Testosterone T

Components and Measurement (21)

There are three kinds of T: (i) free, that is, not bound to any protein (FT), (ii) bound to albumin, and (iii) bound to sex hormone binding globulin (SHBG). Only ^2% of T is in the free form; about 60% of the remainder is weakly bound to albumin and other proteins; and about 40% is bound with a higher binding affinity to SHBG (Fig. 4.2).

Figure 4.2 Testosterone partitions in the serum. [Reprinted with permission from (Testosterone and Aging: Clinical Research Directions) (2004) by the National Academy of Sciences, courtesy of the National Academies Press, Washington, D.C.]

Total T comprises FT with whatever is bound to protein. The part that is most easily available to tissues is referred to as bioavailable testosterone (BAT) and includes both FT and the portion that is bound to albumin.

Total T is measured by radioimmunoassay which is a validated, standardized, and reproducible assay. However, as SHBG increases with age, and therefore a greater percentage of the total T is bound to SHBG, this measure may not be so informative in older men. BAT is measured in several ways including separately calculating the total T and SHBG. Measurement of FT is more difficult and "controversial" (21; p.18).

Segraves and Balon estimate that 200-350 ng/dL of T is required for normal sexual function and that above 450 ng/dL, "it is difficult to demonstrate a relationship between testosterone and sexual activity." (22; p. 216).

Measurement of T is best performed in the morning because of the diurnal variation in blood levels.

Normal Aging Changes in the Quantity

In adult men, T increases greatly from 0.2 to 0.7 nmol/L (50-20 ng/dL) to the normal adult male level of 10-35 nmol/L (^300-1000 mg/dL) by about age 17. The level of BAT (see later) remains balanced until men are in their 30s or 40s and then decreases slowly over the remainder of the man's life at a rate of about 1.2% per year. (The latter contrasts with women who experience a sudden drop in estrogen and progesterone when ovulation ends.) In healthy men, mean serum T levels decrease by ~ 30% between ages 25 and 75. Mean FT levels decrease by as much as 50% over the same period. The steeper decline of FT is explained by the age-associated increase in SHBG. "At any age, the range of values observed, both for T and FT, is very wide... it is evident that... the limits of normality are rather arbitrary and that the sensitivity threshold for androgens might vary from tissue to tissue and possibly, also according to age" (23).

In addition to T, many hormones gradually change in the aging male including growth hormone (GH) and adrenal compounds [dehydroepiandroster-one (DHEA) and its sulfate (DHEAS)].

Origin, Production, and Control

Testosterone in men derives mostly from the testis but a small amount comes from the adrenal cortex. Hormonal control over the production of testicular T begins in the hypothalamus, which secretes gonadotropin-releasing hormone (GnRH) (Fig. 4.3). GnRH, in turn, stimulates the anterior part of the pituitary gland to produce both leutinizing hormone (LH) and follicle stimulating

Testes

Figure 4.3 Regulation of testosterone and sperm production by LH and FSH. (C = cholesterol, T = testosterone). Source: Griffin JE, Wilson JD. Disorders of the testes. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison's Principles of Internal Medicine. 15th ed. New York: McGraw-Hill, 2001:2143. (Reprinted with permission.)

Testes

Figure 4.3 Regulation of testosterone and sperm production by LH and FSH. (C = cholesterol, T = testosterone). Source: Griffin JE, Wilson JD. Disorders of the testes. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison's Principles of Internal Medicine. 15th ed. New York: McGraw-Hill, 2001:2143. (Reprinted with permission.)

hormone (FSH) both of which act on cells in the testes. LH causes the Leydig cells to produce T and FSH induces the Sertoli cells to produce spermatozoa. A negative feedback mechanism results in the testes controlling the output of LH and FSH. In older men, the function of both the testes and the hypothala-mic-pituitary axis are diminished and for both reasons, the output of T is less (24).

About 5-6 mg of T is secreted daily into the plasma of men, usually in a pulsatile manner every 60-90 min, and in a diurnal rhythm in which peak levels occur during the morning (although less pronounced in older men) (25). In addition to intraday fluctuations, there is a wide range of normal levels between different individuals.

Actions

Testosterone can act either (a) directly on target cells or (b) indirectly by being converted first to its principal metabolites, dihydrotestosterone (DHT), and estradiol. Although both T and DHT bind to the androgen receptor, the latter does so more strongly and is therefore more potent. Two enzymes convert T to its metabolites: 5 alpha-reductase, which converts T to DHT and which is found especially in prostate, skin, and reproductive tissues, and aromatase which converts T to estradiol and is found especially in adipose tissue, liver, and some central nervous system nuclei. Thus, the actions of T are widespread throughout the body.

Effects on Sexuality

The sex-related impact of T in men has been demonstrated in two groups: (a) those who have been deprived of this hormone in a significant manner and who are hypogonadal as a result (the most extreme example of which is men who have been castrated—physically or chemically—for any reason and in varying degrees) and (b) those who are generally healthy (including their hormone levels, otherwise referred to as "eugonadal").

The influence of androgens on sexual desire is particularly prominent and was summarized by Bancroft (26; pp. 92-93). From his studies on hypogonadal men, he concluded that within 3-4 weeks of androgen withdrawl: (i) sexual interest declines as measured by the frequency of sexual thoughts (ii) sexual activity appears to diminish (as a result of decreased sexual desire) but is more difficult to assess because of the confounding effects of a sexual partner, and (iii) the capacity for ejaculation disappears. When androgen replacement is given, these phenomena are reversed within 7-10 days. As well, the impact of androgen replacement on sexual desire is dose-related.

Fantasy (or imagery)-associated erections and nocturnal erections are both androgen-dependent, and cease as a result of androgen withdrawal. The fact that only certain aspects of erectile function are affected suggests that the impact in this area is indirect, that is, on the man's central nervous system rather than directly on his genitalia. Segraves suggests that when a man experiences erectile dysfunction in the context of T deprivation, the origin of the difficulty can be described as "performance anxiety" superimposed on a biogenic desire disorder (27; p. 278).

Segraves and Balon summarize the impact of the therapeutic use of T in eugonadal men by saying that "a relatively low level... is sufficient to maintain normal sexual activity, and that there is no demonstrable relationship between sexual function and variations of testosterone above this threshold value" (22; p. 215).

Changes in Effects with Age

The mystery of what happens to T as men age is not easy to unravel and possibly involves three separate issues: changes in production, carrier proteins, and receptor sensitivity.

The decrease in normal levels of T with age (described previously) seems partly explained by a decrease in function of both testicular tissue (Leydig cells) and the pituitary-hypothalamic axis. However, a second factor explaining the diminution may be that the protein SHBG increases with age and therefore, more T is bound and less is free. A third issue is the possible decline in the level of sensitivity of T receptors (especially those in the central nervous system) which might explain both reduced sexual desire in the aging male and the need for large doses of T in treating hypogonadal states in older men.

Segraves and Balon summarized results of the changes in T that accompany aging as follows (22):

Decreased: Production; the number of Leydig cells in the testis; the levels of bound and free hormone; testicular response to LH.

Increased: SHBG; estradiol; FSH; LH.

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