Biomarkers

Target: Testosterone

Testosterone is the primary male sex hormone and anabolic steroid from the androstane class of steroids. It is the most important androgen in potency and quantity for vertebrates. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristics such as increased muscle and bone mass, and the growth of body hair. In addition, testosterone is involved in health and well-being, and the prevention of osteoporosis. Testosterone exerts its action through binding to and activation of the androgen receptor. In mammals, testosterone is metabolized mainly in the liver. Approximately 50% of testosterone is metabolized via conjugation into testosterone glucuronide and to a lesser extent testosterone sulfate by glucuronosyltransferases and sulfotransferases. An additional 40% of testosterone is metabolized in equal proportions into the 17-ketosteroids androsterone and etiocholanolone via the combined actions of 5alpha- and 5beta-reductases, 3alpha-hydroxysteroid dehydrogenase, and 17beta-HSD. Like other steroid hormones, testosterone is derived from cholesterol. The first step in the biosynthesis of testosterone involves the oxidative cleavage of the side-chain of cholesterol by the cholesterol side-chain cleavage enzyme (P450scc, CYP11A1) to give pregnenolone. In the next step, two additional carbon atoms are removed by the CYP17A1 (17alpha-hydroxylase/17,20-lyase) enzyme to yield a variety of C19 steroids. In addition, the 3beta-hydroxyl group is oxidized by 3beta-hydroxysteroid dehydrogenase to produce androstenedione. In the final and rate limiting step, the C17 keto group androstenedione is reduced by 17beta-hydroxysteroid hydrogenase to yield testosterone. Testosterone is synthesized and released by the Leydig cells in the testes that lie between the tubules and comprise less than 5% of the total testicular volume. Testosterone diffuses into the seminiferous tubules where it is essential for maintaining spermatogenesis. Some testosterone binds to an androgen-binding protein (ABP) that is produced by the Sertoli cells and is homologous to the sex-hormone binding globulin that transports testosterone in the general circulation. The ABP carries testosterone in the testicular fluid where it maintains the activity of the accessory sex glands and may also help to retain testosterone within the tubule and bind excess free hormone. Some testosterone is converted to estradiol by Sertoli cell-derived aromatase enzyme. Leydig cell steroidogenesis is controlled primarily by luteinizing hormone with negative feedback of testosterone on the hypothalamic-pituitary axis. The requirement of spermatogenesis for high local concentrations of testosterone means that loss of androgen production is likely to be accompanied by loss of spermatogenesis. Indeed, if testicular androgen production is inhibited by the administration of exogenous androgens then spermatogenesis ceases. This is the basis of using exogenous testosterone as a male contraceptive. The largest amounts of testosterone (>95%) are produced by the testes in men, while the adrenal glands account for most of the remainder. Testosterone is also synthesized in far smaller total quantities in women by the adrenal glands, thecal cells of the ovaries, and, during pregnancy, by the placenta. Testosterone levels fall by about 1% each year in men. Therefore, with increasing longevity and the aging of the population, the number of older men with testosterone deficiency will increase substantially over the next several decades. Serum testosterone levels decrease progressively in aging men, but the rate and magnitude of decrease vary considerably. Approximately 1% of healthy young men have total serum testosterone levels below normal; in contrast, approximately 20% of healthy men over age 60 years have serum testosterone levels below normal. (PMID: 17904450 , 17875487). In addition to its role as a natural hormone, testosterone is used as a medication in the treatment of low testosterone levels in men, transgender hormone therapy for transgender men, and breast cancer in women. In individuals with hypogonadism, a reduced production of blood testosterone is seen in adolescents (13-18 years old) at a concentration of 0.010 +/- 0.013 μM (PMID: 28266512) compared to normal adolescents at a concentration of 0.00125-0.0276 μM. Testosterone has also been linked to 21 Hydroxylase Deficiency and 11 Beta Hydroxylase Deficiency. In adults (>18 years old) with 21 Hydroxylase Deficiency, blood concentration of testosterone is shown to be elevated at a concentration of 0.00198-0.00368 μM (PMID: 11826238)compared to normal adults at a concentration of 0.00139 +/- 0.000763 μM (PMID: 11826238). Similarly, in children (1-13 years old) with 11 Beta Hydroxylase Deficiency, blood concentration of testosterone is shown to be elevated at a concentration of 0.00150-0.00420 μM (PMID: 8933406) compared to normal children at a concentration <0.000400 μM (PMID: 8933406). Testosterone has also been linked with X-Linked ichthyosis, a skin condition caused by the hereditary deficiency of the steroid sulfatase (STS) enzyme that affects 1 in 2000 to 1 in 6000 males. In adults (>18 years old) with X-Linked ichthyosis, testosterone is shown to be elevated in the blood at a concentration of 0.00900-0.0360 μM (PMID: 3864567) compared to normal adults at a concentration of 0.0094 (0-0.023) μM (PMID: 16477341).