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 25% contains no supporting evidence. Moreover, the denominator given, 5560 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, 3338.[ISI][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, 281285.
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, 18.[Abstract]
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, 3639.[ISI][Medline]
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Toppari, J., Larsen, J.C., Christiansen, P. et al. (1995) Male reproductive health and environmental chemicals with estrogenic effects. Danish Environmental Protection Agency, Copenhagen.
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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, 10071017.[ISI][Medline]
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