Testosterone and erectile physiology

The role of testosterone deficiency in sexual dysfunction is an important aspect of aging, because it affects such a large proportion of men over 50 years old. A number of age-related factors can cause sexual dysfunction (in particular erectile dysfunction) and testosterone deficiency, such as chronic illness and multiple medications, and the causative link between hypogonadism and erectile dysfunction is still debated. However, studies in castrated animals have proven that addition of testosterone, and its conversion to dihydrotestosterone, can restore erectile function. It appears that testosterone achieves this by peripheral mechanisms (endothelial dependent and independent) and central mechanisms. Testosterone replacement therapy is therefore effective for erectile dysfunction in men with hypogonadism, with success rates of 35–40%. Testosterone supplementation is also important in men who fail on phosphodiesterase type-5 inhibitors, because a minimum plasma concentration of testosterone is required for the successful restoration of erectile function with these agents. Testosterone gels are now the preferred formulation for testosterone supplementation and they can be highly beneficial in a proportion of men with erectile dysfunction.     

Testosterone therapy in erectile dysfunction

Studies in animals have indicated that the nitric oxide erectile pathway is testosterone-dependent. Castration induces erectile dysfunction and a reduction in nitric oxide synthase-stained nerves in erectile tissue. Furthermore, castration adversely affects penile hemodynamics and smooth muscle content, leading to veno-occlusive dysfunction. Testosterone replenishment reverses these physiological, biochemical and structural changes. Several clinical studies have demonstrated the benefits of a combination of testosterone and sildenafil. A recently published, multicenter study evaluated the safety and efficacy of testosterone gel 1% (Testogel®; Schering AG, Germany/AndroGel®; Solvay Pharmaceuticals) vs. placebo gel in conjunction with sildenafil, in producing an erectile response in hypogonadal men who did not respond to treatment with sildenafil alone for erectile dysfunction. The selection criteria required subjects to have had erectile dysfunction for at least 3 months, to be non-responsive to 100 mg sildenafil and to have low testosterone levels (<?400 ng/dl). The primary efficacy measurement was the mean change from baseline in the Erectile Function domain of the International Index of Erectile Function (IIEF). Secondary outcome measures included the mean change from baseline in the other domains and the total sum of the IIEF. Subjects were randomized to receive either testosterone gel + sildenafil, or placebo gel + sildenafil for 12 weeks. Testosterone therapy with testosterone gel improved the erectile response to sildenafil. Therefore, testosterone therapy may be considered for the treatment of erectile dysfunction in men with low to low-normal testosterone levels, who have failed prior treatment with sildenafil alone. Consequently, it is important to screen for hypogonadism in men who fail PDE5 inhibitors.     

Oral Abstracts

Hypogonadism is associated with a range of disease states that have significant effects on morbidity and mortality, and also affect quality of life. The ESPRIT study (Energy, Sexual desire and body PropoRtions wIth AndroGel®, Testosterone 1% gel therapy) is a 6-month, multinational, open label, observational study in hypogonadal men being treated with transdermal AndroGel® in usual daily clinical practice; 1,700–2,400 patients will be enrolled in Canada, Germany, Central and Eastern Europe, Russia and the Middle East. The main objective will be to evaluate the effect of AndroGel® on symptoms of hypogonadism and quality of life as assessed by the Aging Males' Symptoms scale. Further objectives include evaluating the effect and time to onset of improvement in erectile dysfunction and libido/sexual desire (International Index of Erectile Function), fatigue (Multi-dimensional Fatigue Index) and body composition (waist circumference, body mass index). Subgroup analyses will be performed: <50 years versus ≥ 50 years; absence versus presence of metabolic syndrome. The safety of AndroGel® will also be assessed. The study population will consist of newly diagnosed hypogonadal men (age ≥ 18 years), in whom testosterone deficiency has been confirmed by clinical features and biochemical tests according to international guidelines, who are currently being prescribed AndroGel® (testosterone 1% gel, starting dose 50 mg testosterone per day).     

How to help the aging male? Current approaches to hypogonadism in primary care

Hypogonadism is a common condition which occurs more frequently in older men. It is characterized by low testosterone (T) and is associated with symptoms which are often nonspecific. A key symptom is low libido, but it can also be associated with erectile dysfunction, reduced muscle mass and strength, increased body fat, reduced bone mineral density and osteoporosis, reduced vitality, and depressed mood. Hypogonadism is linked with a variety of comorbid conditions including erectile dysfunction, metabolic syndrome, diabetes, obesity, and osteoporosis. However, the condition is often underdiagnosed. T supplementation in hypogonadism is associated with a range of benefits including improved sexual function, increased lean body mass and/or reduced fat mass, and improved bone mineral density. A variety of T supplementation formulations are available. Although there is no evidence of increased risk of initiating prostate cancer with T supplementation, it is contraindicated in men with prostate cancer. It is important that primary care physicians are aware of both the signs and symptoms of hypogonadism, the monitoring and testing that is required and the merits and advantages of the various T preparations to ensure optimal management of the condition with a treatment approach that best suits patients’ needs.     

Oral testosterone undecanoate (Andriol®) supplement therapy improves the quality of life for men with testosterone deficiency

In a single-blind, placebo-controlled study, the effects of a 3-month oral administration of 160 mg/day testosterone undecanoate (Andriol^®) on the quality of life of men with testosterone deficiency were evaluated. The subjects included ten men with primary hypogonadism and 29 with andropause with sexual dysfunction as the most common problem. The changes in subjective symptoms were evaluated by the PNUH QoL scoring system and the St. Louis University Questionnaire for androgen deficiency in aging males (ADAM). Digital rectal examination (DRE) was performed and serum testosterone, prostate-specific antigen (PSA) and liver profile were monitored. Testosterone undecanoate treatment (n = 33) significantly improved sexual dysfunction and symptom scores of metabolic, cardiopulmonary, musculo-skeletal and gastrointestinal functions compared to baseline and to placebo (n = 6). ADAM score also significantly improved after 3 months of treatment. Serum testosterone was significantly increased compared to pretreatment levels only in the testosterone undecanoate group. In the placebo group, no significant changes compared to baseline were found for testosterone levels and QoL questionnaires. No abnormal findings were detected on DRE or laboratory findings in either group. Adverse events, such as gastrointestinal problems and fatigue, were mild and self-limiting. It is concluded that androgen supplement therapy with oral testosterone undecanoate (Andriol) restores the quality of life through improvement of general body functions in men with testosterone deficiency.     

Age-related testosterone decline is due to waning of both testicular and hypothalamic-pituitary function

Abstract

Hypogonadism is a condition in which the endogenous secretion of testosterone is either insufficient or inadequate to maintain serum testosterone levels within normal range, and may manifest as a variety of signs and symptoms. Age-related hypogonadism is due to a combination of primary hypogonadism (testicular failure) and secondary hypogonadism (hypothalamic-pituitary axis failure). This review provides insight into the mechanisms resulting in the multifactorial nature of acquired androgen-deficiency, and outlines the current controversy regarding testosterone-replacement therapy in aging males.     

Testosterone deficiency and the metabolic syndrome

Evidence is presented to link components of the metabolic syndrome to testosterone deficiency and obesity. Testosterone deficiency in hypogonadism or testosterone deprivation in normo-gonadotropic men increases fat mass as well as fasting insulin levels. Testosterone supplementation (TS) in a dose dependent manner, increase lean body mass (LBM), reduces fat mass, body mass index (BMI) and waist hip ratio in both young and elderly hypogonadal men. A negative association between T and insulin resistance as well as impaired glucose intolerance has been demonstrated and in type 2 diabetic men TS improves metabolic parameters. TS improves most components of the metabolic syndrome and also reduces inflammatory cytokines.     

Prevalence of Sexual Dysfunction and Associated Risk Factors in Middle-Aged and Elderly Korean Men in Primary Care

Although several studies have individually investigated the risk factors for erectile dysfunction (ED), premature ejaculation (PE), and late-onset hypogonadism (LOH), few studies have considered ED, PE, and LOH as categories of sexual dysfunction (SD) within the same population. We therefore aimed to investigate the prevalence of SD and its associated risk factors among men in primary care. Study participants were enrolled by 18 family physicians from 15 hospital-based family practices in Korea between August 2010 and May 2011. Participants answered a questionnaire regarding their demographic characteristics and lifestyle factors as well as the Korean versions of the Androgen Deficiency in the Aging Male, the International Index of Erectile Function, and the Premature Ejaculation Diagnostic Tool questionnaires. SD prevalence was 64.9% among study participants who were ≥ 40 years of age. ED prevalence was 43.7%, PE prevalence was 38.6%, and LOH prevalence was 16.8%. SD prevalence was significantly associated with increased age, overweight, hypertension, diabetes, and depression. These findings highlight the importance of screening questions for SD in primary care, especially among older male patients with the identified risk factors.     

Diagnosing and treating testosterone deficiency in different parts of the world. Results from global market research

Aim. This study analysed variations between different regions of the world in diagnosing and treating testosterone (T) deficiency.

Methods. Physicians were interviewed in Germany, Spain and the United Kingdom, in Brazil, in Saudi Arabia and South Korea. Items in the survey: 1) reasons/motivation to use or not to use T; 2) what category of patients would not receive T on the basis of these concerns; 3) concerns about prostate pathology in the decision not to provide T treatment; 4) phosphodiesterase type 5 (PDE-5) inhibitors are efficacious, but T treatment makes a comeback.

Results. Between 5% and 10% of consulting patients suffered from T deficiency. The fear to induce prostate cancer appeared very powerful. About 68% of physicians associate the use of T more with risks than benefits, more so in Europe than elsewhere. As a result about 35% of hypogonadal men do not receive treatment. The PDE-5 inhibitors are very prominent in the treatment of erectile dysfunction. Of patients suffering from erectile dysfunction, 18% to 29% have T deficiency which is not always diagnosed and treated.

Conclusion. World-wide physicians require more education on diagnosing T deficiency, on the role of T in erectile dysfunction and the relative safety of testosterone treatment.     

Effects of long-term testosterone replacement therapy,with a temporary intermission,on glycemic control of nine hypogonadal men with type 1 diabetes mellitus – a series of case reports

Abstract

Type 2 diabetes mellitus (T2DM) is often associated with obesity and subnormal serum testosterone (T) levels. Until 5 years ago there was no indication that men with type 1 diabetes mellitus (T1DM) had subnormal serum T. But recent studies indicate that about 10% of men with T1DM suffer from hypogonadism, as a rule aged men and men with obesity. While hypogonadal men with T2DM benefit from normalization of their serum T, this has not been investigated in men with T1DM. Nine men with T1DM, erectile dysfunction and hypogonadism (total testosterone?≤?12?nmol/L) received testosterone replacement therapy (TRT). In seven men TRT was intermitted: one man with prostate malignancy and six men because of problems of reimbursement. Incidentally, this provided an opportunity to monitor the effects of withdrawal and of the reinstatement of TRT. In all men, glycemic control (serum glucose and HbA_1c), weight, waist circumference, lipid profiles and erectile function improved upon TRT. The seven men whose TRT was intermitted showed a deterioration which improved again upon reinstatement of TRT. The data suggest that aging and obese men with T1DM might have subnormal T levels and that their glycemic control, lipid profiles and erectile function might benefit from TRT.     

Assessment of andropause awareness and erectile dysfunction among married men in Ile-Ife,Nigeria

Andropause (also known as androgen decline in aging males) has implications for the reproductive health and quality of life of older males. Very few studies have, however, been reported among the Nigerian population on andropause-related issues. This study assesses the perspective and level of awareness of married men in Ile-Ife, South-west Nigeria, of andropause. We also assessed their experience of erectile dysfunction, using a questionnaire based on the review of the International Index of Erectile Dysfunction. The study involved 355 married men, aged between 30 and 70 years. Our result shows a high level of misconception about andropause among our respondents, with 38.9% indicating that it is a myth, and another 23.6% attributing it to various causes other than being a natural aging process. We recorded a prevalence of erectile dysfunction of 43.8% (8.0% severe dysfunction and 35.8% moderate dysfunction). The prevalence of erectile dysfunction increased significantly with age, varying from 38.5% for age 31-40 years to 63.9% for the older age group of 61-70 years. The trend in prevalence of erectile dysfunction with age was significant (p < 0.05). An odds ratio of 2.82 (95% confidence interval 1.19-6.76) was recorded for the prevalence of erectile dysfunction at age 61-70 years compared with age 31-40 years. Our findings indicate a need for health education about andropause in Nigeria, and increased attention to the reproductive health concerns of males, and the older population.     

Testosterone supplementation: what and how to give

Several epidemiological studies have demonstrated a gradual decrease of serum testosterone with aging in men. A considerable number of men will experience hypogonadal androgen levels, defined by the normal range for young men. Thus, in addition to the long-standing use of androgen replacement therapy in the classical forms of primary and secondary hypogonadism, age-associated testosterone deficiency has led to considerable developments in application modes for testosterone. Since oral preparations of testosterone are ineffective, due to the first-pass effect of the liver, or, in case of 17 α-alkylation, cause hepatotoxicity, intramuscular injection of long-acting esters, such as testosterone enanthate, have been the mainstay of testosterone therapy. However, the large fluctuations of serum testosterone levels cause unsatisfactory shifts of mood and sexual function in some men; combined with the frequent injections, this delivery mode is thus far from being ideal. In contrast, the transdermal testosterone patches are characterized by favorable pharmacokinetic behavior and have proven to be an effective mode of delivery. Safety data over 10 years indicate no negative effect on the prostate. Nevertheless, the scrotal testosterone patch system is hampered by the application site, which is not easily accepted by many subjects; the non-scrotal patch has a high rate of skin irritations. In view of the drawbacks of the currently available preparations, the most recent developments in testosterone supplementation appear to be highly promising agents. Androgen, which has been available in the United States since mid-2000, will be introduced this year in most European markets as Testogel ® , a hydroalcoholic gel containing 1% testosterone. Doses of 50-100 mg gel applied once daily on the skin deliver sufficient amounts of testosterone to restore normal hormonal values and to correct the signs and symptoms of hypogonadism. The gel has shown to be very effective and successful in American patients, who have benefited from its availability for almost 3 years. Furthermore, in phase II and III clinical studies, the intramuscular injection of 1000 mg testosterone undecanoate every 12-15 weeks has led to extremely stable serum testosterone levels for a prolonged period of time and has resulted in excellent efficacy. It is very likely in the future that these products will be the mainstay of testosterone supplementation. Whereas the indication for testosterone substitution for men with classical forms of hypogonadism is unequivocal, the use of testosterone in men with ageassociated hypogonadism is less uniformly accepted. Yet, the few studies addressing this question indicate that men with testosterone serum levels below the lower normal limit for young adult men and with lack of energy, libido, depressed mood and osteoporosis may benefit from testosterone supplementation. However, it should be kept in mind that the experience documented in studies is limited. Nevertheless, serious side-effects, especially in regard to the prostate, did not occur, with the longest study extending over 3 years.     

The triad of erectile dysfunction, testosterone deficiency syndrome and metabolic syndrome: findings from a multi-ethnic Asian men study (The Subang Men's Health Study)

The etiology of erectile dysfunction (ED) is multi-factorial. This paper examines the association between ED, testosterone deficiency syndrome (TDS) and metabolic syndrome (MS) in Malaysian men in an urban setting. One thousand and forty-six men aged ≥ 40 years from Subang Jaya, Malaysia were randomly selected from an electoral-roll list. The men completed questionnaires that included: socio-demographic data, self-reported medical problems and the International Index of erectile function (IIEF-5). Physical examination and the following biochemical tests were performed: lipid profile, fasting blood glucose (FBG) and total testosterone. The response rate was 62.8% and the mean age of men was 55.8 ± 8.4 (41-93) years. Ethnic distribution was Chinese, 48.9%; Malay, 34.5%; Indian, 14.8%. The prevalence of moderate-severe ED was 20.0%, while 16.1% of men had TDS (< 10.4 nmol/L) and 31.3% of men had MS. Indian and Malay men were significantly more likely to have ED (p = 0.001), TDS (p < 0.001) and MS (p < 0.001) than the Chinese. Multivariate regression analysis showed that elevated blood pressure, elevated FBG, low high-density lipoprotein and heart disease were predictors of ED while all MS components were independently associated with TDS. Malay and Indian men have a higher disease burden compared to Chinese men and were more likely to suffer with ED, TDS and MS. MS components were closely related to TDS and ED.     

Could gonadal and adrenal androgen deficiencies contribute to the depressive symptoms in men with systolic heart failure?

Background: Testosterone (TT) and dehydroepiandrosterone sulphate (DHEAS) are neurosteroids and their deficiencies constitute the hormone risk factors promoting the development of depression in elderly otherwise healthy men. We investigated the link between hypogonadism and depression in accordance with age and concomitant diseases in men with systolic HF using the novel scale previously dedicated for elderly population.

Methods: We analysed the prevalence of depression and severity of depressive symptoms in population of 226 men with systolic HF (40–80 years) compared to 379 healthy peers. The severity of depression was assessed using the Polish long version of Geriatric Depression Scale (GDS).

Results: In men aged 40–59 years the severity of depressive symptoms was greater in NYHA classes III–IV compared to NYHA classes I–II and reference group. In men aged 60–80 years depressive symptoms were more severe in NYHA class III-IV compared to controls (all p?≤?0.001). In multivariate logistic regression model in men aged 40–59 years advanced NYHA class was associated with higher prevalence of mild depression (OR?=?2.14, 95%CI: 1.07–4.29) and chronic obstructive pulmonary disease (COPD) with higher prevalence of severe depression (OR?=?69.1, 95%CI: 2.11–2264.3). In men aged 60–80 years advanced NYHA class and TT deficiency were related to higher prevalence of mild depression (respectively: OR?=?2.9, 95%CI: 1.3–6.4; OR?=?3.6, 95%CI: 1.2–10.63).

Conclusion: TT deficiency, COPD and advanced NYHA class were associated with higher prevalence of depression in men with systolic HF.     

Testosterone and men's quality of life

As the worldwide population ages, the emphasis on having a reasonable quality of life in old-age is increasing. In men, age-associated testosterone decline is one of the major factors that reduce quality of life. In patients and the physicians treating them, decreased energy levels and impairments to sex-life are perceived as the most important effects of hypogonadism. Two quality of life scales, the Aging Males' Symptoms (AMS) and the Age-Related Hormone Deficiency-Dependent Quality of Life (A-RHDQoL) scales, have recently been developed to specifically assess this patient population, and the A-RHDQoL found that memory, energy and physical capabilities, and sex-life were the factors most adversely affected by low testosterone levels. Unfortunately, there are limited data on the effects of testosterone on the quality of life of men with hypogonadism, but the information that exists suggests that testosterone can improve the quality of life significantly (to the same level as men with normal testosterone levels) and the more severe the symptoms before treatment, the greater the benefits of testosterone replacement. These promising early results need to be confirmed in more detailed quality of life studies.     

Testosterone therapy - what,when and to whom?

Testosterone therapy has been used for more than 60 years in the treatment of male hypogonadism. The classical forms of hypogonadism are comprised of primary testicular failure or insufficient testicular stimulation due to the lack of pituitary gonadotropins. Typical causes of primary hypogonadism are Klinefelter's syndrome, anorchia or acquired disturbances of testicular function. Secondary hypogonadism is characterized by insufficient production of pituitary gonadotropins, due either to pituitary failure or defects at the hypothalamic level. It is unequivocally accepted in clinical practice that any male with inadequately low testosterone production for his age will require androgen therapy. In addition to the classical forms of hypogonadism, the past decade of research has clearly demonstrated that, with increasing age, many men will suffer from decreasing testosterone production. About 15-25% of men over the age of 50 years will experience serum testosterone levels well below the threshold considered normal for men between 20 and 40 years of age. Studies substituting testosterone in elderly men with low serum testosterone have shown that men with clinical symptoms identical to the symptomatology of classical hypogonadism will benefit most from such therapy. Therefore, it is the general consensus to treat men with age-related hypogonadism only when clinical symptoms are present that can be potentially corrected by testosterone administration. Until recently, intramuscular injections of esters, such as testosterone enanthate, have been the mainstay of testosterone therapy. The introduction of testosterone patches has not challenged this approach, since many users of patches suffer from moderate to severe skin reactions. Some oral testosterone formulations have proven to be problematic, as absorption can be variable, bioavailability is frequently poor, due to the first-pass effect of the liver, and frequent administration is often required&lt;citeref rid="b1"&gt;&lt;emph&gt;¹&lt;/emph&gt;&lt;/citeref&gt;. Oral testosterone undecanoate avoids, at least partially, the first-pass effect of the liver. However, plasma testosterone levels generally undergo large fluctuations&lt;citeref rid="b2"&gt;&lt;emph&gt;²&lt;/emph&gt;&lt;/citeref&gt;. The large fluctuations in serum testosterone levels caused by conventional intramuscular injections result in unsatisfactory shifts in mood and sexual function in some men, which, combined with the frequency of injections, make the intramuscular mode of delivery far from ideal. Recently, a hydroalcoholic gel containing 1% testosterone has proven to be as efficient as a testosterone patch, but with fewer side-effects and a higher grade of patient satisfaction&lt;citeref rid="b3"&gt;&lt;emph&gt;³&lt;/emph&gt;&lt;/citeref&gt;^-&lt;citeref rid="b4"&gt;&lt;/citeref&gt;&lt;citeref rid="b5"&gt;&lt;emph&gt;⁵&lt;/emph&gt;&lt;/citeref&gt;. Doses of 50-100 mg gel applied once daily on the skin deliver sufficient amounts of testosterone to restore normal hormonal values and correct the signs and symptoms of hypogonadism. The gel has been shown to be effective and successful in patients in the United States, who have benefited from its availability for almost 3 years. In the near future, intramuscular injections of testosterone undecanoate will become commercially available. Such injections have a very favorable pharmacokinetic profile, with one injection every 3 months maintaining serum testosterone well within the normal range. In phase III studies, intramuscular testosterone undecanoate proved to be as efficient as testosterone enanthate, with only one-quarter of the number of injections required and more stable serum testosterone levels. Thus, the new application modes - hydroalcoholic gel (for example, Testogel®, Schering AG, Germany) and intramuscular testosterone undecanoate (Nebido®, Schering AG, Germany) - appear to be the methods of choice in the near future, one being very suitable for hormone therapy in elderly men, the other for long-term substitution in classical forms of hypogonadism.     

RigiScan data under long-term testosterone therapy: improving long-term blood circulation of penile arteries,penile length and girth,erectile function,and nocturnal penile tumescence and duration

Background: Late-onset hypogonadism (LOH) presents with low serum testosterone (TT) levels and sexual and nonsexual symptoms. Erectile dysfunction affects a man’s self-esteem and as a result partner relationship and quality of life.

Objectives: To investigate the andrological clinical profile outcomes of testosterone therapy (TTh) in men (n?=?88) with symptomatic LOH complaints and symptoms.

Main outcome measures: Erectile function was assessed using the International Index of Erectile Function-5 questionnaire at baseline and at 6 and 12 months of TTh. In addition, penile length was measured at baseline and 12 months. We also evaluated nocturnal penile tumescence (NPT, using RigiScan) and blood flow of cavernous arteries (penile Doppler ultrasonography) at baseline and 12 months of TT.

Materials and methods: Eighty-eight LOH men (M_age 51.1 years) with erectile dysfunction, all with serum TT?<10.4?nmol/L before TTh. Patients received intramuscular long-acting testosterone undecanoate for 12 months.

Results: Following TTh, in all patients, serum TT levels were restored within 3 months to normal levels. Compared with baseline values, erectile function significantly improved at 6 (mean score increase 1.95) and 12 months (mean score increase 2.16). No significant changes in penile length were observed. NPT significantly improved at 12 months in terms of both the frequency (mean increase 1.27 times) and duration of rigidity (mean increase 5.12?min). As regards the blood flow of the cavernous arteries, we observed a significant improvement (decrease of 1.16?cm/s) and end diastolic velocity of the penile arteries.

Conclusion: TTh in men with LOH resulted in improvement of the erectile function, NPT, and to some extent the blood flow of the cavernous arteries.     

ISA,ISSAM, EAU,EAA and ASA recommendations: investigation,treatment and monitoring of late-onset hypogonadism in males

Abstract

Hypogonadism or Testosterone Deficiency (TD) in adult men as defined by low levels of serum testosterone accompanied by characteristic symptoms and/or signs as detailed further on can be found in long-recognized clinical entities such as Klinefelter syndrome, Kallmann syndrome, pituitary or testicular disorders, as well as in men with idiopathic, metabolic or iatrogenic conditions that result in testosterone deficiency. These recommendations do not encompass the full range of pathologies leading to hypogonadism (testosterone deficiency), but instead focus on the clinical spectrum of hypogonadism related to metabolic and idiopathic disorders that contribute to the majority of cases that occur in adult men.