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,testosterone therapy and prostate cancer

Abstract

With prostate cancer not observed in eunuchs and total androgen suppression by castration an effective first-line treatment for advanced prostate cancer, the dramatic regression seen in tumour symptoms after castration, lead to the theory that high levels of circulating androgens were a risk factor for prostate cancer. This theory however, ignored the effects testosterone variations within a physiologic range could have on early tumour events and since the early 2000s, clinical evidence discounting testosterone as a linear mechanistic cause of prostate cancer growth mounted, with alternative mechanistic hypotheses such as the saturation model being proposed. Together with a growing understanding of the negative health effects and decreased quality of life in men with testosterone deficiency or hypogonadism, a paradigm shift away from testosterone as a prostate cancer inducer occurred allowing clinicians to use testosterone therapy as potential treatment for men with difficult and symptomatic hypogonadism that had been previously treated for prostate cancer. In this review we contextualise the idea of testosterone as a risk factor for prostate cancer inducement and compile the most current literature with regards to the influence of testosterone and testosterone therapy in prostate cancer.     

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.     

Clinical experiences with testosterone therapy: prostate safety

Due to a decrease in Leydig cell function, a considerable proportion of men over 50 years of age will develop hypogonadism. Consequently, loss of libido and several other testosterone-dependent symptoms may become evident. When decreased levels of biologically available testosterone are found, and corresponding symptoms are present, these men could be eligible for testosterone substitution therapy. Testosterone treatment in testosterone-deprived men has been shown to improve general well-being, osteoporosis, muscle atrophy, libido and - if present - anemia. Despite these positive effects, testosterone treatment has to be performed with caution. Although it has not been proven that elevation of the serum testosterone level to the normal range results in a greater risk of developing prostate cancer, the effects of testosterone on a prostate cancer already present are well established. Several studies have demonstrated that testosterone treatment does not result in a significant increase in serum levels of prostate-specific antigen (PSA) or prostate volume. The long-term effects, however, are currently unknown. For these reasons, testosterone treatment should be performed only when the presence of prostate cancer is unlikely; i.e. when PSA levels are within normal limits and digital rectal examination does not reveal any suspicious findings. These examinations may still miss some small prostate cancers that could be promoted by testosterone treatment. The determination of PSA levels under testosterone treatment is necessary every 3 months, at least for the first year. Steadily rising PSA levels require immediate cessation of testosterone administration and the initiation of further diagnostic procedures (prostate biopsy), to rule out prostate cancer.     

Validation of an Arabic ADAM questionnaire for androgen deficiency screening in the Arab community

Background.?It is well documented that testosterone levels decline with age, this decline is associated with symptoms which could be assessed denoting androgen deficiency. We investigated the validity of an Arabic version of the Saint Louis University androgen deficiency in ageing men (ADAM) questionnaire to screen for androgen deficiency in Saudi and non Saudi Arabic speaking men.

Methods.?It was a cross sectional study of ambulatory community-based Arabic Saudi men recruited from Volunteers in Riyadh city, Capital of Saudi Arabia, aged 18–80 years. Seven hundred thirty men agreed to fill the Arabic ADAM questionnaire, they were invited to a morning blood sample for total testosterone and sex hormone binding globulin and those who agreed to complete the whole study were only 407 men. Low serum bioavailable testosterone (BT) levels (androgen deficiency) were defined as <10th percentile of serum BT levels in young healthy Saudi men (18–30 years).

Results.?Cronbach's Alpha of 0.71 (n?=?730) showed a good internal consistency of the Arabic ADAM questionnaire. Among participants, 18.2% and 77.6% had low serum BT levels and a positive ADAM questionnaire, respectively. The prevalence of positive ADAM and low serum BT is increasing with age. The Arabic ADAM questionnaire had a high sensitivity of 86.5%, a low specificity of 24.3%, and positive predictive values (+PVs) and negative (?PVs) of 20.3% and 89%, respectively.

Conclusion.?The Arabic ADAM questionnaire has a very good sensitivity but very low specificity for screening of androgen deficiency in Saudi men, therefore biological confirmation is needed especially when clinical symptoms of androgen deficiency are present.     

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 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 effect of testosterone treatment on prostate histology and apoptosis in men with late-onset hypogonadism

Objectives: To investigate the effect of testosterone replacement therapy (TRT) on prostate histology and apoptosis in men with late-onset hypogonadism (LOH).

Methods: The study included 25 men, having LOH with prostate-specific antigen (PSA) level of 4?ng/ml or less. All patients underwent transrectal ultrasound guided prostate biopsy at baseline, and received testosterone undecanoate treatment for 1 year. Prostate biopsy was repeated at the end of 1 year of testosterone therapy. In addition to clinical and biochemical parameters, prostate histology and apoptotic index (AI) were compared before and after the TRT.

Results: The mean serum total testosterone significantly increased from 178.04?±?51.92 to 496.28?±?103.73?ng/dl (p?=?0.001). No significant differences were observed in serum total and free PSA level, prostate volume and maximal urinary flow rate. There were also no significant differences in AI, stroma/epithelial cells ratio, Ki-67 positive cells and atrophy score of prostate tissue before and after the TRT.

Conclusions: This study demonstrated that TRT did not affect serum PSA level, prostate volume and maximal urinary flow rate. This study also suggests that TRT does not cause the risk for prostate cancer development, because of no significant differences in prostate histology after TRT.     

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.     

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.     

Association of DHEA-S and estradiol serum levels to symptoms of aging men

Objectives A number of interactions between agerelated changes in serum levels of dehydroepiandrostendione sulfate (DHEA-S) and estradiol and symptoms of aging men have been proposed, yet data regarding this issue are scant. We therefore set up a prospective study to analyze these associations. Methods In a prospective, cross-sectional study, men aged 45-85 years were recruited. All men completed a questionnaire containing 38 items covering a number of aspects of the aging male. Questionnaires were compiled by using items from previously published and validated questionnaires. Several socioeconomic parameters were also determined. In parallel, serum levels of testosterone, free testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), DHEA-S, estradiol, sex hormone binding globulin and prostate-specific antigen (PSA) were quantified by commercially available immunoassays. Results A total of 375 men with a mean age of 59.9 ± 9.2 years (mean ± standard deviation) were analyzed. Average DHEA-S and estradiol levels of 135.8 ± 90.9 μg/dl and 29.7 ± 14.6 pg/ml, respectively, were recorded. DHEA-S serum levels were negatively correlated to patient age, sexual function score, total score and PSA. Estradiol serum levels were positively correlated to testosterone and free testosterone. None of the other scores or questions revealed a correlation with DHEA-S or estradiol serum levels. Conclusion This prospective study elucidates only small interactions between partial androgen deficiency of the aging male (PADAM)-related symptoms and serum levels of DHEA-S and estradiol. Nevertheless, the data suggest an impact of DHEA-S on sexual function.     

Effects of testosterone replacement therapy withdrawal and re-treatment in hypogonadal elderly men upon obesity,voiding function and prostate safety parameters

Whether testosterone replacement therapy (TRT) is a lifelong treatment for men with hypogonadism remains unknown. We investigated long-term TRT and TRT withdrawal on obesity and prostate-related parameters. Two hundred and sixty-two hypogonadal patients (mean age 59.5) received testosterone undecanoate in 12-week intervals for a maximum of 11 years. One hundred and forty-seven men had TRT interrupted for a mean of 16.9 months and resumed thereafter (Group A). The remaining 115 patients were treated continuously (Group B). Prostate volume, prostate-specific antigen (PSA), residual voiding volume, bladder wall thickness, C-reactive protein (CRP), aging male symptoms (AMS), International Index of erectile function – erectile function (IIEF-EF) and International Prostate Symptoms Scores (IPSS) were measured over the study period with anthropometric parameters of obesity, including weight, body mass index (BMI) and waist circumference. Prior to interruption, TRT resulted in improvements in residual voiding volume, bladder wall thickness, CRP, AMS, IIEF-EF, IPSS and obesity parameters while PSA and prostate volume increased. TRT interruption reduced total testosterone to hypogonadal levels in Group A and resulted in worsening of obesity parameters, AMS, IPSS, residual voiding volume and bladder wall thickness, IIEF-EF and PSA while CRP and prostate volume were unchanged until treatment resumed whereby these effects were reversed. TRT interruption results in worsening of symptoms. Hypogonadism may require lifelong TRT.     

Diagnostic significance of free salivary testosterone measurement using a direct luminescence immunoassay in healthy men and in patients with disorders of androgenic status

The accurate measurement of testosterone remains a challenge. The determination of the blood testosterone concentrations in serum by conventional immunoassays is inaccurate in men and even more so in females and children. A new luminescence enzyme immunoassay (LIA) has been developed and validated. The high analytical (8.7 pmol/L) and functional (17.3 pmol/L) sensitivity allows the quantification of the very low concentration in saliva, as well as in serum, after 1/40 dilution. This study measured salivary testosterone levels and compared the results with the free levels calculated from total testosterone and sex hormone-binding globulin in eugonadal and hypogonadal men. Salivary testosterone concentrations in healthy men in morning hours were 369 pmol/L (mean), range 263–544 pmol/L, which was statistically significantly higher than that in men with androgen deficiency, 215 pmol/L (mean), range 51–249 pmol/L.

Repetitive determination of free testosterone concentrations in saliva (once a week for 5 weeks) showed high stability of results over time, with coefficient of variation 9% (range 5–23%).

In this study we showed that free salivary testosterone levels in morning samples correlated well with calculated free testosterone in blood, both in healthy men (R = 0.754, P = 0.001), and in patients with androgen deficiency (R = 0.889, P = 0.0001), though in cases with very low testosterone, salivary concentrations were systematically higher than calculated free testosterone levels in blood.     

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.     

Diagnosis,pathogenesis and treatment of erectile dysfunction

Introduction: After middle age, some men show androgen-deficiency symptoms leading to so-called PADAM (partial androgen deficiency in aging males). We tested the oral form of testosterone, testosterone undecanoate (Andriol^®, NV Organon, The Netherlands), in men with PADAM and evaluated its efficacy and safety in Korean male patients. Methods: We included those patients with the clinical symptoms of PADAM who had decreased levels of serum total testosterone (< 2.8 ng/ml) or free testosterone (< 13 pg/ml). We excluded patients with biopsy-confirmed prostrate cancer, abnormal findings in digital rectal examination or prostate specific antigen testing (until prostrate cancer was ruled out), breast cancer, severe voiding symptoms and secondary hypogonadism. At the first visit, the International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF) and Korean Andropause Questionnaires were administered; complete blood count, the lipid profile, and levels of total and free testosterone, prolactin, luteinizing hormone, follicle stimulating hormone and prostate specific antigen were measured and a digital rectal examination was given. Patients were administered oral testosterone undecanoate 160 mg daily for 3 weeks. The dosage was then decreased to 80 mg daily and changes in symptoms were assessed at every visit. After 3 months, serum tests, including testosterone, were repeated. Results: We evaluated 28 patients who had received testosterone undecanoate for more than 3 months. The patients' mean age was 56.1 (48-68) years. The score of the Korean Andropause Questionnaire changed from 56.2 ± 21.7 at baseline to 52.9 ± 21.3 (p = 0.03) after 3 weeks, to 49.3 ± 19.3 (p = 0.03) after 8 weeks, and to 46.5 ± 25.6 (p = 0.028) after 12 weeks. With respect to sexual function, mean IIEF scores were 37.2 ± 19.6 at baseline and 38.7 ± 19.2 and 40.2 ± 22.0 (p = 0.033) after 3 and 12 weeks, respectively. Serum total testosterone increased from 2.13 ± 1.20 ng/ml at baseline to 6.04 ± 3.08 ng/ml (p = 0.005) after 12 weeks, and free testosterone was marginally significantly changed from 8.60 ± 2.25 pg/ml to 11.40 ± 3.81 pg/ml (p = 0.13). However, there were no significant changes in liver function tests, red blood cell count or lipid profiles. There were no significant adverse reactions that led to the cessation of the administration of oral testosterone. Conclusion: Oral administration of testosterone undecanoate can improve symptoms of PADAM in Koreans. It may, therefore, be an appropriate treatment option with few adverse effects for PADAM patients.     

Decline of serum levels of free testosterone in aging healthy Chinese men

Objective.?To investigate the age-related change of serum androgen levels in healthy men and to define a cut-off value of serum testosterone for the diagnosis of androgen deficiency in the aging male.

Method.?1080 healthy men aged 20 to ?70 years old were enrolled in Beijing, Shanghai, Xian and Chongqing. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (T), calculated free testosterone (cFT), sex hormone binding globulin (SHBG), 17beta-oestradiol (E2), the T/LH ratio, and T/SHBG as a free testosterone index (FTI) were all determined.

Results.?Serum total T did not significantly decline, but the cFT, T/LH and FTI progressively decreased with aging. To determine androgen deficiency, the 10th percentile value of men <40 years was defined as the lower cut-off value for cFT, T/LH or FTI, which were 0.3 nmol/L, 2.8 nmol/IU, and 0.4 nmol/IU respectively. With the median value of cFT of men aged between 20 and 49 years as the criterion, the level of cFT was lower in 2.82% of men from 40 to 49 years, in 19.53% from 50 to 59 years, in 22.57% from 60 to 69 years, and in 33.19% of men ?70 years. Taking the above value of cFT as the cut-off point, the prevalence of androgen deficiency in men 40–49 years was 13.0%, 31.8% in men 50–59 years, 30.1% in men 60 to 69 years, and 46.7% in men >70 years.

Conclusions.?(i). While serum total T values do not decline with aging, the levels of cFT gradually decline with aging; (ii) when using the value of cFT of the 10th percentile of men aged 20 to 39 years as the cut-off point, the prevalence of androgen deficiency was <15% before the age of 50 years, and about 30% thereafter, approaching 45% after the age of 70 years; and (iii) in this study the values of T/LH paralleled those of cFT closely; therefore, T/LH could serve as a surrogate for cFT.     

Long-term low-dose dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) age-related withdrawal is very likely to be involved in the aging process and the onset of age-related diseases, giving rise to the question of whether preventing or compensating the decline of these steroids may have endocrine and clinical benefits. The aim of the present trial was to evaluate the endocrine, neuroendocrine and clinical consequences of a long-term (1 year), low-dose (25?mg/day) replacement therapy in a group of aging men who presented the clinical characteristics of partial androgen deficiency (PADAM). Circulating DHEA, DHEAS, androstenedione, total testosterone and free testosterone, dihydrotestosterone (DHT), progesterone, 17-hydroxyprogesterone, allopregnanolone, estrone, estradiol, sex hormone binding globulin (SHBG), cortisol, follicle stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were evaluated monthly to assess the endocrine effects of the therapy, while β-endorphin values were used as a marker of the neuroendocrine effects. A Kupperman questionnaire was performed to evaluate the subjective symptoms before and after treatment.

The results showed a great modification of the endocrine profile; with the exception of cortisol levels, which remained unchanged, DHEA, DHEAS, androstenedione, total and free testosterone, DHT, progesterone, 17-hydroxyprogesterone, estrone, estradiol, GH, IGF-1 and β-endorphin levels increased significantly with respect to baseline values, while FSH, LH and SHBG levels showed a significant decrease. The Kupperman score indicated a progressive improvement in mood, fatigue and joint pain.

In conclusion, the present study demonstrates that 25?mg/day of DHEA is able to cause significant changes in the hormonal profile and clinical symptoms and can counteract the age-related decline of endocrine and neuroendocrine functions. Restoring DHEA levels to young adult values seems to benefit the age-related decline in physiological functions but, however promising, placebo-controlled trials are required to confirm these preliminary results.     

Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel

Transdermal testosterone gels represent an effective alternative to injectable testosterone preparations. Shortterm (6 months) data demonstrated positive effects on muscle, bone, fat, libido and mood. This report provides a preliminary analysis of longer-term treatment with a testosterone gel (AndroGel ? or Testogel®) in a group of men aged 19-67 years of age. The positive effects of testosterone treatment on all of the above parameters persisted in this 3-year follow-up. The benefits occurred independent of age (equally in the older and younger subjects). The positive effects of transdermal testosterone gel on bone mineral density previously identified at 6 months of treatment, continued with time. The positive effects on bone mineral density were greater in the spine than the hip. There were minimal effects on lipid levels. Levels of prostate-specific antigen (PSA) increased with testosterone treatment but, in general, remained in the normal range. Three subjects (1.8%) were shown to have elevated PSA and biopsy-proven prostate cancer. It was not possible to determine if this incidence is above the background rate. Monitoring for prostate disease through PSA measurements and digital rectal examination is recommended for hypogonadal men in the older age groups when treated with testosterone.     

Time for international action on treating testosterone deficiency syndrome

Aim. Testosterone deficiency is having an increasing impact on men's health because of global aging, higher levels of obesity, diabetes and metabolic syndrome and adverse environmental factors such as stress xenoestrogens and anti-androgens. The question addressed is to what extent the large body of evidence on the benefits and safety of testosterone therapy is applied in clinical practice.

Methods. Demographic data for men over the age of 50 from different regions of the world have been compared with the number of men in that age group estimated from sales figures to be receiving testosterone treatment.

Results. On the basis of estimate that 20% of men over 50 in the general population of each region could be expected to have testosterone deficiency symptoms, on average only these men (0.69%) in most European countries were receiving treatment. Proportion was higher in the UK (1.00%) and Germany (1.89%), but lower in France (0.49%), Italy (0.51%) and Russia (0.54%). Interestingly, Australia had higher figures (1.64%), in spite of tight state control measures on androgen use. The USA has the highest treatment rate (7.96%) and this is increasing rapidly.

If the basis for the diagnosis was the more conventional combination of symptoms plus biochemical evidence of low total and free testosterone levels, androgen deficiency would be expected in at least 5% of men over 50, and percentage treatment rates therefore four times higher. However, even on that basis, only in the USA do these exceed 10%.

Conclusions. International action is urgently needed to raise awareness in the medical profession in the various countries of these remarkably low levels of testosterone treatment. Improvement in this requires education and motivation of doctors and those regulating the healthcare systems. A public awareness campaign is needed to educate men about the symptoms of testosterone deficiency and its impact on their health.     

The relationship between circulating testosterone and inflammatory cytokines in men

Testosterone is the predominant gonadal androgen in men. Low testosterone levels are found to be associated with an increased in metabolic risk and systematic inflammation. Since adipose tissue is a source of inflammatory cytokines, testosterone may regulate inflammation by acting on adipose tissue. This review aimed to explore the role of testosterone in inflammation and its mechanism of action. Both animal studies and human studies showed that (1) testosterone deficiency was associated with an increase in pro-inflammatory cytokines; (2) testosterone substitution reduced pro-inflammatory cytokines. The suppression of inflammation by testosterone were observed in patients with coronary artery disease, prostate cancer and diabetes mellitus through the increase in anti-inflammatory cytokines (IL-10) and the decrease in pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). Despite these, some studies also reported a non-significant relationship. In conclusion, testosterone may possess anti-inflammatory properties but its magnitude is debatable. More evidence is needed to validate the use of testosterone as a marker and in the management of chronic inflammatory diseases.