Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone can be hydroxylated at a number of positions by CYP3A4, CYP2B6, CYP2C9, and CYP2C19; glucuronidated by UGT2B17; sulfated; converted to estradiol by aromatase; converted to dihydrotestosterone (DHT) by 5α-reductase; metabolized to androstenedione by CYP3A4, CYP2C9, and CYP2C19; or converted to DHT glucuronide. Androstenedione undergoes metabolism by aromatase to form estrone, which undergoes a reversible reaction to form estradiol. Androstenedione can also be converted to 5α-androstanedione by 5α-reductase, which can be further metabolized to 5α-androsterone. DHT can be glucuronidated or sulfated, or metabolized to 5α-androstanediol, androstane-3α,17β-diol, or androstane-3β,17β-diol. DHT can also be reversibly converted to 5α-androstanedione.
Extensive reductive metabolism of testosterone occurs not only in the liver, but also in a variety of extrahepatic tissues, especially in target organs of the sex hormones; the ultimately effective physiological androgen is formed in the target tissues. Testosterone metabolism occurs not only in the prostate and seminal vesicles but also in rat uterus, rabbit placenta, rodent testis and primate brain. In rats, the small intestine is also capable of metabolizing testosterone.
It is transformed to 5-alpha-dehydrotestosterone in target organs such as the prostate, sebaceous glands and seminal vesicles; only the latter compound binds to the androgen-receptor site in these target organs.
Large quantitative differences in testosterone metabolism are evident between female and male rats. The reason for this phenomenon is that many steroid-metabolizing enzymes in rats are either androgen- or estrogen-dependent; the sex hormones thus act in an inductive or a repressive manner.
Esters of testosterone, such as the propionate, the heptanoate, the cypionate, the valerate, the isovalerate, the enanthate and the undecanoate, are partially cleaved in vivo to release the parent compound. This has been demonstrated by oral administration of testosterone undecanoate in oily solution to rats: most of the compound is converted within the intestinal wall, the first step being partial splitting off of the fatty acid moiety. The non-metabolized portion, however, and the metabolite 5-alpha-dihydrotestosterone undecanoate, are absorbed via the lymphatic system and made available for androgenic action to the organism. /Testosterone esters/
IDENTIFICATION AND USE: Testosterone is an anabolic steroid for systemic use. It consists of odorless or almost odorless crystals or crystalline powder. Naturally-occuring anabolic steroids are synthesized in the testis, ovary and adrenal gland. Anabolic steroids are listed as Schedule III controlled substances. HUMAN EXPOSURE AND TOXICITY: The main risks associated with testosterone are those of excessive androgens: menstrual irregularities and virilization in women and impotence, premature cardiovascular disease and prostatic hypertrophy in men. Both men and women can suffer liver damage with oral anabolic steroids containing a substituted 17-alpha-carbon. Psychiatric changes can occur during use or after cessation of these agents. Acute overdosage can produce nausea and gastrointestinal upset. Chronic usage is thought to cause an increase in muscle bulk, and can cause an exaggeration of male characteristics and effects related to male hormones. There is no clear evidence that anabolic steroids enhance overall athletic performance. Precocious prostatic cancer has been described after long-term anabolic steroid abuse. Cases where hepatic cancers have been associated with anabolic steroid abuse have been reported. Testosterone may cause fetal harm when administered to pregnant women due to the potential for virilization of a female fetus. Androgenic effects including clitoral hypertrophy, labial fusion of the external genital fold to form a scrotal-like structure, abnormal vaginal development, and persistence of a urogenital sinus have occurred in the female offspring of women who were given androgens during pregnancy. The degree of masculinization is related to the amount of drug given to the woman and the age of the fetus; masculinization is most likely to occur in a female fetus when exposure to androgens occurs during the first trimester. ANIMAL STUDIES: The effect of testosterone on the prostate of castrated rats was described as a significant increase in prostatic weight which occurred after 6 wk treatment with testosterone. In female mice injected subcutaneously with 25 ug testosterone daily for the first five days after birth, 7/9 developed hyperplastic epithelial lesions, resembling epidermoid carcinomas at about 71 weeks of age. Chronic treatment of rats with testosterone produced a low prostate carcinoma incidence. A high carcinoma incidence can only be produced by chronic treatment with testosterone following administration of carcinogens. Daily subcutaneous injections for 4-8 days of total doses of 0.5-80 mg testosterone into rats between days 10 and 20 of gestation and of total doses of 1-55 mg testosterone propionate between days 12 and 19 of gestation resulted in resorptions, necrosis, lethality, post-partum mortality and various degrees of masculinization in female offspring. Deposteron (testosterone cypionate) was genotoxic and cytotoxic in mice. Testosterone acted both as a mitogenic and genotoxic agent in L929 cells.
Testosterone is considered an anabolic steroid. It plays a key role in the development of male reproductive tissues such as the testis and prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass, and the growth of body hair. High levels of testosterone can lead to masculinization in females or premature puberty in young boys. Chronically high levels in adults increase the incidence of heart attack, stroke and blood clots by lowering the level of HDL (good cholesterol) and increasing the level of LDL (bad cholesterol). Chronic high use of anabolic steroids (such as testosterone) appears to lead to cardiac myopathy and weakening the left ventricle. The development of breast tissue in males, a condition called gynecomastia (which is usually caused by high levels of circulating estradiol), arises because of increased conversion of testosterone to estradiol by the enzyme aromatase. Reduced sexual function and temporary infertility can also occur in males.
The mechanism of testosterone’s action is as follows: Free testosterone is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha reductase. DHT binds to the same androgen receptor even more strongly than testosterone, so that its androgenic potency is about 5 times that of testosterone. Once bound, the ligand-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects.
A single 100mg topical dose of testosterone has an AUC of 10425±5521ng\*h/dL and a Cmax of 573±284ng/dL. Testosterone is approximately 10% bioavailable topically.
90% of an intramuscular dose is eliminated in urine, mainly as glucuronide and sulfate conjugates. 6% is eliminated in feces, mostly as unconjugated metabolites.
Testosterone is absorbed systemically through the skin following topical application as a gel or transdermal system. Following topical application of a hydroalcoholic gel formulation of testosterone (AndroGel, Testim) to the skin, the gel quickly dries on the skin surface, which serves as a reservoir for sustained release of the hormone into systemic circulation. Approximately 10% of a testosterone dose applied topically to the skin as a 1% gel is absorbed percutaneously into systemic circulation. The manufacturer of AndroGel states that increases in serum testosterone concentrations were apparent within 30 minutes of topical application of a 100-mg testosterone dose of the 1% gel, with physiologic concentrations being achieved in most patients within 4 hours (pretreatment concentrations were not described); percutaneous absorption continues for the entire 24-hour dosing interval. Serum testosterone concentrations approximate steady-state levels by the end of the initial 24 hours and are at steady state by the second or third day of dosing of the 1% gel. With daily topical application of the 1% gel (AndroGel), serum testosterone concentrations 30, 90, and 180 days after initiating treatment generally are maintained in the eugonadal range. Administration of 10 or 5 g of AndroGel daily results in average daily serum testosterone concentrations of 794 or 566 ng/dL, respectively, at day 30. Following discontinuance of such topical therapy, serum testosterone concentrations remain within the normal range for 24-48 hours but return to pretreatment levels by the fifth day after the last application.
