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S Contribution to a Better Life for Ageing Men: Part 1 F ORIGINAL ARTICLE The andrologist’s contribution to a better life for ageing men: part 1 F. Comhaire & A. Mahmoud Department of Endocrinology, University Hospital Gent, Gent, Belgium Keywords Summary Antioxidants—hormones—nutraceutical— quality-adjusted life years—testosterone The present opinion paper, explores the possibility that optimal hormone treat- ment and judicious nutraceutical food supplement can help ageing men to gain Correspondence quality-adjusted life years. Testosterone treatment of patients with late-onset Frank Comhaire, Brakelmeersstraat 18, hypogonadism is given via the transdermal route or by intramuscular injec- B 9830 Sint Martens-Latem, Belgium. tions. There is overwhelming evidence that testosterone replacement therapy Tel: 0032 475 618 555; (TRT) has many beneficial effects and increases longevity by approximately 2% E-mail: [email protected] per year. On the basis of knowledge of physiology, animal and human experi- mental data, we explain why TRT reduces the risk of cardiovascular disease Accepted: July 30, 2015 and of prostate cancer. However, the total testosterone load supplied per day should remain within the physiological range, and new galenical formulations doi: 10.1111/and.12485 should be developed, mimicking normal day–night variations. Introduction Hormone therapy in late-onset hypogonadism Men live longer than ever before, mainly because fewer Pathophysiology of late-onset hypogonadism men die early thanks to better hygiene, nutrition and medical care. The main concern has become to improve Decreasing testosterone secretion is a physiological event the quality of life of ageing men (Suzman et al., 2015), during male ageing. It results from reduced testicular increasing the number of quality-adjusted life years response to stimulation by the pituitary gonadotrophin (Qaly’s). Lifestyle is of primordial importance, but it may luteinising hormone (LH) and from diminished function be hard to convince ageing men to exercise regularly, to of the neurosecretory cells of the hypothalamus due to give up tobacco and alcohol consumption and to follow a changed thalamic activity, with blunting of the day–night calorie-restricted so-called healthy diet, although these variation in testosterone secretion. Hence, the total 24-h measures may delay life-threatening diseases and help production of testosterone decreases, and the amount of increasing the number of Qaly’s. this hormone interacting with its target cells is dimin- In the present opinion papers, we develop the concept ished, as can be estimated from the 24-h area under the that judicious hormone treatment and appropriate curve (AUC) of total testosterone concentration in blood nutraceutical food supplementation can help gaining Qaly’s. (Fig. 1). As the testosterone concentration decreases, the quo- tient of oestradiol divided by testosterone increases Materials and methods (Fig. 2). We have integrated personal clinical expertise and This is explained by the fact that there are two major external evidence (Sackett et al., 1996) as available in the sources of oestradiol in man, namely the aromatisation of literature. We did not aim at pursuing indiscriminate testosterone produced in and by the testicular Leydig cells meta-analysis, but rather have attempted to combine the and the metabolisation of dehydroepiandrosterone results of personal research and published evidence into a (DHEA) secreted by the adrenal cortex. The latter is logical opinion. The focus is on present knowledge metabolised by 3-b-hydroxysteroid dehydrogenase to regarding hormone replacement therapy (HRT) and food androstenedione, which is aromatised in the liver to oes- supplementation with nutraceuticals (Part 2). Nutraceuti- trone. Next, oestrone is reduced by the 17-b-hydroxys- cals are composed of natural substances including miner- teroid dehydrogenase to oestradiol. Whereas testicular als, vitamins and herbal extracts. oestradiol secretion decreases in parallel with the secretion © 2015 Blackwell Verlag GmbH 87 Andrologia 2016, 48, 87–98 A better life for ageing men F. Comhaire and A. Mahmoud Fig. 1 24-h serum testosterone concentration (on the vertical axis, in ng dlÀ1) during 24-h observation (time of the day on the horizontal axis) in young men (young men, green line) with typical day–night À variation, in ‘normal’ ageing men (old men, yellow line) with flat Fig. 2 The ratio (on the vertical axis) of oestradiol (pg ml 1) divided curve and in men suffering from late-onset hypogonadism (LOH, by testosterone (ng dLÀ1) is plotted against the total testosterone white line). The testosterone concentration that is drawn on top of concentration in serum (on the horizontal axis, in ng dlÀ1). A higher + the ‘andropause’ curve (LOH BATT, red line) is registered after apply- testosterone concentration is associated with a lower ratio of oestra- ing the sustained release bio-adhesive buccal tablet (BATT) containing diol/testosterone, and vice versa. The regression line and 95% confi- 10 mg of testosterone at 8 a.m. The area under the curve (AUC) of dence interval are represented. The representation is inspired by the young men equals 11 208 ng/24 h, that of ‘normal’ ageing men is Eadie–Hofstee diagram, whereby testosterone is the substrate and 9097 ng/24 h, and it is only 5913 ng/24 h in patients suffering from oestradiol the product of the aromatase enzymatic reaction. late-onset hypogonadism (LOH). The area under the curve of LOH patients treated with BATT is 9821 ng/24 h. Premature LOH Premature LOH occurs when the testis function is of testosterone, oestradiol originating from the metabolisa- impaired earlier in life than normal due to a history of tion of DHEA does not decrease, maintaining a substantial either orchitis or testicular maldescent, or because of the oestradiol concentration in blood (estimated by deduction presence of varicocele (Comhaire & Vermeulen, 1975) À from the Eadie plot at approximately 11–15 pg ml 1, (Fig. 4). which is similar to the adrenal contribution of serum Environmental hormone disrupters, mainly xeno-oe- oestradiol in post-menopausal women). Thus, the adrenal strogens such as the pesticide DDT, plasticisers such as contribution to the total serum oestradiol concentration phthalates, antiseptic agents such as nonylphenol, poly- causes a persistent relatively high oestradiol concentration, chlorinated biphenyls, dioxins and others, that are mainly and subsequent high oestradiol over testosterone ratio, in absorbed through food, suppress the hypothalamo–pitu- spite of a low testosterone concentration. itary–testicular axis, decrease testosterone secretion The higher ratio of oestradiol/testosterone in men with (Dhooge et al., 2001; Croes et al., 2014) and accelerate low testosterone concentration is associated with an the occurrence of LOH (Fig. 5). increased concentration of sex hormone-binding globulin Other important factors contributing to the occurrence (SHBG). As a result the concentration of free, or biologi- of LOH are the metabolic syndrome (Antonio et al., cally active, testosterone diminishes more importantly 2015), obesity (Ng Tang et al., 2013), insulin resistance than does the concentration of total testosterone (Fig. 3) and type 2 diabetes (Grossmann, 2011). Aside from secret- (Comhaire, 2000). ing inflammatory cytokines, fat tissue contains aromatase that metabolises testosterone into oestradiol (Deslypere et al., 1985), and the excessive production of latter inhibits The late-onset hypogonadism syndrome the hypothalamo–pituitary secretion of gonadotrophins. Late-onset hypogonadism (LOH) is a syndrome com- posed of sexual symptoms, changes in mood and cop- Treatment options of LOH ing behaviour and decreased muscular strength related to decreased testosterone levels (Wu et al., 2010). LOH Anti-oestrogen and aromatase inhibitors is associated with metabolic, biological and physical changes which cause deterioration of health and Based on the knowledge of the pathophysiological mecha- well-being. nisms, several approaches can be taken to upregulate the 88 © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 87–98 F. Comhaire and A. Mahmoud A better life for ageing men Fig. 3 Three-dimensional diagram depicting the evolution of the con- centrations of total testosterone (Testo; in ng dlÀ1; yellow band), sex Fig. 5 The hypothalamus secretes the neuro-endocrine substance hormone-binding globulin (SHBG in nmol dlÀ1; grey band) and free luteinising hormone-releasing hormone (LHRH) that stimulates the testosterone (Free Testo; in lglÀ1, red band) (on the vertical axis), in gonadotrophin secretion by the pituitary. Luteinising hormone (LH) relation to age (horizontal axis, in years) in normal ageing men, graph stimulates the secretion of testosterone by the Leydig cells, and folli- from Comhaire (2000) with permission. cle-stimulating hormone (FSH) activates the function of the cells of Sertoli. Xeno-oestrogens (XE) inhibit the LHRH secretion at the hypothalamo–pituitary level and have a direct negative effect on the function of Sertoli cells and spermatogenesis, resulting in oligo-, asth- eno- and teratozoospermia. Premature LOH occurs with low testos- terone concentration and LH not elevated. Fig. 4 Histogram of total testosterone concentration in serum (verti- cal axis in ng dlÀ1), in men without varicocele (normal men, green bars), and men with varicocele (pink bars) in relation to age (horizon- tal axis, grouped per 10 years). Fig. 6 In a cohort of normal, eugonadal men treatment with tamox- ifen 20 mg per day during 3 months resulted
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