Smoking has multiple effects on hormone secretion, some of which are associated with important clinical implications. These effects are mainly mediated by the pharmacological action of nicotine and also by toxins such as thiocyanate. Smoking affects pituitary, thyroid, adrenal, testicular and ovarian function, calcium metabolism and the action of insulin. The major salient clinical effects are the increased risk and severity of Graves’ hyperthyroidism and opthalmopathy, osteoporosis and reduced fertility. Smoking also contributes to the development of insulin resistance and hence type 2 diabetes mellitus. An important concern is also the effect of smoking on the foetus and young children. Passive transfer of thiocyanate can cause disturbance of thyroid size and function. Furthermore, maternal smoking causes increased catecholamine production, which may contribute to under perfusion of the foetoplacental unit.
D Kapoor and T H Jones
D Kapoor, E Goodwin, K S Channer and T H Jones
Objective: Low levels of testosterone in men have been shown to be associated with type 2 diabetes, visceral adiposity, dyslipidaemia and metabolic syndrome. We investigated the effect of testosterone treatment on insulin resistance and glycaemic control in hypogonadal men with type 2 diabetes.
Design: This was a double-blind placebo-controlled crossover study in 24 hypogonadal men (10 treated with insulin) over the age of 30 years with type 2 diabetes.
Methods: Patients were treated with i.m. testosterone 200 mg every 2 weeks or placebo for 3 months in random order, followed by a washout period of 1 month before the alternate treatment phase. The primary outcomes were changes in fasting insulin sensitivity (as measured by homeostatic model index (HOMA) in those not on insulin), fasting blood glucose and glycated haemoglobin. The secondary outcomes were changes in body composition, fasting lipids and blood pressure. Statistical analysis was performed on the delta values, with the treatment effect of placebo compared against the treatment effect of testosterone.
Results: Testosterone therapy reduced the HOMA index (−1.73 ± 0.67, P = 0.02, n = 14), indicating an improved fasting insulin sensitivity. Glycated haemoglobin was also reduced (−0.37 ± 0.17%, P = 0.03), as was the fasting blood glucose (−1.58 ± 0.68 mmol/l, P = 0.03). Testosterone treatment resulted in a reduction in visceral adiposity as assessed by waist circumference (−1.63 ± 0.71 cm, P = 0.03) and waist/hip ratio (−0.03 ± 0.01, P = 0.01). Total cholesterol decreased with testosterone therapy (−0.4 ± 0.17 mmol/l, P = 0.03) but no effect on blood pressure was observed.
Conclusions: Testosterone replacement therapy reduces insulin resistance and improves glycaemic control in hypogonadal men with type 2 diabetes. Improvements in glycaemic control, insulin resistance, cholesterol and visceral adiposity together represent an overall reduction in cardiovascular risk.
A M Smith, K M English, C J Malkin, R D Jones, T H Jones and K S Channer
Objective: In women, sex hormones cause increased morbidity and mortality in patients with coronary heart disease (CHD) and adversely affect the coagulation profile. We have studied the effect of physiological testosterone replacement therapy in men on coagulation factor expression, to determine if there is an increased risk of thrombosis.
Methods: Double-blind, randomized, placebo-controlled trial of testosterone in 46 men with chronic stable angina. Measurements of free, total and bioavailable testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH), estradiol, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, tissue plasminogen activator (tPA) and full blood count were made at 0, 6 and 14 weeks. Results: Bioavailable testosterone levels were: 2.58 ± 0.58 nmol/l at baseline, compared with 3.35 ± 0.31 nmol/l at week 14 (P < 0.001) after treatment compared with 2.6 ± 0.18 nmol/l and 2.44 ± 0.18 nmol/l in the placebo group (P was not significant). There was no change in fibrinogen (3.03 ± 0.18 g/l at baseline and 3.02 ± 0.18 g/l at week 14, P = 0.24), tPA activity (26.77 ± 4.9 Iu/ml and 25.67 ± 4.4 Iu/ml, P = 0.88) or PAI-1 activity (0.49 ± 0.85 Iu/ml and 0.36 ± 0.06 Iu/ml, P = 0.16) with active treatment and no differences between the groups (at week 14, P value 0.98, 0.59 and 0.8 for fibrinogen, PAI-1 and tPA respectively). Haemoglobin concentration did not change over time, in the testosterone group (1.44 ± 0.02 g/l and 1.45 ± 0.02 g/l, P = 0.22).
Conclusion: Physiological testosterone replacement does not adversely affect blood coagulation status.
D Kapoor, S Clarke, R Stanworth, K S Channer and T H Jones
Objective: Serum testosterone levels are known to inversely correlate with insulin sensitivity and obesity in men. Furthermore, there is evidence to suggest that testosterone replacement therapy reduces insulin resistance and visceral adiposity in type 2 diabetic men. Adipocytokines are hormones secreted by adipose tissue and contribute to insulin resistance. We examined the effects of testosterone replacement treatment on various adipocytokines and C-reactive protein (CRP) in type 2 diabetic men.
Design: Double-blinded placebo-controlled crossover study in 20 hypogonadal type 2 diabetic men. Patients were treated with testosterone (sustanon 200 mg) or placebo intramuscularly every 2 weeks for 3 months in random order followed by a washout period of 1 month before the alternate treatment phase.
Methods: Leptin, adiponectin, resistin, tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and CRP levels were measured before and after each treatment phase. Body mass index (BMI) and waist circumference were also recorded.
Results: At baseline, leptin levels significantly correlated with BMI and waist circumference. There was a significant inverse correlation between baseline IL-6 and total testosterone (r=−0.68; P=0.002) and bioavailable testosterone levels (r=−0.73; P=0.007). CRP levels also correlated significantly with total testosterone levels (r=−0.59; P=0.01). Testosterone treatment reduced leptin (−7141.9 ± 1461.8 pg/ml; P=0.0001) and adiponectin levels (−2075.8 ± 852.3 ng/ml; P=0.02). There was a significant reduction in waist circumference. No significant effects of testosterone therapy on resistin, TNF-α, IL-6 or CRP levels were observed.
Conclusion: Testosterone replacement treatment decreases leptin and adiponectin levels in type 2 diabetic men. Moreover, low levels of testosterone in men are associated with pro-inflammatory profile, though testosterone treatment over 3 months had no effect on inflammatory markers.
R D Stanworth, S Akhtar, K S Channer and T H Jones
The TIMES2 (testosterone replacement in hypogonadal men with either metabolic syndrome or type 2 diabetes) study reported beneficial effects of testosterone replacement therapy (TRT) on insulin resistance and other variables in men with diabetes or metabolic syndrome. The androgen receptor CAG repeat polymorphism (AR CAG) is known to affect stimulated AR activity and has been linked to various clinically relevant variables.
To assess the role of AR CAG in the alteration of clinical response to TRT in the TIMES2 study.
Subgroup analysis from a multicentre, randomised, double-blind, placebo-controlled and parallel group study.
Outpatient study recruiting from secondary and primary care.
A total of 139 men with hypogonadism and type 2 diabetes or metabolic syndrome, of which 73 received testosterone during the TIMES2 study.
Testosterone 2% transdermal gel vs placebo.
Main outcome measure
Regression coefficient of AR CAG from linear regression models for each variable.
AR CAG was independently positively associated with change in fasting insulin, triglycerides and diastolic blood pressure during TRT with a trend to association with HOMA-IR – the primary outcome variable. There was a trend to negative association between AR CAG and change in PSA. There was no association of AR CAG with change in other glycaemic variables, other lipid variables or obesity.
AR CAG affected the response of some variables to TRT in the TIMES2 study, although the association with HOMA-IR did not reach significance. Various factors may have limited the power of our study to detect the significant associations between AR CAG, testosterone levels and change in variables with testosterone treatment. Analysis of similar data sets from other clinical trials is warranted.
R D Stanworth, D Kapoor, K S Channer and T H Jones
To determine the relationships between androgen receptor CAG repeat polymorphism length (AR CAG), sex hormones and clinical variables in men with type 2 diabetes (DM2). Men with DM2 are known to have a high prevalence of low testosterone levels. Studies suggest that testosterone replacement therapy may improve insulin sensitivity and glycaemic control in men with DM2 and reduces central obesity and serum leptin. AR CAG is known to correlate negatively with AR sensitivity and positively with body fat, insulin levels, and leptin in healthy men.
Cross-sectional study set in a district general hospital diabetes centre.
Sex hormones, AR CAG and symptoms of hypogonadism were assessed in 233 men with DM2. Associations were sought between these variables and others such as obesity, leptin, glycaemic control, and blood pressure.
Testosterone was negatively associated and AR CAG positively associated with obesity and leptin. The associations of AR CAG with leptin and obesity were independent of testosterone, estradiol, gonadotropins, and age. AR CAG was also independently associated with total, bioavailable and free testosterone, LH, waist circumference, body mass index, leptin, and systolic blood pressure. There was no association of AR CAG with sex hormone binding globulin, estradiol, HbA1C or the symptoms of hypogonadism.
The association of longer AR CAG with obesity and leptin suggests that shorter AR CAG may have an influence in maintaining healthy anthropomorphics and metabolism in men with DM2. Testosterone and LH levels are higher in men with longer AR CAG, probably reflecting reduced negative feedback through a less sensitive receptor.
S A Borg, K E Kerry, J A Royds, R D Battersby and T H Jones
Objectives: Vascular endothelial growth factor (VEGF) is considered to be the most important angiogenic factor involved in the neovascularisation of solid tumours. Regulatory molecules include cytokines and growth factors. Interleukin (IL)1 and IL6 have both been shown to regulate VEGF levels in a variety of tissues. The role of cytokines in the pathogenesis of pituitary tumours remains unclear. We have examined the expression of VEGF and its relationships with IL1 and IL6 in the human pituitary tumour cell line HP75 and a series of human pituitary tumours. We have also looked at the relationship of tumour volume and invasive status to VEGF secretion.
Methods: Surgically resected tumours were routinely cultured in single-cell suspension at 200 K/well (standard unit for culture of dispersed primary pituitary adenoma cells). We measured VEGF, IL1α and IL6 levels by ELISA. Tumour volume and invasion grade were assessed by preoperative magnetic resonance imaging.
Results: VEGF was detected in conditioned medium of HP75 cells (900±52 pg/ml) and in 82% of tumours tested (range 26–16 464 pg/ml). Tumour volume and secretion of VEGF were significantly associated with levels of IL6 (volume, P = 0.056; VEGF, P < 0.001 (P values based on Spearman’s test)) and IL1α produced (volume, P < 0.005; VEGF, P < 0.001). Invasive tumours showed a higher basal secretion of VEGF that that of the non-invasive type; however, this difference was not significant. Addition of exogenous IL1α, but not IL6, significantly increased VEGF production.
Conclusions: The significant associations between VEGF and the levels of IL6 and IL1α suggest an important role for these cytokines in the development of these tumours.