ReviewAndrogens in women are essentially made from DHEA in each peripheral tissue according to intracrinology

- All active androgens in women are made from DHEA in each peripheral tissue independently from the rest of the body.
- Each peripheral tissue has about 30 steroidogenic and steroid-inactivating enzymes to control the tissue-specific transformation of DHEA.
- The androgens made intracellularly in peripheral tissues are inactivated locally with no significant release of active androgens in the circulation.
- Women synthesize about 50% as much androgens as made in men of the same age.
- Serum testosterone remains at biologically inactive concentrations below 260 pg/ml, thus avoiding systemic exposure.

The objective is to review how the cell-specific amounts of intracellular androgens are all made in women from circulating dehydroepiandrosterone (DHEA) in each peripheral tissue, independently from the rest of the body. Following 500 million years of evolution, approximately three dozen cell-specific intracrine enzymes have been engineered in human peripheral tissues whereby the inactive sex steroid precursor DHEA mainly of adrenal origin is transformed into the appropriate minute intracellular amounts of androgens. These intracellular androgens are inactivated in the same cells, with no biologically significant release of active androgens in the circulation. The best estimate is that approximately 50% as much androgens are synthesized in women, compared to men of the same age. The problem with DHEA, however, the exclusive source of androgens in women of all ages, is that DHEA secretion has already decreased by an average of 60% at time of menopause and continues to decrease thereafter. The human-specific and highly sophisticated mechanisms of intracrinology permit each cell to control androgen availability according to its own needs independently from the remaining of the body. Such a mechanism is completely different from classical endocrinology well understood in men where testosterone of testicular origin is transported through the blood and has indiscriminate access to the androgen receptor (AR) in all AR-containing cells of the body. In men, both the endocrine and intracrine mechanisms are in operation while, in women, only the intracrine mechanisms responsible for intracellular formation from DHEA provide androgens.