Canadian Health: Hormone therapy
Hormone therapy
Oestrogens
Diethylstilboestrol
Diethylstilboestrol (DES) is a synthetic oestrogen with a chequered history. Between 1940 and 1970 it was given to approximately 2 to 4 million women in the USA and probably 10 000 women in the UK. DES was given prophylactically in threatened and recurrent abortion. It was also thought to be beneficial in the prophylaxis of pre-eclampsia (toxaemia of pregnancy), prematurity and perinatal mortality, although subsequent results showed this not to be the case. As a consequence of DES exposure, the female and even the male offspring of these women have a high incidence of reproductive tract malformations affecting both fertility and reproductive function. In addition, female offspring have 100 to 1000 times greater incidence of vaginal and cervical clear cell adenocarcinomas than normal. Pregnancy outcome is also adversely affected in daughters of exposed women, with an increased risk of premature labour, low birth weight and antepartum haemorrhage.
Fertility problems in DES-exposed daughters
In 1951-2, a double-blind controlled study of DES use in pregnancy was commenced at the Chicago Lying-in hospital. A group of 840 pregnant women were given DES and a second group of 806 women were given placebo. This study has allowed accurate long-term follow-up of the daughters of both DES-treated women and their controls, and 408 DESexposed daughters and 388 unexposed daughters have been contacted for ongoing study. The long-term influence on fertility was reviewed by Senekjian et ah. Of the total population, 207 exposed and 203 unexposed women had been trying to conceive. Primary infertility was reported by 33% of the exposed and 14% of non-exposed daughters. As
might be expected, the infertility in the exposed daughters was more likely to result from a cervical, uterine or tubal factor than in the non-exposed women. 
None of the infertile control women had abnormalities of the uterine cavity, whereas abnormalities were present in 46% of the DESexposed group. These abnormalities included T shaped or hypoplastic cavities, septate uteri, intrauterine adhesions and irregular uterine margins. Interestingly, tubal defects compatible with pelvic inflammatory disease appeared more common in DES-exposed daughters, although the reasons for this are unclear. Other studies have shown an increased incidence of ovulation defects and second trimester abortion in DES-exposed women. There is conflicting evidence about whether the incidence of endometriosis is increased. Ectopic pregnancies occur in 10 to 14% of DES daughters, presumably secondary to uterine or tubal abnormalities.
Fertility problems in DES-exposed sons
An equal number of male fetuses were exposed to DES during intrauterine life as exposed females. While most of the concern about DES exposure has centred on female offspring, a few studies have investigated males. Reproductive tract abnormalities and sperm defects occur in male offspring. A follow-up study of sons from the Chicago Lying-in hospital’s original double-blind study showed anatomical abnormalities in 25% of DES-exposed males compared with 7% in control males. The most common abnormalities were epididymal cysts, small testes and small penises. 
Severe pathological changes were noted in the semen analyses of 18% of DES-exposed males but only in 8% of control subjects, although in this study few men had attempted conception so fertility could not be determined. Another study reported reduced sperm concentration in DES-exposed offspring compared with a non-exposed group (66.4 million/ml versus 101.4 million/ml). Furthermore in this study, zona-free hamster egg penetration tests, in which human sperm are used to inseminate hamster eggs, were performed. This is a reasonable model of the interaction between human sperm and human eggs. They found that DES-exposed males had poorer results than controls, suggesting reduced fertility.
