The new science of sex steroid physiology after menopause, 500 million years in the making.

A particularly remarkable and highly sophisticated achievement of evolution is intracrinology.

This unique mechanism permits a tissue-specific, local production and inactivation of sex steroids for a strictly local action, without significant release of active sex steroids from the peripheral tissues into the circulation.

At menopause, the secretion of estradiol by the ovaries stops. Afterwards, all estrogens are made intracellularly in the peripheral tissues from dehydroepiandrosterone (DHEA) according to the local needs according to the mechanisms of intracrinology. Accordingly, after menopause, serum estradiol (E2) remains at very low and inactive concentrations (<9.3-10.0 pg/ml) to avoid stimulation of the endometrium and potentially other tissues, including the breast.

After menopause, the only source of sex steroids is DHEA, a compound inactive by itself and mainly of adrenal origin. Serum DHEA begins decreasing at the age of 30 years reaching about 40% of its peak 30-year value at age 50, and continues to decrease thereafter. The variable decrease in serum DHEA, the only source of all sex steroids after menopause synthesized through the mechanism of intracrinology, causes a similar and variable decrease in intracellular estrogens and androgens throughout the body. As demonstrated by accurate mass spectrometry-based measurements of serum sex steroids, this finding is supported by the complete lack of ovarian secretion of E2 common to all postmenopausal women. By demonstrating the absence of E2 and therefore the absence of possibility of a role of ovarian estrogens in explaining the various degrees of severity of menopausal symptoms, it has been established that a variable loss in DHEA activity is the true cause of the severity and variability of the symptoms and signs of menopause.

All efficacious intravaginal estrogen preparations increase serum E2 above normal, as measured by mass spectrometry assays. Only DHEA, based on the mechanism of intracrinology, can provide both the estrogens and androgens required for normal vaginal health, while maintaining serum E2 at normal postmenopausal values with no risk of systemic effects.

In summary, studies of human physiology have established that no estrogen is secreted in the circulation after menopause and sex steroid metabolism (local formation and inactivation) is exclusively intracellular.

At the end of the reproductive years, the ovary stops secreting E2 into the circulation. Consequently, serum E2 levels decrease to very low and biologically inactive concentrations in order to protect the endometrium and potentially other tissues, including breast tissue. In fact, proof of the lack of biological activity of the very low levels of serum E2 is the observation that the endometrium is atrophic in all normal postmenopausal women. It should be mentioned that the endometrium shows general atrophy despite being exposed to significant levels of serum DHEA, an inactive molecule by itself which is not converted into E2 in the endometrium.

The human species

What intracrinology has introduced in the human species is how to maintain serum E2 within low and biologically inactive values in postmenopausal women while providing sex steroids intracellularly according to the needs of each peripheral tissue. This sophisticated strategy has been achieved through 500 million years of evolution, by introducing into each peripheral tissue the appropriate sets of enzymes required to transform the inactive molecule DHEA into the needed amount of estrogens and androgens specific to each tissue. Most importantly, through the mechanism of intracrinology, estrogens and androgens converted intracellularly from DHEA are inactivated in the same cells where their synthesis takes place with no biologically significant active steroid release into the circulation. Before the discovery of intracrinology with the help of highly sensitive mass spectrometry-based sex steroid assays, the observation that the secretion of E2 stops at menopause led to the universal belief that the logical treatment of menopause should be the administration of estrogens in order to replace the lack of ovarian estrogens. However, nature has established that no estrogen should be secreted after menopause and that each tissue should be responsible for making its required small amount of estrogen and androgen for its own use.

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