Pharmacologic and Environmental Endocrine Disruptors in the Pathogenesis of Hypospadias

a Review – Current environmental health reports, 2018



Endocrine disrupting chemicals (EDCs) potentially have a role in causing hypospadias malformation through modifiable in-utero exposure. Considering the emerging literature on the role of potential endocrine disrupting substances on the occurrence of hypospadias and the potential to inform public health efforts to prevent the occurrence of these malformations, we have summarized the current literature, identified areas of consensus, and highlighted areas that warrant further investigation.


Pharmaceuticals, such as diethylstilbestrol, progestin fertility treatments, corticosteroids, and valproic acid, have all been associated with hypospadias risk. Data on exposure to dichlorodiphenyltrichloroethane and hexachlorobenzene pesticides, as well as non-persistent pollutants, particularly phthalates, is less consistent but still compelling. Improving exposure assessment, standardizing sample timing to relevant developmental windows, using clear case identification and classification schemes, and elucidating dose-response relationships with EDCs will help to provide clearer evidence. Promising directions for future research include identification of subgroups with genetic hypospadias risk factors, measurement of intermediate outcomes, and study of EDC mixtures that will more accurately represent the total fetal environment.

Exogenous Sex Steroids

Estrogens were the first chemicals to be studied in the context of maternal exposure and hypospadias. The synthetic nonsteroidal estrogen, diethylstilbestrol (DES), is a known carcinogen formerly administered to pregnant women to prevent miscarriage prior to evidence of adverse health effects and a lack of efficacy for that indication.

An early cohort study conducted in the Netherlands identified four cases of hypospadias among 205 sons of women exposed to DES in utero (~ 2% prevalence) versus 8 cases out of 8729 sons of mothers without DES exposure (0.09% prevalence). This study observed a strong association (prevalence odds ratio (pOR) 21.3; 95% CI 6.5–70.1) between maternal in utero DES exposure and hypospadiac son.

In a US cohort study, maternal DES exposure was related to a higher but not statistically significant increase in risk of offspring hypospadias with ten cases per 2552 live births from exposed mothers and three cases per 1336 live births from unexposed mothers (pOR 1.7; 95% CI 0.4–6.8).

A case-control study surveying 834 mothers with 251 hypospadiac children observed that women exposed to DES in utero were nearly five times more likely to have infants with hypospadias (OR 4.9; 95% CI 1.1–22.3).

A French, multigenerational cohort study also observed a relation between maternal DES exposure during pregnancy and increased prevalence of hypospadias for the next two generations, suggesting that the underlying biological mechanism may be epigenetic

Thus, studies on DES raise the possibility of an association with hypospadias. While no longer prescribed, DES is similar in chemical structure with other xenobiotic compounds and thus, the epidemiologic findings are still of relevance. It is important to note, however, that the studies of DES exposure all suggest a possible epigenetic effect on the development of hypospadias in later generations. While DES is historically important and chemically relevant to this discussion, its effect may derive from interaction with the maternal oocyte rather than the developing male penis itself.


  • Pharmacologic and Environmental Endocrine Disruptors in the Pathogenesis of Hypospadias: a Review, Current environmental health reports, NCBI PubMed PMID: 30578470, 2018 Dec.
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2 Replies to “Pharmacologic and Environmental Endocrine Disruptors in the Pathogenesis of Hypospadias”

  1. Husband 68 was exposed to effects of DES through mother taking Stilboestral in 1955 following an earlier miscarriage.
    He was born with obvious urinary system malformations & had surgery to rectify within days of birth. He was later found to have a congenital heart defect (bicuspid leaflet of aortic valve). This was replaced by an artificial valve at age 40. At age 60 various cardiac malformations were implicated in need for arterial strengthening. At age 67 was diagnosed with dementia associated with diagnosis of Alzheimers. Lifelong depressive illness & effects.

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