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Intracrinology: The New Science of Sex Steroid Physiology in Women

Part of the ISGE Series book series (ISGE)

Abstract

The control of DHEA action is completely different from that of E2 and testosterone, as engineered by the 500 million years of evolution which have added 30 or more intracrine enzymes controlling DHEA action in the human. In fact, the essential characteristics which differentiate the exposure to E2 and testosterone from the exposure to DHEA, an inactive compound by itself, derive from the major differences between endocrinology and intracrinology, which can be summarized as follows:The arrest of estrogen secretion by the ovaries at menopause causes an abrupt decrease of serum estradiol (E2) below the level of biological activity (established at 9.3 pg E2/ml (95th centile)), thus avoiding stimulation of the endometrium and decreasing the risk of endometrial cancer. As much as the arrest of E2 secretion by the ovaries is essential to protect the uterus, it is important that sex steroids continue to be available in the tissues other than the uterus where estrogens and androgens are needed for normal morphology and functioning. To this end, evolution, through 500 million years, has progressively provided the peripheral tissues with the sophisticated sets of enzymes which make androgens and estrogens from dehydroepiandrosterone (DHEA). The biologically inactive precursor DHEA appeared much later or approximately 20 million years ago with the primates. All elements were then in place for the installment of intracrinology or the cell-specific formation and inactivation of estrogens and androgens in peripheral tissues from the precursor DHEA, a molecule inactive by itself.

Contrary to classical endocrinology where specialized glands distribute active hormones to all tissues of the body, intracrinology has equipped each cell within each tissue with a cell-specific set of enzymes able to make intracellularly the locally required small amounts of estrogens and androgens. More than 30 steroid-forming enzymes have thus been engineered over time in the peripheral human tissues. Moreover, humans, contrary to lower species, also possess the appropriate intracellular steroid-inactivating enzymes, especially glucuronyl transferases and sulfotransferases, which prevent the release of a biologically significant amount of E2 or testosterone in the circulation, thus avoiding inappropriate action in the other tissues.

DHEA secretion, unfortunately, starts decreasing at about the age of 30 years at different rates in different women. Moreover, there is no feedback mechanism to increase DHEA secretion when serum DHEA decreases. Most importantly, DHEA is the unique source of sex steroids after menopause. Androgens, on the other hand, are all made intracellularly from DHEA by the mechanisms of intracrinology during the whole life and are always maintained at very low levels in the blood in both pre- and postmenopausal women or below 0.32 ng testosterone/ml.

In addition to the well-demonstrated role of the androgens made locally in prostate cancer as well illustrated by the benefits of combining castration with an antiandrogen or a blocker of androgen formation, especially in castration-resistant prostate cancer, proof of the importance of intracrinology is also provided by the benefits of aromatase inhibitors and antiestrogens for the treatment of breast cancer in postmenopausal women where all estrogens are made in peripheral tissues by intracrine mechanisms. Recognition that all estrogens and androgens are made from DHEA by the mechanisms of intracrinology in peripheral tissues after menopause opens the door for a new understanding of menopause and offers novel opportunities for better therapeutic strategies.

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Labrie, F. (2018). Intracrinology: The New Science of Sex Steroid Physiology in Women. In: Birkhaeuser, M., Genazzani, A. (eds) Pre-Menopause, Menopause and Beyond. ISGE Series. Springer, Cham. https://doi.org/10.1007/978-3-319-63540-8_1

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