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RD Jones, T Hugh Jones and KS Channer

Recent clinical studies have reported that testosterone therapy reduces myocardial ischaemia in men with coronary artery disease, and the beneficial modulation of coronary vascular tone by testosterone has been proposed as an effector mechanism. Maintenance of a correct response to vasoconstrictive and vasodilatory agents is essential in the control of vascular tone. Endothelial dysfunction, most commonly manifested through an elevation in vascular tone, is implicated as an initiating factor in conditions such as hypertension and atherosclerosis. Increased sensitivity to vasoconstrictive stimuli is also proposed in the development of heart failure and hypertensive vascular remodelling, while increased coronary vascular reactivity to vasoconstrictive factors is likely further to restrict coronary blood flow through the partially occluded atherosclerotic vessel. Reduced vasodilatation and enhanced vasoconstriction can also lead to vasospasm and exacerbation of anginal symptoms. Testosterone is well known to elicit direct vasodilatation, but its influence upon responses induced by other vasoactive agents is less coherent, and may depend upon the underlying pathogenic process or gender. The aim of this review is to present the data obtained from both the patient and animal studies conducted to date, to ascertain any influence testosterone may have upon the regulation of vascular tone.

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T Hugh Jones, Joe F Darne and Hugh HG McGarrigle

Jones TH, Darne JF, McGarrigle HHG. Diurnal rhythm of testosterone induced by human chorionic gonadotrophin (hCG) therapy in isolated hypogonadotrophic hypogonadism: a comparison between subcutaneous and intramuscular hCG administration. Eur J Endocrinol 1994;131:173–8. ISSN 0804–4643

When human chorionic gonadotrophin (hCG) is used to stimulate testosterone synthesis and release in males with hypogonadotrophic hypogonadism, it is administered two or three times weekly by intramuscular injection. We have compared the pharmacokinetics of a twice weekly standard dose of hCG (5000 U) given for the first week by intramuscular injection and in the second week by self-administered subcutaneous injection. The patients studied had Kallmann's syndrome, isolated idiopathic hypogonadotrophic hypogonadism or post-traumatic isolated hypogonadotrophic hypogonadism. Salivary testosterone was collected twice daily at 08.00 h and 20.00 h, and serum testosterone was collected after 0, 24 h, 72 h, 120 h and 168 h each week. The cumulated serum and salivary testosterone levels were comparable on both intramuscular and subcutaneous hCG. In normal males there is diurnal variation in testosterone, with peak serum levels in the morning falling to a nadir in the evening. The exact nature and controlling factors of this circadian rhythm have not been established. In four of the subjects, the twice weekly hCG injections, either subcutaneous or intramuscular, produced a regular testosterone diurnal rhythm. The other four patients had fluctuations in testosterone but with no strict diurnal pattern. This study provides evidence that the luteinizing hormone-like action of hCG is necessary to prime the circadian rhythm but only a single bolus of hCG is sufficient to induce the rhythm in the absence of endogenous gonadotrophin production. In conclusion, self-administered subcutaneous hCG is safe and produces comparable levels of serum and salivary testosterone to that administered by the intramuscular route. Moreover, it was very well accepted by the patients and was preferred to conventional treatments. Human hCG in some patients with hypogonadotrophic hypogonadism produces normal physiological changes in daily testosterone levels.

TH Jones, University Department of Medicine, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK

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T. Hugh Jones, Barry L. Brown and Pauline R. M. Dobson

Abstract.

The effect of the kinin, kallidin (lysyl-brady-kinin) on phosphoinositide metabolism and prolactin secretion was examined in male rat anterior pituitary cells in primary culture. Kallidin was found to stimulate both total inositol phosphate production and prolactin release. The stimulation of inositol phosphate was biphasic in nature, similar to that previously reported for bradykinin, although kallidin was approximately 10-fold more potent. Kallidin also stimulated prolactin secretion provoking a maximal stimulation of 193.0±11.1 (sem)% at 1 μmol/l. These findings suggest that kallidin-induced prolactin secretion may be mediated intracellularly by activation of phosphoinositide metabolism. The B2 receptor antagonists had no significant inhibitory effects on kallidin-stimulated phosphoinositide metabolism or prolactin release. The B1 agonist des-Arg9-bradykinin has previously been shown to have no effect on either parameter. As the effects of kinins on anterior pituitary cells do not appear to be mediated by either of the known kinin receptors, they may, therefore, act via a hitherto unrecognised kinin receptor.

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Atish Mathur, Christopher Malkin, Basil Saeed, R Muthusamy, T Hugh Jones and Kevin Channer

The authors and journal apologize for errors in the above paper which appeared in 161 (3) 443–449. On page 444 in the second paragraph under the heading ‘Subjects’ myocardial ischaemia (MI) should read myocardial infarction (MI). On page 448 the two instances of MI should read myocardial ischaemia.

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Vakkat Muraleedharan, Hazel Marsh, Dheeraj Kapoor, Kevin S Channer and T Hugh Jones

Objective

Men with type 2 diabetes are known to have a high prevalence of testosterone deficiency. No long-term data are available regarding testosterone and mortality in men with type 2 diabetes or any effect of testosterone replacement therapy (TRT). We report a 6-year follow-up study to examine the effect of baseline testosterone and TRT on all-cause mortality in men with type 2 diabetes and low testosterone.

Research design and methods

A total of 581 men with type 2 diabetes who had testosterone levels performed between 2002 and 2005 were followed up for a mean period of 5.8±1.3 s.d. years. Mortality rates were compared between total testosterone >10.4 nmol/l (300 ng/dl; n=343) and testosterone ≤10.4 nmol/l (n=238). The effect of TRT (as per normal clinical practise: 85.9% testosterone gel and 14.1% intramuscular testosterone undecanoate) was assessed retrospectively within the low testosterone group.

Results

Mortality was increased in the low testosterone group (17.2%) compared with the normal testosterone group (9%; P=0.003) when controlled for covariates. In the Cox regression model, multivariate-adjusted hazard ratio (HR) for decreased survival was 2.02 (P=0.009, 95% CI 1.2–3.4). TRT (mean duration 41.6±20.7 months; n=64) was associated with a reduced mortality of 8.4% compared with 19.2% (P=0.002) in the untreated group (n=174). The multivariate-adjusted HR for decreased survival in the untreated group was 2.3 (95% CI 1.3–3.9, P=0.004).

Conclusions

Low testosterone levels predict an increase in all-cause mortality during long-term follow-up. Testosterone replacement may improve survival in hypogonadal men with type 2 diabetes.

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Atish Mathur, Christopher Malkin, Basil Saeed, R Muthusamy, T Hugh Jones and Kevin Channer

Introduction

In short-term studies, testosterone replacement therapy has been shown to protect male subjects from exercise-induced ischaemia and modify cardiovascular risk factors such as insulin resistance, fat mass and lipid profiles.

Methods

This randomised parallel group controlled trial was designed to assess the treatment effect of testosterone therapy (Nebido) compared with placebo in terms of exercise-induced ischaemia, lipid profiles, carotid intima-media thickness (CIMT) and body composition during 12 months treatment in men with low testosterone levels and angina.

Results

A total of 15 men were recruited but 13 (n=13) reached adequate duration of follow-up; seven were treated with testosterone and six with placebo. Testosterone increased time to ischaemia (129±48 s versus 12±18, P=0.02) and haemoglobin (0.4±0.6 g/dl versus −0.03±0.5, P=0.04), and reduced body mass index (−0.3 kg/m2 versus 1.3±1, P=0.04) and triglycerides (−0.36±0.4 mmol/l versus 0.3±1.2, P=0.05). The CIMT decreased in the testosterone group more than placebo, but full between group analyses suggested this was only a statistical trend (−0.5±0.1 vs −0.09±0.06, P=0.16). There were no significant effects on serum prostate specific antigen, total or high-density lipoprotein cholesterol; or on mood and symptom scores as assessed by Seattle Angina Score and EuroQol.

Conclusion

The protective effect of testosterone on myocardial ischaemia is maintained throughout treatment without decrement. Previously noted potentially beneficial effects of testosterone on body composition were confirmed and there were no adverse effects.