Neuroreproductive axis disruptions in early childhood: Unveiling hidden links between pediatric inflammation and future fertility risks (A literature review)
DOI:
https://doi.org/10.37800/RM.3.2025.561Keywords:
Neuroreproductive axis, pediatric inflammation, hypothalamic-pituitary-gonadal (HPG) dysfunction, childhood obesity, infertility risk, maternal immune activation, neuroendocrine disruptionAbstract
Relevance: The neuroreproductive axis, regulated by the hypothalamic-pituitary-gonadal (HPG) system, is critical for reproductive development and function. Early-life inflammation due to maternal immune activation, obesity, or infection can disrupt this axis, potentially impairing fertility and endocrine function later in life.
This study aimed to explore how pediatric inflammation affects neuroendocrine programming and reproductive outcomes.
Materials and Methods: A multidisciplinary review of clinical, epidemiological, and animal model studies was conducted to examine associations between early-life immune activation and later reproductive outcomes. Focus was placed on cytokine signaling (e.g., IL-6, TNF-α), hypothalamic development, and epigenetic modifications affecting GnRH and gonadotropin regulation.
Results: Findings reveal that inflammation during fetal and early childhood periods alters GnRH neuron migration and function. Elevated maternal or pediatric cytokines cross the blood-brain barrier, disrupt HPG signaling, and induce epigenetic changes in reproductive genes. These disruptions are associated with delayed puberty, altered menstrual cycles, reduced sperm quality, and conditions like PCOS. Chronic low-grade inflammation from childhood obesity further exacerbates reproductive hormone dysregulation.
Conclusions: Early-life inflammation emerges as a key disruptor of neuroreproductive development, with long-term effects on fertility, metabolism, and mental health. Identifying critical windows of vulnerability and implementing early screening may help prevent or mitigate long-term endocrine and reproductive dysfunction. These findings underscore the developmental origins of adult reproductive health and support targeting early-life inflammation as a strategy to improve future fertility outcomes.
References
1. Agarwal A, Rana M, Qiu E, AlBunni H, Bui AD, Henkel R. Role of oxidative stress, infection and inflammation in male infertility. Andrologia. 2018;50(11):e13126.
https://doi.org/10.1111/and.13126
2. Fauser BCJM, Devroey P, Diedrich K, Balaban B, Bonduelle M, Delemarre-van de Waal HA, Estella C, Ezcurra D, Geraedts J, Howles C, Lerner-Geva L, Serna J, Wells D. Health outcomes of children born after IVF/ICSI: a review of current expert opinion and literature. Reprod BioMed Online. 2013;28(2):162-182.
https://doi.org/10.1016/j.rbmo.2013.10.013
3. HPA HPG axis - The Real Life RD [Internet]. The Real Life RD. 2017 [cited 2025 Aug 20]. Available from:
https://www.thereallife-rd.com/2017/11/healing-your-hormones/hpa-hpg-axes/
4. Haidari F, Abiri B, Haghighizadeh M, Kayedani GA, Birgani NK. Association of hematological parameters with obesity- induced inflammation among young females in Ahvaz, South-West of Iran. Int J Prevent Med. 2020;11(1):55.
https://doi.org/10.4103/ijpvm.ijpvm_35_18
5. Emarloo Z, Doustkam M. Psychological treatment efficacy in primary dysmenorrhea. IAJIR. 2015;2(1):1-9.
https://iaiest.com/iaj/index.php/IAJIR/article/view/837
6. Hassan MS, Mahdi HT, Majed MS, Shakir AF, Alsafah AH, Alkafaji NA. Physiological Investigation of Lycium Barbarum’s Protective Effects on Reproductive Hormones and Antioxidant Status Against Sodium Dichromate-Induced Toxicity in Male Rats. Nat Eng Sci. 2025;10(1):393-402.
https://doi.org/10.28978/nesciences.1651172
7. Khyade VB. Innate Immune Responses in the Silkworm, Bombyx mori. Int Acad J Sci Eng. 2016;3(2):104-115.
https://iaiest.com/iaj/index.php/IAJSE/article/view/IAJSE1510035
8. Henein MY, Vancheri S, Longo G, Vancheri F. The role of inflammation in cardiovascular disease. Int J Mol Sci. 2022;23(21):12906.
https://doi.org/10.3390/ijms232112906
9. Hashemi B, Asgari K. Comparison of Neuropsychological Functions, Depression and Anxiety in postmenopausal and premenopausal Women in Isfahan. Int Acad J Soc Sci. 2016;3(1):90-98.
https://iaiest.com/iaj/index.php/IAJSS/article/view/IAJSS1510010
10. Fufezan ML, Mocanu EV. Obesity and fertility: a literature review of the association between parental obesity at the time of conception and embryo quality. Glob Reprod Health. 2023;8(2):e0069.
https://doi.org/10.1097/grh.0000000000000069
11. Xu X, Wu H, Bian Y, Cui L, Man Y, Wang Z, Zhang X, Zhang C, Geng L. The altered immunological status of children conceived by assisted reproductive technology. Reprod Biol Endocrinol. 2021;19(1):171.
https://doi.org/10.1186/s12958-021-00858-2
12. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: A review of Epidemiologic and Translational studies. Am J Psychiatr. 2010;167(3):261-280.
https://doi.org/10.1176/appi.ajp.2009.09030361
13. Gillman MW. Developmental origins of health and disease. New Engl J Med. 2005;353(17):1848-1850.
https://doi.org/10.1056/nejme058187
14. Kehm RD, Knight JA, Houghton LC, McDonald JA, Schwartz LA, Goldberg M, Chung WK, Frost CJ, Wei Y, Bradbury AR, Keegan THM, Daly MB, Buys SS, Andrulis IL, John EM, Terry MB. Childhood physical activity and pubertal timing: findings from the LEGACY girls study. Int J Epidemiol. 2024;53(1):dyad193.
https://doi.org/10.1093/ije/dyad193
15. Ramachandran S. Comparative Analysis of Antibiotic Use and Resistance Patterns in Hospitalized Patients. Clin J Med Health Pharm. 2023;1(1):73-82.
https://cjmhp.com/index.php/journal/article/view/1.1.06
16. Heerwagen MJR, Miller MR, Barbour LA, Friedman JE. Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. AJP Regul Integr Comp Physiol. 2010;299(3):R711-R722.
https://doi.org/10.1152/ajpregu.00310.2010
17. Reichetzeder C. Overweight and obesity in pregnancy: their impact on epigenetics. Eur J Clin Nutr. 2021;75(12),1710-1722.
https://doi.org/10.1038/s41430-021-00905-6
18. Dhage PC, Thakker RA, Warhade KK. Security Mechanism in MAMATA Healthcare System Using Rule based Algorithm for Maternal Hospitals and Pathology Laboratories. J Internet Serv Inf Secur. 2024;14(4):292-311.
https://doi.org/10.58346/JISIS.2024.I4.018
19. Nithya R, Savitha Devi T. Remote Health Monitoring System for Heart Patients. Int J Adv Eng Emerg Technol. 2020;11(2):99-105.
https://erlibrary.org/erl/ijaeet/article/view/192
20. Sharpe RM. The ‘oestrogen hypothesis’– where do we stand now? Andrology. 2003;26(1):2-15.
https://doi.org/10.1046/j.1365-2605.2003.00367.x
21. Buonacera A, Stancanelli B, Colaci M, Malatino L. Neutrophil to Lymphocyte Ratio: An Emerging Marker of the Relationships between the Immune System and Diseases. Int J Mol Sci. 2022;23(7):3636.
https://doi.org/10.3390/ijms23073636
22. Çintesun FNİ. The association between obesity and hematologic inflammatory markers in the first trimester pregnancies. Perinatal J. 2020;28(1):17-22.
https://doi.org/10.2399/prn.20.0281005
23. De Medeiros SF, Rodgers RJ, Norman RJ. Adipocyte and steroidogenic cell cross-talk in polycystic ovary syndrome. Hum Reprod Update. 2014;27(4):771-796.
https://doi.org/10.1093/humupd/dmab004
24. Jain A, Chatterjee D. The Evolution of Anatomical Terminology: A Historical and Functional Analysis. Glob J Med Term Res Inform. 2024;2(3):1-4.
25. Barabás K, Szabó-Meleg E, Ábrahám IM. Effect of inflammation on female Gonadotropin-Releasing Hormone (GNRH) neurons: mechanisms and consequences. Int J Mol Sci. 2020;21(2):529.
https://doi.org/10.3390/ijms21020529
26. Nirmala MS. Behavioural Analysis of Deaf and Mute People Using Gesture Detection. JOWUA. 2023;14(3):125-142.
https://doi.org/10.58346/JOWUA.2023.I3.010
27. Häggström M. Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle. WikiJ Med. 2014;1(1).
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 NISTEMR Research, N. Kumar, S. Pradhan
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
The articles published in this Journal are licensed under the CC BY-NC-ND 4.0 (Creative Commons Attribution – Non-Commercial – No Derivatives 4.0 International) license, which provides for their non-commercial use only. Under this license, users have the right to copy and distribute the material in copyright but are not permitted to modify or use it for commercial purposes. Full details on the licensing are available at https://creativecommons.org/licenses/by-nc-nd/4.0/.
