Age-related patterns of DHEAS among Turkana males of northern Kenya

This paper is based on presentation given at the 2nd World Congress on the Aging Male, Geneva, Switzerland, February 2000     

Androgen replacement therapy in aging men with secondary hypogonadism

Many animal and human studies show that supraphysiological doses of dehydroepiandrosterone (DHEA) can influence body composition and carbohydrate and lipid metabolism. Most studies have concentrated on women and have not been randomized, thus creating controversial results. With this in mind, we designed a cross-over double-blind placebo-controlled study of 12 men aged 59.0 ± 4.8 years, who received either 50 mg/24 h DHEA or placebo for 3 months to assess the influence of DHEA on the content and distribution of fat tissue and serum insulin, glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels, as well as testosterone, estradiol, DHEA-sulfate (S), prostate-specific antigen (PSA) concentrations and indexes of insulin sensitivity and resistance. Patients were recruited from university employees attending for periodic health checks, with normal hepatic and renal function with endogenous DHEA-S level < 1500 ng/dl. Our results did not reveal any significant changes in study parameters, apart from a statistically significant increase in DHEA-S levels after therapy with active substance.     

Practical consequences of the validation of a mathematical model in assessment of partial androgen deficiency in the aging male using bioavailable testosterone

Partial androgen deficiency or the andropause in the aging male is a complex clinical and biochemical entity that needs to be analyzed at two levels of the constituent structure: the 'deep structure' should come to light with more intensive research, while the 'surface structure' holds the attention of investigators who focus on hormone measurements in the blood to help diagnose the andropause. In this study, it is recognized that bioavailable testosterone decreases progressively during the aging process. This physiological decline may be so important, or so close to castration levels, that aged men may experience numerous symptoms of hypogonadism. The assay for bioavailable testosterone was indirectly validated with a set of equations derived from our knowledge of the law of mass action at equilibrium, as proposed by Vermeulen and colleagues in 1999. With this mathematical model, we have shown that calculated free testosterone was highly correlated with bioavailable testosterone. It is therefore concluded that the evaluation of aged men's androgenicity should rely on at least one of these free testosterone assessments (bioavailable or calculated free testosterone) for the sake of reproducibility in the construction of the 'surface structure' of the andropause in the coming years.     

Testosterone therapy – effects on prostate and bone

This paper is based on a presentation given at the 2nd World Congress on the Aging Male, Geneva, Switzerland, February 2000     

The aging male in the literature

The diagnosis of hypoandrogenism in the aging male is still difficult, since the symptomatology is aspecific and multifactorial, and it is unknown whether the androgen requirements of elderly men are the same as those of young men. Indeed, there are arguments for decreased (increased androgen feed-back sensitivity) as well as for increased (decreased concentration of androgen receptors) requirements in elderly men. In the absence of a reliable, clinically useful, parameter of androgen activity, we have to rely on plasma androgen level, an indirect parameter. In the absence of convincing arguments for altered requirements with age, we consider that the normal range of (free) testosterone levels in young adults is also valid for elderly men, the lower normal limit being 11 nmol/l for total testosterone and 0.225 nmol/l for free testosterone. There are indirect, suggestive clinical arguments for accepting these limit values. The diagnosis of hypoandrogenism in elderly males requires both the presence of clinical symptoms and decreased (free) testosterone levels. The best methods for determining free or bioavailable testosterone, are equilibrium dialysis and ammonium sulfate precipitation, respectively. They are, however, time-consuming techniques which are not easily automated. Calculation of the free androgen index (testosterone/sex hormone binding globulin (SHBG)) is not a valid method for male serum. Calculation of free testosterone from total testosterone, SHBG and albumin concentration, yields values that are in good agreement with values obtained by dialysis or ammonium sulfate precipitation. Several conditions should, however, be fulfilled: reliable methods for the determination of testosterone and SHBG, SHBG measurement in serum and not in plasma, use of fresh serum (not repeatedly frozen and thawed), absence of (exogenous) steroids competing for binding sites on SHBG and blood samples taken between 08.00 and 10.00 in the fasting state. Under these conditions an excellent correlation with dialysis and bioavailable testosterone (ammonium sulfate precipitation) is generally obtained.     

Aging androgens and the metabolic syndrome

Objective: To assess the responses of a symptom complex related to partial androgen deficiency in the aging male (PADAM) to androgen supplementation. Subjects and methods: Eighty-six men from five hospitals in Beijing aged 50-70 years with symptoms related to PADAM received oral testosterone undecanoate for 2 months, and the effects of the therapy were evaluated. Results: After treatment, the symptom scores were significantly improved (all p < 0.001). Serum levels of luteinizing hormone and follicle stimulating hormone were suppressed, and free testosterone and albuminbound testosterone levels were elevated. However, they were not significantly different from the pretreatment values. Waist/hip ratio and blood pressure were markedly decreased, but no changes were found in serum levels of total cholesterol, triglyceride, albumin and prostate specific antigen. Conclusions: Two months of treatment with oral testosterone undecanoate clearly improved the symptoms related to PADAM. No statistical relationship was found between symptom improvement and androgen levels. Androgen therapy for 2 months was beneficial to the waist/hip ratio and blood pressure, and no harm was done to the prostate gland or lipid metabolism.     

Quality-of-life issues in the aging male

This paper is based on a presentation given at the 2nd World Congress on the Aging Male, Geneva, Switzerland, February 2000     

Serum levels of inhibin B in men of different age groups

The decline of testosterone levels in aging men is well documented. However, it is unclear to what extent the Sertoli cell marker inhibin B changes during aging. Herein we report on the determination of serum levels of inhibin B, follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone in 906 patients from 16 to 89 years of age, presenting to our department for different complaints. There was a weak but significant correlation of the levels of inhibin B with age (r = 0.064, p < 0.05). A significant negative correlation of FSH and inhibin B was documented in all age groups (r = -0.423, p < 0.01). Also, the LH levels increased significantly with low inhibin B levels (r = -0.289, p < 0.01). Testosterone levels showed no significant correlation with inhibin B. We conclude from our study that Sertoli cell function as documented by serum levels of inhibin B is stable throughout life. In addition, the ongoing correlation of FSH and inhibin levels also indicates no significant decline of Sertoli cell function in the aging male.     

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.     

The aging male in Malaysia

Interest in clinical investigations about the health-related quality of life (HRQoL) of aging men has increased in recent years. The aim of this paper is to inform the scientific community about a harmonized French Aging Males' Symptoms (AMS) Scale. There were two slightly different French AMS Scales, which both underwent an up-to-date linguistic and cultural translation process, i.e. were valid to be applied in research. However, it was felt to be unfortunate that two versions of one language in one country existed. Therefore, an ad hoc committee of both translation teams were asked to develop a harmonized single French AMS Scale. The harmonization meeting developed a consensus item-by-item and the new French reference scale was agreed upon. It was agreed that only this scale should be published to avoid confusion among future users. The French AMS Scale published in this paper should be used for future research and necessary cultural/linguistic adaptations in the French-speaking world.     

A paradigm shift: from disease to health orientation

The history of science has been described as ‘paradigm shifts’ of sequential overthrow, each new paradigm replacing the previous one. A paradigm is an overarching view-point which guides the articulation of theories and other activities in a particular field. In the exploration of health, two different types of approach can be identified. The pathogenic view, which has dominated the orientation of medicine over the last hundred years, focuses on disease states and underlying factors that modify the chances of entering into one of those states. The competing salutogenic view appears to be undergoing a renaissance in the new strategies of public health and health promotion, and producing theories of health based on more holistic approaches and diverse methods. The two paradigms exist side by side, and both are in a constant state of flux. The advocates of the health-oriented paradigm say it is difficult to reach a true, in-depth understanding of human health on the basis of a disease-oriented approach or from the traditional vantage-point of risk-factor epidemiology, whereas opponents point out that health does not lend itself to exact measurements or experimentation in keeping with the Galilean natural science ideal. The importance and utility of health orientation need to be explored and ascertained in further research. The approach seems, however, to have a number of crucial assets that might help avoid the limitations of the established disease and risk-factor epidemiology approaches and promote new directions of pursuit, including a better understanding of the complex relationships between aging and health, and other current challenges in creating healthy public policy.

This paper was presented at the Second International Workshop on the Aging Male, Weimar, Germany, November 1999     

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.     

Estradiol in elderly men

The role of estrogens in male physiology has become more evident, as a consequence of the discovery of human models of estrogen deficiency such as estrogen resistance or aromatase deficiency. In males, testosterone is the major source of plasma estradiol, the main biologically active estrogen, only 20% of which is secreted by the testes. Plasma estrone, 5% of which is converted to plasma estradiol, originates from tissue aromatization of, mainly adrenal, androstenedione. The plasma concentration of estradiol in males is 2-3 ng/dl and its production rate in blood is 25-40 μg/24 h; both of these values are significantly higher than in postmenopausal women. Plasma levels of estradiol do not necessarily reflect tissue-level activity as peripherally formed estradiol is partially metabolized in situ; thus, not all enters the general circulation, with a fraction remaining only locally active. Of the factors influencing plasma estradiol levels, plasma testosterone is a major determinant. However, the age-associated decrease in testosterone levels is scarcely reflected in plasma estradiol levels, as a result of increasing aromatase activity with age and the age-associated increase in fat mass. Free and bioavailable estradiol levels do decrease modestly with age as does the ratio of free testosterone to free estradiol, the latter testifying to the age-associated increasewd aromatization of testosterone. Estradiol levels are highly significantly positively related to body fat mass and more specifically to subcutaneous abdominal fat, but not to visceral (omental) fat. Indeed, aromatase activity in omental fat is only one-tenth of the activity in gluteal fat. Estrogens in males play an important role in the regulation of the gonadotropin feedback, several brain functions, bone maturation, regulation of bone resorption and in lipid metabolism. Moreover, they affect skin metabolism and are an important factor determining sex interest in man.     

An audit of testosterone measurement in men attending with impotence

As part of the routine assessment of 185 unselected men with undiagnosed impotence, testosterone was measured on a single serum sample to try to detect a subset of men with androgen deficiency who might benefit from testosterone replacement therapy. Those with low levels of testosterone were investigated further with repeat measurements of testosterone and luteinizing hormone (LH). In addition, prostatic specific antigen (PSA) was measured in all the men to exclude concomitant prostate cancer. Testosterone replacement therapy was offered to 20 men with consistently low levels of the hormone but few of the men continued with the therapy because of lack of benefit. It was concluded that either testosterone deficiency is rare in unselected men who actually seek help for impotence orebe our protocol of androgen assessment was not helpful for this group of men. There was correlation between PSA results and testosterone and this may have implications for the investigation of prostate cancer. The results presented here are an audit of a clinical practice and call into question the benefit of routine testosterone measurement in the investigation of all men complaining of impotence.     

Could seasonal variation in testosterone levels in men be related to sleep?

We have previously reported seasonal variations in both total and free testosterone in men living in north Norway. The aim of this cross-sectional study was to determine whether seasonal variation in testosterone also occurs in men living in geographical areas with less extreme seasonal variation in sunlight and temperature. In 915 men aged 24–91 years from Rancho Bernardo, a suburb of San Diego in southern California, we found that neither total nor bioavailable testosterone varied by season, with or without adjustments for age and anthropometric measurements. Of all examined covariates, only physical activity showed a seasonal variation, with a peak in August (p <?0.001), and adjusting for physical activity did not change the lack of seasonal variation in testosterone. In addition, there was no association between testosterone and mean air temperature, or testosterone and possible hours of sunshine. We conclude that men living in southern California show no seasonal variation in testosterone levels. One possible explanation, besides the difference in climate, for the diverging findings between our previous study and the present study is different sleep patterns.     

The effect of androgen supplementation therapy on the prostate

With the recent availability of transdermal formulations, androgen supplementation therapy is increasingly being prescribed for men in their 50s and 60s. With the growing use of testosterone products, there is concern about the long-term risks of androgen supplementation therapy, particularly on the prostate. This article reviews what is known about the safety of testosterone replacement therapy in terms of the potential risks for development of symptomatic benign prostatic hypertrophy (BPH) and prostate cancer. Androgens are undoubtedly involved in the growth of benign prostatic nodules, as a permissive factor in the etiology of prostate carcinoma and in the enhancement of the growth of active prostate cancer. Their role in the initiation of either disease is less clear. Available data support the safety of such treatment in the short term. Caution is still advised in the interpretation of these findings, as the studies producing the data have involved relatively small numbers of participants. Until large, long-term, placebo-controlled studies have been conducted and analyzed, questions about the long-term safety of testosterone supplementation therapy in older men will remain.     

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.     

Performance of Massachusetts Male Aging Study (MMAS) and androgen deficiency in the aging male (ADAM) questionnaires in the prediction of free testosterone in patients aged 40 years or older treated in outpatient regimen

Abstract

Objective: At present, calculated free testosterone assessment is considered as the gold standard in diagnosing male hypogonadism. However, this assessment is not available for all the individuals diagnosed with decreased testicular function. The investigators of this study were, thus, prompted to evaluate whether the androgen deficiency in the aging male (ADAM) and the Massachusetts Male Ageing Study (MMAS) questionnaires could be used to replace biochemical parameters in the diagnosis for hypogonadism in men aged 40 years and above.

Methods: We evaluated 460 men, aged 40 years and above, all volunteers of a screening program for prostate cancer based at the Hospital de Clínicas of Porto Alegre. In this study, we assessed the efficiency of the ADAM and MMAS questionnaires in diagnosing Brazilian men with low levels of total, calculated free and bioavailable testosterone.

Results: The sensitivity of the ADAM questionnaire in diagnosing the calculated free testosterone was 73.6%, whereas specificity was 31.9%. ADAM could be used to properly classify our cohort into normal or hypogonadal individuals in 52.75% of the cases. The sensitivity of the MMAS questionnaire was 59.9%, whereas the specificity was 42.9%, resulting in a successful classification of 51.4% of the patients.

Conclusion: The ADAM and MMAS questionnaires showed adequate sensitivity in diagnosing male patients with low levels of free testosterone. However, because of the lack of specificity, these tools cannot replace calculated free testosterone assessments in men aged 40 years and above.