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.     

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     

The future of hormone replacement therapy 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     

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.     

Prevalence of sarcopenia and its association with functional and nutritional status among male residents in a nursing home in Turkey

Introduction The Aging Male Symptoms' (AMS) scale was designed as a health-related quality of life (QoL) scale and standardized as a self-administered scale, first, to assess symptoms of aging (independent from those which are disease-related) between groups of males under different conditions, second, to evaluate the severity of symptoms/QoL over time, and, third, to measure changes pre- and post-androgen replacement therapy. The scale is in widespread use (17 languages currently available) and a recent review of methodological data documented good psychometric characteristics and ability as a clinical utility. This paper describes test characteristics of the AMS (positive and negative predictive values), taking two internationally established and published screening scales for androgen deficiency as the available standard.

Method A sample of 150 German males aged 40–69 years completed the AMS scale and two screening scales for androgen deficiency: the ADAM scale of Morley and colleagues and the screener of Smith and colleagues. The technique of a computer-assisted telephone interview was applied.

Result The comparison of the AMS with the two screening instruments for androgen deficiency showed sufficiently good compatibility despite conceptual differences. The AMS scale sufficiently predicted the results of the two screening instruments. A positive predictive value of 92% and a negative predictive value of 50% were found regarding the ADAM scale. The respective figures regarding Smith's screener were 65% and 49% for positive and negative predictive values, respectively.

Conclusion The AMS scale obviously measures a similar phenomenon as the two established and widely used screeners for androgen deficiency, although it was not developed as a screening instrument.     

Concurrent training protocol for men with androgen deficiency in the aging male: a randomized clinical trial

Background: The androgen deficiency in the aging male (ADAM) affects physical, sexual, and psychological aspects with characteristics symptoms of middle-aged men. The practice of regular physical activity and physical exercise can attenuate these symptoms. The aim of this randomized clinical trial is to propose a physical exercise protocol based on concurrent training for middle-aged men with ADAM.

Method: Randomized clinical trial with a 6-month intervention will randomly divided into two groups: experimental group (EG) and control group (CG). Four evaluations will be carried out, (1) pre-intervention; (2) in the first month of intervention; (3) in the third month of intervention; (4) post-intervention, evaluating: physical, psychological, sexual, and hormonal aspects. The intervention protocol with concurrent training will have duration of 6 months; frequency of 3 times weekly, with 60?min per session. The two-way ANOVA test will be used for the inter-group and intra-group comparisons with repeated measurements, and also Sydak’s comparison test.

Conclusion: This protocol was developed with the intent of easing the symptoms of ADAM. In addition, it is believed that the concurrent training protocol could be capable to recover hormonal, physical, psychological, and sexual aspect of middle-aged men with ADAM.     

The relationship of salivary testosterone and male sexual dysfunction in opioid-associated androgen deficiency (OPIAD)

Background: Opioids are an effective treatment for chronic non-malignant pain (CNP). Long-term use risks and side effects such as opioid-induced androgen deficiency (OPIAD) exist. This could be measured by saliva testosterone (Sal-T).

Objectives: To evaluate OPIAD in long-term opioid use in CNP patients.

Methods: A cross-sectional study included CNP male outpatients under opioid treatment. Total-Testosterone (Total-T), Free-Testosterone (Free-T), Bio-Testosterone (Bio-T) and Sal-T were measured. Correlations were calculated by Spearman’s rho (SPSS 20).

Results: From 2012 to 2014, 134 from 249 (54%) consecutive male outpatients reported erectile dysfunction (ED), 37% of them related to opioids and 19% evidenced OPIAD. A total of 120 subjects (94 cases and 26 matched-controls) were included. A significantly lower luteinizing hormone, Total-T and Free-T were found, as well as, a significant correlation between Sal-T and Total-T (r?=?0.234, p?=?0.039), Bio-T (r?=?0.241, p?=?0.039), IIEF (r?=?0.363, p?=?0.003) and HAD-anxiety (r =??0.414, p?=?0.012) in OPIAD patients. Sal-T levels were significantly lower in patients with severe–moderate ED versus mild ED (p?=?0.045) and in patients with severe ED versus moderate–mild ED (p?=?0.036).

Conclusions: These data demonstrate the high prevalence of ED in long-term use of opioids, part of this is associated to OPIAD, which can be tested by Sal-T as a non-invasive approach.     

Clinical assessment and validation of an Arabic Aging Male Symptoms questionnaire in patients with androgen deficiency

Aim.?To develop and to validate an Arabic Aging Male Symptoms (AMS) tool and to clinically assess patients with hypoganadism after hormonal treatment.

Methods.?The tool was translated into Arabic and tested on 15 Saudi men. During a period of 9 months all males presented to the andrology clinic of the main University Hospital, King Saud University, Saudi Arabia with signs and symptoms of hypogonadism, were included in the study. Arabic AMS scale was applied in the base line visit, then 12 weeks after treatment. Testosterone was monitored before treatment, 4 weeks and after 12 weeks.

Results.?Ninety-two subjects were included, Cronbach's α of 0.91 showed a very good internal consistency of the Arabic AMS questionnaire. The corresponding α for the subscales were 0.83, 0.84 and 0.73. There was a significant improvement in the mean level of TT after hormonal therapy (HT), this was reflected on the mean differences of improvement in the total Arabic AMS scores and subscales scores after HT, ranged from 31 to 35%.

Conclusion.?The present study revealed a significant association between testosterone levels and AMS tool manifested by a its good ability to measure the effect of treatment on quality of life for patients with hypogonadism.     

Androgens and sexual function: a placebo-controlled,randomized, double-blind study of testosterone vs. dehydroepiandrosterone in men with sexual dysfunction and androgen deficiency

Purpose.?Supplemental administration of androgens has been advocated for men with sexual dysfunction (SD) and hypoandrogenism. The preponderance of evidence indicates that most delivery forms of testosterone (T) are effective but the role of dehydroepiandrosterone (DHEA) is controversial. A placebo-controlled, randomized trial of oral androgen (T versus DHEA) supplementation was carried out to determine their efficacy.

Materials and methods.?Eighty-six men with SD and decreased levels of serum T and/or DHEA, participated in a study receiving oral T undecanoate (OTU) (n?=?29) 80?mg twice daily, DHEA (n?=?28) 50?mg twice daily, or placebo (n?=?29). Outcomes included evaluation of sexual performance by the International Index of Erectile Function (IIEF), the Androgen Deficiency in the Aging Male (ADAM), Aging Male Symtom Scale (AMS), and Global Assessment Questionnaire (GAQ) questionnaires. Biochemical evaluations included measurement of T and DHEA, prolactin, gonadotropins, and PSA.

Results.?Seventy-nine men completed the study. There were no significant differences in outcomes as assessed by four different instruments: the ADAM, IIEF, AMS, and GAQ in regard to sexual interest or erectile function. Biochemically, a significant increase in serum DHEA between baseline and final visit was documented in the group receiving DHEA. The levels of T, on the other hand, increased insignificantly between entry and final visit in the T cohort. No biochemical changes were observed in the placebo group. Levels of PSA remained stable in all three groups.

Conclusions.?This study did not suggest a clinical benefit of OTU or DHEA supplementation in men with hypoandrogenism and SD. The recommended dose of OTU may have been inadequate or poorly absorbed. Increased doses or an alternative T delivery form may result in a different response.     

Effects of oral testosterone undecanoate therapy on bone mineral density and body composition in 322 aging men with symptomatic testosterone deficiency: a 1-year,randomized, placebo-controlled,dose-ranging study

Abstract

Objective: We investigated the effects of oral testosterone undecanoate (TU) on bone mineral density (BMD), lean body mass (LBM) and body fat mass (BFM) in aging men with symptomatic testosterone deficiency (TD).

Methods: Three hundred twenty-two men ≥50 years with TD symptoms and calculated free testosterone <0.26?nmol/L participated in a multicenter, double-blind, placebo-controlled trial. Patients were randomized to placebo, oral TU 80?mg/d, oral TU 160?mg/d, or oral TU 240?mg/d, administered as divided doses with normal meals. BMD of the hip and lumbar spine were evaluated by dual energy X-ray absorptiometry (DEXA), and body composition (LBM and BFM) by whole body DEXA.

Results: Oral TU significantly increased BMD at Month 12 at the lumbar spine (240?mg/d), total hip (240?mg/d), and trochanter and intertrochanter (160 and 240?mg/d) compared with placebo. Oral TU significantly increased LBM at Months 6 and 12 for all oral TU groups compared with placebo. BFM significantly decreased at Month 6 (all oral TU groups) and Month 12 (160?mg/d) compared with placebo. The effects on BMD and body composition showed a clear dose response.

Conclusions: Treatment with oral TU led to improvement in BMD, LBM and BFM in aging men with symptomatic TD.     

Testofen,a specialised Trigonella foenum-graecum seed extract reduces age-related symptoms of androgen decrease,increases testosterone levels and improves sexual function in healthy aging males in a double-blind randomised clinical study

This study examined the effect of Testofen, a specialised Trigonella foenum-graecum seed extract on the symptoms of possible androgen deficiency, sexual function and serum androgen concentrations in healthy aging males. This was a double-blind, randomised, placebo-controlled trial involving 120 healthy men aged between 43 and 70 years of age. The active treatment was standardised Trigonella foenum-graecum seed extract at a dose of 600?mg/day for 12 weeks. The primary outcome measure was the change in the Aging Male Symptom questionnaire (AMS), a measure of possible androgen deficiency symptoms; secondary outcome measures were sexual function and serum testosterone. There was a significant decrease in AMS score over time and between the active and placebo groups. Sexual function improved, including number of morning erections and frequency of sexual activity. Both total serum testosterone and free testosterone increased compared to placebo after 12 weeks of active treatment. Trigonella foenum-graecum seed extract is a safe and effective treatment for reducing symptoms of possible androgen deficiency, improves sexual function and increases serum testosterone in healthy middle-aged and older men.     

Prevalence,incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania

Objective.?Low total testosterone levels (TT) have been associated with increased morbidity and mortality. However, the prevalence and incidence of testosterone deficiency (TD) in association with its risk has not been assessed systematically to date.

Methods.?Data from the prospective population-based Study of Health in Pomerania were used. From the 2117 men aged 20–79 years at baseline, 1490 men with complete TT data were analysed. Crude and age-specific prevalence and incidence rates of TD were estimated by TT levels below the age-specific 10th percentile. Analysis of covariance and Poisson regression models were used to assess the association of socio-demographic characteristics, health-related lifestyle, as well as somatometric, medical and laboratory measures with risk of incident TD.

Results.?TD baseline prevalence was 10.4% (N?=?155) and incidence 11.7 per 1000 person-years. TT levels showed a significant age-related decline with an unadjusted rate of 0.05 nmol/l per year. Obesity, metabolic syndrome, diabetes and dyslipidaemia were identified as risk factors of incident TD. Subpopulations of men without the revealed risk factors at both examinations maintained constant TT levels over time.

Conclusions.?Besides aging alone, lifestyle and different comorbidities were associated with TT level decline, suggesting that the age-related TT decline may be at least partly prevented through the management of potentially modifiable risk factors and health related behaviour.