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.

中文翻译：

---

克罗米芬柠檬酸盐对低睾酮水平的代谢异常男性类固醇分布的影响

男性性腺功能减退症中的克罗米芬 (CC) 通过刺激垂体促性腺激素释放来增加睾酮 (T) 和雌激素水平。我们的小组在一项随机、交叉、双盲试验中证实了这些激素变化，该试验对 21 名 T 水平低的肥胖代谢障碍男性进行了 CC 与安慰剂和二甲双胍的对比。然而，我们假设基于其作用机制，CC 可能直接或间接影响肾上腺类固醇生成。该子研究的目的是更好地了解 CC 治疗引起的类固醇水平和代谢的变化。我们评估了 17α-羟基孕酮 (17αOH-P5)、脱氢表雄酮 (DHEA)、孕酮 (P4)、17α-羟基孕酮 (17αOH-P4)、雄烯二酮 (A)、T、二氢睾酮 (DHT)、雌酮 (E1)、17β-雌二醇(E2)、11-脱氧皮质醇 (11 S)、皮质醇 (F)、每次治疗前后通过 LC-MS/MS 检测可的松 (E) 和通过 ELISA 检测皮质类固醇结合球蛋白 (CBG)。此外，计算了游离 F 和类固醇产物/前体比率。我们观察到与安慰剂相比，CC 诱导的血清水平对 17αOH-P4、DHT、T、E2、E1、F、E 和 CBG 的显着变化，但没有游离 F。此外，与安慰剂相比，CC 诱导更高的 17αOH-P4/P4、E2/E1、17αOH-P4/17αOH-P5、A/17αOH-P4、T/A、E1/A、F/11 S 和 F/ E 比率。因此，除了 CC 对睾丸类固醇生成的刺激作用外，我们的研究显示 F、E 水平增加，但没有游离 F 水平，表明类固醇代谢发生变化，而不是肾上腺分泌刺激。类固醇分析还揭示了 Δ5 而不是 Δ4 通路的 CC 刺激，