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     

Abstracts

Objective: To ascertain if two commonly used health status measures could be successfully self-administered to a group of older men recruited from the community to volunteer for a clinical research project and to correlate responses to the health status questionnaire to testosterone levels. Methods: In a cross-sectional survey 93 men, age 70 or greater, responded to a random mailing to a suburban community. Sixty-eight men were eligible and 47 participated in the study. Two health status questionnaires, the Sickness Impact Profile (SIP) and the Short-form 36 (SF-36), were mailed to participants with instructions to complete the surveys on the same day and return them by mail. Blood samples were obtained for bioavailable and total testosterone measurements. Pearson correlation coefficient analysis was used to compare the responses to the SF-36 and SIP and testosterone levels. Results: Of the eligible volunteers 69% participated and were able to self-administer the SIP and the SF-36. Summation scores for the surveys were above those reported in similar age populations. Perfect scores were reported frequently in all subsets of the SIP; perfect scores were reported in 43-92% of men on various subscales. The responses to the SF-36 were also frequently perfect although perfect scores ranged from 2 to 82% on various subsets. There was moderate correlation between the results from the two surveys. There was no correlation between age, SIP or SF-36 and testosterone level. Conclusions: Healthy older men volunteering for clinical research were able to self-administer both the SIP and SF3-6. Responses to both surveys were skewed toward perfect scores; the SIP failed to reveal many men with functional deficits. Bioavailable testosterone levels did not predict perceived health in this group of men.     

Diagnosis and management of age-related hypogonadism

Many studies show a better state of health in women than men and indicate that life expectancy for men is significantly shorter than that for women in every region of the world. Yet, the health-care systems have so far made surprisingly little effort to reduce these pronounced differences. Consequently, investigation into the state of health of the aging male and relevant health care is breaking new ground in science. From a scientific perspective, the conspicuous differences in physical conditions can be ascribed to a number of causes. Medical, social, and psychological factors are evidently linked by complex interactions out of which interdisciplinary approaches for improving the state of health, in particular that of older men, are derived. Fundamental research questions, necessary for the adaptation of sex-specific health care to benefit both sexes, can then be developed.     

Social demographic aspects

Unlike in women, where instruments are available to measure the severity of symptoms, cross-culturally validated instruments are lacking for aging males. This study set out to conduct a translation and cultural validation of the 'Aging Males' Symptoms' (AMS) scale, originally developed in German, into English for use in North America and the UK. Following international methodological recommendations, the AMS scale was translated in a standardized way consisting of forward translation, quality control, backward translation and a pretest. Five experienced bilingual translators and reviewers were involved. Many difficulties of compatibility between the cultural backgrounds of Germany, the UK and North America were identified and resolved by consensus. This resulted in one version for British and American English. A pretest in volunteers demonstrated clarity and understandability across social classes, but also suggested minor changes in the instrument. A preliminary test-retest comparison of the final scale showed high reliability with a correlation coefficient of 0.93 for the total AMS score. The AMS scale is a valuable tool for assessing symptoms in the aging male. This scale can be used in German and English speaking countries. Flemish and Finnish versions are also in use.     

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'.     

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.     

Male age and progeny

Testicular aging affects simultaneously the individual and his lineage. In the individual, changes in the vascular and endocrine systems, in the blood-testis barrier and in Sertoli cells, because of increasing age, lead to a decrease in the number of spermatozoa and an alteration in their form and motility. Gamete quality is also low in very young men. These changes lead to a gradual decrease of fertility. In the progeny, paternal aging is responsible for new dominant autosomic mutations which themselves cause different malformations such as achondroplasia, Apert's or Recklinghausen disease, Marfan's syndrome, and, perhaps, certain chromosome X-linked recessive mutations such as Duchenne's myopathy or hemophilia A. Moreover, in mouse, rat and man, a very young age and paternal aging seem to be responsible for a gradual lowering in the level of cognitive functions in the progeny. Thus, the curve corresponding to this phenomenon presents an inverted U-shape, of which the top corresponds in man to about 30 years of paternal age. Maternal age does not appear to play a part in this event. These results pose the problem of the optimum age for fatherhood.     

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.     

Gonadal decline-related manifestations in aging hospital doctors

Andropenic manifestations related to declining gonadal function were assessed in a group of aging hospital doctors (50–66 years) and were compared with those of a group of administrative personnel of similar age (50–64 years) and two groups of younger doctors (30–40 years) or other hospital employees (30–40 years). Evaluation included measurements of follicle stimulating hormone (FSH) luteinizing hormone (LH), sex hormone binding globulin (SHBG), thyroid stimulating hormone (TSH) and prolactin (PRL) concentrations and responses to a special questionnaire. Mean testosterone concentration in aging doctors (374 ± 86 ng/ml) was no different from that of hospital employees of the same age (361 ± 77). However, concentrations of LH, SHBG and PRL in the former group were significantly lower (p < 0.04, 0.01 and 0.004, respectively). Furthermore, the testosterone : LH ratio was higher in the aging doctors group (p < 0.001). Mean testosterone concentration in the combined groups of aging men was lower than that of the younger men (p < 0.00001). Andropenic manifestations related to sexual, physical and mental activity were markedly better in the group of aging doctors in comparison to aging hospital employees. By and large, it appeared that aging hospital doctors had a better physical and mental activity than aging employees and this may have been related to their better lifestyle conditions.