A. A. Yassin¹, F. Akhras², A. I. El-Sakka³ & F. Saad^4,5

¹Institute of Urology and Andrology, Segeberger Kliniken, Norderstedt-Hamburg, Germany; ²Consultant Cardiologist, Cromwell Hospital, London SW5 0TU and Cardiac and Medical Healthcare Services, Harley Street, London W1G 7JS, UK; ³Department of Urology, Suez Canal University, Ismailia, Egypt; ⁴Scientific Affairs Men's Healthcare, Bayer Schering Pharma, Berlin, Germany; ⁵Research Department, Gulf Medical University School of Medicine, Ajman, UAE.

Dr Aksam A. Yassin, MD, PhD, EdD, FEBU, Segeberger Kliniken, Rathausallee 94a, 22846 Norderstedt-Hamburg, Germany. Tel.: +49 40 526 21 57; Fax: +49 40 526 28 20;; E-mail: [email protected].

Summary

Traditionally, clinical conditions synonymous with the ageing male included cardiovascular disease (CVD), type 2 diabetes mellitus (DM) and sexual dysfunction, and were widely regarded as independent clinical entities. Over the last decade, interrelationship of clinical conditions has been convincingly demonstrated. Declining testosterone levels in the elderly, once regarded as an academic endocrinological question, appear to be central to the listed pathologies. It is now clear that erectile dysfunction is an expression of endothelial dysfunction. Testosterone deficiency is associated with an increased incidence of CVD and DM. The latter is often the sequel of the metabolic syndrome. Visceral obesity, a pivotal characteristic of the metabolic syndrome, suppresses the hypothalamic-pituitary-testicular axis leading to diminished testosterone production. Conversely, substantial androgen deficiency leads to signs and symptoms of metabolic syndrome. It is erroneous not to include testosterone measurements in the progress of the CVD, DM and erectile dysfunction. These conditions correlate strongly with testosterone deficiency.

Keywords: Cardiovascular, disease—erectile, dysfunction— metabolic, syndrome—testosterone.

British Medical Journal had a venerable tradition of publishing in their end-of-the year issues scientifically robust research whereas, at the same time, amazing and amusing their readership. In December 20, 1997 issue of the British Medical Journal, Davey Smith et al. (1997) published a study with the title ‘Sex and death: are they related? Findings from the Caerphilly cohort study’. The study concluded that mortality risk was 50% lower in the group with high orgasmic frequency than in the group with low orgasmic frequency, with evidence of a dose- response relation across the groups. Whereas death from coronary heart disease and from other causes showed similar associations with frequency of orgasm, the gradient was most marked for deaths from coronary heart disease.

A decade later we are able to offer some perspectives on this association which was difficult to interpret in 1997. It is not far fetched to assume that the men with the highest frequency of orgasm were - statistically speaking - those who were least bothered by erectile dysfunction. Now a host of studies indicate that erectile function and dysfunction are reliable telltales of cardiovascular health in a bi-directional fashion: the quality of erectile function is a reflection of the health of the cardiovascular system and CVD is almost inevitably associated with degrees of erectile dysfunction.

Erectile dysfunction and CVD: two faces of the same coin

Erectile dysfunction (ED) is a local penile expression of generalised vascular pathology with the underlying pathology being endothelial dysfunction. Endothelial dysfunction, which manifests itself clinically as impaired vasodilatation is the hallmark of ED. The endothelium is the single layer of cells lining the surface of blood vessels.

It has become clear that it is not merely a histological structure but it has several important functions in cardiovascular health and disease with regard to vascular tone, inflammation and adhesion of thrombocytes. The process of arteriosclerosis starts at the endothelium (Nacci et al., 2009).

The vascular endothelium is pivotal for vasodilatation which is the physiological basis for adequate tissue perfusion to warrant adequate oxygenation in relation to actual demands. This flexible response depends on the capacity to change the resistance of the vascular system. The underlying physiological mechanism is the production of local agents of which the most significant is nitric oxide (NO). It inhibits platelet aggregation and regulates vascular tone (Nacci et al., 2009). Bioavailable NO can be increased by enhancing its production or reducing its inactivation. NO induces endothelial vasodilatation by increasing the cGMP content of vascular smooth muscle cells, resulting in relaxation. Cardiac risk factors - including dyslipidaemia, hypertension and type 2 diabetes - are all associated with impaired endothelial function (Nacci et al., 2009; Potenza et al., 2009). Evidence is accumulating that ED is an early sign of CVD (El-Sakka & Morsy, 2004; El-Sakka et al., 2004). ED is an important marker of vascular disease throughout the arterial tree (Jackson, 2009).

The Massachusetts Male Aging Study (MMAS), a ran-dom-sample cohort study of men aged 40-70, investigated the relationship between baseline risk factors for coronary heart disease and subsequent ED, on the assumption that subclinical arterial disease might be manifested as ED (Feldman et al., 2000). Overweight [body mass index (BMI): > 28 kg m^-2] and a composite coronary risk score also significantly predicted incident ED (Feldman et al., 2000). Cardiovascular risk factors in mid-life could predict the incidence of ED an average of 25 years later. A study which assessed seven classic CHD risk factors in men aged 30-69 from 1972 to 1974 and then again in 1998, found that mean age, BMI, cholesterol and triglycerides were each significantly associated with an increased risk of ED (Fung et al., 2004).

Erectile function is viewed by almost all men as a significant component of quality of life (Holden et al., 2005) and erectile difficulties (ED) may be a reason to seek medical advice. As indicated above, several studies document now that there is a high concordance between the causes of ED and the causes of CVD, this indirectly by demonstrating that there is an elevated prevalence of the metabolic syndrome and insulin resistance in a population of men with ED as compared with a general population of men (Bansal et al., 2005). The authors argue that the ultimate goal therefore must be not only to treat the erectile problem but also to diagnose and adequately (aggressively) treat any cardiac risk factors that may be found.

The Massachusetts Male Aging Study equally revealed that erectile dysfunction was predictive of the metabolic syndrome. This study supports the idea that erectile dysfunction may provide a warning sign and, at the same time, an opportunity for early intervention in men otherwise considered at lower risk for the metabolic syndrome and subsequent CVD (Kupelian et al., 2006b).

The MMAS has also estimated the frequency of erectile dysfunction progression and remission among ageing men, and assessed the relation of progression/remission to demographics, socioeconomic factors, comorbidities and modifiable lifestyle characteristics (Travison et al., 2007). Natural remission and progression occur in a substantial number of men with erectile dysfunction. Age and BMI were associated with progression and remission of ED. Interventions were nonpharmacological which apparently impacted on remission and delaying progression of ED. The association of BMI with remission and progression, and the association of smoking and health status with progression, offer potential avenues for facilitating remission and delaying progression using nonpharmacological intervention. Lifestyle changes are associated with improvement in sexual function in about one-third of obese men with erectile dysfunction at baseline. Weight loss and increased physical activity appeared to have a favourable effect on erectile and endothelial functions in obese men (Esposito et al., 2004a,b).

The benefits of such interventions for overall men’s health may be far-reaching and support the view that ED is a portal to men’s health.

Shabsigh et al. (2008a,b) have eloquently argued that ED can calculate men’s health risks. Elements in the calculation of health risks (hypertension, diabetes, angina or hyperlipidaemia) in men presenting with ED are health status on a scale of 1-7 (1 = excellent, 7 = poor), waist size, severity of ED, presence/absence of a sexual partner. The calculation produces scores within the range of 1-7. If the score is 1.5-2.5 = medium risk (30-59% probability); > 2.5 = high risk (>60% probability of having the condition) and < 1.5 = low risk ( < 30% probability) (Shabsigh et al., 2008b). A study with a similar message was conveyed by Corona et al. (2008).

Results

Androgens and sexual functioning

As the title indicates, this review addresses erectile dysfunction and CVD as the two faces of the coin of androgen deficiency. This has recently authoritatively been reviewed (Traish et al., 2009a).

When Professor Vermeulen from Ghent, Belgium started his pioneering work on the decline of testosterone levels in old age in the 1970s, his work seemed to most professionals of theoretical interest only (for review: Kaufman & Vermeulen, 2005). Now, 30-40 years later, the pathophysiological implications of the decline, not rarely amounting to testosterone deficiency, have become clear. The understanding of the (patho)physiological functions of testosterone with regard to sexual functioning has undergone a revolutionary development. A decline in testicular function with a consequent decline in testosterone level is recognised as a common occurrence in older men (Morales, 2003; El-Sakka & Hassoba, 2006). It was well- known that hypogonadism in men usually results in loss of libido and potency which can be restored by androgen administration. The original insights into the mechanisms of action of androgens on sexual function indicated a prominent role of testosterone on sexual interest whereas the effects of testosterone on erectile function were less apparent from these early investigations (Bancroft & Wu, 1983). But new research has presented convincing evidence that testosterone has profound effects on tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological substrate of erectile capacity, at least in part reversible upon androgen replacement (Shabsigh, 2004; Gooren & Saad, 2006; Traish et al., 2007; Buvat & Bou Jaoude, 2008). There are androgen receptors in the human corpus cavernosum (Aversa et al., 2003). Several studies show that testosterone plays a critical role in restoring and maintaining the penile trabecular smooth muscle structure and function (Traish et al., 1999, 2003; Yassin & Saad, 2005) as well as regulating the cell apoptosis (Shabsigh, 1997). In line with this, Aversa et al. (2000) reported that the circulating levels of free testosterone, independently of age, positively correlated with the degree of relaxation of the corporal smooth muscle cells and the cavernous endothelial cells, giving support to the potential role of androgens in regulating smooth muscle function in the penis.

Adipocyte accumulation in penile subtunical area of the corpus cavernosum emphasised the potential mechanism for veno-occlusive dysfunction in androgen deficiency (Traish et al., 2005) (for review: Gooren & Saad, 2006). A study of Corona et al. (2009b) shows that pulse pressure as an index of arterial stiffness is associated with androgen deficiency and impaired penile blood flow in men with ED. Testosterone has a positive impact on haemodynamic processes and the veno-occlusive properties in the penile trabecular tissues. Testosterone may repair venous leakage in hypogonadal patients and subjects with metabolic syndrome. The impact of a hormonal factor on veno- occlusive properties of the corpora cavernosa indicates that restoration of testosterone to normal may repair mechanical damage of the corpora cavernosa (Yassin & Saad, 2006; Yassin et al., 2006b; Kurbatov et al., 2008). This has also been found to be the case in laboratory animals.

In a well-designed intervention study Aversa et al. (2003) provided support for this mechanism of action of testosterone on the erectile tissues of the penis. They assessed the effects of androgen administration in 20 patients with arteriogenic ED (confirmed with dynamic colour duplex ultrasound), not responding to treatment with sildenafil 100 mg. The patients’ testosterone levels were in the lower quartile of the normal range. In this placebo-controlled study, treatment with transdermal testosterone raised plasma testosterone levels and led to an increase of arterial inflow into the cavernous tissue and to an improvement of ED thus enhancing the response to treatment with PDE-5-inhibitors. In line with the above Foresta et al. (2004) have documented that normal plasma testosterone is required for erectile function. In severely hypogonadal men (plasma testosterone < 2.0 ng ml^-1) the nocturnal penile tumescence, ultrasound measurement of arterial carvernous inflow and visually stimulated erection in response to sildenafil 50 mg or apomorphine 3 mg were minimal. The responses to these pharmacological stimuli normalised after 6 months of administration of testosterone patches evidencing the significant role of normal levels of testosterone for erectile function.

The phosphodiesterase type 5 inhibitors (PDE5-Is) have revolutionised treatment of erectile dysfunction (ED). But 30-35% of patients fail to respond. Associated testosterone deficiency, not properly diagnosed, has been proposed as one of the reasons for failure. A number of studies suggest that the activity of PDE5-Is as a treatment of ED is androgen-dependent. In rodents castration reduces protein expression and activity of PDE5, and testosterone treatment is capable of upregulation (Traish et al., 1999; Morelli et al., 2004). In addition medical or surgical castration prevents the enhancing effect of PDE5-Is on erections induced by electrostimulation of the cavernous nerves (Traish et al., 1999; Zhang et al., 2005). The expression of NO synthesis (Azadzoi et al., 1992; Burnett, 2004) is regulated by androgens. The expression of PDE5 has been found to be androgen-dependent as well in humans (Morelli et al., 2004). In addition, several clinical studies suggest that testosterone deficiency is a risk factor for poor response to sildenafil (Guay et al., 2001; 2003; Park et al., 2005; Rosenthal et al., 2006; Koulikov et al., 2007; Teloken et al., 2007; Traish et al., 2007). Five uncontrolled studies have also reported beneficial effects of a combination therapy with testosterone and PDE5-Is in men with ED and low or low-normal testosterone who previously had not responded to 100 mg sildenafil (Shabsigh, 2004;Shamloul et al., 2005; Hwang et al., 2006; Rosenthal et al., 2006)or 20 mg tadalafil (Yassin et al., 2006a).

In a well-designed randomised placebo-controlled trial, Rochira et al. (2006) demonstrated that sildenafil is able to restore nocturnal erections of men with almost undetectable levels of testosterone to the same extent as testosterone replacement therapy though the combination was more powerful than either alone.

Androgens and (risk factors of) CVD

Until a decade ago, it was widely regarded that androgens have an atherogenic effect and thus led to CVD, and androgen administration was thought to contribute to the development of CVD. Over the last decade, several papers have examined the relationship of androgens with CVD and concluded that it is no longer tenable to regard testosterone as a culprit in the aetiology of CVD (Liu et al., 2003; Wu & von Eckardstein, 2003; Jones et al., 2005; Shabsigh et al., 2005, 2006; Jones & Saad (2009), unpublished data). Recent epidemiological studies have found that low testosterone levels are a predictor of mortality in elderly men (Shores et al., 2004, 2006; Khaw et al., 2007; Maggio et al., 2007; Laughlin et al., 2008).

Over the last 2 years a large number of review papers have highlighted the significance of depressed levels of testosterone and CVD (Corona et al., 2008, 2009a; Yassin et al., 2008; Traish et al., 2009b).

Both cross-sectional and longitudinal epidemiological studies have convincingly established that low plasma testosterone/low SHBG are correlated with/predict the metabolic syndrome (Laaksonen et al., 2003a; Blouin et al., 2005; Kalme et al., 2005; Muller et al., 2005; Kupelian et al., 2006a). Numerous studies have found inverse associations between the severity of features of the metabolic syndrome and plasma testosterone (Allan et al., 2006, 2007; Kaplan et al., 2006; Mohr et al., 2006; Kalyani & Dobs, 2007; Rodriguez et al., 2007). There is an inverse relationship between waist circumference, a reliable indicator of visceral obesity and testosterone levels over all age groups (Svartberg et al., 2004).

Adiposity with its associated hyperinsulinism suppresses SHBG synthesis and therewith the levels of circulating testosterone (Eckel et al., 2005; Kaufman & Vermeulen, 2005). It also may affect the strength of LH signalling to the testis (Lima et al., 2000). Further, insulin (Pitteloud et al., 2005) and leptin (Isidori et al., 1999) have a suppressive effect on testicular steroidogenesis. Visceral fat cells secrete a large number of cytokines which impair testicular steroidogenesis (Lyon et al., 2003; Trayhurn & Wood, 2004; Eckel et al., 2005). Thus, there are reasons to believe that adiposity is a significant factor in lowering circulating levels of testosterone. While it is clear that disease, and in the context of this contribution, in particular the metabolic syndrome, suppresses circulating testosterone levels, it has also been documented that low testosterone induces the metabolic syndrome (Stellato et al., 2000; Laaksonen et al., 2004). Low testosterone and SHBG levels appeared strongly associated not only with components of the metabolic syndrome, but also with the metabolic syndrome itself, independently of BMI. Furthermore, sex hormones were associated with inflammation and body iron stores. Even in the absence of late-stage consequences such as diabetes and CVD, subtle derangements in sex hormones are present in the metabolic syndrome, and may contribute to its pathogenesis (Laaksonen et al., 2003b).

The relative contributions of each of the individual National Cholesterol Education Program Adult Treatment Panel III components of the metabolic syndrome to low serum testosterone in ageing men have been examined using multiple linear regression modelling. Based on these analyses the presence of diabetes or fasting serum glucose greater than 110 mg dl^-1, BMI 30 kg m^-2 or greater, and triglycerides 150 mg dl^-1 or greater each appeared to have a clinically relevant association with low serum testosterone (Kaplan, 2006). El-Sakka et al. (2008) have recently demonstrated significant associations between low level of total testosterone and DHEA-S and poor control of diabetes. Furthermore, they have reported that there were significant associations between control of diabetes and normal levels of total testosterone at 3- and 6-months follow-up visits (El-Sakka et al., 2009).

The role of testosterone is dramatically demonstrated by findings in men with prostate cancer who undergo androgen ablation therapy (Basaria et al., 2006; Smith & Nathan, 2006), particularly in the longer-term (Brag- Basaria et al., 2006). Another study showed convincingly that acute androgen deprivation reduces insulin sensitivity in young men (Yialamas et al., 2007) and strongly impairs glycaemic control of men with DM (Haidar et al., 2007).

Conclusion

Until a decade ago the ailments of elderly men, such as atherosclerosis, hypertension, DM, lower urinary tract symptoms and erectile dysfunction, were regarded as distinct diagnostic/therapeutic entities but there is a growing recognition that these entities are not disparate but inter-dependent in their aetiology. To improve the health of the ageing male, they require an integral diagnostic and therapeutic approach. Measurement of testosterone is pivotal to adequate health care in most of the ailments of ageing men. While this may be obvious in cases of ED, it should include conditions such as CVD and DM2. This may at first seem unorthodox to physicians treating patients with these conditions.

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