Pituitary radiographic abnormalities and clinical correlates of hypogonadism in elderly males presenting with erectile dysfunction

The prevalence of erectile dysfunction rises rapidly with age and is a frequent complaint presented in clinical practice. Although the etiology of erectile dysfunction is multifactorial, 10-20% of evaluations demonstrate testosterone deficiency. Testosterone deficiency due to secondary hypogonadism increases with age. Despite a higher prevalence of secondary hypogonadism in the elderly, there are no studies addressing hypothalamic-pituitary structural abnormalities in elderly impotent men with testosterone deficiency. We retrospectively reviewed the records of all elderly men who presented for general outpatient evaluation of erectile dysfunction from 1996 to 1999. To obtain a cohort control population, the records of 300 patients without erectile dysfunction were also reviewed. Amongst the erectile dysfunction patients, 225 were found to be testosterone deficient (testosterone < 300 ng/dl). Of these patients, 29 were additionally diagnosed with secondary hypogonadism based on a luteinizing hormone (LH) < 13 mIU/ml. Magnetic resonance imaging (MRI) or computed tomography (CT) imaging was available and reviewed in all patients diagnosed with secondary hypogonadism. Ten per cent of these patients had hypothalamic-pituitary imaging abnormalities. The prevalence of pituitary tumors within our population was not significantly elevated compared to the previous general population studies. Small-vessel white matter disease, hyperlipidemia and history of compression fractures were significantly increased in both univariate and multivariate analysis in the erectile dysfunction group compared with the control cohort. This study does not suggest that the use of hypothalamic-pituitary imaging in the evaluation of impotence in elderly men, in the absence of clinical characteristics of other hormonal loss or sella compression symptoms, will increase diagnosis of structural hypothalamic-pituitary abnormalities over that of the general population. However, the yield may increase with very low testosterone levels. These data suggest that there is an increase in ischemic white matter disease in elderly men with hypogonadism that may reflect microvascular injury to the hypothalamic-pituitary. Furthermore, these data confirm that low testosterone is associated with hyperlipidemia in the elderly. Future studies are required to assess the role of hypogonadism and hyperlipidemia, and to determine if treatment of the hormone deficiency improves the lipid profile.     

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 (&lt;?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.     

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.     

Increase in the prevalence of metabolic syndrome among workers according to age

Androgen levels decline over a man's lifetime. In a proportion of men (increasing with age), levels fall below values that have been established by conventional laboratory criteria as indicative of hypogonadism. Testosterone has a wide range of non-reproductive actions: it preserves bone and muscle mass, it acts on non-sexual mental functioning and it stimulates red blood cell formation. Long-term androgen deficiency has a great impact on quality of life. The first intervention studies provide indications that androgen treatment of men with true androgen deficiency is helpful. Obviously, only men who are testosterone-deficient will benefit from androgen supplementation. The diag nosis of testosterone deficiency in old age is not unambiguous. Signs and symptoms of aging sometimes clinically overlap with those of testosterone deficiency. The groups that are at higher risk of testosterone deficiency are those men with disease (pulmonary disease, gastrointestinal disease, rheumatoid disease, etc.). Usually, sex hormone binding globulin levels increase with aging, leading to lower levels of free, biologically available testosterone. For the time being, arbitrary criteria for testosterone deficiency in aging men have to be adopted. The best practical approach is to calculate the free testosterone level. The calculation can be found at www.issam.ch under 'Tools'.     

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.     

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).     

Testosterone and penile erection

Male sexual function depends upon a complex inter-relationship between psychological, neurological, vascular and hormonal factors. Testosterone is responsible for the initiation, development and maintenance of primary and secondary sexual characteristics as well as having a role in male sexual behavior and potency. In adults, testosterone deficiency is associated with reduced libido and potency, infertility, lethargy and a number of behavioral modifications. This article reviews what is known about the role of testosterone on the mechanism of penile erection and describes the results of the experimental designs and animals models used in the study of erectile physiology. In animals, testosterone seems to have an action on some neurotransmitters of erectile mechanism, while in man, its role is mainly on the behavioral aspects.     

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.     

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.     

Why can patients with erectile dysfunction be considered lucky? The association with testosterone deficiency and metabolic syndrome

Metabolic syndrome (MetS) is a diagnostic category, based on a cluster of risk factors (hyperglycemia/diabetes, abdominal obesity, hypertriglyceridaemia, low HDL cholesterol and hypertension), which identifies subjects at high risk for forthcoming type 2 diabetes mellitus and cardiovascular (CV) diseases. Recently, a close association between MetS, erectile dysfunction (ED) and male hypogonadism has been reported. In patients with MetS, hypogonadism can exacerbate sexual dysfunction and arteriogenic ED because of its typical symptoms, such as decreased sexual desire and mood disturbances. On the other hand, hypogonadism per se has been associated with an increased risk of CV and overall mortality. Obesity and in particular central obesity is nowadays considered the most important determinant of MetS-induced hypogonadism whereas hypertension and diabetes play a major role in ED associated with MetS. This review analyses the current literature regarding the relationship between ED, MetS and hypogonadism emphasising the epidemiological and psychopathological aspects and stressing the concept that ED subjects are ‘lucky’, because ED offers a unique chance to undergo medical examination and therefore to improve not only their sexual but, most importantly, their overall health.     

Testosterone and body functions

Testosterone supplementation can help reduce many of the symptoms associated with androgen deficiency in the aging male by its effects on various parts of the body. Bone mineral density can decrease in the hypogonadal man and this may contribute to the increased fracture rate in the elderly. Testosterone therapy can improve bone mineral density and bone architecture by increasing bone formation and decreasing bone resorption – the possible benefits on fracture rate are unknown. Testosterone also improves body composition by reducing body fat mass and increasing lean body mass, and by increasing epidermal thickness, but its effects on muscle strength are still debated. In patients with diabetes and androgen deficiency, testosterone supplementation appears to reduce blood glucose and this could have important implications for cardiovascular risk reduction in patients with diabetes or the metabolic syndrome. The wide-ranging benefits of testosterone therapy in young and old men are clear and it appears that the route of administration (intramuscular, oral, or transdermal) does not alter this fact, but future work could illustrate even more profound effects of testosterone (e.g., in reducing cardiovascular risk) that could result in its recommended use in a wider range of patients.     

Effects of testosterone supplementation on prevention of age-related penile remodeling

Abstract

Erectile dysfunction develops among 46.2% of men between 40 and 70 years. Studies demonstrated substitution on detrusor muscle by collagen due testosterone deprivation. It is clear the correlation among aging and oxidative stress, accelerating apoptosis process in many tissues. This study aims to demonstrate the collagen substitution over the muscle fibers on muscle structure of rat’s penis and the effects of testosterone supplementation. Sixteen senescent Wistar rats were divided into two groups: treatment (receiving standard supplementation testosterone dose) and control (receiving equivalent saline solution). Testosterone was dosed on D0 and D56 of study. All penises were prepared with picrosirius colored histology; stereology was applied to determine the volumetric density of collagen fibers (Vv). Analysis of variance demonstrated testosterone group’s replacement therapy to be effective, while the androgenic decline continued by the time of experiment in control group (p?<?0.05). Testosterone group had Vv of 20.6%, lower than control group (47.8%); t-test (p?<?0.001). Pearson’s correlation demonstrated an inverse correlation between the Vv and testosterone’s levels (p?<?0.001). This is a pioneer study on demonstration of structural alterations over the cavernous corpora muscle caused by deprivation of testosterone on elderly rat. These finding implicate that the testosterone levels can influence, not only the libido, but also the erectile function.     

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.     

Testosterone/estradiol ratio,is it useful in the diagnosis of erectile dysfunction and low sexual desire?

Erectile dysfunction and low sexual desire are multifactorial diseases. The decrease in testosterone levels is one of the causes, but the effect of estradiol is not well known. Moreover, study has shown that the testosterone/estradiol ratio has more influence over sexuality than does estradiol alone. The aim of the study was to determine whether the balance between testosterone and estradiol has any relation to some aspects of sexual function. It was an ambispective study of 230 patients with urological problems unrelated to sexuality. They underwent a detailed history and hormone study including total, free, bioavailable testosterone and estradiol. They completed the Sexual Health Inventory for Men and questions 11 and 12 of the IIEF15 were used to assess impairment in sexual desire. The T/E ratio was calculated, and the relationship between the different parameters and erectile function and sexual desire were studied by univariate and multivariate analysis. The mean age was 66.32?±?8.17 years. The percentage of patients with erectile dysfunction was 60.9% (7% severe, 14.3% moderate, 12.6% mild to moderate and 27% mild) and decreased sexual desire was 46.5%. Age, free and biodisponible testosteron were the only variables with a positive linear association with erectile dysfunction and decreased sexual desire. Age was the only independent variable for both, erectile dysfunction and sexual desire, in the multiple linear regression. There was no association between a testosterone/estradiol imbalance and an alteration in erectile function and sexual desire. Consequently, in the clinical study of these patients, it is not necessary to request estradiol in the laboratory analyses.     

Testosterone and the brain

Gender differences in spatial recognition, and age-related declines in cognition and mood, point towards testosterone as an important modulator of cerebral functions. Testosterone appears to activate a distributed cortical network, the ventral processing stream, during spatial cognition tasks, and addition of testosterone improves spatial cognition in younger and older hypogonadal men. In addition, reduced testosterone is associated with depressive disorders. The relationship between depression and testosterone appears to partly depend upon the androgen receptor genotype of the patient, and in appropriate patients with low testosterone levels, testosterone substitution can increase positive mood and decrease negative mood. The much publicized link between testosterone and aggression is probably only of importance in athletes who supplement their testosterone levels to excessively high levels, whereas in hypogonadal men, testosterone supplementation only enhances the positive aspects of aggression such as vigour and energy. Current data suggest that testosterone supplementation in hypogonadal men of all ages will enhance many aspects of mood and cognition.     

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.