Impact of Clomiphene Citrate on the Steroid Profile in Dysmetabolic Men with Low Testosterone Levels

Clomiphene citrate (CC) in male hypogonadism increases testosterone (T) and estrogen levels by stimulating pituitary gonadotropin release. Our group confirmed these hormonal changes in a randomized, cross-over, double-blind trial of CC versus placebo in addition to metformin, conducted in 21 obese dysmetabolic men with low T levels. However, we hypothesize that based on its mechanism of action, CC may directly or indirectly affect adrenal steroidogenesis. The aim of this sub-study was to better understand the changes in steroid levels and metabolism induced by CC treatment. We assessed 17 alpha -hydroxypregnelone (17 alpha OH-P5), dehydroepiandrosterone (DHEA), progesterone (P4), 17 alpha -hydroxyprogesterone (17 alpha OH-P4), androstenedione (A), T, dihydrotestosterone (DHT), estrone (E1), 17 beta -estradiol (E2), 11-deoxycortisol (11S), cortisol (F), and cortisone (E) by LC-MS/MS, and corticosteroid binding globulin (CBG) by ELISA, before and after each treatment. In addition, free-F and steroid product/precursor ratios were calculated. We observed a significant change in serum levels induced by CC compared with placebo for 17 alpha OH-P4, DHT, T, E2, E1, F, E, and CBG, but not free-F. In addition, compared to placebo, CC induced higher 17 alpha OH-P4/P4, E2/E1, 17 alpha OH-P4/17 alpha OH-P5, A/17 alpha OH-P4, T/A, E1/A, F/11S, and F/E ratios. Therefore, besides the CC stimulating effect on testis steroidogenesis, our study showed increased F, E, but not free-F, levels, indicating changes in steroid metabolism rather than adrenal secretion stimulation. The steroid profiling also revealed the CC stimulation of the Delta 5 rather than the Delta 4 pathway, thus indicating considerable testicular involvement in the increased androgen secretion.

Automated summary

The study investigated the effects of CC treatment on steroid hormone levels and metabolism in males, finding that CC influenced multiple steroid levels and promoted androgen secretion, while also indicating a decrease in adrenal activity. These results offer insights into the mechanisms of CC action and its impact on steroid metabolism.