In most cases, the cause of this birth defect is not fully understood. Treatment with hormones such as progesterone during pregnancy may increase the risk of hypospadias. Certain hormonal fluctuations, such as failure of the fetal testes to produce enough testosterone or the failure of the body to respond to testosterone, increase the risk of hypospadias and other genetic problems. Sometimes hypospadias is inherited.[citation needed]
There may also be an increased risk of hypospadias in infant males born to women of an advanced age or those who used in vitro fertilization (IVF) to conceive. The connection to IVF may be due to the mother's exposure to progesterone, a natural hormone, or to progestin, a synthetic form of progesterone, administered during the IVF process.[citation needed]
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 severe hypospadias a very mild form of intersex (under-virilization 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.[citation needed]
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 2008, it was suggested that maternal use of diethylstilbestrol, a synthetic estrogen, resulted in a 20-fold increase in prevalence of hypospadias[3] although a follow-up study showed the risk, though present, to be much lesser.[4]
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.[citation needed]
Genetic factors are likely involved in at least some cases, as there is about a 7% familial recurrence risk. A 2010 Article[5][6] found a 2.5 times increase in the condition for boys with a specific genetic defect that was carried on the X (maternally contributed sex) chromosome.
Rare iatrogenic urethral injuries similar to hypospadias after procedures such as surgery, catheterization, or circumcision have been reported.[citation needed]