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The link between diabetes and male infertility: mechanisms and implications.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: The link between diabetes and male infertility: mechanisms and implications.
Συγγραφείς: Haffez H; Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Capital University (Formerly Helwan University), Cairo, 11795, Egypt. hesham.haffez@pharm.capu.edu.eg.; Center of Scientific Excellence 'Helwan Structural Biology Research, (HSBR)', Capital University (Formerly Helwan) Helwan University, Cairo, 11795, Egypt. hesham.haffez@pharm.capu.edu.eg.; Capital University (Formerly Helwan University), Cairo, 11795, Egypt. hesham.haffez@pharm.capu.edu.eg., Mosaad M; Benha Fertility and ICSI Centre, Qalyubia, 13511, Egypt., Rezk AY; Obstetrics & Gynecology Department, Faculty of Medicine, Benha University, Qalyubia, 13511, Egypt., Sayed A; Genomics Research Program, Children's Cancer Hospital 57357, 11562, Cairo, Egypt., Hassan ZA; Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Capital University (Formerly Helwan University), Cairo, 11795, Egypt.
Πηγή: Scientific reports [Sci Rep] 2026 Jul 24; Vol. 16 (1). Date of Electronic Publication: 2026 Jul 24.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
Imprint Name(s): Original Publication: London : Nature Publishing Group, copyright 2011-
Ιατρικοί όροι (MeSH): Infertility, Male*/metabolism , Infertility, Male*/etiology , Infertility, Male*/pathology , Diabetes Mellitus*, Testosterone/blood ; Luteinizing Hormone/blood ; Glycated Hemoglobin/metabolism ; Follicle Stimulating Hormone/blood ; Spermatozoa/metabolism ; Spermatozoa/pathology ; Caspase 3/metabolism ; Humans ; Male ; Apoptosis ; Adult ; DNA Fragmentation ; Sperm Motility ; Semen Analysis
Περίληψη: Diabetes mellitus (DM) is a growing global health crisis affecting male reproductive function, yet the enhanced combined effects of diabetes with pre-existing fertility abnormalities remain poorly understood. This study aims to investigate the individual and combined effects of diabetes and abnormal semen parameters on male reproductive function and the underlying apoptotic mechanisms. Thirty-nine men were enrolled and stratified into two phases: a validation cohort (nondiabetic vs. diabetic; fertile vs. abnormally infertile) and a four-group mechanistic study (normal nondiabetic (n = 10), abnormal nondiabetic (n = 11), normal diabetic (n = 10), and abnormal diabetic (n = 8)). We assessed HbA1c, FSH, LH, testosterone, semen parameters, sperm apoptosis (Annexin V/PI flow cytometry), DNA fragmentation (diphenylamine), and expression of apoptotic markers (caspase-3, cytochrome c, Bax, and Bcl-2) at gene and protein levels. Diabetic patients had significantly higher HbA1c (9.6 ± 2.31% vs. 5.49 ± 0.42%, p < 0.001), elevated FSH and LH, and reduced testosterone. Abnormal infertile patients showed impaired motility and morphology. The abnormal diabetic group had the most severe dysfunction: lowest rapid progressive motility (11.3 ± 3.10%, p < 0.001 vs. control) and highest early apoptosis (58.9 ± 8.79%, p < 0.0001). Protein analysis showed a pro-apoptotic shift with an elevated Bax/Bcl-2 ratio (3.64), increased cytochrome-c, and caspase-3 activation exclusively in this group (p < 0.0001). Diabetes and abnormal semen parameters exert enhanced combined detrimental effects on male fertility via enhanced activation of the intrinsic mitochondrial apoptotic pathway. Diabetic men with pre-existing fertility abnormalities exhibit the most severe phenotype and require prioritized clinical intervention.
(© 2026. The Author(s).)
Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol was approved by the Faculty of Pharmacy, Capital University (formerly Helwan University) Ethics Committee (Approval No. 02H2022). All participants provided written informed consent after receiving detailed information about the study objectives, procedures, potential risks, and benefits. Participants were assured of confidentiality and their right to withdraw at any time without affecting their medical care.
References: Hossain, M. J., Al-Mamun, M. & Islam, M. R. Diabetes mellitus, the fastest growing global public health concern: Early detection should be focused. Health Sci. Rep. 7, e https://doi.org/10.1002/hsr2.2004 (2024).
Khattab, M. et al. From guidelines to practice: an Egyptian expert opinion on type 2 diabetes mellitus management in primary care settings. BMC Prim. Care. 26, 392. https://doi.org/10.1186/s12875-025-03091-7 (2025). (PMID: 10.1186/s12875-025-03091-74129930712687541)
Agarwal, A. et al. Male infertility. Lancet 397, 319–333. https://doi.org/10.1016/S0140-6736(20)32667-2 (2021). (PMID: 10.1016/S0140-6736(20)32667-233308486)
Jain, C. & Khan, W. Psychosocial Concomitants of Infertility: A Narrative Review. Cureus 17, e80250. https://doi.org/10.7759/cureus.80250 (2025). (PMID: 10.7759/cureus.802504019607811975149)
Dena, S. M., Adeleye, A. O., Mohlala, K., Langa, B. C. & Opuwari, C. S. The Impact of Diabetes Mellitus-Related Oxidative Stress on Male Fertility: A Review. J. Diabetes. 17, e70157. https://doi.org/10.1111/1753-0407.70157 (2025). (PMID: 10.1111/1753-0407.701574112347312542312)
Osadchuk, L. V. & Osadchuk, A. V. Individual Lifestyle and Male Fertility. Hum. Physiol. 49, 196–207. https://doi.org/10.1134/S0362119722600527 (2023). (PMID: 10.1134/S0362119722600527)
Whittaker, J. Dietary trends and the decline in male reproductive health. Horm. (Athens Greece). 22, 165–197. https://doi.org/10.1007/s42000-023-00431-z (2023). (PMID: 10.1007/s42000-023-00431-z)
Zhang, W., Tong, L., Jin, B. & Sun, D. Diabetic testicular dysfunction and spermatogenesis impairment: mechanisms and therapeutic prospects. Front. Endocrinol. (Lausanne). 16, 1653975. https://doi.org/10.3389/fendo.2025.1653975 (2025). (PMID: 10.3389/fendo.2025.16539754092729012414793)
Alaei, A., Azizi, M. M. & Homayoun, M. Diabetes and male infertility: A review of sperm chromatin damage and epigenetic effects. Int. J. Reprod. Biomed. 23, 775–786. https://doi.org/10.18502/ijrm.v23i10.20312 (2025). (PMID: 10.18502/ijrm.v23i10.20312)
Hao, Y., Yang, Z., Feng, Y., Zhao, Y. & Ren, Y. Inflammation-mediated effects of diabetes mellitus on male fertility: a systematic review and meta-analysis. Front. Endocrinol. 16–2025. https://doi.org/10.3389/fendo.2025.1600565 (2025).
Kamal, E. E. et al. Semen parameters in Egyptian diabetic patients and its correlation with glycosylated hemoglobin level: A case - control study. Hum. Androl. 11, 1–6. https://doi.org/10.21608/ha.2020.29700.1061 (2021). (PMID: 10.21608/ha.2020.29700.1061)
Li, L. et al. Hormone Regulation in Testicular Development and Function. Int. J. Mol. Sci. 25 https://doi.org/10.3390/ijms25115805 (2024).
Akhtar, A. The flaws and human harms of animal experimentation. Camb. Q. Healthc. ethics: CQ : Int. J. Healthc. Ethics Committees. 24, 407–419. https://doi.org/10.1017/s0963180115000079 (2015). (PMID: 10.1017/s0963180115000079)
Zhang, W., Tong, L., Jin, B. & Sun, D. Diabetic testicular dysfunction and spermatogenesis impairment: mechanisms and therapeutic prospects. Front. Endocrinol. 16–2025. https://doi.org/10.3389/fendo.2025.1653975 (2025).
Wali, J. A., Masters, S. L. & Thomas, H. E. Linking metabolic abnormalities to apoptotic pathways in Beta cells in type 2 diabetes. Cells 2, 266–283 (2013). (PMID: 10.3390/cells2020266247097003972679)
Saddam, M. et al. Emerging biomarkers and potential therapeutics of the BCL-2 protein family: the apoptotic and anti-apoptotic context. Egypt. J. Med. Hum. Genet. 25 https://doi.org/10.1186/s43042-024-00485-7 (2024).
Peña-Blanco, A., García-Sáez, A. J. & Bax Bak and beyond — mitochondrial performance in apoptosis. FEBS J. 285, 416–431. https://doi.org/10.1111/febs.14186 (2018). (PMID: 10.1111/febs.1418628755482)
Ghea Farmaning Thias, P. & Zahara Nurfatihah, Z. Bax/Bcl-2 Ratio as the Golden Marker of Apoptosis: Molecular Mechanisms and Regulatory Pathways. Int. J. Cell. Biomed. Sci. 4 https://doi.org/10.59278/cbs.v4i10.65 (2025).
Aladaileh, S. H. et al. Modulation of Oxidative Stress, Inflammation, and Apoptosis and Restoration of Sirt1/Nrf2/HO-1 Signaling by Diosmin Protect Against Diabetes-Induced Testicular Damage in Rats. Int. J. Mol. Sci. 27 https://doi.org/10.3390/ijms27031268 (2026).
Graziani, A., Scafa, R., Grande, G. & Ferlin, A. Diabetes and male fertility disorders. Mol. Aspects Med. 99, 101303. https://doi.org/10.1016/j.mam.2024.101303 (2024). (PMID: 10.1016/j.mam.2024.10130339084095)
ElSayed, N. A. et al. 2. Classification and Diagnosis of Diabetes: Standards of Care in Diabetes-2023. Diabetes care 46, S19-s40, https://doi.org/10.2337/dc23-S002 (2023).
Lakshmi, G. & Mahadevan, S. Diabetes and Hypogonadism in Males. 22, 199–207, https://doi.org/10.1177/09760016251332088 (2025).
Louters, M., Pearlman, M., Solsrud, E. & Pearlman, A. Functional hypogonadism among patients with obesity, diabetes, and metabolic syndrome. Int. J. Impot. Res. 34, 714–720. https://doi.org/10.1038/s41443-021-00496-7 (2022). (PMID: 10.1038/s41443-021-00496-734775481)
Monageng, E., Offor, U., Takalani, N. B., Mohlala, K. & Opuwari, C. S. A Review on the Impact of Oxidative Stress and Medicinal Plants on Leydig Cells. Antioxid. (Basel Switzerland). 12 https://doi.org/10.3390/antiox12081559 (2023).
HE, Z., YIN, G., LI, Q. Q., ZENG, Q. & DUAN, J. Diabetes Mellitus Causes Male Reproductive Dysfunction: A Review of the Evidence and Mechanisms. Vivo 35, 2503–2511. https://doi.org/10.21873/invivo.12531 (2021). (PMID: 10.21873/invivo.12531)
Bhattacharya, S., Kalra, S., Dutta, D., Khandelwal, D. & Singla, R. The Interplay Between Pituitary Health and Diabetes Mellitus - The Need for ‘Hypophyseo-Vigilance’. Eur. Endocrinol. 16, 25–31. https://doi.org/10.17925/ee.2020.16.1.25 (2020). (PMID: 10.17925/ee.2020.16.1.2532595766)
Mallidis, C., Agbaje, I., McClure, N. & Kliesch, S. [The influence of diabetes mellitus on male reproductive function: a poorly investigated aspect of male infertility]. Der Urologe Ausg A. 50, 33–37. https://doi.org/10.1007/s00120-010-2440-3 (2011). (PMID: 10.1007/s00120-010-2440-321207007)
Dandona, P., Dhindsa, S. & Update Hypogonadotropic hypogonadism in type 2 diabetes and obesity. J. Clin. Endocrinol. Metab. 96, 2643–2651. https://doi.org/10.1210/jc.2010-2724 (2011). (PMID: 10.1210/jc.2010-2724218968953167667)
Wittert, G., Grossmann, M. & Obesity type 2 diabetes, and testosterone in ageing men. Rev. Endocr. Metabolic Disorders. 23, 1233–1242. https://doi.org/10.1007/s11154-022-09746-5 (2022). (PMID: 10.1007/s11154-022-09746-5)
Khanna, D., Peltzer, C., Kahar, P. & Parmar, M. S. Body Mass Index (BMI): A Screening Tool Analysis. Cureus 14, e22119. https://doi.org/10.7759/cureus.22119 (2022). (PMID: 10.7759/cureus.22119353087308920809)
Lee, C. M., Huxley, R. R., Wildman, R. P. & Woodward, M. Indices of abdominal obesity are better discriminators of cardiovascular risk factors than BMI: a meta-analysis. J. Clin. Epidemiol. 61, 646–653. https://doi.org/10.1016/j.jclinepi.2007.08.012 (2008). (PMID: 10.1016/j.jclinepi.2007.08.01218359190)
Lontchi-Yimagou, E. et al. An Atypical Form of Diabetes Among Individuals With Low BMI. Diabetes care. 45, 1428–1437. https://doi.org/10.2337/dc21-1957 (2022). (PMID: 10.2337/dc21-1957355220359184261)
AbbasiHormozi, S. et al. How much obesity and diabetes do impair male fertility? Reprod. Biol. Endocrinol. RB&E. 21 (48). https://doi.org/10.1186/s12958-022-01034-w (2023).
Chovsepian, A. et al. Diabetes increases mortality in patients with pancreatic and colorectal cancer by promoting cachexia and its associated inflammatory status. Mol. Metabolism. 73, 101729. https://doi.org/10.1016/j.molmet.2023.101729 (2023). (PMID: 10.1016/j.molmet.2023.101729)
Johannes, L. & Westcott, G. P. Weight Loss With Rising Blood Glucose: Challenges in Distinguishing Conventional Type 2 Diabetes From Pancreatic Cancer-Associated Hyperglycemia. Clin. Diabetes Publ. Am. Diabetes Assoc. 41, 477–480. https://doi.org/10.2337/cd22-0085 (2023). (PMID: 10.2337/cd22-0085)
Björndahl, L. & Kirkman Brown, J. The sixth edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen: ensuring quality and standardization in basic examination of human ejaculates. Fertil. Steril. 117, 246–251. https://doi.org/10.1016/j.fertnstert.2021.12.012 (2022). (PMID: 10.1016/j.fertnstert.2021.12.01234986984)
Minhas, S. et al. European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2025 Update on Male Infertility. Eur. Urol. 87, 601–616. https://doi.org/10.1016/j.eururo.2025.02.026 (2025). (PMID: 10.1016/j.eururo.2025.02.02640118737)
Minhas, S. et al. European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2021 Update on Male Infertility. Eur. Urol. 80, 603–620. https://doi.org/10.1016/j.eururo.2021.08.014 (2021). (PMID: 10.1016/j.eururo.2021.08.01434511305)
Concepción-Zavaleta, M. et al. Assessment of hormonal status in male infertility. An update. Diabetes Metabol. Syndrome. 16 https://doi.org/10.1016/j.dsx.2022.102447 (2022).
Zambrano Serrano, C. A. & Carvajal Obando, A. Diagnosis and hormonal treatment of male infertility. Actas Urol. Esp. 44, 321–327. https://doi.org/10.1016/j.acuro.2019.10.013 (2020). (PMID: 10.1016/j.acuro.2019.10.01332241672)
Sokol, R. Z. Endocrinology of male infertility: evaluation and treatment. Semin. Reprod. Med. 27, 149–158. https://doi.org/10.1055/s-0029-1202303 (2009). (PMID: 10.1055/s-0029-120230319247916)
Pierik, F. H., Vreeburg, J. T., Stijnen, T., De Jong, F. H. & Weber, R. F. Serum inhibin B as a marker of spermatogenesis. J. Clin. Endocrinol. Metab. 83, 3110–3114. https://doi.org/10.1210/jcem.83.9.5121 (1998). (PMID: 10.1210/jcem.83.9.51219745412)
Jankowska, K. et al. Inhibin-B and FSH Are Good Indicators of Spermatogenesis but Not the Best Indicators of Fertility. Life (Basel Switzerland). 12 https://doi.org/10.3390/life12040511 (2022).
Jangid, T., Jain, A., Bhardwaj, G. S., Jangir, R. N. & Jain, G. C. Diabetes mellitus-induced disruptions of male reproductive functions: A comprehensive review. 14, 194–210, https://doi.org/10.4103/apjr.apjr&#95;214&#95;25 (2025).
Kim, H. H., DiVall, S. A., Deneau, R. M. & Wolfe, A. Insulin regulation of GnRH gene expression through MAP kinase signaling pathways. Mol. Cell. Endocrinol. 242, 42–49. https://doi.org/10.1016/j.mce.2005.07.002 (2005). (PMID: 10.1016/j.mce.2005.07.00216144737)
DiVall, S. A. et al. Insulin receptor signaling in the GnRH neuron plays a role in the abnormal GnRH pulsatility of obese female mice. PloS one. 10, e0119995. https://doi.org/10.1371/journal.pone.0119995 (2015). (PMID: 10.1371/journal.pone.0119995257809374363364)
Schoeller, E. L., Schon, S. & Moley, K. H. The effects of type 1 diabetes on the hypothalamic, pituitary and testes axis. Cell Tissue Res. 349, 839–847. https://doi.org/10.1007/s00441-012-1387-7 (2012). (PMID: 10.1007/s00441-012-1387-7225266205402694)
Sliwowska, J. H. et al. Insulin: its role in the central control of reproduction. Physiol. Behav. 133, 197–206. https://doi.org/10.1016/j.physbeh.2014.05.021 (2014). (PMID: 10.1016/j.physbeh.2014.05.021248747774084551)
Brüning, J. C. et al. Role of brain insulin receptor in control of body weight and reproduction. Sci. (New York N Y). 289, 2122–2125. https://doi.org/10.1126/science.289.5487.2122 (2000). (PMID: 10.1126/science.289.5487.2122)
La Vignera, S., Condorelli, R., Vicari, E., D’Agata, R. & Calogero, A. E. Diabetes mellitus and sperm parameters. J. Androl. 33, 145–153. https://doi.org/10.2164/jandrol.111.013193 (2012). (PMID: 10.2164/jandrol.111.01319321474785)
Lotti, F. & Maggi, M. Effects of diabetes mellitus on sperm quality and fertility outcomes: Clinical evidence. Andrology 11, 399–416. https://doi.org/10.1111/andr.13342 (2023). (PMID: 10.1111/andr.1334236416060)
Barkabi-Zanjani, S., Ghorbanzadeh, V., Aslani, M., Ghalibafsabbaghi, A. & Chodari, L. Diabetes mellitus and the impairment of male reproductive function: Possible signaling pathways. Diabetes Metabolic Syndrome. 14, 1307–1314. https://doi.org/10.1016/j.dsx.2020.07.031 (2020). (PMID: 10.1016/j.dsx.2020.07.03132755827)
Minas, A., Camargo, M., Alves, M. G. & Bertolla, R. P. Effects of diabetes-induced hyperglycemia on epigenetic modifications and DNA packaging and methylation during spermatogenesis; A narrative review. Iran. J. Basic. Med. Sci. 27, 3–11. https://doi.org/10.22038/ijbms.2023.69604.15173 (2024). (PMID: 10.22038/ijbms.2023.69604.151733816448210722482)
Aitken, R. J. Impact of oxidative stress on male and female germ cells: implications for fertility. Reproduction 159, R189–R201. https://doi.org/10.1530/REP-19-0452 (2020). (PMID: 10.1530/REP-19-045231846434)
Aitken, R. J. & Drevet, J. R. The Importance of Oxidative Stress in Determining the Functionality of Mammalian Spermatozoa: A Two-Edged Sword. Antioxid. (Basel Switzerland). 9 https://doi.org/10.3390/antiox9020111 (2020).
Sengupta, P., Pinggera, G. M., Calogero, A. E. & Agarwal, A. Oxidative stress affects sperm health and fertility-Time to apply facts learned at the bench to help the patient: Lessons for busy clinicians. Reprod. Med. Biol. 23, e12598. https://doi.org/10.1002/rmb2.12598 (2024). (PMID: 10.1002/rmb2.12598)
Rong, J., Leng, X., Jiang, K., Tan, J. & Dong, M. Systemic impacts of diabetes on spermatogenesis and intervention strategies: multilayered mechanism analysis and cutting-edge therapeutic approaches. Reprod. Biol. Endocrinol. RB&E. 23 (122). https://doi.org/10.1186/s12958-025-01454-4 (2025).
Menkveld, R., Stander, F. S., Kotze, T. J., Kruger, T. F. & van Zyl, J. A. The evaluation of morphological characteristics of human spermatozoa according to stricter criteria. Hum. Reprod. (Oxford England). 5, 586–592. https://doi.org/10.1093/oxfordjournals.humrep.a137150 (1990). (PMID: 10.1093/oxfordjournals.humrep.a137150)
Roessner, C., Paasch, U., Kratzsch, J., Glander, H. J. & Grunewald, S. Sperm apoptosis signalling in diabetic men. Reprod. Biomed. Online. 25, 292–299. https://doi.org/10.1016/j.rbmo.2012.06.004 (2012). (PMID: 10.1016/j.rbmo.2012.06.00422796231)
Cai, L. et al. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes 51, 1938–1948. https://doi.org/10.2337/diabetes.51.6.1938 (2002). (PMID: 10.2337/diabetes.51.6.193812031984)
El Hayek, M. S., Ernande, L., Benitah, J. P., Gomez, A. M. & Pereira, L. The role of hyperglycaemia in the development of diabetic cardiomyopathy. Arch. Cardiovasc. Dis. 114, 748–760. https://doi.org/10.1016/j.acvd.2021.08.004 (2021). (PMID: 10.1016/j.acvd.2021.08.00434627704)
Sakkas, D., Alvarez, J. G. & Sperm DNA fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. Fertil. Steril. 93, 1027–1036. https://doi.org/10.1016/j.fertnstert.2009.10.046 (2010). (PMID: 10.1016/j.fertnstert.2009.10.04620080235)
Shaha, C., Tripathi, R. & Mishra, D. P. Male germ cell apoptosis: regulation and biology. Philos. Trans. R. Soc. Lond. B Biol. Sci. 365, 1501–1515. https://doi.org/10.1098/rstb.2009.0124 (2010). (PMID: 10.1098/rstb.2009.0124204038662871916)
Shen, H. M., Dai, J., Chia, S. E., Lim, A. & Ong, C. N. Detection of apoptotic alterations in sperm in subfertile patients and their correlations with sperm quality. Hum. Reprod. (Oxford England). 17, 1266–1273. https://doi.org/10.1093/humrep/17.5.1266 (2002). (PMID: 10.1093/humrep/17.5.1266)
Simon, L., Castillo, J., Oliva, R. & Lewis, S. E. Relationships between human sperm protamines, DNA damage and assisted reproduction outcomes. Reprod. Biomed. Online. 23, 724–734. https://doi.org/10.1016/j.rbmo.2011.08.010 (2011). (PMID: 10.1016/j.rbmo.2011.08.01022036908)
Fortes, M. R. S. et al. Sperm protamine deficiency correlates with sperm DNA damage in Bos indicus bulls. 2, 370–378, https://doi.org/10.1111/j.2047-2927.2014.00196.x (2014).
Aitken, R. J. & Koppers, A. J. Apoptosis and DNA damage in human spermatozoa. Asian J. Androl. 13, 36–42. https://doi.org/10.1038/aja.2010.68 (2011). (PMID: 10.1038/aja.2010.6820802502)
Vasiee, M. & Agha-Rahimi, A. Complex in vitro fertilization laboratory factors affecting sperm DNA integrity: A narrative review. Int. J. Reprod. Biomed. 23, 971–984. https://doi.org/10.18502/ijrm.v23i12.20710 (2025). (PMID: 10.18502/ijrm.v23i12.20710)
Weng, S. L. et al. Caspase activity and apoptotic markers in ejaculated human sperm. Mol. Hum. Reprod. 8, 984–991. https://doi.org/10.1093/molehr/8.11.984 (2002). (PMID: 10.1093/molehr/8.11.98412397210)
Sakkas, D., Mariethoz, E. & St. John, J. C. Abnormal Sperm Parameters in Humans Are Indicative of an Abortive Apoptotic Mechanism Linked to the Fas-Mediated Pathway. Exp. Cell Res. 251, 350–355. https://doi.org/10.1006/excr.1999.4586 (1999). (PMID: 10.1006/excr.1999.458610471320)
Nallella, K. P. et al. Relationship of interleukin-6 with semen characteristics and oxidative stress in patients with varicocele. Urology 64, 1010–1013. https://doi.org/10.1016/j.urology.2004.05.045 (2004). (PMID: 10.1016/j.urology.2004.05.04515533496)
Eldamnhoury, E. M., Elatrash, G. A. & Rashwan, H. M. El-Sakka, A. I. Association between leukocytospermia and semen interleukin-6 and tumor necrosis factor-alpha in infertile men. Andrology 6, 775–780. https://doi.org/10.1111/andr.12513 (2018). (PMID: 10.1111/andr.1251329981212)
Dutta, S., Bocu, K. & Agarwal, A. Role of leukocytospermia in the management of male infertility: decoding a mystery for the busy clinicians. World J. Men’s Health. 43, 465 (2024). (PMID: 10.5534/wjmh.240152)
Yoshida, S. et al. A combination of interleukin-6 and its soluble receptor impairs sperm motility: implications in infertility associated with endometriosis. Hum. Reprod. (Oxford England). 19, 1821–1825. https://doi.org/10.1093/humrep/deh324 (2004). (PMID: 10.1093/humrep/deh324)
Sanocka, D., Jedrzejczak, P., Szumała-Kaekol, A., Fraczek, M. & Kurpisz, M. Male genital tract inflammation: The role of selected interleukins in regulation of pro-oxidant and antioxidant enzymatic substances in seminal plasma. J. Androl. 24, 448–455. https://doi.org/10.1002/j.1939-4640.2003.tb02693.x (2003). (PMID: 10.1002/j.1939-4640.2003.tb02693.x12721221)
Fabian, M. R., Sonenberg, N. & Filipowicz, W. Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 79, 351–379. https://doi.org/10.1146/annurev-biochem-060308-103103 (2010). (PMID: 10.1146/annurev-biochem-060308-10310320533884)
Vogel, C. & Marcotte, E. M. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet. 13, 227–232. https://doi.org/10.1038/nrg3185 (2012). (PMID: 10.1038/nrg3185224114673654667)
Asadi, A., Ghahremani, R., Abdolmaleki, A. & Rajaei, F. Role of sperm apoptosis and oxidative stress in male infertility: A narrative review. Int. J. Reprod. Biomed. 19, 493–504. https://doi.org/10.18502/ijrm.v19i6.9371 (2021). (PMID: 10.18502/ijrm.v19i6.9371)
Wang, S., Chung, J. P. W. & Chan, D. Y. L. Reactive Oxygen and Nitrogen Species in Male Reproductive Health: From Molecular Mechanisms to Clinical Consequences. 15, 795 (2026).
Aitken, R. J. & Baker, M. A. Causes and consequences of apoptosis in spermatozoa; contributions to infertility and impacts on development. Int. J. Dev. Biol. 57, 265–272. https://doi.org/10.1387/ijdb.130146ja (2013). (PMID: 10.1387/ijdb.130146ja23784837)
Czabotar, P. E. & Garcia-Saez, A. J. Mechanisms of BCL-2 family proteins in mitochondrial apoptosis. Nat. Rev. Mol. Cell Biol. 24, 732–748. https://doi.org/10.1038/s41580-023-00629-4 (2023). (PMID: 10.1038/s41580-023-00629-437438560)
Yaribeygi, H., Sathyapalan, T., Atkin, S. L. & Sahebkar, A. Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus. Oxidative Med. Cell. Long. 8609213, https://doi.org/10.1155/2020/8609213 (2020).
Zhao, Y. et al. Exacerbation of diabetes-induced testicular apoptosis by zinc deficiency is most likely associated with oxidative stress, p38 MAPK activation, and p53 activation in mice. Toxicol. Lett. 200, 100–106 (2011). (PMID: 10.1016/j.toxlet.2010.11.00121078376)
Kilarkaje, N. & Al-Bader, M. M. Diabetes-induced oxidative DNA damage alters p53-p21CIP1/Waf1 signaling in the rat testis. Reproductive Sci. (Thousand Oaks Calif). 22, 102–112. https://doi.org/10.1177/1933719114533729 (2015). (PMID: 10.1177/1933719114533729)
Murphy, C. J. & Richburg, J. H. Implications of Sertoli cell induced germ cell apoptosis to testicular pathology. Spermatogenesis 4, e979110. https://doi.org/10.4161/21565562.2014.979110 (2014). (PMID: 10.4161/21565562.2014.97911026413394)
De León-Ramírez, Y. M., Nicolás-Toledo, L. & Pérez-Sánchez, E. & Arroyo-Helguera, O. Chronic Variable Stress May Induce Apoptosis in the Testis and Epididymal Sperm of Young Male Rats. Biology 14, https://doi.org/10.3390/biology14060690 (2025).
Sinha Hikim, A. P. & Swerdloff, R. S. Hormonal and genetic control of germ cell apoptosis in the testis. Rev. Reprod. 4, 38–47. https://doi.org/10.1530/ror.0.0040038 (1999). (PMID: 10.1530/ror.0.004003810051101)
Hikim, A. P., Wang, C., Leung, A. & Swerdloff, R. S. Involvement of apoptosis in the induction of germ cell degeneration in adult rats after gonadotropin-releasing hormone antagonist treatment. Endocrinology 136, 2770–2775. https://doi.org/10.1210/endo.136.6.7750502 (1995). (PMID: 10.1210/endo.136.6.77505027750502)
Cory, S. & Adams, J. M. The Bcl2 family: regulators of the cellular life-or-death switch. Nat. Rev. Cancer. 2, 647–656. https://doi.org/10.1038/nrc883 (2002). (PMID: 10.1038/nrc88312209154)
Ilacqua, A., Izzo, G., Emerenziani, G. P., Baldari, C. & Aversa, A. Lifestyle and fertility: the influence of stress and quality of life on male fertility. Reprod. Biol. Endocrinol. RB&E. 16, 115. https://doi.org/10.1186/s12958-018-0436-9 (2018). (PMID: 10.1186/s12958-018-0436-9)
Odetayo, A. F., Akhigbe, R. E., Bassey, G. E., Hamed, M. A. & Olayaki, L. A. Impact of stress on male fertility: role of gonadotropin inhibitory hormone. Front. Endocrinol. 14–2023. https://doi.org/10.3389/fendo.2023.1329564 (2024).
Zakariah, M., Molele, R. A., Mahdy, M. A. A., Ibrahim, M. I. A. & McGaw, L. J. Regulation of spermatogenic cell apoptosis by the pro-apoptotic proteins in the testicular tissues of mammalian and avian species. Anim. Reprod. Sci. 247, 107158. https://doi.org/10.1016/j.anireprosci.2022.107158 (2022). (PMID: 10.1016/j.anireprosci.2022.10715836435053)
Zhang, W., Tong, L., Jin, B. & Sun, D. Diabetic testicular dysfunction and spermatogenesis impairment: mechanisms and therapeutic prospects. Vol 16– https://doi.org/10.3389/fendo.2025.1653975 (2025).
Xu, Y. R., Dong, H. S. & Yang, W. X. Regulators in the apoptotic pathway during spermatogenesis: Killers or guards? Gene 582, 97–111. https://doi.org/10.1016/j.gene.2016.02.007 (2016). (PMID: 10.1016/j.gene.2016.02.00726861610)
Xu, Y. R., Dong, H. S. & Yang, W. X. Regulators in the apoptotic pathway during spermatogenesis: Killers or guards? Gene 582, 97–111. https://doi.org/10.1016/j.gene.2016.02.007 (2016). (PMID: 10.1016/j.gene.2016.02.00726861610)
Fertility preservation in. patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil. Steril. 112, 1022–1033. https://doi.org/10.1016/j.fertnstert.2019.09.013 (2019). (PMID: 10.1016/j.fertnstert.2019.09.013)
Fertility preservation in. patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil. Steril. 100, 1214–1223. https://doi.org/10.1016/j.fertnstert.2013.08.012 (2013). (PMID: 10.1016/j.fertnstert.2013.08.012)
Dimitriadis, F., Borgmann, H., Struck, J. P., Salem, J. & Kuru, T. H. Antioxidant Supplementation on Male Fertility-A Systematic Review. Antioxid. (Basel Switzerland). 12 https://doi.org/10.3390/antiox12040836 (2023).
Showell, M. G. et al. Antioxidants for male subfertility. Cochrane Database Syst. Rev., Cd007411, https://doi.org/10.1002/14651858.CD007411.pub3 (2014).
Kroemer, G., Galluzzi, L. & Brenner, C. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87, 99–163. https://doi.org/10.1152/physrev.00013.2006 (2007). (PMID: 10.1152/physrev.00013.200617237344)
Faul, F., Erdfelder, E., Lang, A. G. & Buchner, A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods. 39, 175–191. https://doi.org/10.3758/bf03193146 (2007). (PMID: 10.3758/bf0319314617695343)
Cohen, J. Statistical power analysis for the behavioral sciences (2nd ed.). (1988).
Colling, C., Atlas, S. J. & Wexler, D. J. Application of 2021 American Diabetes Association Glycemic Treatment Clinical Practice Recommendations in Primary Care. Diabetes care. 44, 1443–1446. https://doi.org/10.2337/dc21- (2021). (PMID: 10.2337/dc21340166188247510)
Chung, E., Atmoko, W., Saleh, R., Shah, R. & Agarwal, A. Sixth edition of the World Health Organization laboratory manual of semen analysis: Updates and essential take away for busy clinicians. Arab. J. Urol. 22, 71–74. https://doi.org/10.1080/20905998.2023.2298048 (2024). (PMID: 10.1080/20905998.2023.229804838481407)
Rohlfing, C. L., Hanson, S., Tennill, A. L. & Little, R. R. Effects of Whole Blood Storage on Hemoglobin A1c Measurements with Five Current Assay Methods. Diabetes. Technol. Ther. 14, 271–275. https://doi.org/10.1089/dia.2011.0136 (2012). (PMID: 10.1089/dia.2011.013622032202)
Verdi, A., Nasr-Esfahani, M. H., Forouzanfar, M. & Tavalaee, M. The Effect of Recombinant Human Follicle-Stimulating Hormone on Sperm Quality, Chromatin Status and Clinical Outcomes of Infertile Oligozoospermic Men Candidate for Intracytoplasmic Sperm Injection: A Randomized Clinical Trial. Int. J. fertility Steril. 15, 1–7. https://doi.org/10.22074/ijfs.2021.6210 (2021). (PMID: 10.22074/ijfs.2021.6210)
Agarwal, R., Pandey, T., Verma, D. & Kumar, A. Forensic significance of ELISA technique for hormone assessment: a comprehensive review. J. Immunoassay Immunochem. 47, 1–17. https://doi.org/10.1080/15321819.2025.2603249 (2026). (PMID: 10.1080/15321819.2025.260324941420869)
Wald, G. et al. Assessing the clinical value of the Kruger strict morphology criteria over the World Health Organization fourth edition criteria. F&S Rep. 2, 176–180. https://doi.org/10.1016/j.xfre.2021.04.003 (2021). (PMID: 10.1016/j.xfre.2021.04.003)
Abdelaal, M. R., Soror, S. H., Elnagar, M. R. & Haffez, H. Revealing the potential application of EC-synthetic retinoid analogues in anticancer therapy. Molecules 26, 506 (2021). (PMID: 10.3390/molecules26020506334779977835894)
Haffez, H., Osman, S., Ebrahim, H. Y. & Hassan, Z. A. Growth inhibition and apoptotic effect of pine extract and abietic acid on MCF-7 breast cancer cells via alteration of multiple gene expressions using in vitro approach. Molecules 27, 293 (2022). (PMID: 10.3390/molecules27010293350115268746537)
Bullying et al. Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach. Int. J. Mol. Sci. 23, 9442 (2022). (PMID: 10.3390/ijms23169442)
Burton, K. A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. Biochem. J. 62, 315–323. https://doi.org/10.1042/bj0620315 (1956). (PMID: 10.1042/bj0620315132931901215910)
Gibb, R. K. & Gercel-Taylor, C. Use of diphenylamine in the detection of apoptosis. Methods Mol. Med. 39, 679–680. https://doi.org/10.1385/1-59259-071-3:679 (2001). (PMID: 10.1385/1-59259-071-3:67921340829)
Gibb, R. K. et al. Apoptosis as a measure of chemosensitivity to cisplatin and taxol therapy in ovarian cancer cell lines. Gynecol. Oncol. 65, 13–22. https://doi.org/10.1006/gyno.1997.4637 (1997). (PMID: 10.1006/gyno.1997.46379103385)
Haffez, H., Sanad, H. H., Ebrahim, H. & Hassan, Z. A. Synergistic effects of abietic acid combined with doxorubicin on apoptosis induction in a human colorectal cancer cell line. Sci. Rep. 15, 16102. https://doi.org/10.1038/s41598-025-99616-2 (2025). (PMID: 10.1038/s41598-025-99616-24034122212062260)
Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402–408, https://doi.org/10.1006/meth.2001.1262 (2001).
Paoli, D. et al. Sperm glyceraldehyde 3-phosphate dehydrogenase gene expression in asthenozoospermic spermatozoa. Asian J. Androl. 19, 409–413. https://doi.org/10.4103/1008-682x.173934 (2017). (PMID: 10.4103/1008-682x.173934270804765507084)
Silva, C. et al. Further Insights on RNA Expression and Sperm Motility. Genes 13 https://doi.org/10.3390/genes13071291 (2022).
Min, K. S., Byambaragchaa, M., Kim, H. & Park, M. H. Identification of Sperm mRNA Biomarkers Associated with Sex-Determination in Korean Native Cows. J. Anim. Reprod. Biotechnol. 34, 111–116. https://doi.org/10.12750/JARB.34.2.111 (2019). (PMID: 10.12750/JARB.34.2.111)
Contributed Indexing: Keywords: Apoptosis; Diabetes mellitus; Hormones; Male infertility; Semen
Substance Nomenclature: 3XMK78S47O (Testosterone)
9002-67-9 (Luteinizing Hormone)
0 (Glycated Hemoglobin)
9002-68-0 (Follicle Stimulating Hormone)
EC 3.4.22.- (Caspase 3)
Entry Date(s): Date Created: 20260724 Date Completed: 20260724 Latest Revision: 20260728
Update Code: 20260728
PubMed Central ID: PMC13400617
DOI: 10.1038/s41598-026-63095-w
PMID: 42498725
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2045-2322
DOI:10.1038/s41598-026-63095-w