US EPA

8172654 

Journal Article 

Dehydroepiandrosterone (DHEA) as potential hormone replacement therapy 

Labrie, F 

2001 

8 

5 

317-322 

English 

A new understanding of the endocrinology of menopause is that women, at menopause, are not lacking only estrogens resulting from cessation of ovarian activity but have also been progressively deprived for a few years of androgens and some estrogens originating from adrenal dehydroepiandrosterone (DHEA). In fact, serum DHEA decreases by about 60% between the maximal levels seen at 30 years of age to the age of menopause. This decreased secretion of DHEA and DHEA-S by the adrenals is responsible for a parallel decrease in androgen and estrogen formation in peripheral tissues by the steroidogenic 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 of each peripheral target tissue from the adrenal precursor DHEA. These androgens and estrogens exert their action in the same cells where their synthesis takes place and they are released from these target cells and then measurable in the circulation as derivatives only after being inactivated. To further understand the effect of DHEA in women, we have administered this steroid in post-menopausal women for 12 months. Such treatment resulted in increased bone formation and higher bone mineral density accompanied by elevated levels of osteocalcin, a marker of bone formation. Vaginal maturation was stimulated while no effect was observed on the endometrium. Predinical studies, on the other hand, have shown that, due to its predominant conversion into androgens, DHEA prevents the development and inhibits the growth of dimethylbenz(a)anthracene-induced mammary carcinoma in 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 DHEA on breast cancer is due to an androgenic effect of testosterone and dihydrotestosterone made locally from DHEA. When used as replacement therapy, DHEA is thus free of the potential risk of breast and uterine cancer while it stimulates bone formation and vaginal maturation and decreases insulin resistance. The combination of DHEA with a fourth generation SERM, such as EM-652, a compound having pure and potent antiestrogenic activity in the mammary gland and endometrium could provide major benefits for women at menopause (inhibition of bone loss and serum cholesterol and triglyceride levels) with the associated major advantages of preventing breast and uterine cancer. 

Androgens; Breast Cancer; DHEA; Estrogens; Intracrinology; Osteoporosis; Prevention; Uterine Cancer