Hyperuricemia is a disease of abnormal purine metabolism caused by various causes in the body, resulting in increased uric acid levels in the blood. Relevant studies have confirmed that hyperuricemia is an independent risk factor for chronic kidney disease, kidney stones, cardiovascular and cerebrovascular diseases, atherosclerosis, abnormal glucose metabolism, dyslipidemia, stroke, hypertension and other diseases [1, 2, 14]. The incidence of hyperuricemia in males is significantly higher than that in females, and the prevalence of hyperuricemia in males in China is as high as 12.39 % [15]. A study has confirmed that hyperuricemia causes serious harm to human health, especially metabolic diseases of male, which have a certain impact on male reproductive health, such as decreased testosterone level and erectile dysfunction [16]. In clinic, the decrease of testosterone level may cause male reproductive problems such as gonadal dysfunction, male infertility and physical deterioration. Testosterone is one of the main components of androgens, which is closely related to sperm growth and maturation, reproductive function and maintenance of normal sexual desire.
Total testosterone refers to the sum of the concentrations of protein-bound and unbound testosterone in circulation. It is known that at least four structurally distinct binding proteins can bind testosterone in human circulation, namely, SHBG, human serum albumin (HAS), corticosteroid-binding globulin (CBG), and orosomucoid (ORM). Among these, testosterone is tightly bound to SHBG, and weakly bound to HAS, CBG, and ORM. Only 1–4 % of circulating testosterone is unbound or free. HSBG has been recognized as high-affinity binding protein for testosterone, which is getting much attention [17]. Relevant studies have confirmed that TT has obvious limitations in the diagnosis of hypogonadism, and has no obvious correlation with the questionnaire on symptoms of hypogonadism. TT is mainly used in patients with hypothalamic-pituitary or testicular lesions, but not in men with hypogonadism due to aging [18, 19]. FT is more sensitive to diagnosis of hypogonadism than TT, FT is also significantly correlated with blood lipids, blood glucose, blood pressure. According to the diagnostic criteria for delayed male hypogonadism of the International Society of Andrology (ISA) and the European Urology Association (EAU) [20], FT ≤ 225pmol/L, IIEF-5 score < 21 points, and answering “yes” to any 3 questions in the ADAM questionnaire were considered as the diagnostic criteria for male hypogonadism in this study.
A survey conducted by Deng et al. [21] found that there was no significant difference in WC, BMI, SBP, DBP, HbA1C, TC, TG, LDL-C, HDL-C in male diabetic patients with hypogonadism compared with those of normal gonadal function. Li et al. [22] confirmed that BMI, TG, TC, and FBG of delayed-onset male hypogonadism were statistically different from those of healthy men (P < 0.05, respectively), while age and WC were not significantly different from those of healthy men (P > 0.05, respectively). The results of this study showed that the age, course of disease, the levels of SBP, DBP, HbA1c, TC, HDL-C, LDL-C, GGT, AST, BUN, SCr, the prevalence of GA, CHD, HBP, T2DM, history of smoking and drinking of hypogonadism group and normal group were comparable (P > 0.05). The BMI, WC, and the levels of FPG, FINS, HOMA-IR, TG, SUA, ALT, and the prevalence of NAFLD, HLP, OB in the hypogonadism group were higher than the normal group (P < 0.05). The levels of TT, FT, E2, 25(OH)D3 in the hypogonadism group were lower than the normal group (P < 0.05). These results suggest that FPG, FINS, HOMA-IR, TG, SUA, ALT levels increase, and TT, FT, E2, 25(OH)D3 levels decrease in male hyperuricemia patients with hypogonadism. But it is not the same as previous studies, which may be caused by different patients and different regions.
Vitamin D is a key factor in the regulation of bone mineralization and calcium homeostasis in both genders. Vitamin D deficiency is widespread worldwide [23]. A recent study has confirmed that vitamin D receptors are widely present in ovary, testis, pituitary, hypothalamus, and the reproductive system is one of the target organs of vitamin D, indicating that vitamin D may be involved in the regulation of gonadal function [24]. Vitamin D needs to be catalyzed by 25-hydroxylase and 1α-hydroxylase in turn in vivo, and converted into the active form of 1,25-hydroxyvitamin D3, thus exerting biological effects. A cross-sectional survey of 3369 community men aged 40–79 conducted by Lee et al. [25] showed that vitamin D deficiency is associated with hypogonadism. SUA is the production of purine metabolism in the constituent nucleic acid and is closely related to metabolic diseases. Cao et al. [26] confirmed that SUA was negatively correlated with serum TT in male T2DM patients, suggesting that SUA was an independent risk factor for low total testosterone. Mukhin et al. [27] found that injecting exogenous androgen into hypogonadism rats could restore the uric acid metabolism level of the rats. HOMA-IR is an index used to evaluate the level of insulin resistance of an individual. In different populations, insulin resistance is negatively correlated with testosterone levels [28]. TG is one of the components of lipids, which are normally in dynamic equilibrium in the body. Haffner et al. [29] confirmed that testosterone was negatively correlated with TG. Svartberg et al. [30] also confirmed that TG level was closely related to testosterone. The results of this study showed that BMI, WC, HOMA-IR, TG, SUA, TT, FT, 25(OH)D3, and E2 were positively correlated with hypogonadism (P < 0.05). Logistic regression analysis found that the above indicators are risk factors for hypogonadism, suggesting that male hyperuricemia patients with hypogonadism are closely related to BMI, WC, HOMA-IR, TG, SUA, TT, FT, 25(OH)D3 and E2. The mechanism of hypogonadism caused by low 25(OH)D3 levels in male hyperuricemia patients may be as follows: (1) 25(OH)D3 will increase intracellular Ca2+ release, and reduce the mobility of sperm and acrosomal reaction of mature sperm. Vitamin D deficiency will lead to dysregulation of testicular nucleus stromal cells, which will interfere with their normal functions and lead to sperm synthesis dysfunction, thus affecting gonadal function. (2) By regulating the calcium-dependent luteinizing hormone response, luteinizing hormone can cause the secretion of cyclic adenosine-phosphate and the concentration of calcium ions in the testicular stromal cells to produce testosterone. When the level of 25(OH)D3 in the body decreases, the intracellular calcium ion release mediated by vitamin D receptors decreases, and the effect of regulating calcium-dependent luteinizing hormone on adult male reproductive tract, male germ cells and mesenchymal cells decreases. Thus, the synthesis of testosterone in the male reduced, thereby affecting the function of the gonads. In male patients with hyperuricemia, the mechanism of hypogonadism caused by HOMA-IR may be that insulin resistance reduces the level of hypothalamic gonadotropin and affects the level of testosterone; insulin resistance may directly affect the secretion of testosterone in Leydig cells of the testis. In male patients with hyperuricemia, the possible mechanism of TG-induced hypogonadism is that hypertriglyceridemia is often associated with insulin resistance and obesity, and the above two factors are related to hypogonadism. Also, TG is involved in the synthesis, secretion and conversion of active products of testosterone. Increased TG will reduce the synthesis of testosterone, resulting in decreased libido and reduced reproductive capacity. In male patients with hyperuricemia, the main mechanism of hypogonadism caused by SUA is not yet clear. It may be due to the metabolic syndrome affecting the gonadal function, and further mechanism research is still needed.
There are some limitations in this study. First, this is a single-center prospective study, certain selection bias is hard to avoid, and the sample size was limited. Second, this study did not perform subgroup analysis of male hyperuricemia patients with hypogonadism with different levels of BMI, WC, HOMA-IR, TG, SUA, TT, FT, 25(OH)D3, and E2. In addition, the prevalence and treatment outcomes of hypogonadism were not assessed in this study, which need further research.
