by Ed Barillas, Staff Writer
Androgen drugs can be found in many places. Because they are popular among athletes and bodybuilders, androgen drugs can be found easily in the black market. Physicians also prescribe androgens, legally, for many conditions.
Despite the strong presence of legal and illegal androgen use, the science of androgen effects has greatly lagged behind the understanding of the biological effects of estrogen and indications for estrogen replacement therapy. Female oral contraceptives have been in use for many years, but only recently have we seen studies regarding hormone contraceptive agents in men. Although there are a few very well defined clinical syndromes of male hypogonadism, which requires androgen therapy, their use in other clinical situations, such as mild hypogonadism and hypogonadism associated with aging, is less well known.
The following should be able to dispel some of the mystery of androgen therapy in older men:
As far as normal androgen physiology, we know that testosterone is present in very low levels in boys prior to puberty. Once the boy hits puberty a pulsatile secretion of GnRH causes the anterior pituitary to produce LH and FSH. This circulating LH induces the Leydig cells of the testicles to produce testosterone, with the following development of secondary sex characteristics. As the level of testosterone rises in the blood circulation, there is a negative feedback on the production of GnRH at the hypothalamic level, and LH and FSH at the pituitary level.
A high intra-testicular level of testosterone is an absolute prerequisite for sperm production. The levels in the seminiferous tubules stay high due to the proximity of production in the Leydig cells, and well as by binding in the tubules by androgen binding-protein or ABP. This binding to ABP probably also prevents fluctuation of the levels by maintaining a reservoir of hormone immediately available to buffer changes in production. Although testosterone is the only absolute requirement for sperm production, FSH has a promotional effect and quantitatively normal spermatogenesis requires the action of FSH on the Sertoli cell. When sperm production is proceeding in a quantitatively normal manner, a peptide hormone called inhibin is released into the circulation and by the Sertoli cell, which is responsible for negative feedback of FSH, but not LH production, by the pituitary.
Circulating testosterone is present in several forms. Testosterone may be present as a free hormone, which is not bound to any protein, or bound relatively weakly to albumin. The majority of testosterone in circulation, however, is bound to sex hormone binding globulin or SHBC. The testosterone bound to SHBC is not available for biological activity. Both the free testosterone and that weakly bound to alburnin comprise the so-called “bioavailable” testosterone fraction, which is responsible for peripheral androgenic effects. So the most important measurement in diagnosing hypogonadism, the total T, or free T remains controversial.
Testosterone is converted to other clinically important compounds in the peripheral circulation and/or peripheral tissues. Dihydrotestosterone (DHT) is produced by reduction through the action of 5-reductase, which is ever so present in prostate, skin and the genital tissue. DHT is responsible for prostatic growth and has other trophic effects on the prostatic tissue. Estradiol (E2) is produced by the esterification of testosterone. Its good to note that the rate of conversion of T to E2 can be increased in obese men and in men with liver failure and elevated levels of E2 can bring down the hypothalamic-pituitary-gonadal axis which results in decreased gonadotropin secretion and decreased circulating T levels.
As far as changes in testosterone levels, with aging there is no corollary of the menopause seen in females as men age. The menopause in women is caused by ovarian failure. No such similar event of complete testicular failure occurs in men. However, it has been well established that mean T levels drop progressively with age, and the percentage of men with T levels in the abnormal range increases. So when one looks at the levels of bioavailable testosterone (a probably more accurate measure of the decreasing androgenic effects) more marked changes may be evident. Other evidence of a relatively hypogonadal state in older men includes elevated LH, as well as an exaggerated response of LH to the administration of GnRH is staged testing.
Although T levels drop with aging, it is less understood whether any of the generalized manifestations of aging such as osteoporosis, impotence, CNS changes are due to the decrease in circulating androgen. Because it is not established that these age-related changes are due to hormonal deficiencies, the simple presence of a decline in circulating hormones cannot be taken as de facto evidence that hormone replacement therapy will be beneficial in reversing or preventing these changes.