TESTOSTERONE AND ESTROGEN SYNTHESIS
Under the control of the anterior pituitary, three glands produce steroid hormones involved in reproduction: the adrenal cortex responding to adrenocorticotropic hormone (ACTH), and the ovary and testis, both under the inﬂuence of the gonadotropin luteinizing hormone (LH). For the majority of sex hormones that result from this stimulation, cholesterol is the precursor molecule.
In each of these organs, side chains are degraded from cholesterol to form pregnenolone and dehydroepiandrosterone (DHEA). In humans, DHEA is the dominant sex steroid and precursor or prohormone to all other steroid sex hormones, including testosterone and estrogens. In the blood, most DHEA is found in its sulfate-bound form, DHEAS, and not in the free form. DHEA supplements are often used as muscle-building or performance-enhancing drugs by athletes. However, randomized placebo-controlled trials have found that DHEA supplementation has no effect on lean body mass, strength, or testosterone levels. Pregnenolone is converted to progesterone, which by degradation of its side chain is converted to androstenedione and then to testosterone. The latter two of these hormones are the main products of testicular Leydig cells. Androstenedione, also termed “andro,” is an FDA-banned dietary supplement that is also taken by athletes to improve performance. In the ovary, synthesis of androstenedione by theca interna cells and its subsequent conversion to estrone in follicular granulosa cells, along with conversion of testosterone to estradiol by aromatases, com- prise the main secretory products. With polycystic ovary syndrome, enzymatic conversion of testosterone to estradiol in the ovary is impaired and DHEAS levels are elevated, leading to an androgenized phenotype in affected women. Estriol, a product of estrone metabolism in the placenta during pregnancy, is the third major estrogenic hormone in the female but is the least potent biologically.
About 5% of normal daily testosterone product is derived from the adrenal cortex, and the remainder is secreted by the testis into the systemic circulation. In the plasma, testosterone is virtually entirely bound (98%) by proteins such as sex hormone binding globulin or albumin. The remainder of testosterone (2%) exists in a free or unbound form, which is the active fraction. Testosterone is conjugated in the liver and excreted by the kidney in this water-soluble form. Circulating estrogens have a similar bioavailability proﬁle and are also carried on plasma proteins, notably albumin. Inactivation of estrogen occurs in the liver through conversion to less active metabolites (estrone, estriol), by conjugation to glucuronic acid, or by oxidation to inert compounds. There is also considerable enterohepatic circulation of estrogens in the bile. Estrogen, testosterone, and their metabolites are ultimately excreted by the kidney, for the most part in the form of 17-ketosteroids in which a ketone group is present on the steroid ring. Examples of 17- ketosteroids include androstenedione, androsterone, estrone, and DHEA.
Although important for premenopausal women, the value of estrogen and progesterone supplementation in postmenopausal women is controversial. A randomized, controlled trial of 15,730 women in the Women’s Health Initiative was stopped early, after 5.6 years, because of the ﬁnding that risks (including stroke, blood clots, and breast cancer) outweighed beneﬁts (lower risk of hip fractures and colon cancer) among subjects taking hormone supplements. Similarly, the value of testosterone supplements in older men who have reached andropause (androgen deﬁciency with age) is even more controversial, as large, randomized, placebo controlled trials of sufﬁcient duration to assess longterm clinical outcomes and events have not been undertaken.