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,
Denmark
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.
*Report from a SCOPE/IUPAC project: Implication of
Endocrine Active Substances for Human and Wildlife (J. Miyamoto and
J.Burger, editors). Other reports are published in this issue,
pp. 1617-2615.
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