebral venous catheters and is therefore unlikely to cause brain stem damage.

Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group.

Patients with acromegaly have a reduced life expectancy, with the accepted causes for premature death being vascular and respiratory disease. Increased mortality from malignant disease has also been reported. We, therefore, performed a multicenter retrospective cohort study of 1362 patients with acromegaly and investigated the relationships of mortality and cancer incidence with GH levels, duration of disease, and age at diagnosis. The overall cancer incidence rate [standardized incidence ratio, 0.76; 95% confidence interval (CI), 0.60-0.95] was lower than that in the general population of the United Kingdom, and there was no significant increase in site-specific cancer incidence rates. The overall cancer mortality rate was not increased, but the colon cancer mortality rate (standardized mortality ratio, 2.47; 95% CI, 1.31-4.22) was higher than expected. Mortality rates due to colon cancer, all malignant disease, cardiovascular disease and overall mortality were increased with higher posttreatment GH levels (P for trends, <0.02, <0.05, <0.02, and <0.0001). The overall mortality rate in patients with acromegaly with posttreatment GH levels less than 2.5 ng/mL (5 mU/L) was comparable to that in the general population of the United Kingdom (standardized mortality ratio, 1.10; 95% CI, 0.89-1.35). We conclude that high posttreatment GH levels are associated with an increased overall mortality rate and increased mortality rates due to colon cancer, cardiovascular disease, and all malignant disease. Posttreatment GH levels less than 2.5 ng/mL (5 mU/L) result in an overall mortality rate similar to that in the general population.

Comparison of the diagnostic utility of the simplified and standard i.m. glucagon stimulation test (IMGST).

OBJECTIVE: To compare the peak GH and cortisol responses to the simplified and standard i.m. glucagon stimulation test (IMGST) in order to determine whether the use of a simplified form of this test results in a loss of diagnostic utility. PATIENT AND DESIGN: A retrospective study of 35 consecutive patients with pituitary disease who underwent a standard IMGST to measure GH (n = 34) or cortisol (n = 21) reserve at the programmed investigation unit of the Northern General Hospital, Sheffield. MEASUREMENTS: Cortisol, glucose and GH levels were measured at baseline and 30, 60, 90, 120, 150, 180, 210 and 240 min during the standard IMGST. We used the hormone levels at baseline, 150 and 180 min for the simplified IMGST and compared the cortisol and GH responses achieved. RESULTS: The median (range) peak GH and cortisol responses to simplified and standard IMGST were comparable 4.2 (0.5-47.5) vs 5.4 (0.5-47.5) mU/l (P = 0.75) and 635 (306-1669) vs 647 (306-1669) nmol/l (P = 0.801), respectively. Using the standard 'cut-off' points to assess GH (9 mU/l) or cortisol deficiency (580 nmol/l) there was no significant loss of diagnostic utility (P = 0.98 and P = 1.00, respectively). CONCLUSIONS: The simplified and standard IMGST have a similar diagnostic utility. The simplified IMGST could replace the standard IMGST as a screening test for GH and cortisol reserve in pituitary disease. The insulin-induced hypoglycaemia stress test can be reserved for cases in which a second assessment of pituitary reserve is clinically indicated or because of an indeterminate biochemical result.

The effect of treatment variables on mood and social adjustment in adult patients with pituitary disease.

OBJECTIVE: Studies of mood in hypopituitary adults have yielded inconsistent results. This investigation was carried out to investigate whether treatment characteristics may be responsible for the inconsistent results. DESIGN AND MEASUREMENTS: We compared three groups of patients with a group of matched healthy controls on self-report measures of mood and social adjustment (Beck depression inventory, State-trait anxiety inventory, Social adjustment scale (modified)) and a measure of quality of life (Nottingham health profile, NHP). PATIENTS: The patient groups were those treated with transfrontal surgery (n = 23), transsphenoidal surgery (n = 23) or medication only (n = 23). In addition, a close informant of each subject was asked to complete a social adjustment measure about the subject's level of adjustment. RESULTS: On the self-report mood and social adjustment measures and the emotion sub-scale of the NHP, the transsphenoidal and medication patient groups rated themselves as being more depressed, anxious and having poorer social adjustment than the transfrontal or control groups. The close informants, however, rated all three patient groups as having poorer social adjustment than the controls. Patients treated with surgery and without radiotherapy reported fewer symptoms of depression than those treated with radiotherapy. Realistic self-appraisal of social adjustment in surgical patients was found only in those treated with transsphenoidal surgery without radiotherapy. CONCLUSIONS: Patients treated for pituitary tumour, excepting those treated with transfrontal surgery and to a lesser extent those treated with radiotherapy, suffer from mild mood disturbance and self-perceived decreased social adjustment. All patient groups are seen by others as having decreased social adjustment, raising the possibility that the transfrontal patients and possibly those who have had radiotherapy, lack insight. This may explain some of the discrepancies in the previous literature and needs to be taken into account when using self-report measures with these patients.

Cognitive dysfunction in patients treated for pituitary tumours.

Assessment of neuropsychological status and mood was carried out on 36 patients who had been treated for pituitary tumour and on 36 healthy controls. Impairments in memory and executive function were exhibited by the patients even when other known causes of cognitive dysfunction had been excluded. There was no difference in mood between the two groups, and the deficits in cognitive dysfunction were not related to mood disturbance or to the effects of radiotherapy. The defects were however, related to the presence of surgery, although not to the type of surgery. Reasons for the cognitive dysfunction are unclear but are likely to be multifactorial possibly including the effects of neurosurgery and/or hormone imbalance resulting from pituitary surgery.

Comparison of tests of stress-released cortisol secretion in pituitary disease.

OBJECTIVES: We wished to compare peak and incremental rise in plasma cortisol in response to insulin induced hypoglycaemia (IIH) stress test, i.m. glucagon stimulation test (IMGST) and short Synacthen test (SST) in patients with pituitary disease, using a modern radioimmunoassay for cortisol. We compared the three stimulants using receiver operator characteristic (ROC) plots, assuming a cortisol threshold of 500 nmol/l or 580 nmol/l for the IIH stress test which we used as the standard from which to evaluate the SST and the IMGST. PATIENTS AND DESIGN: We prospectively studied 16 patients (8F, 8M mean age 43.69 +/- 3.72 years) admitted to the investigation ward for IIH stress test and who were asked to undergo two additional tests (IMGST and SST) on consecutive days. MEASUREMENTS: We measured serum cortisol at baseline, 30, 45, 60, 90 and 120 minutes during the IIH stress test; baseline, 150 and 180 minutes during GST, and baseline and 30 minutes during the SST. RESULTS: There was a significant rise in cortisol from baseline in all tests (P < 0.001). There was no significant difference among the peak plasma cortisol responses or the incremental rises in plasma cortisol following IMGST, SST and IIH stress test (repeated measures ANOVA F = 0.704, P = 0.503; F = 0.238, P = 0.79). The ROC plots clearly showed that the SST has poor diagnostic utility at both IIH thresholds, compared with the IMGST. CONCLUSION: The peaks and incremental rises in cortisol following all three tests are comparable. Using the insulin induced hypoglycaemia stress test as a reference and peak cortisol thresholds of 500 and 580 nmol/l as discriminating variables, the short Synacthen displayed poor diagnostic utility when compared to the i.m. glucagon stimulation test. The short Synacthen may be misleading if used as a screening test as advocated by a number of authors.

Is a low skinfold thickness an indicator of osteoporosis?

OBJECTIVE: The association between thin skin and osteoporosis has been known for some years. We wished to assess a simple measure of skinfold thickness (SFT) as a screening test for osteoporosis and to study the effect of chronological and menopausal age on SFT in a group of osteoporotic women and normal controls. DESIGN: A case control study of 225 consecutive women who attended an osteoporosis clinic. PATIENTS: We studied 225 women, 141 with osteoporosis (mean age 61.8 +/- 10.5 years) and 65 normal controls (mean age 59.9 +/- 8.8 years), with 19 exclusions. METHODS: Each patient had routine biochemistry, spinal X-rays and a dual-energy X-ray absorptiometry (DEXA) scan of lumbar spine and femoral neck. In addition they had skinfold thickness measured by a single observer using Holtain Tanner Whitehouse callipers over the 4th metacarpal of the right hand. RESULTS: Mean skinfold thickness was lower in the osteoporotic group, 1.6 +/- 0.4 mm compared to normals 1.8 +/- 0.3 mm (P < 0.0001). SFT did not decline significantly with chronological or menopausal age in the normals (correlation coefficients r = -0.06, r = -0.09) in contrast to the osteoporotic group (correlation coefficients r = -0.52, P < 0.001; r = -0.27, P < 0.0001). Subjects with a SFT of < or = 1.5 mm had a higher probability of osteoporosis (odds ratio 3.12, 95% confidence interval 1.58-6.14). Subjects with a SFT of > or = 2.1 mm had a lower probability of osteoporosis (odds ratio 0.305, 95% confidence interval 0.126-0.740). CONCLUSION: Our results demonstrate a lower mean SFT in osteoporotic compared with normal women, with a negative correlation between SFT and chronological and menopausal age in osteoporotics, but not in normal controls. A low skinfold thickness appears to be an indicator of developing osteoporosis and a high SFT may indicate a normal bone mass.

Comparison of changes in bone mineral in idiopathic and secondary osteoporosis following therapy with cyclical disodium etidronate and high dose calcium supplementation.

OBJECTIVE: Our clinical practice has been to offer treatment with cyclical disodium etidronate and high dose calcium supplements (1500-1600 mg/day) to all female patients with osteoporosis who are unable or unwilling to take hormone replacement therapy (HRT), and male osteoporotics. In a retrospective study we compared the effect of this treatment on measures of bone mineral over a 12-month period in women with post-menopausal and secondary osteoporosis. We also assessed its effects in 10 male osteoporotics. DESIGN: A retrospective analysis of 83 consecutive patients with osteoporosis who completed 12 months of treatment with disodium etidronate and calcium and who had a dual energy X-ray absorptiometry (DEXA) scan at baseline and following 12 months of therapy. PATIENTS: The study included 73 women (45 post-menopausal and 28 secondary osteoporotics) and 10 men with established osteoporosis as shown by spinal and femoral bone mineral densities (BMD) > 2 standard deviations (SD) below young normals, and radiological evidence of osteoporosis. MEASUREMENTS: Each patient had routine biochemistry at baseline, an X-ray of thoracic and lumbar spine and a DEXA scan of lumbar spine (L2-L4) and femoral neck. The DEXA scan was repeated following 12 months of therapy. RESULTS: There was no difference between increase in spinal BMD in the post-menopausal (5.7%) versus secondary osteoporotic group (6.7%). There was a significant increase in spinal BMD at 12 months in the 10 male osteoporotics (9.0%, P < 0.01). No overall change in femoral neck BMD was noted. CONCLUSIONS: Cyclical disodium etidronate given with high dose calcium supplements is equally effective in increasing spinal bone mineral density in post-menopausal and secondary osteoporosis. It also results in a significant rise in spinal bone mineral density in male osteoporotics. Whether this produces a reduction in fracture rates is unknown.

Thyrotoxicosis increases right to left shunt in congenital cyanotic heart disease.

We wish to report two cases of congenital cyanotic heart disease in whom coexisting thyrotoxicosis increased the right to left shunt. We review the literature on the cardiac and respiratory effects of thyroid hormone to try to explain this phenomenon. Two patients, one with Fallot's tetralogy (diagnosed at 68 years of age), the other with a ventricular septal defect, developed thyrotoxicosis which resulted in a dramatic but reversible deterioration in their cardiac condition. We conclude that thyrotoxicosis increases right to left shunt in congenital cyanotic heart disease. This effect is profound but reversible. We suggest that when an unexplained rapid deterioration occurs in patients with congenital cyanotic heart disease, thyrotoxicosis should be excluded.

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.