Book Reviews

1. Aitken, C. G. G. Statistics and the Evaluation of Evidence for Forensic Scientists, p. 155
2. Bartholomew, D. J. Uncertain Belief: Is it Rational to be a Christian?, p. 156
3. Conolly, B. and Vajda, S. A Mathematical Kaleidoscope: Applications in Industry, Business and Science, p. 157
4. Dorling, D. A New Social Atlas of Britain, p. 157
5. Fleming, M. C. and Nellis, J. G. International Statistics Sources: Subject Guide to Sources of International Comparative Statistics, vols 1, 2, p. 158
6. Gilks, W. R., Richardson, S. and Spiegelhalter, D. J. ( eds ) Markov Chain Monte Carlo in Practice, p. 158
7. Glasserman, P. and Yao, D. D. Monotone Structure in Discrete Event Systems, p. 159
8. Hernández-Lerna, O. and Lasserre, J. B. Discrete-time Controlled Markov Processes: Basic Optimality Criteria, p. 160
9. Marcoulides, G. A. and Schumacker, R. E. ( eds ) Advanced Structural Equation Modelling: Issues and Techniques, p. 161
10. Rao, C. R. and Toutenberg, H. Linear Models: Least Squares and Alternatives, p. 162
11. Smithers, G. Advanced Modular Mathematics: Pure Mathematics 1; Westover, G. Advanced Modular Mathematics: Statistics 1, p. 163
12. Wickens, T. D. The Geometry of Multivariate Statistics, p. 164     

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.     

Androgens and the risk of cardiovascular disease

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

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.     

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.     

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.     

Congress Calendar

Aging is a complex process modulated by multiple interactions between environmental and genetic factors. Myotonic dystrophy (DM 1) is an autosomal dominant disorder caused by an unstable (CTG)_n repeat expansion in the DM1 protein kinase (DMPK) gene. The affected male patients' life expectancy at birth (53.2 years) is more than two decades below that observed in most occidental populations. The DMPK gene expression is pleiotropic and includes the premature expression of several agerelated signs, symptoms and metabolic disturbances including hormonal dysfunctions, progressive decrease in muscular mass, presenile cataracts, alopecia, reduced alertness, insulin resistance, dyslipidemia, erectile dysfunction and hypogonadism. The aim of this study was to analyze the relationship between aging covariates and the severity of DM1 expression in 136 DM1 male subjects. DM1 clinical expression was assessed on a validated neuromuscular disability rating scale and was correlated with plasma total testosterone (r_s = -0.31, p < 0.001), luteinizing hormone (LH) (r_s = 0.52, p < 0.001) and follicle stimulating hormone (FSH) (r_s = 0.54, p < 0.001) levels. Following LH releasing hormone stimulation, FSH and LH concentrations increased as a function of DM1 severity (p < 0.05). Muscular disability in DM1 was also positively associated with fasting plasma insulin and triglyceride concentrations (p < 0.05). The association of plasma apolipoprotein B and low-density lipoprotein cholesterol levels with DM1 was not linear across their distribution and tended to reflect cell membrane damage progression. These results suggest that DM1, a simple M endelian trait, can represent a valuable model to illustrate the complex relationships between variables associated with male aging.     

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     

Accounting for Follow-up Bias in Estimation of Human Immunodeficiency Virus Incidence Rates

The objective of this paper is to describe methods for estimating current incidence rates for human immunodeficiency virus (HIV) that account for follow-up bias. Follow-up bias arises when the incidence rate among individuals in a cohort who return for follow-up is different from the incidence rate among those who do not return. The methods are based on the use of early markers of HIV infection such as p24 antigen. The first method, called the cross-sectional method, uses only data collected at an initial base-line visit. The method does not require follow-up data but does require a priori knowledge of the mean duration of the marker (μ). A confidence interval procedure is developed that accounts for uncertainty in μ. The second method combines the base-line data from all individuals together with follow-up data from those individuals who return for follow-up. This method has the distinct advantage of not requiring prior information about μ. Several confidence interval procedures for the incidence rate are compared by simulation. The methods are applied to a study in India to estimate current HIV incidence. These data suggest that the epidemic is growing rapidly in some subpopulations in India.     

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.