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Pure Appl. Chem., 2003, Vol. 75, No. 11-12, pp. 2023-2038

Male reproductive disorders and the role of endocrine disruption: Advances in understanding and identification of areas for future research

R. M. Sharpe and N. E. Skakkebaek

MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The University of Edinburgh Academic Centre, 49 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4SB, UK; University Department of Growth & Reproduction, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen OE,


Abstract: This review addresses whether there is a secular increasing trend in male reproductive developmental disorders (cryptorchidism, hypospadias, testis cancer, low sperm counts), and highlights the limitations of available data and how these issues are being addressed. These disorders are considered to represent a syndrome of disorders [testicular dysgenesis syndrome (TDS)] with a common origin in fetal life, and in which "endocrine disruption" plays a central role. The potential involvement of environmental estrogens in the etiology of these disorders is reviewed in light of new understanding about the pathways and dose-effect relationships of estrogen action on male reproductive development. Several new pathways of estrogen action have been identified, including suppression of the production of testosterone and insulin-like factor-3 by fetal/neonatal Leydig cells and suppression of androgen receptor expression in androgen target tissues. It is tentatively concluded that identified environmental chemicals are unlikely to activate these pathways because of their intrinsically weak estrogenicity. However, chemicals that may alter endogenous estrogen production, bioavailability, or inactivation represent a new focus of concern. Additionally, environmental chemicals that alter endogenous levels of androgens in the rat fetus (certain phthalates) induce a similar collection of disorders to TDS. Whether human exposure to such compounds might contribute to TDS remains to be shown, but studies in animals should help to define susceptible pathways for induction of TDS.