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 17α-hydroxypregnelone (17αOH-P5), dehydroepiandrosterone (DHEA), progesterone (P4), 17α-hydroxyprogesterone (17αOH-P4), androstenedione (A), T, dihydrotestosterone (DHT), estrone (E1), 17β-estradiol (E2), 11-deoxycortisol (11 S), 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 17αOH-P4, DHT, T, E2, E1, F, E, and CBG, but not free-F. In addition, compared to placebo, CC induced higher 17αOH-P4/P4, E2/E1, 17αOH-P4/17αOH-P5, A/17αOH-P4, T/A, E1/A, F/11 S, 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 Δ5 rather than the Δ4 pathway, thus indicating considerable testicular involvement in the increased androgen secretion.
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