Human Reproduction, Vol. 17, No. 2, 520-521,
February 2002
© 2002 European Society of Human Reproduction and Embryology
Letters to the editor |
Myths about endocrine disruption and the male reproductive system should not be propagated
Department of Epidemiology and Public Health Imperial College School of Medicine St Marys Campus, Norfolk Place London W2 1PG, UK E-mail: m.joffe{at}ic.ac.uk
Dear Sir,
A recent paper (Thayer et al., 2001
) states that each year in the USA and Europe, the number of women who continue taking the contraceptive pill during undetected early pregnancy is `approximately 2 million' (abstract) and `between 2 and 5% of 55 to 60 million' (introduction). A moment's reflection would show that this cannot be true: there are about 10 million births annually in these two regions (the exact number depends on the definition of Europe), so this would constitute around 20% of all pregnancies. The reference given for this statement (Smithells, 1981) is not only 20 years old, its assertion of the figure of 2–5% contains no supporting evidence. Moreover, the denominator given, 55–60 million, must refer to the number of women thought to be taking the oral contraceptive pill, not the number of women who conceive each year. The impression given grossly inflates the potential numerical scale of any problem that could exist from embryonic or fetal exposure to ethinyl estradiol (or other estrogen) contained within the pill. Let us hope that this does not become propagated uncritically in the future literature.
For this is what has happened in relation to the evidence of the relationship between DES (diethylstilboestrol) and impairments of the male reproductive system. The statement that hypospadias is one of the endpoints associated with in-utero DES exposure is encountered later in the paper (Thayer et al., 2001), and in countless other papers, as well as literature reviews and research proposals. In the present instance, three references are given for the consequences of DES exposure on the developing male (Bibbo et al., 1977; Stillman, 1982; Giusti et al., 1995). However, only the second of these mentions hypospadias, and does not consider that it merits inclusion in the summary table of male effects; its mention is in the context of reporting the findings of an earlier paper (Henderson et al., 1976), and it is the latter paper that has been widely misquoted: one case of hypospadias and nine of urethral stenosis have entered the literature as 10 cases of hypospadias. In view of the role of hypospadias as part of the `testicular dysgenesis syndrome' (Skakkebaek et al., 2001), this is an important detail.
The DES tragedy has been repeatedly cited as evidence that environmental chemicals with estrogenic activity may underlie a possible increase in the manifestations of the testicular dysgenesis syndrome (Toppari et al., 1995). If that were true, DES exposure would be a perfect test: it is highly potent, was given in large doses to a large number of pregnant women, in many instances early enough to coincide with male reproductive development, and the consequences have been studied in randomized controlled trials. The effects would be expected to be larger and clearer than those of environmental chemicals with far lower potency and exposure levels than pharmaceutical-dose DES (Safe, 1995).
Of the four endpoints of the testicular dysgenesis syndrome, only cryptorchidism is clearly linked to DES (Henderson et al., 1976; Bibbo et al., 1977; Stillman, 1982; Giusti et al., 1995). Sperm density has been found to have an association with DES exposure in some studies (Bibbo et al., 1977; Gill et al., 1979; Stillman, 1982) but not others (Vessey et al., 1983), but even when present, its magnitude was only comparable with the fall observed in single-centre studies with good data, e.g. Paris (Auger et al., 1995). Testicular cancer may be associated with intra-uterine DES exposure, with a relative risk estimate possibly as high as 2.0 (Toppari et al., 1995)—smaller than the observed rise in age-specific incidence observed in a large number of countries in recent decades (Pearce et al., 1987; Stone et al., 1991; Adami et al., 1994)—but not all reviews agree that a link is present (US National Cancer Institute, 1993).
Although the DES episode is often cited in support of the idea that estrogens are implicated in the testicular dysgenesis syndrome, it is actually rather strong evidence against (Joffe, 2001). It is time to stop propagating this myth.
References
Adami, H-O., Bergstrom, R., Mohner, M. et al. (1994) Testicular cancer in nine northern European countries. Int. J. Cancer, 59, 33–38.[Web of Science][Medline]
Auger, J., Kunstmann, J.M., Czyglik, F. et al. (1995) Decline in semen quality among fertile men in Paris during the past 20 years. N. Engl. J. Med., 332, 281–285.
Bibbo, M., Gill, W.B., Azizi, F. et al. (1977) Follow-up study of male and female offspring of DES-exposed mothers. Obstet. Gynecol., 49, 1–8.[Web of Science][Medline]
Gill, W.B., Schumacher, G.F.B., Bibbo, M. et al. (1979) Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities. J. Urol., 122, 36–39.[Web of Science][Medline]
Giusti, R.M., Iwamoto, K. and Hatch, E.E. (1995) Diethylstilbestrol revisited: a review of the long-term health effects. Ann. Int. Med., 122, 778–788.
Henderson, B.E., Benton, B., Cosgrove, M. et al. (1976) Urogenital tract abnormalities in sons of women treated with diethylstilbestrol. Pediatrics, 58, 505–507.[Abstract]
Joffe, M. (2001) Are problems with male reproductive health caused by endocrine disruption? Occ. Env. Med., 58, 281–288.
Pearce, N., Sheppard, R.A., Howard, J.K. et al. (1987) Time trends and occupational differences in cancer of the testis in New Zealand. Cancer, 59, 1677–1682.[Web of Science][Medline]
Safe, S.H. (1995) Environmental and dietary estrogens and human health: is there a problem? Environ. Health Perspect., 103, 346–351.[Web of Science][Medline]
Skakkebaek, N.E., Rajpert-De Meyts, E. and Main, K.M. (2001) Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum. Reprod., 16, 972–978.
Smithells, R.W. (1981) Oral contraceptives and birth defects. Develop. Med. Child Neurol., 23, 369–383.[Web of Science][Medline]
Stillman, R.J. (1982) In utero exposure to diethylstilbestrol: adverse effects on the reproductive tract and reproductive performance in male and female offspring. Am. J. Obstet. Gynecol., 142, 905–921.[Web of Science][Medline]
Stone, J.M., Cruickshank, D.G., Sandeman, T.F. et al. (1991) Trebling of the incidence of testicular cancer in Victoria, Australia (1950–1985). Cancer, 68, 211–219.[Web of Science][Medline]
Thayer, K.A., Ruhlen, R.L., Howdeshell, K.L. et al. (2001) Altered prostate growth and daily sperm production in male mice exposed prenatally to subclinical doses of 17
-ethinyl oestradiol. Hum. Reprod., 16, 988–996.
Toppari, J., Larsen, J.C., Christiansen, P. et al. (1995) Male reproductive health and environmental chemicals with estrogenic effects. Danish Environmental Protection Agency, Copenhagen.
US National Cancer Institute. SEER cancer statistics review: 1973–1990. (1993) In Miller, B.A., Ries, L.A.G., Hankey, B.F. et al. (eds.) No. 93–2789. National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Vessey, M.P., Fairweather, D.V., Norman-Smith, B. et al. (1983) A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy: long-term follow-up of mothers and their offspring. Br. J. Obstet. Gynaecol., 90, 1007–1017.[Web of Science][Medline]
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