Comprehensive approach to managing climacteric syndrome considering new pathogenetic mechanisms: Therapy and prevention

Climacteric Syndrome (CS) is a complex condition that extends beyond vasomotor symptoms (VMS) to include psychoemotional disorders, sleep disturbances, metabolic dysfunctions, and increased risks of somatic pathology. These changes affect up to 97.5% of women during peri- and postmenopause, impairing quality of life and elevating the risks of cardiovascular, neurodegenerative, and oncological diseases. This review provides analysis of current data from international electronic bibliographic and scientific databases (PubMed, Scopus, Web of Science, eLIBRARY.RU), as well as Cochrane Library and peer-reviewed medical journals. It focuses on several insufficiently elucidated pathophysiological aspects of postmenopausal disturbances, including the mechanisms of narrowing the hypothalamic thermoneutral zone, dysfunction of the serotonergic and noradrenergic neurotransmitter systems, the role of oxidative stress and decreased antioxidant enzyme activity, DNA damage and carcinogenesis, and the development of dyslipidemia, insulin resistance, and endothelial dysfunction. The review provides a detailed argument for the necessity of implementing a comprehensive therapeutic approach to CS, aimed not at isolated symptom relief but at the simultaneous correction of key interconnected pathogenetic links. It presents a detailed analysis of modern fundamental and clinical data demonstrating the efficacy of various active molecules, including β-alanine, isoflavones, 5-hydroxytryptophan, and vitamins C, E, and B. Their effects are examined in terms of stabilizing the thermoregulation center in the hypothalamus, selective modulation of estrogen receptors, improving lipid profile and insulin sensitivity, as well as restoring serotonin levels, homocysteine balance, and suppressing oxidative stress. This multicomponent patient management strategy ensures not only effective symptomatic control of vasomotor and psychoemotional manifestations of CS but also long-term prevention of cardiovascular, metabolic, and neurodegenerative complications, aligning with the principles of women’s active longevity.

1. Avis NE, Crawford SL, Green R. Vasomotor Symptoms Across the Menopause Transition: Differences Among Women. Obstet Gynecol Clin North Am. 2018;45(4):629–640. https://doi.org/10.1016/j.ogc.2018.07.005.

2. Smetnik SA, Ivanov IA, Ermakova EI, Tabeeva GI. Characteristics of menopausal hormone therapy use in Russia: results of a large-scale survey of periand postmenopausal women. Akusherstvo i Ginekologiya (Russian Federation). (In Russ.) 2025;(8):196–208. https://doi.org/10.18565/aig.2025.200.

3. Jia Y, Zhou Z, Xiang F, Hu W, Cao X. Global prevalence of depression in menopausal women: A systematic review and meta-analysis. J Affect Disord. 2024;358:474–482. https://doi.org/10.1016/j.jad.2024.05.051.

4. Ryczkowska K, Adach W, Janikowski K, Banach M, Bielecka-Dabrowa A. Menopause and women’s cardiovascular health: is it really an obvious relationship? Arch Med Sci. 2023;19(2):458–466. https://doi.org/10.5114/aoms/157308.

5. Doshi SB, Agarwal A. The role of oxidative stress in menopause. J Midlife Health. 2013;4(3):140–146. https://doi.org/10.4103/0976-7800.118990.

6. Li J, Liu F, Liu Z, Li M, Wang Y, Shang Y et al. Prevalence and associated factors of depression in postmenopausal women: a systematic review and meta-analysis. BMC Psychiatry. 2024;24(1):431. https://doi.org/10.1186/s12888-024-05875-0.

7. Freeman EW. Depression in the menopause transition: risks in the changing hormone milieu as observed in the general population. Womens Midlife Health. 2015;1(1):2. https://doi.org/10.1186/s40695-015-0002-y.

8. McKinlay SM, Brambilla DJ, Posner JG. “Reprint of” The normal menopause transition. Maturitas. 2008;61(1-2):4–16. https://doi.org/10.1016/j.maturitas.2008.09.005.

9. Huang S, Wang Z, Zheng D, Liu L. Anxiety disorder in menopausal women and the intervention efficacy of mindfulness-based stress reduction. Am J Transl Res. 2023;15(3):2016–2024. Available at: https://e-century.us/files/ajtr/15/3/ajtr0148421.pdf1.

10. Vaziri‐Harami R, Kazemi SN, Vaziri‐harami S, Hazari V, Farokh P, Valadbeigi T. The prevalence of depression and anxiety in premenopausal and menopausal women: A cross‐sectional study. Health Sci Rep. 2024;7(7):e2267. https://doi.org/10.1002/hsr2.2267.

11. Salari N, Hasheminezhad R, Hosseinian-Far A, Rasoulpoor S, Assefi M, Nankali S et al. Global prevalence of sleep disorders during menopause: a meta-analysis. Sleep Breath. 2023;27(5):1883–1897. https://doi.org/10.1007/s11325-023-02793-5.

12. Skibiak K, Dębski J, Przybyłowski J, Walędziak M, Różańska-Walędziak A. The influence of menopausal status on sleep quality in different populations – a narrative review. Menopausal Review. 2025;24(1):53–65. https://doi.org/10.5114/pm.2025.150450.

13. Jeon G-H. Insomnia in Postmenopausal Women: How to Approach and Treat It? J Clin Med. 2024;13(2):428. https://doi.org/10.3390/jcm13020428.

14. Yu Y, Yapeng H, Liu Z, Fang L, Li J, Luan Y et al. Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review). Int J Mol Med. 2025;56(6):215. https://doi.org/10.3892/ijmm.2025.5656.

15. Gava G, Orsili I, Alvisi S, Mancini I, Seracchioli R, Meriggiola MC. Cognition, Mood and Sleep in Menopausal Transition: The Role of Menopause Hormone Therapy. Medicina. 2019;55(10):668. https://doi.org/10.3390/medicina55100668.

16. Forma E, Urbańska K, Bryś M. Menopause Hot Flashes and Molecular Mechanisms Modulated by Food-Derived Nutrients. Nutrients. 2024;16(5):655. https://doi.org/10.3390/nu16050655.

17. Pachman DR, Jones JM, Loprinzi CL. Management of menopause-associated vasomotor symptoms: Current treatment options, challenges and future directions. Int J Womens Health. 2010;2:123–135. https://doi.org/10.2147/IJWH.S7721.

18. Wang H, Sun Y, Wang W, Wang X, Zhang J, Bai Y et al. Mapping the 5-HTergic neural pathways in perimenopausal mice and elucidating the role of oestrogen receptors in 5-HT neurotransmission. Heliyon. 2024;10(6):e27976. https://doi.org/10.1016/j.heliyon.2024.e27976.

19. Gombert-Labedens M, Vesterdorf K, Fuller A, Maloney SK, Baker FC. Effects of menopause on temperature regulation. Temperature. 2025;12(2):92–132. https://doi.org/10.1080/23328940.2025.2484499.

20. Rekkas PV, Wilson AA, Lee VWH, Yogalingam P, Sacher J, Rusjan P et al. Greater Monoamine Oxidase A Binding in Perimenopausal Age as Measured With Carbon 11–Labeled Harmine Positron Emission Tomography. JAMA Psychiatry. 2014;71(8):873. https://doi.org/10.1001/jamapsychiatry.2014.250.

21. Xu X, Pang Y, Fan X. Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances. Signal Transduct Target Ther. 2025;10(1):190. https://doi.org/10.1038/s41392-025-02253-4.

22. Sánchez-Rodríguez MA, Zacarías-Flores M, Arronte-Rosales A, Mendoza--Núñez VM. Association between hot flashes severity and oxidative stress among Mexican postmenopausal women: A cross-sectional study. PLoS ONE. 2019;14(9):e0214264. https://doi.org/10.1371/journal.pone.0214264.

23. Chandankhede M, Gupta M, Pakhmode S. Assessment of Psychological Status and Oxidative Stress in Postmenopausal Women: A Cross-Sectional Study. J Menopausal Med. 2021;27(3):155. https://doi.org/10.6118/jmm.20035.

24. Liang G, Kow ASF, Yusof R, Tham CL, Ho Y-C, Lee MT. Menopause--Associated Depression: Impact of Oxidative Stress and Neuroinflammation on the Central Nervous System – A Review. Biomedicines. 2024;12(1):184. https://doi.org/10.3390/biomedicines12010184.

25. Vassalle C. On oxidative status and cardiovascular risk in women: Keeping pink at heart. World J Cardiol. 2009;1(1):26. https://doi.org/10.4330/wjc.v1.i1.26.

26. Choi Y-J, Kim GS. Transitions in metabolic syndrome clustering patterns before and after menopause: a latent transition analysis in Korean women. Menopause. 2026;33(4):449–459. https://doi.org/10.1097/GME.0000000000002689.

27. Leanza G, Conte C, Cannata F, Isgrò C, Piccoli A, Strollo R et al. Oxidative Stress in Postmenopausal Women with or without Obesity. Cells. 2023;12(8):1137. https://doi.org/10.3390/cells12081137.

28. Fang K, Dong H, Wang D, Gong J, Huang W, Lu F. Soy isoflavones and glucose metabolism in menopausal women: A systematic review and meta‐analysis of randomized controlled trials. Mol Nutr Food Res. 2016;60(7):1602–1614. https://doi.org/10.1002/mnfr.201501024.

29. Steinberg FM, Murray MJ, Lewis RD, Cramer MA, Amato P, Young RL et al. Clinical outcomes of a 2-y soy isoflavone supplementation in menopausal women. Am J Clin Nutr. 2011;93(2):356–367. https://doi.org/10.3945/ajcn.110.008359.

30. Mao C, Yuan J-Q, Lv Y-B, Gao X, Yin Z-X, Kraus VB et al. Associations between superoxide dismutase, malondialdehyde and all-cause mortality in older adults: a community-based cohort study. BMC Geriatr. 2019;19(1):104. https://doi.org/10.1186/s12877-019-1109-z.

31. Abulajiang Y, Liu T, Wang M, Abulai A, Wu Y. The influence of menopause age on gynecologic cancer risk: a comprehensive analysis using NHANES data. Front Oncol. 2025;15:1541585. https://doi.org/10.3389/fonc.2025.1541585.

32. Dibaba DT, Ogunsina K, Braithwaite D, Akinyemiju T. Metabolic syndrome and risk of breast cancer mortality by menopause, obesity, and subtype. Breast Cancer Res Treat. 2019;174(1):209–218. https://doi.org/10.1007/s10549-018-5056-8.

33. Stachowiak G, Pertyński T, Pertyńska-Marczewska M. Metabolic disorders in menopause. Menopausal Review. 2015;1:59–64. https://doi.org/10.5114/pm.2015.50000.

34. Hallajzadeh J, Khoramdad M, Izadi N, Karamzad N, Almasi-Hashiani A, Ayubi E et al. Metabolic syndrome and its components in premenopausal and postmenopausal women: a comprehensive systematic review and meta-analysis on observational studies. Menopause. 2018;25(10):1155–1164. https://doi.org/10.1097/GME.0000000000001136.

35. Torshin IY, Gromova OA, Limanova OA. Rapid effect of beta-alanine in the therapy of hot flashes: a comparative biophysical modeling of interactions beta-alanine, taurine and glycine with the glycine receptors. Gynecology. 2012;14(2):65–69. (In Russ.) Available at: https://gynecology.orscience.ru/2079-5831/article/view/33323.

36. Gromova OA, Torshin IY, Limanova OA, Nikonov AA. The pathophysiology of vegetative-vascular paroxysms (hot flashes) in menopausal women and the mechanism of action of β-alanine. A new clinical and pharmacological concept. Gynecology. 2010;12(2):29–36. (In Russ.) Available at: https://medi.ru/info/950.

37. Zarochentseva NV, Dzhidzhikhiia LK. Possibilities of using klimalanin in menopausal women with vasomotor paroxysms. Russian Bulletin of Obstetrician-Gynecologist. 2012;12(3):92–97. (In Russ.) Available at: https://www.mediasphera.ru/issues/rossijskij-vestnik-akushera-ginekologa/2012/3/031726-61222012320.

38. Yevtushenko ID, Petrov IA, Petrova MS, Tkachev VN, Kislyak SV. The use of beta-alanine for the treatment of estrogen deficiency in surgical menopause. Akusherstvo i Ginekologiya (Russian Federation). 2014;(4):93–95. (In Russ.) Available at: https://aig-journal.ru/articles/Primenenie-alaninadlya-terapii-deficita-estrogenov-pri-hirurgicheskoi-menopauze.html.

39. Schneider MN. Nature’s Relief: Efficacy of Plant-Based Therapies vs. Placebo in Easing Vasomotor Menopausal Symptoms. Nursing Capstones. 2025;383:1–24. Available at: https://commons.und.edu/nurs-capstones/383.

40. Biniwale P, Biniwale V, Phadke A, Qamra A. Soy isoflavones in postmenopausal women: a review of current evidence. Am J Clin Exp Obstet Gyneco. 2022;8(1):1–13. Available at: https://e-century.us/files/ajceog/8/1/ajceog0144070.pdf.

41. Luan H, Liu Q, Guo Y, Fan H, A S, Lin J. Effects of soy isoflavones on menopausal symptoms in perimenopausal women: a systematic review and metaanalysis. PeerJ. 2025;13:e19715. https://doi.org/10.7717/peerj.19715.

42. Jacobs A, Wegewitz U, Sommerfeld C, Grossklaus R, Lampen A. Efficacy of isoflavones in relieving vasomotor menopausal symptoms – A systematic review. Mol Nutr Food Res. 2009;53(9):1084–1097. https://doi.org/10.1002/mnfr.200800552.

43. Mbu RE, Abauleth YR, Koffi A, Keita N, Dolo A, Lankoande J. Effect of daily supplementation of soy isoflavones on hot flashes and night sweats in African menopausal women. Open J Obstet Gynecol. 2014;4(1):42–46. https://doi.org/10.4236/ojog.2014.41008.

44. Prediger CC da C, Olinto MTA, Nácul LC, Ziegler DR, Pattussi MP. Effects of soy protein containing isoflavones on women’s lipid profile: a metaanalysis. Revista de Nutrição. 2011;24(1):161–172. https://doi.org/10.1590/S1415-52732011000100016.

45. Yang S, Zeng Q, Huang X, Liang Z, Hu H. Effect of Isoflavones on Blood Lipid Alterations in Postmenopausal Females: A Systematic Review and Meta-Analysis of Randomized Trials. Adv Nutr. 2023;14(6):1633–1643. https://doi.org/10.1016/j.advnut.2023.09.008.

46. Mannino G, Serio G, Gaglio R, Maffei ME, Settanni L, Di Stefano V et al. Biological Activity and Metabolomics of Griffonia simplicifolia Seeds Extracted with Different Methodologies. Antioxidants. 2023;12(9):1709. https://doi.org/10.3390/antiox12091709.

47. Murray MT. 5-Hydroxytryptophan. In: Textbook of Natural Medicine. Elsevier; 2013, pp. 820–832. https://doi.org/10.1016/B978-1-4377-2333-5.00098-5.

48. Maffei ME. 5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology. Int J Mol Sci. 2020;22(1):181. https://doi.org/10.3390/ijms22010181.

49. Javelle F, Lampit A, Bloch W, Häussermann P, Johnson SL, Zimmer P. Effects of 5-hydroxytryptophan on distinct types of depression: a systematic review and meta-analysis. Nutr Rev. 2020;78(1):77–88. https://doi.org/10.1093/nutrit/nuz039.

50. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198. https://doi.org/10.1002/14651858.CD003198.

51. Sutanto CN, Xia X, Heng CW, Tan YS, Lee DPS, Fam J et al. The impact of 5-hydroxytryptophan supplementation on sleep quality and gut microbiota composition in older adults: A randomized controlled trial. Clin Nutr. 2024;43(3):593–602. https://doi.org/10.1016/j.clnu.2024.01.010.

52. Iqbal Kh, Alam Kh, Khattak MMA. Biological Significance of Ascorbic Acid (Vitamin C) in Human Health – A Review. Pak J Nutr. 2003;3(1):5–13. https://doi.org/10.3923/pjn.2004.5.13.

53. El Mashad GM, ElSayed HM, Nosair NA. Effect of vitamin C supplementation on lipid profile, serum uric acid, and ascorbic acid in children on hemodialysis. Saudi J Kidney Dis Transpl. 2016;27(6):1148–1154. https://doi.org/10.4103/1319-2442.194602.

54. McRae MP. Vitamin C supplementation lowers serum low-density lipoprotein cholesterol and triglycerides: a meta-analysis of 13 randomized controlled trials. J Chiropr Med. 2008;7(2):48–58. https://doi.org/10.1016/j.jcme.2008.01.002.

55. Montoya-Estrada A, García-Cortés AY, Romo-Yañez J, Ortiz-Luna GF, Arellano-Eguiluz A, Belmont-Gómez A et al. The Administration of Resveratrol and Vitamin C Reduces Oxidative Stress in Postmenopausal Women – A Pilot Randomized Clinical Trial. Nutrients. 2024;16(21):3775. https://doi.org/10.3390/nu16213775.

56. Ozemek C, Hildreth KL, Groves DW, Moreau KL. Acute ascorbic acid infusion increases left ventricular diastolic function in postmenopausal women. Maturitas. 2016;92:154–161. https://doi.org/10.1016/j.maturitas.2016.08.007.

57. Vijayakumar TM, Pavitra K, Muthunarayanan L. Comparative assessment of methylcobalamin and ascorbic acid on cognitive function in postmenopausal women – A randomized, double-blind trial. Contemp Clin Trials Commun. 2017;8:175–180. https://doi.org/10.1016/j.conctc.2017.10.006.

58. Farshbaf-Khalili A, Ostadrahimi A, Mirghafourvand M, Ataei-Almanghadim K, Dousti S, Iranshahi AM. Clinical Efficacy of Curcumin and Vitamin E on Inflammatory-Oxidative Stress Biomarkers and Primary Symptoms of Menopause in Healthy Postmenopausal Women: A Triple-Blind Randomized Controlled Trial. J Nutr Metab. 2022;2022:6339715. https://doi.org/10.1155/2022/6339715.

59. Feduniw S, Korczyńska L, Górski K, Zgliczyńska M, Bączkowska M, Byrczak M et al. The Effect of Vitamin E Supplementation in Postmenopausal Women – A Systematic Review. Nutrients. 2022;15(1):160. https://doi.org/10.3390/nu15010160.

60. Takahashi M, Miyashita M, Park JH, Kawanishi N, Bae SR, Nakamura Y et al. Low-volume exercise training and vitamin E supplementation attenuates oxidative stress in postmenopausal women. J Nutr Sci Vitaminol. 2013;59(5):375–383. https://doi.org/10.3177/jnsv.59.375.

61. Milart P, Woźniakowska E, Wrona W. Selected vitamins and quality of life in menopausal women. Men Rev. 2018;17(4):180–184. https://doi.org/10.5114/pm.2018.81742.

62. Song Y, Cook NR, Albert CM, Van Denburgh M, Manson JE. Effect of Homocysteine-Lowering Treatment With Folic Acid and B Vitamins on Risk of Type 2 Diabetes in Women. Diabetes. 2009;58(8):1921–1928. https://doi.org/10.2337/db09-0087.

63. Pan L, Jaroenporn S, Yamamoto T, Nagaoka K, Azumano I, Onda M et al. Effects of pantothenic acid supplement on secretion of steroids by the adrenal cortex in female rats. Reprod Med Biol. 2012;11(2):101–104. https://doi.org/10.1007/s12522-011-0113-6.

64. Lü J, Lin PH, Yao Q, Chen C. Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. J Cell Mol Med. 2010;14(4):840–860. https://doi.org/10.1111/j.1582-4934.2009.00897.x.

65. Ramos-Tovar E, Muriel P. Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver. Antioxidants. 2020;9(12):1279. https://doi.org/10.3390/antiox9121279.

66. Trimarco V, Rozza F, Izzo R, De Leo V, Cappelli V, Riccardi C, Di Carlo C. Effects of a new combination of nutraceuticals on postmenopausal symptoms and metabolic profile: a crossover, randomized, double-blind trial. Int J Womens Health. 2016;8:581–587. https://doi.org/10.2147/IJWH.S115948.

67. Shikh EV, Grebenshhikova LY. A rational grant of micronutrients as a way to improve quality of life of climacteric syndrome patients. Meditsinskiy Sovet. 2017;(13): 166–171. (In Russ.) https://doi.org/10.21518/2079-701X-2017-13-166-171.