Combination therapy with clomiphene citrate and anastrozole appears to be safe and effective for hypoandrogenic subfertile males, according to a study published in BJU International

Clomiphene citrate is a selective estrogen receptor modulator that increases production of gonadotropin and indirectly stimulates androgen synthesis; it is associated with higher estradiol levels. Anastrozole is an aromatase inhibitor that reduces the conversion of testosterone to estradiol.

To evaluate safety and efficacy of this therapy, study authors gathered data on patients treated with the combination from 2014 to 2017. Patients’ total testosterone, bioavailable testosterone, estradiol, and testosterone:estradiol ratio were measured prior to combination therapy (clomiphene citrate alone) and at combination therapy follow-ups. Prostate-specific antigen, hematocrit levels, and treatment side effects were analyzed as part of the safety assessment. 

Data from the study (N=51) showed significant increases in total testosterone, bioavailable testosterone, and estradiol levels with just clomiphene citrate. Anastrozole was then given to patients with hyperestrogenemia (estradiol >50pg/mL) or testosterone:estradiol ratio <10. Patients treated with the combination therapy maintained therapeutic total testosterone and bioavailable testosterone levels and had normal estradiol levels and testosterone:estradiol ratio  . 

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The most common side effects associated with therapy was anxiety/irritability (N=5), followed by decreased libido (N=4) and elevated hematocrit (>54%) (N=2). 

The authors concluded that “combination therapy with [clomiphene citrate + anastrozole] is an effective and safe alternative for patients with elevated estradiol level or low testosterone:estradiol ratio.”

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