Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
Biol Reprod. 2018 Jul 1;99(1):101-111. doi: 10.1093/biolre/ioy059.
Herein we summarize important discoveries made over many years about Leydig cell function and regulation. Fetal Leydig cells produce the high levels of androgen (testosterone or androstenedione, depending upon the species) required for differentiation of male genitalia and brain masculinization. Androgen production declines with loss of these cells, reaching a nadir at postpartum. Testosterone then gradually increases to high levels with adult Leydig cell development from stem cells. In the adult, luteinizing hormone (LH) binding to Leydig cell LH receptors stimulates cAMP production, increasing the rate of cholesterol translocation into the mitochondria. Cholesterol is metabolized to pregnenolone by the CYP11A1 enzyme at the inner mitochondrial membrane, and pregnenolone to testosterone by mitochondria and smooth endoplasmic reticulum enzymes. Cholesterol translocation to the inner mitochondrial membrane is mediated by a protein complex formed at mitochondrial contact sites that consists of the cholesterol binding translocator protein, voltage dependent anion channel, and other mitochondrial and cytosolic proteins. Steroidogenic acute regulatory protein acts at this complex to enhance cholesterol movement across the membranes and thus increase testosterone formation. The 14-3-3γ and ε adaptor proteins serve as negative regulators of steroidogenesis, controlling the maximal amount of steroid formed. Decline in testosterone production occurs in many aging and young men, resulting in metabolic and quality-of-life changes. Testosterone replacement therapy is widely used to elevate serum testosterone levels in hypogonadal men. With knowledge gained of the mechanisms involved in testosterone formation, it is also conceivable to use pharmacological means to increase serum testosterone by Leydig cell stimulation.
在此，我们总结了多年来关于 Leydig 细胞功能和调节的重要发现。胎儿 Leydig 细胞产生高水平的雄激素（睾酮或雄烯二酮，取决于物种），这是男性生殖器分化和大脑男性化所必需的。随着这些细胞的丧失，雄激素的产生下降，在产后达到最低点。然后，随着干细胞向成年 Leydig 细胞的发育，睾酮逐渐增加到高水平。在成年期，促黄体生成素（LH）与 Leydig 细胞 LH 受体结合，刺激 cAMP 的产生，增加胆固醇向线粒体转移的速率。胆固醇在内质网中由 CYP11A1 酶代谢为孕烯醇酮，然后由线粒体和光滑内质网酶代谢为睾酮。胆固醇向线粒体内部转移是由线粒体接触部位形成的蛋白质复合物介导的，该复合物由胆固醇结合转运蛋白、电压依赖性阴离子通道和其他线粒体和细胞质蛋白组成。类固醇急性调节蛋白（StAR）在该复合物中发挥作用，增强胆固醇穿过膜的运动，从而增加睾酮的形成。14-3-3γ 和 ε 衔接蛋白作为类固醇生成的负调节剂，控制形成的类固醇的最大量。许多衰老和年轻男性的睾酮生成能力下降，导致代谢和生活质量的变化。睾酮替代疗法广泛用于提高性腺功能减退男性的血清睾酮水平。随着对睾酮形成机制的了解，也可以想象通过刺激 Leydig 细胞来使用药理学手段增加血清睾酮。
