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Objective: This study aimed to understand the effect of time to remission of acromegaly on survival in people living with acromegaly., Design, Patients and Measurement: This cross-sectional study used data from the UK Acromegaly Register. We considered remission of acromegaly growth hormone controlled at ≤2 μg/L following the diagnosis of acromegaly. We used the accelerated failure time model to assess the effect of time to remission on survival in acromegaly., Results: The study population comprises 3569 individuals with acromegaly, with a median age of diagnosis of 47.3 (36.5-57.8) years, 48% females and a majority white population (61%). The number of individuals with the first remission of acromegaly was 2472, and the median time to first remission was 1.92 (0.70-6.58) years. In this study, time to first remission in acromegaly was found to have a significant effect on survival (p < .001); for every 1-year increase in time to first remission, there was a median 1% reduction in survival in acromegaly. In an analysis adjusted for covariates, the survival rate was 52% higher (p < .001) in those who underwent surgery as compared to those who did not have surgery, 18% higher (p = .01) in those who received treatment with somatostatin analogues (SMA) as compared to those with dopamine agonists and 21% lower (p < .001) in those who received conventional radiotherapy as compared to those who did not receive radiotherapy., Conclusion: In conclusion, this population-based study conducted in patients with acromegaly revealed that faster remission time, surgical intervention and treatment with SMA are linked to improved survival outcomes., (© 2024 John Wiley & Sons Ltd.)

Context: Epidemiological studies involving patients with acromegaly have yielded conflicting results regarding cancer incidence and causes of mortality in relation to control of growth hormone (GH) excess., Objective: The objective of this retrospective cohort study is to clarify these questions and identify goals for treatment and monitoring patients., Methods: We studied 1845 subjects from the UK Acromegaly Register (1970-2016), obtaining cancer standardised incidence rates (SIR) and all causes standardised mortality rates (SMR) from UK Office for National Statistics, to determine the relationship between causes of mortality-age at diagnosis, duration of disease, post-treatment and mean GH levels., Results: We found an increased incidence of all cancers (SIR, 1.38; 95% CI: 1.06-1.33, p < .001), but no increase in incidence of female breast, thyroid, colon cancer or any measure of cancer mortality. All-cause mortality rates were increased (SMR, 1.35; 95% CI: 1.24-1.46, p < .001), as were those due to vascular and respiratory diseases. All-cause, all cancer and cardiovascular deaths were highest in the first 5 years following diagnosis. We found a positive association between post-treatment and mean treatment GH levels and all-cause mortality (p < .001 and p < .001), which normalised with posttreatment GH levels of <1.0 µg/L or meantreatment GH levels of <2.5 µg/L., Conclusion: Acromegaly is associated with increased incidence of all cancers but not thyroid or colon cancer and no increase in cancer mortality. Excess mortality is due to vascular and respiratory disease. The risk is highest in the first 5 years following diagnosis and is mitigated by normalising GH levels., (© 2024 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Introduction: Patients with severe GH deficiency (GHD) suffer with a reduced quality of life in addition to diverse changes in cardiac size and performance. So far, the cardiac reserve ability to maintain the circulation during peak exercise has not been measured. We tested the hypothesis that patients with severe GHD have reduced cardiac reserve function compared with healthy controls and that this could explain, in part, their reduced quality of life., Aims: Eighteen patients with severe GHD and an assessment of GHD in adults (AGHDA) score > or =11 (mean 20.0, range 12-25) were studied and compared with 18 age-, sex- and body mass index-matched healthy controls. Peak cardiac power and cardiorespiratory fitness were investigated using noninvasive haemodynamic measurements during maximal cardiopulmonary exercise testing., Results: Compared with matched controls, the cardiac power of GHD patients during exercise to volitional exhaustion was significantly reduced by 15% (mean +/- SD 4.4 +/- 1.0 W vs. 5.2 +/- 1.0 W, P = 0.02). Patients with GHD also had lower cardiac chronotropic reserve (peak heart rate 154 +/- 21/min vs. 174 +/- 11/min, P = 0.001) and a lower cardiac pressure-generating capacity (systolic blood pressure 160 +/- 25 mmHg vs. 200 +/- 15 mmHg, P < 0.0001). We found no correlation between any measure of peak cardiac power or function and the AGHDA score., Conclusion: Using this robust noninvasive method of assessing functional cardiac pumping capacity, we have for the first time shown that, while patients with severe GHD have a significantly impaired cardiac functional reserve associated with chronotropic incompetence and impaired pressure-generating capacity, this does not correlate with their reduced quality of life assessed using the current standard AGHDA score.

Objective: To investigate the loading regimen for intramuscular (IM) testosterone undecanoate (Nebido) to determine whether testosterone and bioavailable testosterone levels achieved correlate with age or body size of subjects studied., Design: Retrospective observational study of testosterone naïve patients and patients previously treated with an alternative testosterone therapy., Patients: 51 hypogonadal men (35, 68.6% secondary hypogonadism). 8 (16%) had not previously received testosterone therapy., Measurements: Patients received an IM injection of Nebido (1000 mg) at baseline and a second injection after 6 weeks. Serum was assayed at baseline and 18 weeks after commencing Nebido for total testosterone (TT) and SHBG. Bioavailable testosterone was calculated (cBioT) using TT and SHBG. Measurements were taken for weight, body mass index (BMI) and body surface area (BSA)., Results: Baseline TT (mean 11.5 nmol/l, range 0.3-54.8) increased by 50% after commencing Nebido (17.2 nmol/l (5.4-32.8), P = 0.0001). 75% of subjects had a TT within the reference range (8.0-25.0 nmol/l). Subjects with primary hypogonadism had a higher 18-week TT [20.9 nmol/l (9.8-32.8) vs. 15.5 (5.4-32.6), P = 0.02] and SHBG [39.2 nmol/l (11-82) vs. 25.7 (9.0-60.0), P = 0.003] although the cBioT was not significantly different [4.9 nmol/l (2.9-7.3) vs. 4.2 (2.0-7.9), P = 0.12]. The 18-week TT positively correlated with age (R = 0.36, P = 0.01) and negatively correlated with weight (R = -0.38, P = 0.006), BMI (R = -0.42, P = 0.002) and BSA (R =-0.38, P = 0.007). Similarly cBioT correlated with age (R = 0.28, P = 0.04), weight (R = -0.29, P = 0.03), BMI (R = -0.30, P = 0.03) and BSA (R = -0.27, P = 0.05). Age (t = 2.04, P = 0.05) and baseline testosterone (t = -9.26, P < 0.0001) were independent variables of the increase in TT at 18 weeks., Conclusion: This starting regimen is simple and provides the majority of men with a TT within the reference range. Age and baseline TT are independent variables of the increase in TT with IM testosterone undecanoate. At week 18 age and body size correlated with the cBioT and TT and this may then be used to estimate dosing frequency for this therapy.

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.

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.

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.

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.

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.

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.

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.

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.

Isolated ACTH deficiency is a rare disorder. We report four cases of this disease which presented to the Department of Endocrinology at Leeds General Infirmary over a one-year period. The diagnostic clinical and biochemical features of each case are discussed and the pertinent literature is reviewed. The clinical investigations vary somewhat between cases as the four patients presented in markedly different ways. Well validated dynamic endocrine investigations were employed including glucagon stimulation test (GST) and the corticotrophin releasing hormone (CRH) test (using 100 micrograms of human CRH with samples for ACTH and cortisol). Two patients probably had CRH deficiency and two had ACTH deficiency. All the cases are instructive, illustrating different features of this heterogeneous condition. We conclude that the diagnosis of this condition may be difficult due to the varied clinical presentation. We suggest that it is commoner than previously thought and that the precision of diagnosis can be improved using the CRH test.