Diabetes Mellitus Causes Male Reproductive Dysfunction

in vivo 35 : 2503-2511 (2021) doi:10.21873/invivo.12531

Review

Diabetes Mellitus Causes Male Reproductive Dysfunction: A Review of the Evidence and Mechanisms ZUBIN HE 1, GUOCHAO YIN 2, QINGDI QUENTIN LI 3, QIONGFANG ZENG 1 and JINLIANG DUAN 1

1924 Hospital of PLA Joint Logistic Support Force, Guilin, P.R. China; 2Guilin Rehabilitation and Recuperation Center, Guilin, P.R. China; 3Scientific Review Branch, Division of Extramural Research and Training, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, U.S.A.

Abstract. The metabolic disorders caused by diabetes can million worldwide and is estimated to increase to 578 million lead to various complications, including dysfunction of the by 2030. male reproductive system. In patients with diabetes, long- DM is due to the absolute or relative deficiency of insulin term hyperglycemia results in diabetic vascular neuropathy, (INS) and insulin resistance (IR), which lead to a decrease oxidative stress injury, abnormal zinc metabolism, and in the INS utilization rate and metabolic disorder. In patients insulin resistance syndrome. In addition, insulin deficiency with DM, long-term hyperglycemia can cause diabetic and resistance in diabetes can damage the hypothalamus, vascular neuropathy. Diabetes induced metabolic disorder pituitary gland, gonads, and perigonads. This can reduce the also leads to oxidative stress, abnormal zinc metabolism, and secretion of sex hormones including gonadotropin-releasing IR syndrome, all of which affect male fertility and hormone, follicle stimulating hormone, luteinizing hormone, reproductive health. It has been shown that decreased semen and testosterone, and can lead to testicular atrophy, stromal quality and impaired reproductive function occur to nearly cell atrophy, seminiferous tubule damage, spermatogenic cell half of male patients with diabetes. DM incidence is higher damage, and other structural injuries of the male in China compared to other countries. The number of male reproductive organs. These actions can affect male fertility patients with diabetes is gradually increasing, and so are the and reproductive health. Herein, we review studies that fertility problems of the male population. Therefore, male report a causative role of diabetes in male reproductive reproduction is attracting more and more attention. In this function. We also discuss the evidence-based mechanisms article, we provide an overview and a review of the involved in the processes of diabetes-related male sexual and reproductive pathology of DM males, and evidence on the reproductive dysfunction as well as the progress in treatment. mechanisms involved in the processes, leading us to conclude that further investigation would benefit our Diabetes mellitus (DM) is a metabolic disease that seriously understanding of DM-induced male reproductive dysfunction endangers human health. The incidence rate of DM is very and would aid in the development of novel ways to improve high, and the age of onset has been decreasing worldwide. male reproductive health. The latest data from the International Diabetes Federation (IDF) show the number of adults with diabetes is up to 463 Diabetes Mellitus Affects Male Reproduction

DM affects male reproduction in four conditions, including erectile dysfunction, ejaculation, structural changes in This article is freely accessible online. reproductive organs, and changes in the semen quality. Studies have found that 59% of diabetic men have erectile Correspondence to: Dr. Jinliang Duan, 924 Hospital of PLA Joint dysfunction (ED). The vast majority of patients with diabetic Logistic Support Force, 1 Xinqiaoyuan Road, Xiangshan District, impotence (DMED) have penile nerve thickening or beaded Guilin 541002, P.R. China. Tel: +86 18907738262, e-mail: [email protected] neuropathy. The decrease in serum testosterone (T) caused by DM also affects vascular endothelial function. Nitric Key Words: Diabetes mellitus, male fertility, male sexual dysfunction, oxide (NO) is an important neurotransmitter in penile male reproductive dysfunction, influencing mechanism, review. erection, and the relaxation effect of NO on smooth muscle

2503 in vivo 35 : 2503-2511 (2021) cells in corpus cavernosum and microvessels of the penis is ruptured. Further, mitochondria are found to be transformed at the core of penile erection (1). Hyperglycemia leads to into spiral and/or doughnut like organelles, and the number increased levels of reactive oxygen species (ROS), increased of vesicular organelles is reduced. advanced glycation end products (AGEs), inhibition of The main DM-caused changes in the semen quality are the endothelial nitric oxide synthase (eNOS) metabolism, and a decrease in sperm density and motility and the increase in decrease in endothelial synthesis and the release of NO, that sperm DNA fragmentation and apoptosis (6-8). In diabetic leads to ED. Neuropathy causes a decrease in NO and an rats the mitochondria of spermatogonia show vacuolar increase in vasoconstrictor endothelin (ET) levels, which are changes, the transformation of spermatogonia to primary related to erectile function. DM causes metabolic changes in spermatocytes is decreased, the number of inactive sorbitol metabolism bypass, arteriosclerosis, and disturbance spermatogonia is increased, and the number of epididymal in neurotrophic supply (2), resulting in glycogen deposition, sperm is decreased significantly. DM also affects sperm thickening of the basal membrane of somatic nerve sheath DNA integrity. Compared with healthy controls, 52% of men cells, and disintegration of axons leading to sensory and with diabetes have mitochondrial DNA deletions. The motor nerve damage, while the demyelination of pelvic increase in sperm DNA fragmentation, advanced glycation sympathetic nerves leads to the inhibition of sympathetic end products (AGEs) and receptor for advanced glycation nerves and eventually DMED (3). end products (RAGEs), as well as the changes in The mechanism of ejaculation is coordinated by pelvic spermatogenic genes, all lead to the decrease in sperm sympathetic nerve fibers. Peripheral neuropathy affects the quality. NO can inactivate superoxide anion, protect sperm pelvic sympathetic nerve resulting in the weakening of membrane from being damaged by lipid peroxide, stabilize bladder neck sphincter contraction, while abnormal cell and lysosomal membranes, increase cGMP content in contraction of the external urethral sphincter leads to the sperm cells, and facilitate sperm activation and capacitation. obstruction of semen discharge and return to the bladder, NO regulates both sperm motility and sperm lipid which is called retrograde ejaculation. The appearance of peroxidation and affects spermatogenesis. Endothelin (ET) retrograde ejaculation symptoms indicates that diabetic is a vasoconstrictor peptide, which plays an important role neuropathy is very serious. Unexplained retrograde in sperm maturation. ET and NO are closely related to male ejaculation should suggest the possibility of diabetes. reproductive hormone secretion and spermatogenesis. NO As for the diabetes-induced structural and functional can inhibit the secretion of ET. Deng and coworkers (9) have changes in reproductive organs, a decrease in testicular blood shown that ET levels in diabetic patients are increased flow velocity has been detected in diabetic rats by Doppler significantly, whereas NO levels are decreased significantly, (4). It is believed that the decrease in vascular endothelial and ET/NO imbalance leads to endothelial function damage. growth factor (VEGF) expression leads to the impairment of Due to dyslipidemia, hypertension, and NO synthesis vascular endothelial cell (EC) function, and microcirculation impairment, VEGF expression is decreased, and vascular disturbance leads to testicular morphological and structural basement membrane thickening leads to testicular changes. DM can delay gonadal development in immature microcirculation disorder, which affects spermatogenesis and rats, decrease sexual behavior and testosterone (T) synthesis, capacitation. NOS plays an important role in regulating and promote gonadal atrophy. Atrophy of seminiferous androgen levels in Leydig cells. INS signaling regulates the tubules (STs), thinning of spermatogenic epithelium, and the number of Sertoli cells as well as testicular size and sperm rate of empty tubules are higher. In some STs, multinucleated production. The regulation of the proliferation of immature cells with two or three nuclei are found, the vascular Sertoli cells by follicle stimulating hormone (FSH) also degeneration and germ cell apoptosis are increased, and the requires INS signaling pathway. Furthermore, the lack of content of cytoplasmic debris in Sertoli cells near the ST INSR in Sertoli cells inhibits the activation of the Akt cavity is increased. Ultrastructure has shown that Sertoli signaling pathway and decreases the expression of the cells have irregular basement membranes and the numbers follicle stimulating hormone receptor (FSHR) gene. Some of Sertoli cells is significantly reduced. Also, the oval nuclei studies have used lentiviral vectors to achieve stable in Sertoli cells become irregular and the smooth endoplasmic expression of INS in Sertoli cells for the purpose of reticulum in these cells is decreased. Likewise, Leydig cells developing gene therapy (10). have irregular nuclei, abundant heterochromatin, and lipid droplets. In addition, the structure of Leydig cell is damaged, Effect of Oxidative Stress on Male Reproduction its mitochondria are swollen, and endoplasmic reticulum is in Diabetes Mellitus decreased with dilatation. Liu and colleagues (5) have also found that the amount of sperm in epididymis is decreased Reactive oxygen species (ROS) is the main cause of cell significantly, the epididymal epithelium shows vacuole like damage, and one of its main sources is mitochondria. The changes, and a part of the cell nucleus is dissolved and American Diabetes Association points out that oxidative

2504 He et al : Diabetes and Male Reproductive Dysfunction (Review) stress (OS) is a common mechanism of diabetic may lead to increased excretion of zinc from urine resulting complications, and OS and microcirculation disorders are the in decrease of plasma zinc concentration. Zinc deficiency main causes of reproductive system damage. OS can cause may induce SOD mutant conformation and cause insulin resistance (IR) by activating protein kinase C (11), endoplasmic reticulum (ER) chronic stress, OS, DNA N-terminal kinase pathway (12), and transcription factors damage, apoptosis, hypogonadism, spermatogenesis disorder, (13). Long-term blood sugar stimulation leads to up- and sperm morphological defects. Furthermore, the testis and regulation of the number of mitochondria in tissue cells, and epididymis maintain their function through zinc uptake. lipid peroxidation causes damage to the antioxidant defense Taravati et al . (18) have shown that the concentration of zinc system. Long-term hyperglycemia in vivo up-regulates the in seminal plasma of asthenospermia is decreased level of mitochondria in tissue cells. The increase in oxygen significantly, which suggested the correlation between zinc radicals and AGEs and their interaction with NO induces the and sperm motility. During ejaculation, sperm can obtain secretion of peroxynitrite anion (ONOO -) leading to DNA zinc ions from seminal plasma and improve its motility. Zinc damage. Hyperglycemia then interacts with NO in vascular is an important mediator of signal transduction (19) and has endothelial cells to secrete peroxynitrite anion (ONOO -) been shown to enhance the effect of INS (20). Cellular zinc leading to DNA damage. DNA repair enzymes are then homeostasis is maintained by a large number of zinc activated in response to DNA damage, and tissue damage is transporters (ZnTs) in cells. ZnTs have been shown to eventually caused by protein kinases and advanced glycation function in reducing cell damage, and zinc homeostasis is end products (14). Because mitochondrial DNA is almost precisely regulated by zinc transporters (5). Impaired zinc entirely composed of coding regions, it is easily targeted by homeostasis underlies the pathogenesis of many human ROS because there are no protective mechanisms for diseases (1, 2). Altered expression of ZnTs not only mitochondrial DNA. ROS can directly interfere with interferes with zinc homeostasis in organelles, but also leads mitochondrial DNA and RNA replication, resulting in to organelle dysfunction. In T2DM, the expression of ZnT mitochondrial structure damage and dysfunction (15) and genes is significantly reduced. Is there an association decreased glucose oxidation and ATP production, which is a between zinc homeostasis and islet β-cells (21)? All characteristic of IR and hyperglycemia, and mitochondrial members of the SLC30 family (ZnTs) are expressed in damage in turn leads to ROS production. Due to excessive human islet β- cells, and all ZnTs can be detected in human oxidation products, the aldose pathway is activated, and as a and mouse β- cells except ZnT3. ZnT8 is mainly expressed result, glucose is converted into sorbitol, nicotinamide in adult mouse Leydig cells, and the zinc transporters ZnT1- adenine dinucleotide phosphate (NADPH) is consumed, and 5, 7, 8, and 10 have important roles in immune response (5, glutathione (GSH) levels are decreased further exacerbating 22). ZnT8 is also expressed in islet β- cells. Over-expression OS. Oxidative damage of islet β cells results in their of ZnT8 increases the zinc content of β- cells and promotes apoptosis and reduction in their number. Testosterone (T) is glucose-stimulated INS secretion, and ZnT8 also plays a role positively correlated with mitochondrial function and INS in T production through the protein kinase A (PKA) sensitivity. In men, the decrease of T affects mitochondrial signaling pathway. ZnT1 is expressed at the plasma function and promotes the occurrence and progress of membrane of testicular cells, the cytoplasm of spermatogenic diabetes (16). T can regulate the levels of glucose cells, and in Leydig cells. In summary, the disturbance of metabolism by protecting mitochondrial function (17), while zinc metabolism can diminish male fertility, and the altered OS can induce dominant lethal mutations in male gametes ZnT expression in the gonads of DM patients affects zinc and lead to embryo death early in pregnancy. homeostasis.

Effect of Abnormal Zinc Metabolism in Males Role of Hypothalamic Pituitary Gonadal Axis With Diabetes Mellitus in the Reproduction of Diabetic Men

Zinc is a powerful antioxidant which can stabilize and Spermatogenesis is regulated by the hypothalamic-pituitary- maintain the integrity of sperm cell membrane structure by gonadal axis (HPGA), and abnormal HPGA can lead to resisting lipid oxidation of sperm membrane. Semen and abnormal spermatogenesis. INS stimulates the expression testis are rich in zinc. Seminal plasma zinc is positively and secretion of gonadotropin-releasing hormone (GnRH) in correlated with free T levels, and zinc regulates T secretion. the hypothalamus and promotes the function of HPGA (23). The concentration of zinc in islet β- cells is high, and the In vitro INS also promotes the secretion of gonadotropin highest zinc concentration is within INS containing secretory (GN) induced by luteinizing hormone-releasing hormone granules in islet β- cells. The distribution of zinc in tissues (LHRH). Insufficient secretion of INS in DM patients can and body fluids of patients with DM is disturbed. Studies damage the HPGA. Glucose metabolism in anterior pituitary have shown that polyuria in type 2 diabetes mellitus (T2DM) cells depends on the secretion of INS. Lack of INS causes

2505 in vivo 35 : 2503-2511 (2021) glucose utilization disorders, which lead to decreased (mTOR) pathway has a regulatory effect on kisspeptin pituitary protein synthesis and decreased GN secretion. mRNA expression and gene transcription. In the central Hyperglycemia interferes with the secretion of GnRH, nervous system, GnRH expression is mediated through the thereby reducing the secretion of GN and prolactin (PRL), mTOR signaling pathway. Activation of mTOR stimulates which in turn leads to a significant decrease in the secretion the expression of kisspeptin and increases the secretion of of T from Leydig cells and ultimately to spermatogenesis LH. Rapamycin, an inhibitor of mTOR, can block the above disorders. Because of the DM-mediated damage of Sertoli effects. In conclusion, INS regulates kisspeptin protein cells or Leydig cells, the secretion of T is decreased resulting through the mTOR pathway and affects HPGA function, and in an increase in the levels of FSH and LH through the GnRH regulates reproductive function through kisspeptin negative feedback effect of HPGA. INS receptors and INS and kisspeptin neurons. signaling proteins are widely distributed in the central nervous system. There is an important relationship between Effect of Insulin Resistance on Male Reproduction brain INS signal transduction and reproduction. INS is a messenger linking metabolism and HPGA reproductive Insulin resistance (IR) is an important pathogenic factor and function. The neuronal expression of INS receptors plays an a pathological characteristic of T2DM (10). There is a causal important role in HPGA through its effect on LH secretion. relationship between IR and reproductive hormones: The most important pathological changes in reproductive reproductive hormones can affect INS sensitivity and function caused by HPGA sexual endocrine disorder are androgens can ameliorate IR and slow down the hyperandrogenemia and IR. In the model of INS receptor development of DM. Androgens are closely related to DM knockout, the secretion of sex hormone is insufficient, (30). T levels are significantly lower in DM patients leading to infertility and metabolic syndrome. INS receptor compared to healthy individuals. The lower the T levels, the has different expression patterns in hypothalamus and higher the incidence rates of DM. IR is the key link between pituitary. Nirko mice (INS receptor gene neuron specific T and DM. Decreases in androgen promote the development knockout mice) cannot maintain the function of Leydig cells of IR and DM. Dehydroepiandrosterone (DHEA) can reduce due to hypothalamic dysfunction and insufficient GN serum triglycerides, interleukin-6, TNF- α, and other secretion. Approximately 20% of seminiferous tubules (STs) inflammatory factors (31). A prospective cohort study of lack lumen and have almost no mature spermatogenic cells, non-diabetic elderly men shows that the prevalence of DM indicating that the fertility of Nirko mice is decreased. is lower in patients with higher levels of total T and free T, The pathogenesis of male infertility and sexual and sex hormone binding protein (SHBG) still exists after dysfunction caused by abnormal HPGA may be related to the the effect is removed (32). Several groups have found that abnormal INS signaling and the dysregulation of kisspeptin the levels of total T, free T, and SHBG in DM patients are expression in hypothalamus (24). G-protein-coupled receptor significantly lower than those in non-DM patients, and T and 54 (GPR54) combined with kisspeptin functions in SHBG are negatively correlated with IR (33, 34). T promotes hypothalamic GnRH neurons to activate the HPGA axis and glucose uptake, glycolysis, and oxidative phosphorylation. cause GnRH secretion. Kisspeptin/GPR54 complex is the Additionally, T ameliorates IR by enhancing glucose key to maintain HPGA function and an important factor transport, inhibiting inflammatory response, improving determining GnRH secretion (25, 26). Kisspeptin is also a mitochondrial function, and inhibiting adipocyte and tissue “molecular switch” initiating puberty, and its gene mutation proliferation. These indicate that T plays an important role leads to hypogonadotropic hypogonadism (HH). The in maintaining INS sensitivity. In ovariectomized rats, the deficiency of INS reduces kisspeptin protein expression in sensitivity to INS is increased, and androgen the hypothalamus, resulting in decrease in GnRH secretion supplementation ameliorates IR in and out of the liver (35). leading to HH. Supplementation of INS can correct the There is evidence (36, 37) showing that with the increase of abnormality of GnRH (27). Compared with the peripheral homeostatic model assessment of insulin resistance (HOMA- gonads, abnormal levels of INS have a greater impact on IR) index, T presents a downward trend, and the percentage hypothalamus and pituitary. Lin et al . (28) demonstrated that of sperm forward movement shows a downward trend (36, the upregulation of kisspeptin expression in the preoptic area 37). There is no significant difference between T and sperm can be involved in the stimulation of HPGA function in male concentration or total number ( p>0.05). HOMA-IR is rats. A study on the Gnv-3 cell line of GnRH-expressing negatively correlated with serum T and progesterone (PR) hypothalamic neurons showed that neurons are INS sensitive (p<0.05). However, Verit and colleagues (38) observed that tissues and express INS receptors (29). The increased HOMA-IR shows no significant correlation with sperm expression of kisspeptin in the preoptic area of the count, motility, and morphology. Zag (zinc alpha hypothalamus indicates that INS affects the expression of glycoprotein) (39) is a new type of adipokines, which plays kisspeptin in the Gnv-3 cell line, and the target of rapamycin an important role in alleviating IR. It can enhance INS signal

2506 He et al : Diabetes and Male Reproductive Dysfunction (Review) transduction and affect the expression of adipokines and stress and improving microcirculation are expected to inflammatory factors. Zag can be synthesized in epithelial become important means for the prevention and treatment of cells and secreted into the semen to affect physiological diabetic complications. Many natural products have processes such as fertilization. significant antioxidant capacity. Breviscapine can be used as a supplement for the prevention or treatment of diabetic Progression in the Treatment of Diabetes complications. Scutellarin (SCU) is another one. Although Mellitus-Related Male Reproductive Dysfunction SCU cannot regulate blood glucose levels, it reduces oxidative stress and has antioxidant effects. SCU improves It is a challenge to treat DM-related male reproductive microcirculation by increasing VEGF expression, reducing dysfunction, and blood sugar control is still the key. In the blood viscosity, and inhibiting platelet aggregation, thus recent years, great efforts have been made to investigate reducing testicular damage (44, 45). Acupuncture has been therapeutic approaches for the improvement and treatment of widely used in the treatment of T2DM in China. It has been diabetes mellitus erectile dysfunction (DMED). These include shown that acupuncture improves IR and increases glucose stem cell transplantation, gene therapy, vascularization metabolism in T2DM rats. It has also been confirmed that technology, INS treatment, mecobalamin and lipoic therapy, acupuncture and moxibustion have antioxidant effects, scutellarin (SCU) therapy, acupuncture and moxibustion, improving the levels and activity of SOD, protecting the androgen therapy, and antioxidant therapy (40-46). morphology and structure of mitochondria, and improving It has been found that stem cells can have a paracrine ATP synthesis in mitochondria. effect on surrounding tissues, and can also differentiate into Androgen therapy is another treatment of choice for DMED. a variety of functional cells such as neurons, endothelium, Androgen inhibits inflammatory response, improves and smooth muscle, thereby repairing damaged tissues mitochondrial function, enhances glucose transport through caused by DM and improving erectile function (40). glut (glucose transporter), improves glucose metabolism, and Therefore, stem cell transplantation can be a new treatment reduces IR. It has been shown that T supplementation can slow method for DMED in the clinic. down the damage of the reproductive system of diabetics. Gene therapy is also a new direction. The target genes of Lastly, antioxidant therapy has been shown to be effective DMED patients mainly include vascular endothelial growth in the treatment of DMED. Antioxidant therapy reduces OS- factor (VEGF) and NOS genes, and the therapy involving induced damage to sperm via stimulating the secretion of these genes can also help improve erectile function. A recent FSH and LH as well as T synthesis. Coenzyme Q10 and N- study shows that gene repair therapy activates related cell acetylcysteine improve sperm quality by increasing T and signal transduction pathways and induces nerve and vascular inhibin B; while vitamin C, vitamin E, and glutathione can regeneration (41). In addition, vascularization technology has be used as adjuvant therapy for improving sperm quality. The been used to achieve cavernous smooth muscle angiogenesis antioxidant L-carnitine improves the levels of antioxidants and has broad prospects in DMED treatment. in seminal plasma and promotes spermatogenesis and Regarding the treatment of diabetic retrograde ejaculation, maturation (46). Early antioxidant treatment reduces islet cell blood sugar control is the key, including intensive INS damage and promotes islet cell proliferation. Vitamin C and treatment and recovery of pelvic autonomic nerve function. antioxidant SOD can delay the process of islet cell apoptosis. Mecobalamin can repair nerves, and lipoic acid has SOD also improves autonomic nerve conduction velocity and antioxidant and endothelial functions. Some recent studies restores endothelial function. It has been demonstrated that have shown that mecobalamin combined with lipoic acid has increasing zinc intake reduces the severity of type 1 diabetes better effect on the treatment of diabetic neuropathy; in animal models, and Zag also reduces IR through a variety however, Ma et al. showed that mecobalamin combined with of mechanisms. lipoic acid does not achieve a better therapeutic effect as In general, the treatment of DM-induced male compared with each agent alone (42). For patients with reproduction-related complications requires comprehensive fertility requirements, in-vitro fertilization, and embryo treatment, and blood sugar control is the key strategy. Only transfer (IVF-ET) is highly recommended. when blood sugar is well controlled, it can be possible to Traditional Chinese medicine (TCM)-related therapy is a prevent peripheral vascular disease and diabetic neuropathy. promising treatment approach for DMED. As the onset of When diabetic retrograde ejaculation and DMED occur, and DM is getting younger, reproductive dysfunction caused by testicular tissue structure and semen quality are changed, it DM has gradually attracted attention. Oxidative stress and is very important to control blood sugar , together with other vascular microcirculation disorders caused by DM can treatment strategies, such as improving lipid metabolism, induce cell apoptosis and cause damage to organ function protecting nerves and blood vessels, as well as zinc (43), and it is considered to be the main cause of damage to supplementation and related antioxidants, and all these are the reproductive system. Therefore, regulating oxidative helpful to improve semen quality and male reproductive

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Figure 1. A schematic diagram illustrating a hypothetical model of the impact of diabetes mellitus (DM)-caused metabolic disorder and insulin abnormality on male sexual and reproductive dysfunction. This schematic diagram shows that glucose metabolism disorder and IR in DM cause angioneuropathy through decreases in synthesis and release of NO and VEGF and increases in ET and AGEs in the endothelium leading to ED and retrograde ejaculation. On the other hand, abnormal glucose metabolism can lead to oxidative stress and the loss of zinc. Oxidative stress is a common mechanism underlying diabetic complications, and it also promotes changes in the above processes. Zinc is a strong antioxidant, and zinc deficiency aggravates oxidative stress injury. In addition, insulin deficiency in diabetic patients also causes HPGA damage, thereby reducing secretion of GnRH, FSH, LH, and T and leading to testicular atrophy, stromal cell (Sertoli and Leydig) atrophy, ST damage, and spermatogenic cell damage. All of these factors may act cooperatively to suppress sexual and reproductive function in men. Such a mechanism may serve to integrate the roles of these factors in the reduction of sperm density and motility and increase of deformity rate and sperm DNA fragmentation index, which may underlie the mechanisms through which DM caused male fertility and reproductive dysfunction. See the text for details. IR: Insulin resistance; NO: nitric oxide; VEGF: vascular endothelial growth factor; ET: endothelin; AGE: advanced glycation end product; ED: erectile dysfunction; HPGA: hypothalamic-pituitary-gonadal axis; GnRH: gonadotropin-releasing hormone; FSH: follicle stimulating hormone; LH: luteinizing hormone; T: testosterone; ST: seminiferous tubule; DFI: sperm DNA fragmentation index.

function. Finally, TCM treatment as well as acupuncture and and reproductive dysfunction is as yet not completely moxibustion can improve microcirculation, protect blood known, abundant evidence shows that multiple factors and vessels, and eliminate oxygen free radicals. It has been mechanisms are involved in the process ( Figure 1 ). demonstrated that TCM is an effective treatment for DM- Oxidative stress is a common mechanism underlying diabetic caused male reproductive dysfunction. complications. Microcirculation disturbance and oxidative stress are considered to be the main factors causing Conclusion and Future Directions reproductive system damage. Hyperglycemia leads to the impairment of vascular endothelial function, including the DM is a hormonal and metabolic disorder which causes decrease in endothelial NO (eNO) synthesis, the increase of many complications and affects multiple organs and systems oxidative stress, and the glycosylation of elastic fibers in in the human body including the male reproductive system. vascular wall. Finally, hyperglycemia causes peripheral Although the molecular basis of diabetes-caused male sexual neurovascular diseases, leading to DMED and bladder

2508 He et al : Diabetes and Male Reproductive Dysfunction (Review) dysfunction. Semen quality is characterized by decreased Conflicts of Interest sperm concentration and motility, as well as high incidence of sperm DNA damage, DNA breakage, and sperm The Authors declare that they do not have any competing interests apoptosis. DM causes HPGA damage, reduces hypothalamic regarding this article. GnRH secretion, and decreases plasma LH, FSH, PRL and T, resulting in spermatogenesis disorders. Impaired glucose Authors’ Contributions utilization due to insulin deficiency leads to decreased pituitary protein synthesis and reduced gonadotropin ZH and GY were involved in the design of the work, literature search, analysis and interpretation of data, and drafted the article. secretion. Zinc has a strong antioxidant effect and plays a QQL, QZ, and JD supervised the study and were involved in the key role in scavenging free radicals. Zinc can inhibit lipid critical revision of the article. JD conceived the project and oxidation of sperm membrane and maintain the integrity of obtained the funding. All Authors have approved the final version cell membrane structure. Oxidative stress affects zinc of the article. homeostasis and influences the expression of zinc transporters. IR is an important pathogenic factor and a Acknowledgements pathological characteristic of T2DM. IR leads to erectile dysfunction and hypogonadism. Androgen ameliorates IR by This work was supported by a grant for Omics evaluation and high increasing glucose transport, improving mitochondrial precision genetic screening of embryo implantation potential in officers and soldiers of the PLA (No. 17js008) and a grant by Guilin function, inhibiting inflammatory response, and suppressing Scientific Research and Technology Development Plan (No. the proliferation of adipocytes and adipoprogenitor cells, all 20180106-4-7). The Authors would also like to thank Diane Cooper, of which slow down the development of DM. NIH Library, for reviewing the article. Accumulating evidence shows that oxidative stress plays a very important role in the occurrence and development of References DM, and therefore it is of great significance for the prevention and treatment of diabetes-related male 1 Castela Â and Costa C: Molecular mechanisms associated with reproductive dysfunction. There are still many key scientific diabetic endothelial-erectile dysfunction. Nat Rev Urol 13(5) : issues regarding the mechanism regulating oxidative stress, 266-274, 2016. PMID: 26878803. DOI: 10.1038/nrurol.2016.23 2 Li Y, Liu L, Li F, Zhang X, Zhang B and Wang Y: Study and including how cells perceive oxidative stress, the ROS treatment of male erectile dysfunction induced by diabetes threshold for activating key antioxidant molecules, and the mellitus. 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In summary, at: https://d.wanfangdata.com.cn/periodical/ChlQZXJpb2RpY2 as more and more mechanisms of action of oxidative stress FsQ0hJTmV3UzIwMjEwNjA4EhB6Z25reHp6MjAyMDA1MDA yGggyazh6dDk1bw%3D%3D [Last accessed on June 14, 2021] in DM are unveiled, our understanding of the impact of DM 6 Imani M, Talebi AR, Fesahat F, Rahiminia T, Seifati SM and on male reproduction will increase, and new and better Dehghanpour F: Sperm parameters, DNA integrity, and approaches to improve reproductive health in men and to protamine expression in patients with type II diabetes mellitus. treat DM-caused male sexual and reproductive dysfunction J Obstet Gynaecol 41(3) : 439-446, 2021. PMID: 32705912. will be developed. DOI: 10.1080/01443615.2020.1744114

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