#4184 male chronic kidney disease is a state of premature testicular aging

Abstract Background and Aims Sex steroid levels have been reported to be decreased in male patients with chronic kidney disease (CKD), parallel to the severity of the kidney dysfunction. These studies, at large, used immuno-assays, a method that is inferior to gold standard chromatography measurements and, in addition, failed to give insights into the underlying pathophysiology as they lacked data on gonadotropin levels. The aim of this study was to comprehensively map the gonadal status in male CKD patients not yet on dialysis and age- and BMI-matched controls, using gold standard techniques. Method We performed a case-control study in 120 male CKD patients (age 65.0 y, BMI 26.8 kg/m2), matched (1:1) with non-CKD controls for age and BMI. We divided CKD patients into 3 categories based on KDIGO classification: CKD 1–2 (n = 24), CKD 3 (n = 42) and CKD 4–5 (n = 54). We measured total testosterone (T) and estradiol (E2) using liquid chromatography tandem mass-spectrometry. Sex hormone binding globulin (SHBG), prolactin, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured on the Roche Cobas 8000 platform. Free T levels were calculated via Vermeulen formula. Inhibin B (a readout for testicular Sertoli cell function) was measured by ELISA. Results CKD patients showed lower total T (426.0 ng/dL [297.5-516.5] vs. 541.0 ng/dL [452.0-647.8]; p<0.0001) and free T levels (7.4 ng/dL ±3.2 vs. 9.4 ng/dL +/-2.2; p<0.0001) as compared to non-CKD counterparts. SHBG and E2 levels, conversely, were comparable in cases and controls. Inhibin B levels were lower in CKD patients as well (112.7 pg/mL [38.1-189.0] vs. 181.1 [122.2-236.4]; p<0.0001). LH and FSH levels were higher in CKD patients (9.1 IU/L [5.4-16.2] vs. 5.4 IU/L [3.6-8.1]; p<0.0001 and 7.8 IU/L [5.0-20.2] vs. 5.6 IU/L [4.0-9.7]; p<0.0001 respectively). Consequently, the T/LH ratio and inhibin B/FSH ratio, respectively reflecting Leydig and Sertoli cell function, were markedly depressed in CKD (1.8 nmol/IU [0.7-3.0] vs. 4.0 nmol/IU [2.4-5.2]; p<0.0001 and 14.4 ng/IU [1.2-33.6] vs. 32.2 ng/IU [32.2 [16.3-56.7]; p<0.0001). In the CKD cohort, regression analysis identified eGFR and age as independent determinants of T/LH ratio (R2 0.29). According to the T/LH ratio a male CKD patient of 45y old has a testicular age of an 81y old control. Conclusion Male patients with CKD not yet on dialysis show low total and free T levels, confirming CKD as a risk factor for male hypogonadism. The low T/LH and inhibin B/FSH ratio point to testicular failure as the underlying pathophysiological mechanism.