DES drastically reduces Insl3 gene expression

image of Protein_INSL3

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.
  • Protein INSL3 featured image credit wikipedia.

DES exposure in utero associated with cryptorchidism, testicular hypoplasia and semen abnormalities

Severe pathological changes found in many DES Sons’ sperm.


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.

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