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.
