Key Words: clomiphene citrate, Hypospadias, ovulation induction.

In this year (2006), nearly 45 years will have passed after the first description of a 'chemically' induced ovulation with clomiphene citrate[1]. Over this period it has maintained a solid footing in reproductive medicine .Worldwide, clomiphene citrate is used for inducing ovulation[2], as it is the first-line therapy for physicians practicing general gynecology when initiating treatment of infertility due to ovulatory dysfunction[3,4].

Clomiphene Citrate is a synthetic, non-steroidal estrogen receptor agonist/antagonist. This anti-estrogenic activity is the mechanism of its action in inducing ovulation. Structurally clomiphene citrate is related to diethylstilbestrol. It has a racemic mixture of two 'isomers', zuclomiphene and enclomiphene. The active isomer is enclomiphene, (trans-isomer with only anti-oestrogenic activity), and has a short half life. On the opposite side, the relatively inactive one (zuclomiphene), has a very long half life. As a result, the half life of clomiphene citrate is about 5 - 7 days, but its metabolites have been found in blood samples on day 22 of the menstrual cycle, and in the faeces up to 6 weeks after administration[5]. In addition, clomiphene citrate displays a tendency for prolonged nuclear receptor occupancy[6] upon repetitive administration ,and this has given rise to speculations about its toxicity and possible teratogenic effects[7].

The extensive experience, gained over a long period of prescribing clomiphene citrate, makes it safe to use ,however , this conclusion is empirical rather than a result of properly designed studies[8], especially in view of the teratogenic and toxic effects that have been described in animals. The aim of our study was to assess the risk of hypospadias among males conceived following the use of clomiphene citrate as an ovulation induction drug.

A retrospective survey of all cases of hypospadias in the period between the 1st of January 1999 until 31 of December 2003. These cases were collected from the Obstetric-Gynecological Department and the Neonatal Care Unit in the Royal Medical Services Hospitals in south of Jordan. All data was collected from three sources:

• Birth registry in each hospital which contains information on the mother, date and time of delivery , assurance number, the mode of delivery, delivery outcome (male, female and any congenital abnormalities ), midwife name and any comments.
• Neonatal care unit registry also contains information about the newborn taken by the pediatrician and staff nurse.
• Pharmacy registries in selected hospitals which contain data on all prescriptions for clomiphene citrate (Clomid ). All mothers with epilepsy, diabetes and those diagnosed with pre-eclampsia were excluded from this study, as it has been associated with increased risk for hypospadias. Also mothers other than Jordanians (immigrant ) were excluded from this study as some countries of origin (e.g. Turkish) have an increased risk for hypospadias.

In this population based case-control study , odds ratios were calculated for the probability of a genital anomaly (hypospadias) after exposure to clomiphene citrate using conditional logistic regression analysis adjusted for maternal age and birth order (95% confidence intervals).

Of the 27,329 male newborns that were enrolled in this population based case - control study, we found a total of 104 cases of hypospdias in all hospitals. Cases were distributed into two groups; those who conceived after ovulation induction by clomiphene citrate 0.37% (19/5119), and those, control groups, who conceived spontaneously 0.38% (85/22210).

Odds ratios were calculated for the probability of a genital anomaly (hypospadias) after exposure to clomiphene citrate using conditional logistic regression analysis adjusted for maternal age and birth order, and it was 0.0 for hypospadias associated with clomiphene citrate. ( see Table I).

The analysis of these results revealed that, there was no significant differences between the two groups in the incidence of hypospadias (0.37%) compared with (0.38%) in the control one.

Thus fear of hypospadias in women conceived after clomiphene citrate, or who used it incidentally during early pregnancy can be reduced towards the null, as seen in figure -1

Embryologic formation of the penile urethra takes place between 9 and 12 weeks after ovulation and depends on the secretion of testosterone by the fetal testes[9], and by 12-14 weeks gestation, differentiation of internal genital ducts and external genitalia along either male or female is complete[10], therefore, we considered exposure during the 1st trimester to be most important.

Hypospadias is a developmental anomaly considered one of the most prevalent urogenital malformations, the etiology of which, is still not clearly understood11,and affects 1 in 250 male newborns[12].

In 2002, an increased risk of hypospadias was reported for sons of women exposed to diethyl-stilbestrol (DES) in utero, which is a non-steroidal estrogen, and nowadays it is no longer used in obstetric patients of childbearing age. Because of the fact that clomiphene citrate and DES are related structurally, the latter was reported to be responsible for the appearance of clear cell adenocarcinoma of the vagina of female offsprings[13], and the development of benign epididymal cysts in DES-exposed men [14-19] , fear about clomiphene citrate teratogenicity and concern has been raised over a possible increase in disorders of the male reproductive tract, specifically hypospadias.

Fortunately, clomiphene citrate is a well tolerated drug (in 1997 only one of 113 patients dropped out because of drug side-effects in a study by Kousta et al [20]). According to our knowledge of current literature, the potential effects of clomiphene on the fetus have been investigated in animal studies, while others (human studies) investigate the effect of sex hormones exposure to the urogenital system as shown in Table II.

The overall clinical experience up till now indicates that the use of clomiphene citrate is associated with an incidence of birth defects similar to that observed in the general population[20,21]. Similar observation was reported in our study in which there was no significant differences between the two groups in the incidence of hypospadias (0.37%) compared with (0.38%) in the control one.

At the present time, despite the fact that all collected data was based on routine daily records, and while the comparison must be interpreted cautiously in light of possible selection bias, it may be concluded that clomiphene citrate is not associated with any increased risk of hypospadias.

In this study, we found that, there was no association between clomiphene citrate and external genital malformation specifically Hypospadias. Thus, women exposed to clomiphene citrate after conception, may be assured there is no increased risk of urogenital anomalies (Hypospadias).