Abstract
Testosterone deficiency is associated with sickle cell disease (SCD), but its underlying mechanism is not known. We investigated the possible occurrence and mechanism of testosterone deficiency in a mouse model of human SCD. Transgenic sickle male mice (Sickle) exhibited decreased serum and intratesticular testosterone and increased luteinizing hormone (LH) levels compared with wild type (WT) mice, indicating primary hypogonadism in Sickle mice. LH-, dbcAMP-, and pregnenolone- (but not 22-hydroxycholesterol)- stimulated testosterone production by Leydig cells isolated from the Sickle mouse testis was decreased compared to that of WT mice, implying defective Leydig cell steroidogenesis. There also was reduced protein expression of steroidogenic acute regulatory protein (STAR), but not cholesterol side-chain cleavage enzyme (P450scc), in the Sickle mouse testis. These data suggest that the capacity of P450scc to support testosterone production may be limited by the supply of cholesterol to the mitochondria in Sickle mice. The sickle mouse testis exhibited upregulated NADPH oxidase subunit gp91phox and increased oxidative stress, measured as 4-hydroxy-2-nonenal, and unchanged protein expression of an antioxidant glutathione peroxidase-1. Mice heterozygous for the human sickle globin (Hemi) exhibited intermediate hypogonadal changes between those of WT and Sickle mice. These results demonstrate that testosterone deficiency occurs in Sickle mice, mimicking the human condition. The defects in the Leydig cell steroidogenic pathway in Sickle mice, mainly due to reduced availability of cholesterol for testosterone production, may be related to NADPH oxidase-derived oxidative stress. Our findings suggest that targeting testicular oxidative stress or steroidogenesis mechanisms in SCD offers a potential treatment for improving phenotypic changes associated with testosterone deficiency in this disease.
Highlights
sickle male mice (Sickle) cell disease (SCD) is a hemoglobinopathy resulting from the expression of abnormal sickle hemoglobin (HbS) [1, 2]
We demonstrated that Sickle mice exhibited decreased serum and intratesticular testosterone levels, indicating that testosterone deficiency occurs in these mice as is observed in patients with Sickle cell disease (SCD) [6,7,8,9,10,11,12]
We further established that the type of “hypogonadism” is primary in Sickle mice and identified a possible basis for the testicular defect resulting in impaired steroidogenesis
Summary
Sickle cell disease (SCD) is a hemoglobinopathy resulting from the expression of abnormal sickle hemoglobin (HbS) [1, 2]. Substitutes a charged amino acid glutamic acid for uncharged valine This results in aggregation of HbS molecules under deoxygenated conditions and red blood cell rigidity, leading to poor blood flow with vaso-occlusion, tissue hypoxia, and ischemia [1, 2]. The mechanism underlying testosterone deficiency in SCD is not clear, as both increased and decreased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been measured in SCD patients. Elevated LH and FSH levels observed in patients with SCD suggests that testicular failure (primary hypogonadism) underlies dysfunctional testosterone production [6, 10, 11]. Decreased testosterone levels in SCD patients with decreased LH and FSH suggest the association of secondary hypogonadism (hypothalamo–pituitary dysfunction) with SCD [8, 15].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
