Farid Farid, M.D.

Introduction

Aging is associated with progressive alterations in hormonal environment. These changes are easily recognized in women with estrogen deficiency who no longer have menses, experience hot flashes and vaginal dryness or develop fractures from osteoporosis. In men, the progressive decline in androgen production was well defined over 50 years ago, but fell into a long period of disrepute and only recently gained recognition. It has been called andropause, androgen decline in the aging male (ADAM), male climacteric, shifting hormones in the aging male (SHAM) or more whimsically as the machopause. The reason that andropause had not been extensively studied was that androgen replacement therapy did not fulfill the expectations of relieving the manifestations of male aging. The latter proved to be a result of deterioration of multiple organ and system functions rather than only androgen decline. Moreover, a number of adverse effects were attributed to the use and abuse of sex steroids.

Demographic studies clearly indicate that the United States population is aging. Currently, there are 35 million people over the age of 65 years, and this group will grow to 70 million by the year 2030.¹ It is also striking that fastest growing segment of the population is over 85, currently 4 million and expected to double in the next 30 years. Moreover, the average life expectancy is increasing. At age 65, the mean life expectancy for men is 15.2 years and 18.8 years for women. At age 75, it is 9.4 years for men and 11.9 for women and at age 85, it is 5.3 years for men and 6.6 years for women.² Worldwide, there are currently about 600 million people aged 60 years and older, which will increase to 1.2 billion by the year 2005 and to 2 billion by 2050.³

The biochemical diagnosis of andropause remains a controversial issue. The levels of total testosterone must be interpreted with caution in the old and the obese. High levels of sex hormone binding globulin (SHBG) render a large proportion of free testosterone by RIA, and it is not a credible method of diagnosis. Measuring free testosterone by equilibrium dialysis is a reliable method that is difficult to perform. A calculated free testosterone is an indirect but a reliable method with equivalence to bioavailable testosterone.

Because there are no universal guidelines regarding testosterone values, physicians must rely on the normal values provided by the lab. Serum testosterone of 3001000 ng/dL is considered normal. Because of diurnal variation, borderline levels should be repeated on samples taken between 8:00 am and 9:00 am.

Hypogonadism can be due to primary testicular failure with elevated levels of FSH and LH. It can be secondary to decreased gonadotropin secretion resulting in inadequate Leydig cell stimulation and testosterone production. Major causes of primary hypogonadism include Kleinfelter's Syndrome, mumps orchitis, testicular trauma, alcoholism, chemotherapy and radiation exposure. The major causes of secondary hypogonadism are hypothalamic tumors, pituitary tumors and surgery, hyperprolactinemia, obesity and aging.

Men with low testosterone levels may not notice the benefits of testosterone supplementation at first. But with continued treatment, most will note an improvement in sexual desire and function, more positive outlook on life, and rate their overall health as improved. Testosterone supplements can be beneficial to those with mild testosterone deficiency not just to those with severe testosterone deficiency.

It has been estimated that about 25% of men at age 60 develop mild to moderate hypogonadism. In addressing the treatment of andropause, one should always manage the aging process as a whole, being aware of other prevalent illnesses.^4,5,6

Testosterone is associated with the maintenance of secondary sexual characteristics, certain metabolic actions, central nervous system effects including sexual arousal, emotional activation, cognitive functions and behavioral patterns of male dominance, aggression and submission.

There is a well-established progressive decline in hypothalamic/pituitary/gonadal function in men starting at the age of 30, free testosterone declines 1% a year. After age 60, 25% of men are clinically hypogonadal. Other causes of decreased testosterone production include stress, illness, medications, malnutrition, obesity, and psychiatric conditions. Below normal serum testosterone levels may be found at any age but are most apparent in middle-aged men. Testosterone deficiency occurs in about 24% of men aged 50-60 years and 40% in men aged 60-80.⁷ Decreased plasma testosterone levels can be found in healthy elderly individuals. In others, an insidious constellation of signs and symptoms occur but are often attributed to aging or other etiologies. These symptoms include diminished muscle energy and strength with decreased muscle mass (sarcopenia), increased fat mass with visceral adiposity (apple shape and increased waist to hip ratio), decreased exercise tolerance, sense of weakness, fatigue, irritability, anxiety, dysphoria, diminished intellectual capacity and memory, changes in sleep pattern, decreased sex drive, erectile dysfunction and nocturnal erections, reduced body hair and skin changes, anemia from impaired hematopoesis, decreased bone mineral density and osteoporosis, and a general decreased quality of life. Several changes can be attributed to alterations in other hormones (thyroxine, DHEA, growth hormone, melatonin) as well as multiple organ/system functional deterioration.

Men with documented androgen deficiency exhibit large individual variations, and different organs/systems are affected with varying intensity and response to treatment.^8,9 The response to androgens in men with sexual dysfunction is prompt often within 3 months. The increased sexual interest occurs in 2/3 of the patients while an improvement in erectile capacity is evident in only 1/3 of the patients. Improvement in bone mineral density may be seen over 1 year. The gain in energy and a better outlook on life occurs early and causes enthusiasm and determination on the part of the patient to continue treatment.¹⁰

In one long-term placebo controlled study, middle aged and older men wore either a daily testosterone patch or an identical placebo patch without testosterone for 3 years.¹⁰ Those using the placebo patch reported a progressive decline in their health starting at month 6 and accelerating throughout the 36 months of the study. In contrast, the men using testosterone replacement reported a prompt and sustained improvement in their health that persisted throughout the entire 3-year duration of the study.

Absence of response to androgen replacement therapy calls for a search for other co-morbidities. The drawbacks of androgen replacement therapy include the need for close monitoring for the duration of treatment (often for life) and the cost of medication, particularly the newer delivery forms. Some risks of testosterone therapy include fluid retention, polycythemia, and congestive heart failure. Development of gynecomastia, precipitation or worsening of sleep apnea, and significant obstructive uropathy represent partial contraindication. Prostate cancer is an absolute contraindication.¹¹ Unease about androgen replacement therapy and coronary artery disease is dissipating rapidly.¹² However, the decrease of HDL remains a cause of legitimate concern. Oral methyltestosterone should be avoided with liver toxicity, and liver function tests need to be monitored closely. Body hair may increase whereas scalp hair recedes, and acne may worsen.

Athletes using supraphysiologic testosterone doses to increase their muscle mass may learn that their endogenous testosterone shuts off. Men who abuse steroids by taking more than what their body needs suffer significant side effects. They often devise a unique pharmacologic code talk labeled the "array" to help them cope.

Excessive levels of androgen increase the skin's sebum production leading to acne which they treat with antibiotics. Testosterone in high doses causes fluid retention and edema which they treat with furosemide diuretic. Testosterone is metabolized to DHT causing male baldness for which they use finasteride. Also testosterone would be metabolized to estradiol causing male breast enlargement (gynecomastia), for which they use an anti-androgen (Tamoxifen). Those who resort to unwarranted supra-physiologic androgen and anabolic steroid use should be discouraged because of the inherent risks and physical/psychological side effects.^13,14

Conclusion

Androgen replacement therapy has recently resurfaced as a field of interest for both basic scientists and clinicians. A variety of medical specialties are now interested in both andropause and androgen replacement therapy. The pharmaceutical industry has also realized the enormous importance and potential of androgen replacement therapy in a rapidly increasing aging male population.

These two factors have resulted in the formation of national and international societies completely or partially involved in dealing with the concept of androgen decline in the aging male. This in turn has increased public and professional awareness of the condition and brought into focus the need for better understanding of its management.

Until solid information becomes available in regards to long-term effects of androgen replacement therapy, careful monitoring of men receiving therapy is essential. But by the same token, symptomatic hypogonadal men should not be denied therapy on the basis of real dangers that can be readily reversed or hypothetical changes that may never materialize.

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