REVIEW The relationship between hypogonadism and erectile dysfunction

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1 (2008) 20, & 2008 Nature Publishing Group All rights reserved /08 $ REVIEW The relationship between hypogonadism and erectile dysfunction TIS Hwang 1,2,3 and Y-C Lin 1 1 Division of Urology, Department of Surgery, Shin Kong WHS Memorial Hospital, Taipei, Taiwan; 2 School of Medicine, Fu-Jen Catholic University Taipei, Taipei, Taiwan and 3 School of Medicine, Taipei Medical University, Taipei, Taiwan It is well known that testosterone enhances sexual interest leading to an increased frequency of sexual acts and an increase in the frequency of sleep-related erections. However, it has little effect on fantasy- or visually induced erections. Exact contribution to erection from testosterone in men remains unclear. Animal studies have well demonstrated that testosterone plays critical physiological (activity of nitric oxide synthases and phosphodiesterases), biochemical (through an endothelial-independent pathway and adrenergic tonicity) and structural (change of fibroelasticity and hollow cell accumulation) roles in erectile function. The supplementation of testosterone to castrated animals can restore erectile function. Clinically, reports of patients with erectile dysfunction (ED) combined with hypogonadism who receive testosterone therapy have inconsistent results. However, testosterone may ameliorate the expression of the phosphodiesterase- 5 (PDE5) inhibitor, and the use of testosterone in conjunction with the PDE5 inhibitor revealed convincing results. Because of potential risks in clinical use, testosterone therapy should be individualized, carefully considered and closely monitored, especially, in patients with possible occult prostate cancer, and large benign prostatic hyperplasia. Lower urinary tract symptoms might be worsened by this treatment, since the prostate is an androgen-dependent tissue. (2008) 20, ; doi: /sj.ijir ; published online 28 February 2008 Keywords: hypogonadism; erectile dysfunction; testosterone replacement Introduction Erectile dysfunction (ED) is thought to be multifactorial and hypogonadism is one of the etiologies. However, there was still an obscure relationship between hypogonadism and ED. Several previous reports failed to demonstrate a strong connection between these two diseases especially in epidemiological studies. 1,2 Nevertheless, accumulating evidence showed testosterone replacement can improve ED in hypogonadal and near-hypogonadal male patients. 3 7 Supplementation of testosterone can also enhance the effects of phosphodiesterase-5 (PDE5) inhibitor. These evidences may indirectly imply the connection between hypogonadism and ED. In this review, we intend to give current Correspondence: TIS Hwang, Division of Urology, Department of Surgery, Shin Kong WHS Memorial Hospital, 95 Wen Chang Road, Shih Lin District, Taipei 11120, Taiwan. M001009@ms.skh.org.tw Received 10 September 2007; revised 30 October 2007; accepted 5 December 2007; published online 28 February 2008 evidences regarding the relationship between hypogonadism and ED in basic science and clinical studies. A medline research using the key words of hypogonadism, ED, androgen deficiency and testosterone replacement was performed. Among the search result, 33 papers were selected and reviewed. Hypogonadism Although there is no universal consensus regarding to the definition of hypogonadism, the prevalence of hypogonadism ranged % in several large studies in Western countries. 8,9 If serum total testosterone (T) of o300 ng per 100 ml (10.4 nmol l 1 ) is defined as hypogonadism, people aged years had a prevalence ranging 19 33% in Taiwan depending on the type of assay used to determine T. 10 Frequently, hypogonadism is associated with nonspecific clinical features such as fatigue, weakness, decreased libido and energy, ED, reduced muscle and bone mass, and increased abdominal fat. Although the Androgen Deficiency of Aging Males (ADAM) questionnaire developed by Morley et al. 11 provides excellent sensitivity as a screening

2 232 tool for men with low T levels, the specificity and reliability of the instrument are limited. Other screening questionnaires have similar constraints. 12,13 In the elderly, the diagnosis of hypogonadism is more problematic because of the difficulty in determining the extent of symptoms caused by aging, hypogonadism or both. 10 Symptomatology provides only 48% sensitivity and 66% specificity for diagnosing hypogonadism. 1 Loss of sexual interest and ED are common symptoms As a consequence, the ADAM questionnaire might not be a suitable single measurement for androgen deficiency or late-onset hypogonadism, and should be used together with biochemical markers (that is, total T (o11 nmol l 1 ), free T (0.23 nmol l 1 ), or bioavailable T (5 nmol l 1 )). 8 10,12,13 Erectile dysfunction and the relationship with hypogonadism The prevalence of ED increases with age, from 5% in 40 years old (severe type) to 15% in 70 years old men. 2 In Taiwan, the prevalence is 17.7% in people aged of years. 14 Major risk factors for ED include hypertension, cardiovascular disease (CVD), diabetes, depression and smoking. Organic causes are often classified into neurogenic, vasculogenic and hormonal groups. The majority of organic causes are vasculogenic (72%) and neurogenic (12%), while 10 20% of ED cases may involve hormonal abnormalities. 8,9,15 The prevalence of hypogonadism in men with ED varies widely from 1.7 to 35% ; the wide variation is due to studies of different patient populations, and the use of various definitions of ED and hypogonadism, and methodologies. Most available studies failed to demonstrate a significant correlation between plasma T levels and erectile function which would support a major role of T in erections. However, most men included in those studies were either eugonadal or mildly hypogonadal. 13,17 In men with more-severe androgen deficiency, a correlation between ED and T can be demonstrated and deserves further investigation. Basic research on T and erectile function In animal studies, androgens exert a direct effect on penile tissues to maintain erectile function through physiological, biochemical and structural pathways (Figure 1). This basic model was produced by Traish et al. 18,19 It was comprised of stimulating the pelvic nerve of an animal and monitoring the subsequent erection. A castrated animal did not respond, but erectile function was restored after replacement of T. Figure 1 Effects of orchiectomy and testosterone replacement on the penile tissue through three different pathways of physiological, biochemical and structural, which control erection and flaccidity. Physiological pathways. In the rabbit model, castration induces ED and reductions in NO synthase and PDE5 in erectile tissues. 18 PDE5 is the predominant enzyme responsible for cgmp hydrolysis in trabecular smooth muscle. Activation of PDE5 terminates NO-induced, cgmp-mediated smooth muscle relaxation, resulting in smooth muscle contractility and penile flaccidity. An androgen deficiency diminishes protein expression and enzymatic activity of endogenous nitric oxide synthase (enos and nnos) and PDE5. Androgen replacement upregulates the expression of PDE5 activity and this result indicates a T-dependent physiological erectile pathway. Morelli et al. 20 also observed that androgen deprivation reduces PDE5 expression; while T supplementation restores PDE5 gene and protein expressions in the rabbit corpus cavernosum. This implies that T is necessary for full PDE5- inhibitor responsiveness. Hence, T is important not only for allowing cgmp formation through the positive modulation of NO synthase, but also for increasing cgmp degradation. This androgeninduced two-step regulation of NO activity and cgmp formation in the corpus cavernosum might be relevant for the timely synchronization of penile erections with sexual acts, which are clearly androgen dependent. Moreover, in organ bath assays (in vitro) and pelvic nerve stimulation (in vivo), Traish et al. 18 and Morelli et al. 20 also demonstrated that androgen deprivation reduced the facilitative

3 effect of sildenafil on neurogenic relaxation. This facilitation was restored in tissues of castrated animals treated with T. These data suggest that androgens are critical not only for NOS activity, but also for modulating PDE5 activity. Biochemical pathways. Rajfer et al. 21 reported that T affects endothelial cells by showing decreased nitric oxide activity in castrated animals and restoration with T replacement. By biochemically blocking endothelial function, erections are inhibited after pelvic stimulation in castrated animals. Under these conditions, T administration produces a moderate erectile response, indicating an endothelial-independent pathway. T may also affect adrenergic penile tone. 22 Noradrenaline is one of the putative vasoconstrictors of penile arterioles and sinusoids that help maintain the penis in a flaccid state. In an animal study, Mills et al. 22 proposed that androgens are critical for maintaining erectile function by supporting the responsiveness of vascular smooth muscle to vasoactive drugs. In addition to these trophic effects through transcriptional regulation, androgens may also regulate vascular smooth muscle contractility by nongenomic mechanisms, such as relaxation of coronary arteries by activating potassium channels and inhibiting calcium channels. 23 Reilly et al. 24 showed that the responsiveness to phenylephrine, an a 1 -adrenergic agonist, was nearly six times greater in castrated rats than those with normal T levels. Therefore, T can indirectly enhance erections by attenuating the a-adrenergic vasoconstrictor activity in vascular smooth muscles of the corpus cavernosum. Structural pathways In animal models, Traish et al. 18 and Rogers et al. 25 demonstrated that androgen deprivation results in a significant reduction in trabecular smooth muscle content (apoptosis) and a marked increase in connective tissue deposition. In intact animals, smooth muscle cells exhibited a normal morphology and were arranged in clusters. Although there was no significant difference in the smooth muscle contents between intact, castrated and T-treated castrated animals, transmission electron microscopy showed marked differences in the morphology of smooth muscle cells. Myocytes in cavernosal tissue from castrated animals exhibited larger intercellular spaces and decreased amounts of cytoplasmic myofilaments. Tissue from T-treated castrated rats had myocytes that were similar in appearance to those of sham-operated animals. Changes in the fibroelastic properties of penile tissue may alter penile compliance and hemodynamics, resulting in ED. In addition to changes in connective tissue and smooth muscle Traish et al. 19 revealed hollow cellular structures in the subtunical region of the corpus cavernosum that were distinct from cavernous spaces in an orchidectomized rat model. Those hollow cells resembled adipocytes and were consistently present in tissues of orchidectomized animals but were absent from tissues of control animals. The mechanism of androgens-regulated growth and differentiation of trabecular smooth muscle cells and/or adipocytes in the penis remains poorly understood. T may also contribute to the penile venous occlusion mechanism that maintains erections. 22 The veno-occlusive mechanism depends on the integrity of neural, vascular and endocrine systems, as well as on the fibroelastic properties of the cavernosal tissue. In summary, an androgen deficiency produces reductions in trabecular smooth muscle content and fibroelastic properties, and increased deposition of extracellular matrix, resulting in the accumulation of hollow cells in the subtunical region of the corpus cavernosum. These structural imbalances reduce blood inflow and cause failure of the veno-occlusive mechanism, resulting in ED. Clinical implications Studies evaluating the effect of T replacement on erectile function in hypogonadal men have yielded mixed results. Data derived from those studies are difficult to interpret due to lack of placebo groups in most trials, or only a relatively small number of patients. Steidle et al. 26 reported a large (n ¼ 406), short-term trial of 90-day duration, in which sexual function (erection and libido) improved in hypogonadal elderly men with administration of T gel as compared with placebo. However, in a 6-month non-placebo-controlled study, Mulhall et al. 3 showed that improvement in erection with transdermal and intramuscular T therapy decreased after 1 month of treatment. Clinically, a relationship between restoration of serum T concentrations and improvement in sexual function was proposed by Seftel et al. 4 Concentration of serum T was positively correlated to sexual desire, frequency of night time erections and frequency of intercourse. Zitzmann et al. 27 reported that ED was identified as a composite pathology of metabolic risk factors, smoking and depressions. Testosterone contributed to ED only when the T concentrations were below 8 nmol l 1. Human studies designed to examine a possible direct vasodilator effect of T on penile arterial circulation are lacking; however, Aversa et al. 5 demonstrated indirect evidence of a correlation between serum levels of free T and cavernous vasodilation assessed by duplex ultrasound in 52 eugonadal men with ED (r ¼ 0.37, Po0.01). Becker et al. 28 showed that 233

4 234 plasma T levels increased during penile tumescence after sexual arousal in the systemic and cavernous vasculature in both healthy men and patients with ED with low-normal total T levels. Hwang et al. 6 demonstrated that men with ED and low T levels had decreased responsiveness to sildenafil. Additionally in Aversa s report, men with hypogonadism who failed to respond to sildenafil responded well when T was administered. Although T therapy improves erectile function in men with hypogonadism, the efficacy of T monotherapy might not be adequate, because of the multifactorial nature of the pathophysiology of ED. There are emerging evidence-based benefits on combination of T and PDE5 inhibitors. Shabsigh et al. 29 evaluated the safety and efficacy of a 1% T gel plus sildenafil vs a placebo gel plus sildenafil on erectile responses in hypogonadal men who had failed prior sildenafil treatment alone for ED. After 12 weeks of treatment, the group with the T gel combined with sildenafil showed significantly improved erectile function, orgasmic function and patient satisfaction. The response rate for erectile improvement was 65.4 as compared to 16.7% for the placebo. Hwang et al. 6 also demonstrated that hypogonadal patients who were initially unresponsive to sildenafil highly responded (67%) to T alone or the combination of T and sildenafil. Wang et al. 30 reported androgen replacement that showed an improvement on the sexual function, mood, muscle strength and body composition in male with hypogonadal status. The mechanisms whereby T improves the response to PDE5 inhibitors are unclear; the enhancement of libido by T is most likely a contributing factor. Moreover, it is possible that both T and PDE5 inhibitors act on the same pathway in the penis, that is, the NO cgmp Figure 2 Effects of castration and androgen replacement on phosphodiesterase type 5 (PDE5) activity in the corpus cavernosum of the rabbit. PDE5 activity was determined by cgmp hydrolysis. C, control; V, vehicle; T, castrated treated with testosterone; E, castrated treated with estradiol. *Po0.02 (Credited to Traish et al. 13 ). pathway, as demonstrated in animal models (Figure 2). According to the previous evidence, it is important to screen all men with ED for hypogonadism, especially those with a history of inadequate response to prior PDE5 inhibitors. The combination of T plus PDE5 inhibitors may be considered for those with an inadequate response to PDE5 inhibitors alone. Monitoring patients on testosterone replacement therapy Prostate-specific antigen (PSA) is monitored 6 12 weeks after beginning androgen therapy, with semiannual follow-up thereafter. 31 The presence of a palpable nodule on follow-up of DRE or a PSA velocity of ng ml 1 per year, should prompt further investigation with a prostate biopsy. Evaluation of the clinical response to testosterone replacement therapy should include assessments of physical function, sexual function, lipid profile and bone mineral density, especially, in patients who have documented osteoporosis or osteopenia at the baseline. 32,33 Serial measurements of serum T usually are not indicated unless patients demonstrate a poor clinical response or signs of any adverse effects of treatment. Other laboratory examinations obtained on a routine basis include an annual hematocrit and lipid profile. 34 Clinical perspectives Hypogonadism remains a basically underdiagnosed and undertreated condition. This is mainly because of the difficulty on differentiation of this entity from other nonspecific and often co-morbid diseases. Although convincing evidence suggests that T plays an important role in erectile function, the minimal threshold of circulating level of T necessary to maintain an erection is not yet known. Further studies investigating the correlation of circulating T and erectile function in men with different degrees of hypogonadism are mandatory. Moreover, ED in men increases with age, so as CVD. Major risk factors of CVDs are similar to ED such as metabolic syndrome and insulin resistance. Further investigation should be performed on the association between hypogonadism, metabolic syndrome and insulin resistance. If short-term efficacy is established, long-term, large-scale studies to assess the risks and benefits should be continued. Furthermore, randomized, placebo-controlled trials on short- and long-term bases to investigate the effects of T on erectile function in elderly men with hypogonadism should be carried out.

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