DHEA and its transformation into androgens and estrogens in peripheral target tissues: Intracrinology

A new understanding of the endocrinology of menopause is that women, at men opause, are not only lacking estrogens resulting from cessation of ovarian activity but have also been progressively deprived for a few years of andro gens and some estrogens originating from adrenal DHEA and androstenedione ( 4-dione). In fact, serum DHEA decreases by about 60% between the maximal le vels seen at 30 years of age to the age of menopause. This decreased secret ion of DHEA and DHEA-S by the adrenals is responsible for a parallel decrea se in androgen and estrogen formation in peripheral tissues by the steroido genic enzymes specifically expressed in each cell type in individual target tissues. This new field of endocrinology, called intracrinology, describes the local synthesis of androgens and estrogens made locally in each cell o f each peripheral tissue from the adrenal precursors DHEA and 4-dione. Thes e androgens and estrogens exert their action in the same cells where their synthesis takes place and they are released from these target cells only af ter being inactivated. To further understand the effect of DHEA in women, D HEA has been administered in postmenopausal women for 12 months. Such treat ment resulted in increased bone formation and higher bone mineral density a ccompanied by elevated levels of osteocalcin, a marker of bone formation. V aginal maturation was stimulated, while no effect was observed on the endom etrium. Preclinical studies, on the other hand, have shown that, due to its predominant conversion into androgens, DHEA prevents the development and i nhibits the growth of dimethylbenz(a)anthracene-induced mammary carcinoma i n the rat, a model of breast cancer. DHEA also inhibits the growth of human breast cancer ZR-75-1 xenografts in nude mice. The inhibitory effect of DH EA on breast cancer is due to an androgenic effect of testosterone and dihy drotestosterone made locally from DHEA. When used as replacement therapy, D HEA is free of the potential risk of breast and uterine cancer, while it st imulates bone formation and vaginal maturation and decreases insulin resist ance. The combination of DHEA with a fourth generation SERM, such as EM-652 (SCH 57068), a compound having pure and potent antiestrogenic activity in the mammary gland and endometrium, could provide major benefits for women a t menopause (inhibition of bone loss and serum cholesterol levels) with the associated major advantages of preventing breast and uterine cancer. A wid ely used application of intracrinology is the treatment of prostate cancer where the testicles are blocked by an LHRH agonist while the androgens made locally in the prostate from DHEA are blocked by a pure antiandrogen. Such treatment, called combined androgen blockade, has led to the first demonst ration of a prolongation of life in prostate cancer.