Impact Of Anogenital Distance On Hypospadias

Relevance of anogenital distance. AGD is the distance from the center of the anus to the external genitals, the base of the scrotum or penis in male and vagina in female. It develops from the growth and maturity of the genital tubercle, genital swellings, and cloacal membrane into the penis, scrotum and anus in male or clitoris, labia majora and anus in female. It is sexually dimorphic in man and other mammals and has been used as a standard method to determine gender in newborn rats. Normal males have AGD that is twice as long as that of normal females due to the difference on the impact of androgen on different genders. AGD, a sensitive and quantitative biomarker is used for studies of animal reproductive toxicology to determine intra uterine exposure to androgen and anti-androgen.

In fact the U. S Agency for Environmental Protection has identified AGD as one of the sensitive end point for reproductive toxicology in humans. This is because the development of external genitalia and AGD is regulated by androgen, and the amount of androgen available for fetal tissue development and growth can be interrupted by some endocrine disrupting chemicals that act as antiandrogens. Therefore, AGD at birth acts as a true reflection of prenatal androgenic status. Longer anogenital distance has been recorded in girls with congenital adrenal hyperplasia and multi-follicular ovaries when compared to normal female variants. These further support the fact that perineal growth and anogenital length is a hormone dependent process. Researchers have highlighted that measurement of AGD in humans provides a noninvasive method to predict neonatal and adult reproductive disorders17,28 and can be clinically useful in assessment of both male and female anomalies.

Over the years, AGD has been clinically utilized to monitor various congenital and acquired reproductive pathologies in human. Reports of shorter AGD in male infants prenatally exposed to environmental chemicals such as phthalates, bisphenol A, and dioxins support the use of this measurement as a biomarker of endocrine disruption in humans. Some series have shown that male children with genital anomalies like hypospadias and cryptorchidism have decreased anogenital length. Recent studies recorded that anogenital length appears to reflect the spermatogenic potential of the testes. The ability to father a child has been shown to correlate with anogenital distance and men with short AGD were prone to infertility or sub-fertilit, while longer anogenital length predicted a good reproductive potentials in men. Also AGD offered insight into the intrinsic function of the testis and may help clinicians to determine and select men more likely to benefit from varicocelectomy38. Also some studies observed that reduced anogenital length in male adults may be associated with increased risk of cancer of the prostate. Similarly, some authors have demonstrated positive correlation between penile length and AGD, implying that AGD can be used as a measure of genital development in males. In some rural areas in developing countries, mothers take herbal concoctions during pregnancy and scientists have shown that some of these herbs have androgenic activities. Asafo-Agyei et al found that AGD was significantly increased in male babies whose mothers took herbs during pregnancy.

There was also an increment in AGD in female counterparts but the increment was not statistically significant. Health workers with limited medical training as obtained in rural areas can suspect female infant virilization by dictating increased female AGD. Routine measurement of AGD in all neonates may be a helpful noninvasive tool for early detection of disorders of sex development. Correlation between anogenital distance and hypospadiasLiN et al in one of his studies revealed that hypospadias and shortened AGD occurred in rats exposed to phthalates during early gestation. This is demonstrated as shorter AGD in human infants with hypospadias and cryptorchidism and in adult men with testicular dysfunction. In human, Gilboa et al prenatally assessed the correlation between anogenital distance and hypospadias in 52 fetuses and found out that there was significantly shorter prenatal anogenital distance in fetuses with isolated hypospadias compared with the normal population. He observed that shorter AGD in fetuses correlated with objective sonographic parameter for prenatal diagnosis of hypospadias and can help in counseling of future parents on abnormal male external genitalia of their expected offspring64. Hsieh et al measured AGD under anesthesia in 32 boys with cryptorchidism, 47 boys with hypospadias and 40 controls undergoing surgery for other urological conditions. They noticed that AGD was reduced in boys with hypospadias and cryptorchidism. However, the subject groups were unmatched for age in this evaluation28.

In their subsequent study, they measured AGD in an age-matched racially homogenous sample of boys within 2 years of age. 26 of these boys had hypospadias while the other 26 had normal genitals. They equally noted that AGD was significantly shorter in boys with hypospadias. In another analysis by Thankamony et al, AGD was measured in 639 boys less than 2 years of age; 81 of them had hypospadias, 71 had cryptorchidism while the remaining 487 were healthy boys used as control. They found out again that AGD was notably shorter in boys with hypospadias when compared to those with cryptorchidism and control group. Furthermore, they observed a progressive reduction in AGD with increase in severity of hypospadias, but this was not statistically significant, probably due to a small group of patients with posterior hypospadias in the study sample35. Singal et al in a three-year period studied a larger population size of 453 pre-pubertal boys between the ages of 5 months to 14 years. 180 of the boys had hypospadias and the remaining 272 boys had normal genitalia. They noted too that AGD was remarkably shorter in boys with hypospadias.

The study also observed a progressive reduction in AGD with increase in severity of hypospadias. Similarly, Cox et al compared 31 boys with normal genitalia who had circumcision and 59 boys with hypospadias by measuring their anogenital distance under anesthesia. The hypospadias patients were divided into two groups based on severity: 40 patients in group 1 (distal penile, subcoronal and glanular) and 19 patients in group 2 (perineal, penoscrotal and midshaft). They as well observed that more severe types of hypospadias were associated with shorter anogenital distance. Most importantly, they discovered that the severity of hypospadias in 7 patients was re-classified after straightening the penis; four of the seven patients had more proximal hypospadias while the remaining three had more distal type of hypospadias after release of chordee39. However, the preoperative and intraoperative severities of hypospadias were not independently correlated with AGD in this study.