Testosterone is both a paracrine regulator of spermatogenesis (see Chap. 113) and a hemocrine hormone. The testicular content of testosterone is ˜50 μg (1 μg/g testis), whereas the blood production rate is ˜5000 μg per day, indicating that only a small portion of the testosterone produced each day is stored in the testes. The testosterone precursor steroids, including pregnenolone, 17-OH pregnenolone, dehydroepiandrosterone (DHEA), progesterone, 17α-hydroxyprogesterone, and
androstenedione, are also secreted by the testis, and the relative concentrations of these steroids in spermatic vein blood are proportional to their testicular concentrations.6 The release of precursor steroids into the circulation may indicate that they are unnecessary by-products in the orderly biotransformation of pregnenolone to testosterone, because none is known to have a physiologic action in the male. Androstenedione is of special interest because it is used as a performance-enhancing drug. Androstenedione is bioconverted to testosterone and to estrone, but there is little published information on the endocrine profile following androstenedione administration.

A single sample of blood, generally drawn in the morning, can be used to measure testosterone. The usual normal range in morning samples is 3 to 10 ng/mL (10–40 nmol/L). There is a diurnal variation in testosterone in adult men, with highest levels in the early morning, followed by a progressive fall throughout the day, reaching the lowest levels in the evening and during the first few hours of sleep. Peak and nadir values differ by ˜15%, although more pronounced differences are sometimes observed.7 The diurnal rhythm is blunted with aging8 and in men with testicular failure.9 The metabolic clearance of testosterone is not thought to vary throughout the day, so that the diurnal testosterone rhythm is presumed to result from a day-night difference in testosterone production. Because there are no parallel changes in serum LH levels, however, the origin as well as physiologic significance of the diurnal testosterone rhythm remains uncertain. It is important to measure testosterone in the morning, because reference ranges are based on morning values. Frequent sampling of spermatic venous blood reveals testosterone secretory pulses at a frequency of ˜1 pulse per hour,6 but because of this rapid frequency and relatively low pulse amplitude only small fluctuations occur in peripheral plasma. Testosterone secretory bursts are more readily defined in the peripheral blood when pulse frequency is low.7 There is a good correlation between the plasma testosterone level at first sampling and the mean of multiple samples taken over 1 year, so that one morning sample is reasonably representative,10 although abnormal and borderline values should be confirmed.

There is a prominent sleep-related increase in serum testosterone in pubertal boys, with abrupt rises from female to adult male levels.11 This difference can be used clinically to evaluate boys with delayed puberty (see Chap. 92), because the rise to a higher testosterone value in the morning may precede pubertal testis growth and indicates that puberty has begun.12 Men with hypogonadism and hyperprolactinemia have an exaggerated diurnal testosterone rhythm, leading to very low levels in the afternoon and evening, which can explain clinical hypogonadism despite a normal morning total testosterone level,9 as sometimes occurs in men with a prolactinoma. The testosterone level tends to rise during intense exercise because of hemoconcentration13 and to decline 12 to 24 hours later because gonadotropin-releasing hormone (GnRH) secretion is reduced.14 Testosterone levels are also reduced in acute and chronic illness15 and with fasting for at least 48 hours. These factors can confound an evaluation of testicular function.

The metabolism of testosterone is shown in Figure 114-1. Testosterone is metabolized into two biologically important products, dihydrotestosterone (DHT) and estradiol, by the enzymes 5α-reductase and aromatase, respectively. Most of the metabolism of testosterone occurs in the liver, however, via 3α- and 3β-hydroxysteroid dehydrogenase, 5α- and 5β-steroid reductase, and oxidation of the D-ring to the 17-keto-steroids androsterone (3α-hydroxy-5α-androstane-17-one) and etiocholanolone (3α-hydroxy-5β-androstane-17-one), which are then excreted in the urine. Most of the 10 to 25 mg per day of keto-steroids in the urine of men is of adrenal origin, however, so that the urinary 17-ketosteroid excretion is not a test of testicular function. Testosterone metabolites are also conjugated to sulfuric and glucuronic acids at the 3- or 17-position and excreted in the urine and bile. A small fraction (2%) of the circulating testosterone is excreted unchanged in the urine.