Hypospadias pathophysiology

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Steven C. Campbell, M.D., Ph.D.


Most hypospadias are sporadic, without inheritance or family recurrence. For most cases, no cause can be identified though a number of hypotheses related to inadequate androgen effect, or environmental agents interfering with androgen effect, have been offered. Among the suspected environmental agents have been various chemicals, sometimes termed endocrine disruptors, that interact with steroid receptors. Putative endocrine disruptors include phthalates, DDT, and PCB. A recent questionnaire study of mothers who bore infants with hypospadias reported fivefold higher risk association with vegetarian diet (with plant phytoestrogens the hypothetical link) during pregnancy, and weaker associations with iron supplementation or influenza during early pregnancy [1]. The associations are as yet uncorroborated by additional surveys or other methods.

Prenatal testosterone, converted in the genital skin to dihydrotestosterone, causes migration of skin fibroblasts to fully enclose the urethral groove in fetal males, normally resulting in an enclosed penile urethra by the second trimester of pregnancy. Failure of adequate prenatal androgen effect is therefore thought to be involved in many cases, making hypospadias a very mild form of intersex (undervirilization of a genetic male). Since postnatal androgen deficiency can only be demonstrated in a minority of cases, it has been proposed that transient deficiency of testosterone can occur during critical periods of fetal genital development, due to elevation of anti-müllerian hormone or more subtle degrees of pituitary-gonadal dysfunction. More recently, abnormalities of transcription factors have been proposed.

In animals, several teratogenic drugs or chemicals can cause hypospadias by interfering with androgen action in the embryo. Speculation that environmental agents-- endocrine disruptors-- might be interfering with human hormone systems has not been proven. The agents that have caused hypospadias in a small number of boys have been maternal use of synthetic progestins and finasteride in the first two trimesters of pregnancy. In 2002, it was suggested that maternal use of diethylstilbestrol, a synthetic estrogen, resulted in a 20-fold increase in prevalence of hypospadias[2] although a followup study showed the risk, though present, to be much lesser. [3]

In a minority of cases a postnatal deficiency of, or reduced sensitivity to, androgens (testosterone and dihydrotestosterone) can be demonstrated. These are often associated with a chordee, and in severe cases a residual perineal urogenital opening and small phallus. This combination of birth defects is referred to as pseudovaginal perineoscrotal hypospadias and is part of the spectrum of ambiguous genitalia. Treatment with testosterone postnatally does not close the urethra.

Genetic factors are likely involved in at least some cases, as there is about a 7% familial recurrence risk.

Rare iatrogenic urethral injuries similar to hypospadias after procedures such as surgery, catheterization, or circumcision have been reported.


  1. North, K. (Jaunary 2000). "A maternal vegetarian diet in pregnancy is associated with hypospadias". Brit. Jnl. Urol. BJU International. 85 (1): 107–113. doi:10.1046/j.1464-410x.2000.00436.x. Retrieved 2007-03-09. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  2. Klip, H. (March 2002). "Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study". The Lancet. 359 (9312): 1081–1082. PMID 11943257. Retrieved 2007-04-24. Unknown parameter |coauthors= ignored (help)
  3. Brouwers, MM. (March 2006). "Hypospadias: a transgenerational effect of diethylstilbestrol?". Hum. Reprod. 21 (3): 666–669. PMID 16293648. Retrieved 2007-04-24. Unknown parameter |coauthors= ignored (help)

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