Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD, United States.
Front Endocrinol (Lausanne). 2022 May 3;13:892184. doi: 10.3389/fendo.2022.892184. eCollection 2022.
Hypogonadism is common in men with sickle cell disease (SCD) with prevalence rates as high as 25%. Testicular failure (primary hypogonadism) is established as the principal cause for this hormonal abnormality, although secondary hypogonadism and compensated hypogonadism have also been observed. The underlying mechanism for primary hypogonadism was elucidated in a mouse model of SCD, and involves increased NADPH oxidase-derived oxidative stress in the testis, which reduces protein expression of a steroidogenic acute regulatory protein and cholesterol transport to the mitochondria in Leydig cells. In all men including those with SCD, hypogonadism affects physical growth and development, cognition and mental health, sexual function, as well as fertility. However, it is not understood whether declines in physical, psychological, and social domains of health in SCD patients are related to low testosterone, or are consequences of other abnormalities of SCD. Priapism is one of only a few complications of SCD that has been studied in the context of hypogonadism. In this pathologic condition of prolonged penile erection in the absence of sexual excitement or stimulation, hypogonadism exacerbates already impaired endothelial nitric oxide synthase/cGMP/phosphodiesterase-5 molecular signaling in the penis. While exogenous testosterone alleviates priapism, it disadvantageously decreases intratesticular testosterone production. In contrast to treatment with exogenous testosterone, a novel approach is to target the mechanisms of testosterone deficiency in the SCD testis to drive endogenous testosterone production, which potentially decreases further oxidative stress and damage in the testis, and preserves sperm quality. Stimulation of translocator protein within the transduceosome of the testis of SCD mice reverses both hypogonadism and priapism, without affecting intratesticular testosterone production and consequently fertility. Ongoing research is needed to define and develop therapies that restore endogenous testosterone production in a physiologic, mechanism-specific fashion without affecting fertility in SCD men.
性腺功能减退症在镰状细胞病（SCD）男性中很常见，患病率高达 25%。睾丸衰竭（原发性性腺功能减退症）被确立为这种激素异常的主要原因，尽管也观察到了继发性性腺功能减退症和代偿性性腺功能减退症。SCD 小鼠模型阐明了原发性性腺功能减退症的潜在机制，涉及睾丸中 NADPH 氧化酶衍生的氧化应激增加，这会降低类固醇急性调节蛋白的蛋白质表达，并将胆固醇转运到莱迪希细胞的线粒体中。在包括 SCD 男性在内的所有男性中，性腺功能减退症会影响身体生长和发育、认知和心理健康、性功能以及生育能力。然而，尚不清楚 SCD 患者身体、心理和社会健康领域的下降是否与低睾酮有关，或者是否是 SCD 其他异常的后果。阴茎异常勃起是 SCD 为数不多的并发症之一，在性腺功能减退症的背景下进行了研究。在这种阴茎长时间勃起而没有性兴奋或刺激的病理情况下，性腺功能减退症会加剧阴茎中已经受损的内皮型一氧化氮合酶/cGMP/磷酸二酯酶-5 分子信号。虽然外源性睾酮可缓解阴茎异常勃起，但它会不利地降低睾丸内睾酮的产生。与外源性睾酮治疗相反，一种新方法是针对 SCD 睾丸中睾酮缺乏的机制来驱动内源性睾酮的产生，这可能会进一步减少睾丸中的氧化应激和损伤，并保持精子质量。刺激 SCD 小鼠睾丸转导体中的转位蛋白可逆转性腺功能减退症和阴茎异常勃起，而不影响睾丸内睾酮的产生，从而不影响生育能力。需要开展进一步的研究，以确定和开发恢复内源性睾酮产生的治疗方法，使其以生理、机制特异性的方式恢复，而不影响 SCD 男性的生育能力。
