Clomiphene administration for cases of nonobstructive azoospermia: a multicenter study

Clomiphene citrate is a well-established agent that has been empirically used in cases of idiopathic oligospermia. Clomiphene increases endogenous gonadotropin-releasing hormone secretion from the hypothalamus and gonadotropin hormone secretion directly from the pituitary and, thus, increases intratesticular testosterone concentration. Using intracytoplasmic sperm injection (ICSI), very few sperm may be required for fertilization. The objective of this study was to determine if the application of clomiphene citrate in males with nonobstructive azoospermia might produce sufficient sperm for ICSI, either by resulting in sperm identified in the ejaculate or by potentially improving outcomes of surgical testicular sperm extraction. Forty-two patients with nonobstructive azoospermia (age range, 25-39 years) from 3 international centers were evaluated with routine history, physical examination, and hormonal assessment. Initial testicular biopsy demonstrated maturation arrest in 42.9% and hypospermatogenesis in 57.1% of patients. Clomiphene citrate was administered, with the dose titrated to achieve serum testosterone levels between 600 ng/dL and 800 ng/dL, and semen analyses were performed at periodic intervals. In patients remaining azoospermic on semen analysis, surgical testicular biopsy and sperm extraction were performed. After clomiphene citrate therapy, 64.3% of the patients demonstrated sperm in their semen analyses ranging from 1 to 16 million sperm/mL, with a mean sperm density of 3.8 million/mL. Sufficient sperm for ICSI was retrieved by testicular sperm extraction in all patients, even though 35.7% remained azoospermic. Additionally, clomiphene citrate administration resulted in a statistically significant increase in testis biopsy patterns associated with greater likelihood of sperm obtained by surgical extraction (P < .05). We conclude that clomiphene citrate administration may result in sperm in the ejaculate of patients with nonobstructive azoospermia or the simplification of testis sperm retrieval. Surgeons may consider a course of clomiphene citrate administration prior to surgical sperm retrieval in patients with nonobstructive azoospermia.