Demonstration of the long-term efficacy of GH replacement in GH-deficient adults has depended on a combination of single-centre studies and data from large multinational databases, which, by virtue of their size, are likely to detect rare adverse events and also permit analysis of mortality rates. The Pharmacia International Metabolic Surveillance (KIMS) study (a pharmacoepidemiological survey of the safety and efficacy of GH replacement in adults, sponsored by Pharmacia) is currently the largest database, with information on over 8000 patients from a total of 27 countries. Abundant epidemiological evidence confirms that hypopituitarism is associated with premature mortality, with an increase in cardiovascular and cerebrovascular disease as a primary underlying cause. Central adiposity, hyperlipidaemia, insulin resistance, and diabetes mellitus are common in adults with hypopituitarism. GH replacement is associated with improvements in central fat mass and mean reductions in serum total and low-density lipoprotein cholesterol which may be additive to those achieved with hydroxymethylglutaryl-coenzyme A reductase inhibitors. These beneficial effects are maintained for at least 2 Years after initiation of therapy, as are reductions in central adiposity, with similar benefits seen in men and women when the GH dose is titrated to achieve a serum IGF-I between the median and the upper end of the age-related reference range. Fasting plasma glucose and glycated haemoglobin increase, usually within the reference range, during prolonged GH replacement, but do not tend to rise further above baseline in subjects with pre-existing impaired glucose tolerance. Bone remodelling increases during GH replacement therapy, but indices tend to return to baseline within 5 Years of commencing treatment. Bone mineral density increases in men whereas, in women, improvement is limited to stabilisation of bone density. Data from the KIMS study demonstrate that prolonged GH replacement is associated with a reduction in the number of patients requiring assistance with daily living and a significant reduction in sick leave and hospital admissions. GH replacement therapy improves psychological well-being, particularly in those patients with the greatest deficit prior to treatment, with improvement maintained beyond 6 Months of therapy and sustained during long-term follow-up. Data from the KIMS population show that there is no increase in the overall occurrence of de novo neoplasia or the rate of regrowth of primary pituitary tumours. There is an apparent increase in intracranial neoplasia, which may be an artefact of comparing a surveillance population with general population data. Unlike mortality in untreated hypopituitary GH-deficient patients, mortality in the KIMS study is currently similar to that predicted for the normal population.
MO Savage, WM Drake, PV Carroll and JP Monson
While the benefits of growth hormone (GH) therapy in adult hypopituitary patients with GH deficiency (GHD) are established, the role of continued GH therapy after final height in adolescent GH-deficient patients remains unclear. Preliminary data suggest that cessation of GH on completion of linear growth may be associated with impairment of somatic development and adverse changes in body composition. For the present time, the decision whether to continue GH treatment in adolescent patients with GHD is best made on an individual basis. For such patients, continuity of care is crucial. Children and adults with GHD are usually managed by physicians in separate departments, who may focus on different aspects of treatment and care. Close collaboration between paediatric and adult physicians is essential to ensure smooth transition and to minimize the drop-out rate from follow-up. Given the previous period of treatment during childhood, paediatric physicians should be best placed to discuss the potential benefits of continuing GH therapy and instigate retesting of GH secretion. Many children with isolated idiopathic GHD will produce normal GH responses if retested at adult height. Patients with multiple pituitary hormone deficits are more likely to have ongoing GHD, as are patients who have received CNS irradiation. Quality of life does not appear to be decreased in adolescents with GHD who stop treatment, so achievement of satisfactory bone mass is a major determinant of the decision whether to continue therapy.
WM Drake, F Miraki, A Siddiqi, M Yateman, NC Barnes, C Camacho-Hubner and JP Monson
Mesenchymal tumours are a well recognised cause of spontaneous hypoglycaemia. The mechanism is thought to relate to hypersecretion by tumour cells of high molecular mass insulin-like growth factor-II (pro-IGF-II), with consequent suppression of growth hormone (GH) secretion. The use of recombinant human (rh)GH has been reported to alleviate hypoglycaemia in non-islet cell tumour hypoglycaemia, and the mechanism is thought to relate to GH-mediated increments in serum levels of IGF-binding protein-3 (IGFBP-3), thereby reducing the bioavailability of IGF-II. We report the effect of increasing doses of rhGH on the clinical condition and serum IGF-I and IGFBP-3 levels in two patients with solitary pleural fibrous tumours causing severe hypoglycaemia. Hypoglycaemia was successfully alleviated in each patient although, despite using large doses of rhGH, the observed increments in IGFBP-3 were only modest. We postulate that the beneficial effects of rhGH in this situation are likely to be multifactorial and not simply related to increments in serum IGFBP-3 levels.
WM Drake, C Parkinson, SA Akker, JP Monson, GM Besser and PJ Trainer
BACKGROUND/OBJECTIVE: Pegvisomant is a pegylated analogue of human GH and functions as a potent GH receptor antagonist. This novel mode of action gives it the potential to achieve biochemical control in patients with acromegaly whose disease activity cannot be satisfactorily controlled by conventional therapy. We have documented the clinical details of seven patients with residual active acromegaly after surgery and/or radiation therapy successfully treated with pegvisomant. PATIENTS/METHODS: Seven patients (four male, mean age 47 years, range 34-67 years) who participated in two separate clinical trials of pegvisomant have completed 2 years (four patients) or 1 year (three patients) of treatment. All had active acromegaly (mean serum GH level >5 mU/l; serum IGF-I elevated for age) that could not be controlled with standard medical therapy (dopamine agonist and/or a somatostatin analogue) following appropriate primary treatment with surgery and/or radiotherapy. RESULTS: On a median dose of 20 mg/day (range 15-40) pegvisomant, serum IGF-I fell from a mean of 920+/-351 ng/ml (s.d.) to 258+/-91 ng/ml and was normalised in all seven patients. These changes were associated with improvements in soft tissue enlargement and general well being. Treatment was well tolerated and no change in pituitary tumour size was evident on MRI scans performed every 6 months. CONCLUSIONS: Treatment with pegvisomant is safe and efficacy is maintained after 2 years. Serum IGF-I may be normalised in patients who are refractory to conventional therapy.
SJ Aylwin, A King, A Blenke, JF Geddes, DF Wood, JP Monson and JM Burrin
OBJECTIVE: GH-secreting pituitary adenomas frequently co-secrete prolactin and glycoprotein hormone alpha-subunit (alphaSU), but expression of additional hormones is considered unusual. The aim of this study was to establish the frequency with which acromegalic tumours secrete intact glycoprotein hormones LH, FSH and TSH, in comparison with other types of pituitary adenoma. DESIGN AND METHODS: Pituitary tumours were studied by cell culture, measuring the basal secretion of anterior pituitary hormones in vitro. Light microscopy was used to exclude tumours where normal pituitary tissue was present, and immunocytochemistry was employed to confirm the clinical diagnosis and for comparison with tissue culture data. RESULTS: TSH secretion was observed in vitro in 15/23 somatotroph adenomas, but from only 1/8 lactotroph, 4/29 null cell, 2/12 gonadotroph and 1/10 corticotroph adenomas; moreover, somatotroph adenomas secreted the largest amounts of TSH (P < 0.(001). Somatotroph adenomas also secreted LH (7/23) and FSH (2/23) but less frequently than gonadotroph adenomas. Immunocytochemistry demonstrated glycoprotein expression in somatotroph adenomas (LHbeta: 13%, FSHbeta: 26%, TSHbeta: 30%, alphaSU: 46%) more frequently than in lactotroph, corticotroph and null cell adenomas. A strong correlation was found between alphaSU secretion and TSH secretion in somatotroph adenomas (rho= 0.683, P < 0.001. CONCLUSIONS: TSHbeta is frequently expressed by somatotroph adenomas, often associated with alphaSU expression. Both GH and TSHbeta are dependent on the transcription factor, Pit-1, which is frequently expressed in somatotroph adenomas, although the expression of alphaSU requires an alternative explanation. Increased expression of alphaSU compared with TSHbeta may account for the secretion of free alphaSU by somatotroph adenomas.
JA Hunter, RH Skelly, SJ Aylwin, JF Geddes, J Evanson, GM Besser, JP Monson and JM Burrin
OBJECTIVE: Pituitary tumour transforming gene (PTTG) is a recently identified protooncogene, ubiquitously expressed in pituitary tumours at levels higher than those detected in normal pituitary. Although the precise function of PTTG protein is unknown, in vitro experiments have shown that it induces angiogenesis. In this study, we have examined the potential relationship between the level of PTTG expression and tumour phenotype, tumour size, in vitro pituitary hormone secretion and release of vascular endothelial growth factor (VEGF), a potent angiogenic factor. METHODS: Pituitary tumours (12 somatotroph, five lactotroph, five corticotroph and 18 non-functioning) were studied by cell culture, measuring the basal secretion of anterior pituitary hormones and VEGF in vitro. Immunocytochemistry was used to confirm the clinical diagnosis and tumour phenotype. PTTG mRNA expression was investigated by comparative RT-PCR. Tumour Volume was quantitated from pre-operative MRI scans. RESULTS: PTTG expression was significantly increased 2.7-fold in somatotroph tumours compared with non-functioning adenomas (P<0.01, ANOVA). A positive correlation was demonstrated between PTTG expression and in vitro GH secretion (r=0.41, P<0.01, Spearman) but no correlations were found for any of the other pituitary hormones. In 16 out of 40 pituitary tumours, we were able to determine the in vitro secretion of VEGF and relate this to PTTG expression. All of the adenomas tested secreted measurable VEGF but there was no correlation between the amount of VEGF secreted and either the tumour phenotype or PTTG expression. Neither PTTG expression nor VEGF secretion correlated with tumour Volume. CONCLUSIONS: Our studies have confirmed the presence of PTTG in pituitary adenomas and demonstrated a higher level of expression in somatotroph tumours and a significant correlation with GH secretion. We failed to demonstrate a relationship between PTTG expression and production of the angiogenic factor, VEGF, or tumour Volume. Thus, although PTTG induces angiogenesis experimentally, it seems unlikely that a VEGF-mediated angiogenic mechanism occurs during pituitary tumour progression.
WM Drake, SV Rowles, ME Roberts, FK Fode, GM Besser, JP Monson and PJ Trainer
AIM AND METHOD: Insulin resistance leading, in some cases, to glucose intolerance is an important contributory factor to the cardiovascular morbidity and mortality associated with acromegaly. The aim of this study was to document changes in insulin sensitivity (IS) in a group of seven patients with acromegaly (three male, four female, mean+/-s.d. age 59+/-13 Years) treated initially with a stable dose of depot octreotide (OT; median dose 30 mg four times weekly, range 10-30 mg) for a median of 18 Months (range 16-19 Months) and who were then transferred to treatment with pegvisomant (median dose 15 mg daily, range 10-20 mg) for a median of 8 Months (range 7-9 Months). IS was assessed by homeostatic model assessment (HOMA) using fasting glucose and insulin concentrations and by a short insulin tolerance test (sITT). Body composition was assessed by dual energy X-ray absorptiometry. RESULTS: Mean+/-s.d. serum IGF-I concentrations during therapy with OT and with pegvisomant were not statistically different (283+/-119 ng/ml on OT vs 191+/-39 ng/ml on pegvisomant (P=0.4)). However, mean+/-s.d. fasting plasma glucose fell from 6.2+/-1.0 mmol/l on OT to 5.2+/-0.6 mmol/l on pegvisomant (P=0.017) and was lower on pegvisomant in all seven patients. In four patients, fasting plasma glucose fell from values diagnostic of diabetes mellitus or impaired fasting glucose on OT to within the normal range on pegvisomant. Mean+/-s.d. peripheral IS (by sITT) increased from 139+/-39 micromol/l per min on OT to 169+/-59 micromol/l per min on pegvisomant (P=0.037). Mean+/-s.d. IS (by HOMA %S) was unchanged over the course of the study (149.1+/-43.7% on OT vs 139.9+/-76.6% on pegvisomant, P=0.28). Mean+/-s.d. pancreatic beta-cell secretory function (HOMA %B) improved significantly on pegvisomant compared with OT (49.4+/-19.2% vs 82.4+/-43.5%, P=0.01). No statistically significant change in total fat (P=0.3), % fat (P=0.28) or circulating non-esterified fatty acids (P=0.35) was observed. CONCLUSIONS: IS and glucose tolerance improved in patients converted from OT therapy to pegvisomant, without a change in body composition and even when serum IGF-I concentrations remained equally well controlled. This may be an important factor in the choice of medical therapy for patients with acromegaly.
CW le Roux, PJ Jenkins, SL Chew, C Camacho-Hubner, AB Grossman, GM Besser and JP Monson
OBJECTIVE: Epidemiological studies have shown an increased risk for prostate carcinoma in men with serum IGF-I in the upper part of the age-related reference range. Recombinant human GH (rhGH) is widely used in patients with GH deficiency, usually raising the serum IGF-I levels into the normal range: safety surveillance is therefore mandatory, with particular regard to neoplasia. The aim was to examine whether rhGH replacement in hypopituitary adults is associated with changes in serum prostate-specific antigen (PSA) as a surrogate marker of changes in prostatic growth. DESIGN AND METHODS: A prospective longitudinal study was used with a median follow-up of 22 (range 2.5-32) months, in which 41 men aged over 50 years with adult onset hypopituitarism and GH deficiency during rhGH replacement were examined. Serum PSA and IGF-I were measured at baseline and at latest follow-up. RESULTS: Mean serum PSA remained unchanged during rhGH replacement, with a median follow-up of 2 years. No correlation was found between the individual changes in serum IGF-I and changes in serum PSA. CONCLUSIONS: These data are reassuring thus far regarding the safety of GH replacement in relation to the prostate in this patient group.
AG Rockall, SA Sohaib, D Evans, G Kaltsas, AM Isidori, JP Monson, GM Besser, AB Grossman and RH Reznek
OBJECTIVE: Hepatic steatosis may occur in association with insulin resistance and obesity, two features commonly seen in Cushing's syndrome (CS). The aim of this report is to assess the prevalence of hepatic steatosis in patients with active CS using computed tomography (CT) and to identify any associations between hepatic steatosis, endocrine and biochemical variables and body fat distribution. PATIENTS AND MEASUREMENTS: We identified 50 patients with active CS in whom appropriate CT was available to allow measurement of liver and spleen attenuation. In 26 patients, abdominal fat measurements were also available. Serum markers of CS and liver function tests were recorded. RESULTS: Ten of 50 patients had a liver-to-spleen CT attenuation ratio (L/S) of less than 1, indicating hepatic steatosis. There was a significant negative correlation between both liver attenuation and L/S ratio with total abdominal fat area, visceral fat area, the percentage of visceral fat and the visceral to subcutaneous fat ratio; the strongest negative correlation was found between visceral fat area and L/S ratio (r=-0.638, P<0.001, n=26). L/S ratio positively correlated with alkaline phosphatase levels (r=+0.423, P=0.044, n=23) but with no other serum marker of CS activity or liver enzyme. CONCLUSIONS: We have demonstrated hepatic steatosis on CT in 20% of patients with active CS. The presence of hepatic steatosis was significantly correlated with total abdominal fat area and visceral fat area.
AG Rockall, SA Sohaib, D Evans, G Kaltsas, AM Isidori, JP Monson, GM Besser, AB Grossman and RH Reznek
OBJECTIVE: Our aims were to describe the abdominal fat distribution in male patients with Cushing's syndrome (CS) on computerised tomography (CT), to compare our findings with non-cushingoid patients, to validate previous reports of increased visceral fat in female patients with CS and to identify any correlations between fat distribution and biochemical findings. DESIGN: Retrospective and observational. PATIENTS: Appropriate CT scans were identified in 31 patients (seven male) with active CS. MEASUREMENTS: Total, visceral and subcutaneous fat areas were obtained. The percentage of visceral fat and the visceral to subcutaneous fat ratio (V:S ratio) were calculated. Biochemical data were recorded. Control data of fat distribution were obtained from the literature. RESULTS: There was a significant increase in the V:S ratio in male patients with CS when compared with non-cushingoid controls (1.175+/-0.59 vs 0.77+/-0.39, 95% confidence interval (CI) 0.0817-0.728). There was a significant increase in the V:S ratio in female patients with CS (0.845+/-0.53 vs 0.38+/-0.19, 95% CI 0.269-0.661). There was no difference in the V:S ratio between male and female patients with CS (1.175+/-0.59 vs 0.845+/-0.53, 95% CI -0.144-0.804). No significant correlations between fat distribution and glucose levels, circulating cortisol, ACTH or lipids were found. CONCLUSIONS: Our data demonstrate an increase in visceral fat distribution in both male and female patients with CS, with the abolition of the normal male to female difference in visceral fat. Increased visceral fat may increase the risk of the metabolic syndrome in this group of patients.