Endocrine and Intracrine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone

Abstract

Serum androgens as well as their precursors and metabolites decrease from the age of 30-40 yr in women, thus suggesting that a more physiological hormone replacement therapy at menopause should contain an androgenic compound. It is important to consider, however, that most of the androgens in women, especially after menopause, are synthesized in peripheral intracrine tissues from the inactive precursors dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) of adrenal origin. Much progress in this new area of endocrine physiology called intracrinology has followed the cloning and characterization of most of the enzymes responsible for the transformation of DHEA and DHEA-S into androgens and estrogens in peripheral target tissues, where the locally produced sex steroids are exerting their action in the same cells in which their synthesis takes place without significant diffusion into the circulation, thus seriously limiting the interpretation of serum levels of active sex steroids. The sex steroids made in peripheral tissues are then inactivated locally into more water-soluble compounds that diffuse into the general circulation where they can be measured. In a series of animal models, androgens and DHEA have been found to inhibit breast cancer development and growth and to stimulate bone formation. In clinical studies, DHEA has been found to increase bone mineral density and to stimulate vaginal maturation without affecting the endometrium, while improving well-being and libido with no significant side effects. The advantage of DHEA over other androgenic compounds is that DHEA, at physiological doses, is converted into androgens and/or estrogens only in the specific intracrine target tissues that possess the appropriate physiological enzymatic machinery, thus limiting the action of the sex steroids to those tissues possessing the tissue-specific profile of expression of the genes responsible for their formation, while leaving the other tissues unaffected and thus minimizing the potential side effects observed with androgens or estrogens administered systemically.

Postmenopausal Serum Sex Steroids and Risk of Hormone Receptor–Positive and -Negative Breast Cancer: a Nested Case–Control Study

“…The specific role that androgens may have in breast cancer etiology has long been debated (33,38). One concept is that androgens (androstenedione and testosterone), convert into estrogens (estrone and estradiol, respectively), thus stimulating the growth and division of breast cells (33).…”

Age at first childbirth and oral contraceptive use are associated with risk of androgen receptor-negative breast cancer: the Malmö Diet and Cancer Cohort

“…Androgens exert stimulating effects directly on breast cancer cells through binding to the AR, as well as indirect effects through androgen aromatization into estrogens, which in turn bind to the ER (19)(20)(21). The levels of circulating androgens are most likely affected by hormonal factors, such as reproductive history and anthropometric measures (22,23).…”

Deficiência androgênica na mulher

“…For this reason, many authors support increasing testosterone prescriptions, despite a lack of consensus regarding their efficacy for sexual dysfunction 6 . Furthermore, it should also be taken into account that prescribing testosterone without estrogens, does not provide benefits in terms of libido or coital frequency, irrespective of the route of administration 7 .…”