Diet and exercise results in an increased testosterone, while addition of enclomiphene citrate significantly increases free-testosterone and improves lean body mass

Introduction: Clomiphene citrate is a compound which has been used for 40+ years for ovulation induction in women and has been used off-label for elevating Testosterone (T) in men. Enclomiphene (one of two isomers of Clomiphene) is currently in development by Repros Therapeutics for treatment of secondary hypogonadism in men. It has been shown that enclomiphene is an estrogen antagonist that raises endogenous production of T and that zuclomiphene (the second isomer) is inactive with regards to T elevation. The objective of this study seeks to show secondary hypogonadism is reversible with weight loss and raising endogenous testosterone provides benefit while attempting to diet and exercise. Materials and Methods: Study ZA-205 was a randomized, double blind, placebo-controlled, multi-center study of men with secondary hypogonadism which evaluated the effect of treatment with enclomiphene along with diet and exercise. Commercial diet (Nutrasystem; 1500 calories/day) ended at 6 months. A personal trainer was provided to each subject (3X/week) for 12 months. Obese subjects (BMI >30 and waist circumference 40 inches or more) between the ages of 18 and 60 had two assessments of T under 300ng/dL for randomization. 49 subjects were randomized at 5 sites. Results: Subjects meeting entry criteria had a mean screening T of 229ng/dL by commercial antibody based assay and/or 273ng/dL when T was assessed by LCMS. 33 subjects had T by LCMS less than 300ng/dL. Using the free-T equilibrium method of calculation, 36 subjects 73.5%) had free-T less than 64 pg/ml and the overall mean was 56 pg/ml. This interim report describes data collected at 6 months. Men in the placebo arm lost more weight, and an increase in T was seen. Enclomiphene arms gained lean mass while placebo arm lost lean mass. At baseline the majority of men had a mean free-T measured of 56.27 pg/ml, an indication of secondary hypogonadism. At 6 months the majority on men administered enclomiphene increased mean free-T to 129.03 pg/ml (12.5 mg enclomiphene 92.86) and 154.24 pg/ml (25 mg enclomiphene). Men administered placebo after 6 months had a mean free-T of 57.14 pg/ml. Conclusions: After 6 months of diet and exercise alone mean T increased in both groups. Subjects administered enclomiphene showed an increase of 61.5%, pooled data, and placebo subjects showed an increase of 28.2%. Interestingly, 5/14 (35.17%) of men administered placebo increased free-T to above 64 pg/ml. On the other hand, men administered enclomiphene showed an increased free-T to above 64 pg/ml in 13/14 (92.86) and 10/11 (90.91%) men, 12.5 and 25 mg enclomiphene, respectively. Enclomiphene, a compound shown to act as an estrogen antagonist blocking the action of estrogen on the pituitary produces highly increased concentrations of T and free-T in synergy with diet and exercise.