Chunhua Deng

Guihua Liu

Haolin Chen

Jiajie Yu

Kai Xia

Renshan Ge

Frontiers in Endocrinology

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Frontiers in EndocrinologyOPEN ACCESSEDITED AND REVIEWED BYClaus Yding Andersen,University of Copenhagen, Denmark*CORRESPONDENCEChunhua Dengdch0313@163.comRECEIVED 18 April 2023ACCEPTED 10 May 2023PUBLISHED 19 May 2023CITATIONXia K, Yu J, Liu G, Chen H, Ge R andDeng C (2023) Editorial: Agingand male hypogonadism.Front. Endocrinol. 14:1207907.doi: 10.3389/fendo.2023.1207907COPYRIGHT© 2023 Xia, Yu, Liu, Chen, Ge and Deng.This is an open-access article distributedunder the terms of the Creative CommonsAttribution License (CC BY). The use,distribution or reproduction in otherforums is permitted, provided the originalauthor(s) and the copyright owner(s) arecredited and that the original publication inthis journal is cited, in accordance withaccepted academic practice. No use,distribution or reproduction is permittedwhich does not comply with these terms.TYPE EditorialPUBLISHED 19 May 2023DOI 10.3389/fendo.2023.1207907Editorial: Aging andmale hypogonadismKai Xia1, Jiajie Yu2, Guihua Liu3, Haolin Chen4,5,Renshan Ge4 and Chunhua Deng2*1Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-senUniversity, Guangzhou, China, 2Department of Urology and Andrology, The First Affiliated Hospital ofSun Yat-sen University, Guangzhou, China, 3Reproductive Medicine Center, Sixth Affiliated Hospital ofSun Yat-sen University, Guangzhou, China, 4Department of Gynecology and Obstetrics, The SecondAffiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China,5Department of Anesthesiology, Perioperative Medicine, Zhejiang Province Key Lab of Anesthesiology,The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University,Wenzhou, ChinaKEYWORDShypogonadism - hypotestosteronemia - androgen deficiency, aging, male, Leydigcell, testosteroneEditorial on the Research TopicAging and male hypogonadismMale hypogonadism, characterized by testosterone deficiency, is common in malesover 40 years old (1, 2). Male hypogonadism can lead to sexual and reproductivedysfunction, as well as age-related diseases such as cardiovascular diseases and metabolicdisorders, seriously affecting male quality of life and health. Currently, exogenoustestosterone replacement therapy is the main clinical treatment for male hypogonadism,but it can only partially alleviate symptoms and cannot cure the disease. Besides, it also hasobvious side effects, such as increasing the risk of cardiovascular diseases, exacerbatingobstructive sleep apnea syndrome, and increasing the risk of prostate cancer (3, 4).Therefore, it is necessary to explore safer and more effective methods of testosteronesupplementation. Leydig cells (LCs) located in the interstitium of the testis and are themain source of testosterone. Their dysfunction is the core mechanism of age-related malehypogonadism (5, 6). Exploring the intrinsic mechanism of Leydig cell aging can help usbetter understand male hypogonadism and develop new treatment strategies.Age-related male hypogonadism is the result of both primary and secondary factors,however, the association of chemical exposure remains unclear. Phthalates are widely usedplasticizers and can be found in many products, including food packaging, toys andmedical devices (7). A recent retrospective study, utilizing data from the National Healthand Nutrition Examination Survey (NHANES), found a positive association betweenexposure to Di(2-ethylhexyl) phthalate (DEHP) metabolites and the risk of age-relatedmale hypogonadism in men over 40 years old (Liu et al.). The odds ratio increased with theconcentration of DEHP metabolites, and a dose-dependent effect was observed. Liu et al.highlight for the first time the role of phthalates exposure in the etiology of age-related malehypogonadism, contributing to our understanding of this disease.frontiersin.org01Xia et al. 10.3389/fendo.2023.1207907In addition to the complex pathophysiology, the diagnosticcriteria and symptom assessment of age-related malehypogonadism have been controversial. Insulin-like peptide 3(INSL3) is a hormone secreted by mature LCs, and is commonlyused to assess the functional status of LCs (8). Ivell et al. collectedand analyzed data from over 3000 men in the European Male AgingStudy (EMAS) cohort, finding that INSL3 is a more effective markerthan testosterone (T) for evaluating primary hypogonadism, as wellas secondary and compensated hypogonadism. Elevated INSL3levels are associated with age-related diseases such ascardiovascular disease and hypertension. However, this study alsosuggests that INSL3 may play a causal role in promoting healthybone metabolism. These findings suggest that INSL3 may be auseful biomarker for identifying individuals at risk of developingage-related male hypogonadism and related comorbidities.Testosterone deficiency associated with aging can lead to adecline in semen quality, indicating impaired spermatogenesis.Conventional semen quality assessments primarily includequantifiable parameters such as total sperm count, sperm volume,and progressive sperm motility, but fail to provide insight into theunderlying biological significance of these parameters. Recently,metabolomics and proteomics analyses were conducted on semenfrom aging males (Guo et al.). Guo et al. established a biomarkerpanel consisting of four metabolites (Pipamperone, 2,2-Bis(hydroxymethyl)-2,2’,2’’-nitrilotriethanol, Arg-Pro, Triethylphosphate), providing a potential diagnostic tool for identifyingaging semen. The combination of metabolomics and proteomicsanalyses revealed the enrichment of energy metabolism andoxidative stress-related pathways. These findings suggest thatalterations in energy consumption and increased oxidative stresscould be responsible for the decline in sperm motility and DNAintegrity observed with aging. Overall, this study highlights theimportance of understanding changes in semen metabolome andsperm proteome with aging and their implications for malereproductive health.Currently, testosterone replacement therapy (TRT) remains animportant treatment option for hypogonadism, although its clinicalapplication has been limited due to serious adverse effects. TRT hastraditionally been associated with adverse prostate events (9).However, a recent meta-analysis of 35 studies with over 7,700participants reported that TRT does not lead to abnormal prostategrowth, and may even reduce the risk of prostate cancer (Zenget al.). Intramuscular administration appears to be more effective inreducing the risk of prostate cancer. Although high-quality clinicalresearch are still required to confirm this observation, it suggeststhat clinicians should consider the route of administration whenprescribing TRT to minimize the risk of adverse effects.In addition to TRT, seeking alternative drugs for testosteronemay be a safer and more effective treatment strategy for malehypogonadism. Martinez-Arguelles et al. reported that the oraladministration of small molecule peptides derived from VDAC1can act within the HPG axis to increase testosterone levels in maleFrontiers in Endocrinology 02rats, suggesting a promising new method of testosteronesupplementation. This approach may have significantimplications for the treatment of male hypogonadism, particularlyin cases where traditional testosterone replacement therapy is notfeasible or desirable.Given that the decline in LC function is the key mechanism ofage-related male hypogonadism (5, 6), targeting LCs for treatmentmay provide a fundamental solution to testosterone deficiency,which is superior to symptomatic treatments such as TRT.However, the molecular mechanisms of LC aging remain largelyunknown. Luo et al. reported that LCs in both natural aging miceand diet-induced obese mice exhibit senescence phenotypes.Mechanistic studies revealed that p38 MAPK is a key molecule inLeydig cell aging. Inhibiting p38 MAPK activity has been shown toreverse Leydig cell senescence and increase testosterone synthesis,highlighting the important role of this pathway in malehypogonadism. This study deepens our understanding of themolecular mechanisms underlying LC aging and provides apotential therapeutic target for age-related male hypogonadism.In conclusion, age-related male hypogonadism is a complex andmultifactorial condition that demands further investigation. Recentadvances in clinical and epidemiological research, testosteronesupplementation, biomarkers for hypogonadism, semen quality,and Leydig cell aging offer promising avenues of research andtherapeutic targets. By continuing to explore these areas, we canbetter understand the mechanisms underlying male hypogonadismand develop more effective treatments for this disease, ultimatelyimproving the quality of life for affected men.Author contributionsKX and JY wrote the draft. GL, HC, RG and CD revised the text.All authors contributed to the article and approved thesubmitted version.Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.frontiersin.orgXia et al. 10.3389/fendo.2023.1207907References1. Tajar A, Huhtaniemi IT, O’Neill TW, Finn JD, Pye SR, Lee DM, et al.Characteristics of androgen deficiency in late-onset hypogonadism: results from theEuropean Male aging study (EMAS). J Clin Endocrinol Metab (2012) 97(5):1508–16.doi: 10.1210/jc.2011-25132. Liu ZY, Zhou RY, Lu X, Zeng QS, Wang HQ, Li Z, et al. Identification of late-onset hypogonadism in middle-aged and elderly men from a community of China.Asian J Androl (2016) 18(5):747–53. doi: 10.4103/1008-682X.1608833. Kaufman JM, Lapauw B, Mahmoud A, T’Sjoen G, Huhtaniemi IT. Aging and theMale reproductive system. Endocr Rev (2019) 40(4):906–72. doi: 10.1210/er.2018-001784. La Marca A, Sighinolfi G, Radi D, Argento C, Baraldi E, Artenisio AC, et al. Anti-mullerian hormone (AMH) as a predictive marker in assisted reproductive technology(ART). Hum Reprod Update (2010) 16(2):113–30. doi: 10.1093/humupd/dmp036Frontiers in Endocrinology 035. Chen H, Hardy MP, Huhtaniemi I, Zirkin BR. Age-related decreased leydig celltestosterone production in the brown Norway rat. J Androl (1994) 15(6):551–7.doi: 10.1002/j.1939-4640.1994.tb00498.x6. Zirkin BR, Chen H. Regulation of leydig cell steroidogenic function during aging.Biol Reprod (2000) 63(4):977–81. doi: 10.1095/biolreprod63.4.9777. Frederiksen H, Skakkebaek NE, Andersson AM. Metabolism of phthalatesin humans. Mol Nutr Food Res (2007) 51(7):899–911. doi: 10.1002/mnfr.2006002438. Ivell R, Anand-Ivell R. Biology of insulin-like factor 3 in human reproduction.Hum Reprod Update (2009) 15(4):463–76. doi: 10.1093/humupd/dmp0119. Klotz L. Testosterone therapy and prostate cancer–safety concerns are wellfounded. Nat Rev Urol (2015) 12(1):48–54. doi: 10.1038/nrurol.2014.338frontiersin.org

Editorial: Aging and male hypogonadism

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Editorial: Aging and male hypogonadism

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