A DES (diethylstilbestrol) Task Force formed in February by the Office of the Assistant Secretary for Health, examined the health effects of DES in pregnancy. This report is an outline of the Task Force’s recommendations.
Physicians should advise women to whom they prescribe the drugs of their exposure and of the need for follow-up medical care for themselves and their offspring. Physicians are also to provide patients inquiring of possible past DES exposure, complete and accurate information whenever possible, and such information should be provided free of charge.
The incidence of clear cell adenocarcinoma for DES-exposed daughters is between 1.4/100 to 1.4/10,000. Periodic examination, rather than active therapeutic intervention (e.g., surgery) is recommended for patients with adenosis. For asymptomatic DES daughters, periodic screening examinations should start at age 14 or at menarche; vaginal bleeding/discharge should be promptly evaluated. Hystersosalpingography should not be used as a routine screening procedure in DES daughters but should be reserved for cases of repeated pregnancy loss or infertility.
Asymptomatic DES mothers should have routine screening (e.g., annual pelvic exam including bimanual palpation and Pap smear; breast exam) appropriate for women with no prior estrogen exposure.
DES exposed males have been known to have:
history of cryptochirdism;
and sperm abnormalities (low sperm counts, decreased motility).
DES males should have physical examination, appropriate medical follow-up or corrective measures, as the case may be.
Use of DES postcoital contraception should be limited to situations where the fully informed patient or her physician deems that there is no alternative.
Induction of urogenital anomalies and some tumors in the progeny of mice receiving diethylstilbestrol during pregnancy, Clinical toxicology, NCBI PubMed, PMID: 37020, 1979 Mar.
Journal of Endocrinological Investigation, June 2003
Cryptorchidism is the most frequent developmental abnormality in boys, present in more than 1% of infants above three months of age. It is associated with an increased risk of infertility and testicular cancer. The etiological quest is often disappointing, except in bilateral cases or associated malformations. Recent focus is on genetic and environmental aspects.
Animal models have revealed the role of genes encoding for proteins implicated in testicular migration (InsI3, Hoxa 10), but in humans results are less convincing. While some degree of endogenous hormonal abnormality is suspected in some patients, the endocrine disruptor hypothesis is also tested. It is unclear whether the incidence of cryptorchidism has really increased, or whether there is only a better screening for this condition. However, other male reproductive problems, such as subfertility, hypospadias and testicular cancer seem on the rise. This secular trend suggests the possible in utero impact of hormonally active environmental factors, such as pesticides with estrogenic or antiandrogenic effect, and is consistent with the increased risk of cryptorchidism observed in the sons of mothers exposed to diethylstilbestrol during pregnancy.
From a therapeutic point of view, there is an agreement that the correction of cryptorchidism is needed, but there is controversy on the best medical and/or surgical approach and on the optimal timing. There is a recent trend in proposing early therapeutic intervention, before 1 yr of age, in the hope of improving fertility; however, there is no proof that such a strategy can reduce the risk of testicular cancer.
Update on cryptorchidism: endocrine, environmental and therapeutic aspects NCBI PubMed PMID: 12952375, 2003 Jun.
In rodents, administration of DES during the second half of gestation resulted in a drastic reduction of Insl3 gene expression and testosterone levels, even though the expression of Sf-1 was unaltered
2000 Study Abstract
Male sexual differentiation relies upon testicular secretion of the hormones testosterone, Mullerian inhibiting substance, and insulin-3 (Insl3).
Insl3 is responsible for testicular descent through virilization and outgrowth of the embryonic gubernaculum.
In mouse, prenatal exposure to 17beta-estradiol and the nonsteroidal synthetic estrogen diethylstilbestrol (DES) disturbs the endocrine balance, causing demasculinizing and feminizing effects in the male embryo, including impaired testicular descent (cryptorchidism).
In the current study, we show that maternal exposure to estrogens, including 17alpha- and beta-estradiol, as well as DES, specifically down regulates Insl3 expression in embryonic Leydig cells, thereby providing a mechanism for cryptorchidism.
These experiments may have implications for the widespread use of estrogenic substances in agriculture and the environment.
Sources and more information
A molecular basis for estrogen-induced cryptorchidism, Developmental biology, NCBI PubMed PMID: 10926772, 2000 Aug.
Cryptorchidism in mice mutant for Insl3 featured image credit media.nature.
DES exerts its anti-androgen effects mainly through classical ER signaling, particularly via ERα
2007 Study Abstract
Failure of the testes to descend into the scrotum (cryptorchidism) is one of the most common birth defects in humans.
In utero exposure to estrogens, such as 17beta-estradiol (E2) or the synthetic estrogen diethylstilbestrol (DES), down-regulates insulin-like 3 (Insl3) expression in embryonic Leydig cells, which in turn results in cryptorchidism in mice.
In humans, the offspring of pregnant women treated with diethylstilbestrol (DES), exhibited an increased incidence of cryptorchidism and hypoplastic testes. In rodents, we and others have shown that administration of DES or E2 during the second half of gestation resulted in a drastic reduction of Insl3 gene expression and testosterone levels, even though the expression of Sf-1 was unaltered.
To identify the molecular mechanism whereby xenoestrogens block Insl3 gene transcription, we performed a microarray analysis of wild-type or estrogen receptor (ER) alpha-mutant testes exposed in utero to pharmacological doses of E2 or DES.
Six and 31 genes were respectively down-regulated and up-regulated by estrogen exposure (> or =4-fold). All six genes down-regulated by estrogen exposure, including Insl3 and the steroidogenic genes steroidogenic acute regulatory protein and cytochrome P450 17alpha-hydroxylase/17,20-lyase, were done so by an ERalpha-dependent mechanism. In contrast, up-regulation was mediated either by ERalpha for 12 genes or by an independent mechanism for the 19 remaining genes. Finally, we show that Insl3 gene expression and testicular descent were not affected by in utero exposure to E2 or DES in ERalpha mutant mice, whereas absence of ERbeta did not influence the effect of these estrogens.
Collectively, these data demonstrate that xenoestrogens inhibit the endocrine functions of fetal Leydig cells through an ERalpha-dependent mechanism.
Sources and more information
Full text (free access) : Estrogen receptor alpha is a major contributor to estrogen-mediated fetal testis dysgenesis and cryptorchidism, Endocrinology, NCBI PubMed PMID: 17673513, 2007 Nov.
Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities, The Journal of urology, NCBI PubMed PMID: 37351, 1979 Jul.
Epididymal cysts and/or hypoplastic testes have been found in 31.5 per cent of 308 men exposed to diethylstilbestrol in utero, compared to 7.8 per cent of 307 placebo-exposed controls.
Analyses of the spermatozoa have revealed severe pathological changes (Eliasson score greater than 10) in 134 diethylstilbestrol-exposed men (18 per cent) and 87 placebo-exposed men (8 per cent).
Further investigation of the 26 diethylstilbestrol-exposed men with testicular hypoplasia has revealed that 65 per cent had a history of cryptorchidism.
Only 1 of the 6 placebo-exposed controls with testicular hypoplasia had a history of testicular maldescent.
Although none of our Diekmann’s lying-in study group has had carcinoma to date one must keep in mind the reported increased risk of testicular carcinoma in testes that are or were cryptorchid.
A 25-year-old man who was not part of the study group was treated recently by us for a testicular carcinoma ( mixed anaplastic seminoma plus embryonal cell carcinoma) and he had a history of diethylstilbestrol exposure in utero and cryptorchidism.