DHEA and intracrinology at menopause, a positive choice for evolution of the human species.

Menopause has been chosen by evolution as the convergence of three factors, namely cessation of ovarian function (reproduction and estrogen secretion), high circulating dehydroepiandrosterone (DHEA), and intracrine enzymes able to convert DHEA into active sex steroids in peripheral tissues. The arrest of estrogen secretion by the ovaries at menopause causes a decrease of circulating estradiol below the threshold of biological activity, thus eliminating stimulation of the endometrium and risk of endometrial cancer. As much as the arrest of secretion of estradiol by the ovaries is essential to protect the uterus, it is of major importance that sex steroids continue to be made available in most other tissues which need estrogens and/or androgens for their normal functioning. Evolution, through 500 million years, has progressively provided the peripheral tissues with the enzymes able to make androgens and estrogens while high levels of DHEA, the precursor of all sex steroids, have appeared much later with the primates approximately 20 million years ago. All elements were thus in place for the functioning of intracrinology or the cell-specific formation of estrogens and androgens in peripheral tissues from the inactive precursor DHEA, with no significant release of active sex steroids in the circulation, thus eliminating the risks of adverse effects in the other tissues, especially the uterus. The presence of subthreshold levels of circulating estradiol combined with the formation of sex steroids from DHEA in specific peripheral tissues (intracrinology) makes menopause a positive characteristic supporting many years of good-quality postmenopausal life, useful for taking care of children and grandchildren. DHEA, however, decreases with age and is present at very different concentrations between different women, with the consequence that approximately 75% of postmenopausal women have too low circulating DHEA levels and suffer from symptoms/signs of hormone deficiency.