Menopause: biological causes, cinical consequences, and evidence-based management

Öz

Menopause is a physiological life stage defined by at least 12 consecutive months of amenorrhea, most commonly occurring between 45 and 55 years of age (median, 51 years). With increasing life expectancy, this post-reproductive period can extend to one-third of a woman’s life, amplifying its clinical and societal impact. Biologically, the process is driven by lifelong atresia and depletion of a fixed, non-renewable oocyte/follicle pool established in fetal life. This mechanism renders reproductive ageing earlier and steeper than somatic ageing. Although evolutionary biology points to several potential advantages of menopause at the population level, it remains a challenging period for many women. In clinical practice, the main concerns cluster around vasomotor symptoms, sleep and mood disturbances, cognitive complaints, genitourinary syndrome of menopause (GSM), bone loss/osteoporosis, and increased cardiometabolic risk. For management, hormone replacement therapy (HRT) is the most effective option for vasomotor symptoms in appropriately selected patients; when HRT is contraindicated or not preferred, SSRIs/SNRIs, gabapentinoids, and behavioral interventions are reasonable alternatives.

Anahtar Kelimeler

• menopause; ovar!an reserve
• hormone replacement therapy

Menopoz: Biyolojik Nedenler, Klinik Sonuçlar ve Kanıta Dayalı Yönetim

Öz

Menopoz, kadınlarda en az 12 ardışık ay adet görmeme ile tanımlanan; çoğunlukla 45–55 yaş aralığında ortaya çıkan (ortanca, 51 yıl) fizyolojik bir yaşam evresidir. Günümüzde yaşam süresinin uzamasıyla birlikte bu post-reprodüktif dönem kadın hayatının üçte birine kadar uzayabilmekte, dolayısıyla klinik ve toplumsal etkisi belirginleşmektedir. Biyolojik olarak süreci tetikleyen temel mekanizma, fetal dönemde belirlenen ve yenilenmeyen oosit/folikül havuzunun yaşam boyu atrezisi ile oositlerin tüketilmesidir. Bu durum reprodüktif yaşlanmayı somatik yaşlanmadan daha erken ve keskin hâle getirir. Evrimsel biyoloji açısından birçok faydası olduğu görülse de menopoz kadın hayatının zor bir dönemidir. Klinik pratikte başlıca sorunlar vazomotor yakınmalar, uyku ve duygu durum bozuklukları, bilişsel şikâyetler, genitoüriner sendrom (GSM), kemik kaybı/osteoporoz ve kardiyometabolik risklerde artış etrafında toplanır. Yönetimde, uygun hastada hormon replasman tedavisi (HRT) vazomotor semptomlar için en etkili seçenektir; HRT’nin uygun olmadığı ya da tercih edilmediği durumlarda SSRI/SNRI, gabapentinoidler ve davranışsal yaklaşımlar değerlendirilebilir.

Anahtar Kelimeler

• Menopoz
• over rezervi
• hormon replasman tedavisi

Kaynakça

1. Santoro N, Randolph JF, Allshouse A, et al. Menopause: An Endocrine Society Scientific Statement. J Clin Endocrinol Metab. 2022;107(4):1051–80.
2. Broekmans FJ, Soules MR, Fauser BC, et al. Ovarian aging: mechanisms and clinical consequences. Endocr Rev. 2009;30(5):465–93.
3. Maclaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med. 2004;350(4):367–78.
4. Manson JE, Kaunitz AM, Shifren JL, et al. Menopause management getting clinical care back on track. N Engl J Med. 2023;388(13):1173–6.
5. Ellis S, Fricke H, Bender N, et al. The evolutionary puzzle of menopause. Trends Ecol Evol. 2022;37(6):507–20.
6. Gurven M, Kaplan H. Longevity among hunter-gatherers: a cross-cultural examination. Popul Dev Rev. 2007;33(2):321–65.
7. Hawkes K, O'Connell JF, Blurton Jones NG, et al. Grandmothers and the evolution of human longevity. Am J Hum Biol. 1998;10(4):385–95.
8. Crimmins EM, Zhang YS, Seeman TE, et al. Historical changes in life expectancy: Implications for health. Annu Rev Public Health. 2022;43:145–60.

9. Hawkes K. Grandmother effects. Curr Biol. 2010;20(21):R894–6.
10. Hale GE, Hughes CL, Burger HG, et al. Endocrine features of the menopausal transition. Maturitas. 2009;63(2):131–9.
11. Broekmans FJ, Soules MR, Fauser BC, et al. Female reproductive ageing: current knowledge and future trends. Trends Endocrinol Metab. 2022;33(10):685–97.
12. Gruhn JR, Zielinska AP, Costanzo V, et al. Oocyte aging and chromosomal instability. Hum Reprod Update. 2023;29(2):147–63.
13. Broekmans FJ, Knauff EA, te Velde ER, et al. Ovarian reserve tests. Fertil Steril. 2006;86(5):S223–33.
14. Richardson SJ, Nelson JF, Follicle D, et al. The biology of aging oocytes and follicles. Reproduction. 2021;162(6):F139–55.
15. Gosden RG, Laing SC, Felicio LS, et al. Ovarian aging in primates. Biol Reprod. 2000;62(6):1512–21.
16. Steuerwald N, Barritt JA, Adler R, et al. Mitochondrial DNA content of individual human oocytes correlates with implantation potential. J Assist Reprod Genet. 2000;17(10):529–32.
17. Tilly JL. Apoptosis and ovarian function. Rev Reprod. 1996;1(3):162–72.
18. Bentov Y, Casper RF. The aging oocyte—can mitochondrial function be improved? Fertil Steril. 2013;99(1):18–22.
19. Grondahl ML, Yding AC, Meinertz H, et al. Oocyte quality and aging. Mol Hum Reprod. 2012;18(3):87–93.
20. Albertini DF. Oocyte–granulosa cell heterologous gap junctions are required for the coordination of nuclear and cytoplasmic meiotic competence. Dev Biol. 2000;226(2):167–79.
21. Plancha CE. Germ-Somatic Cell Interactions Are Involved in Establishing the Follicle Reserve in Mammals. Front Cell Dev Biol. 2021;9:674137.
22. Canipari R. Oocyte–granulosa cell interactions. Hum Reprod Update. 2000;6(3):279–89.
23. Griffith LG, Sheldon MR, Ferrante RS, et al. Menstruation: science and society. Am J Obstet Gynecol. 2020;223(5):624–64.
24. Loprinzi CL. Chemotherapy-induced ovarian failure: manifestations and management. Drug Saf. 2005;28(5):401–16.
25. Laven JS. Genetics of Early and Normal Menopause. Semin Reprod Med. 2015;33(6):377–83.
26. Bertone-Johnson ER, Whitcomb BW, Missmer SA, et al. Cigarette Smoking and Risk of Early Natural Menopause. Am J Epidemiol. 2018;187(4):696–704.
27. Várbíró S, Kósa B, Szabó M, et al. The Importance of Nutrition in Menopause and Perimenopause—A Review. Nutrients. 2023;16(1):72.
28. Nappi RE. Impact of climate and environmental change on the menopause. Maturitas. 2023;178:107825.
29. Rocca WA. Long-term health consequences of premature or early menopause and considerations for management. Climacteric. 2015;18(4):483–91.
30. Loprinzi CL. Chemotherapy-induced ovarian failure: manifestations and management. Drug Saf. 2005;28(5):401–16.
31. Madsen BL, Giudice L, Donaldson SS, et al. Radiation-induced premature menopause: a misconception. Int J Radiat Oncol Biol Phys. 1995;32(5):1461–4.
32. Santoro N, Roeca C, Peters BA, et al. The Menopause Transition: Signs, Symptoms, and Management Options. J Clin Endocrinol Metab. 2021;106(1):1–15.
33. Seckin S, Ramadan H, Mouanness M, et al. Ovarian response to intraovarian platelet-rich plasma (PRP) administration: hypotheses and potential mechanisms of action. J Assist Reprod Genet. 2022;39(1):37–61.
34. Hoang VT, Nguyen HP, Nguyen VN, et al. Adipose-derived mesenchymal stem cell therapy for the management of female sexual dysfunction. Front Cell Dev Biol. 2022;10:956274.
35. Oktay KH, Marin L, Petrikovsky B, et al. Delaying Reproductive Aging by Ovarian Tissue Cryopreservation and Transplantation. Trends Mol Med. 2021;27(8):753–61.
36. Silber SJ, Goldsmith S, Castleman L, et al. In Vitro Maturation, In Vitro Oogenesis, and Ovarian Longevity. Reprod Sci. 2024;31(5):1234–45.
37. Cameron CR, Cohen S, Sewell K, et al. The Art of Hormone Replacement Therapy in Menopause Management. J Pharm Pract. 2024;37(3):736–40.
38. Troìa L, Martone S, Morgante G, et al. Management of perimenopause disorders: hormonal treatment. Gynecol Endocrinol. 2021;37(3):195–200.
39. Magraith K, Jang C. Management of menopause. Aust Prescr. 2023;46(3):48–53.
40. Gosset A, Pouillès JM, Trémollieres F, et al. Menopausal hormone therapy for the management of osteoporosis. Best Pract Res Clin Endocrinol Metab. 2021;35(6):101551.
41. Marcellou EG, Stasi S, Giannopapas V, et al. Effect of pelvic floor muscle training on urinary incontinence symptoms in postmenopausal women. Eur J Obstet Gynecol Reprod Biol. 2025;304:134–40.
42. Russo E, Caretto M, Giannini A, et al. Management of urinary incontinence in postmenopausal women: An EMAS clinical guide. Maturitas. 2021;143:223–30.
43. Gu Y, Han F, Xue M, et al. The benefits and risks of menopause hormone therapy for the cardiovascular system. BMC Womens Health. 2024;24(1):60.
44. Zhang GQ, Chen JL, Luo Y, et al. Menopausal hormone therapy and women's health: An umbrella review. PLoS Med. 2021;18(8):e1003731.
45. Rozenberg S, Di Pietrantonio V, Vandromme J, et al. Menopausal hormone therapy and breast cancer risk. Best Pract Res Clin Endocrinol Metab. 2021;35(6):101577.
46. Crandall CJ, Mehta JM, Manson JE, et al. Management of Menopausal Symptoms: A Review. JAMA. 2023;329(5):405–20.
47. Rennert G, Rennert HS, Pinchev M, et al. Use of hormone replacement therapy and the risk of colorectal cancer. J Clin Oncol. 2009;27(27):4542–7.
48. Bitoska I, Krstevska B, Milenkovic T, et al. Effects of Hormone Replacement Therapy on Insulin Resistance. Open Access Maced J Med Sci. 2016;4(1):83–8.
49. Hodis HN, Mack WJ. Menopausal Hormone Replacement Therapy and Reduction of All-Cause Mortality. Cancer J. 2022;28(3):208–23.
50. Mehta J, Kling JM, Manson JE, et al. Risks, Benefits, and Treatment Modalities of Menopausal Hormone Therapy. Front Endocrinol (Lausanne). 2021;12:564781.
51. Cho L, Kaunitz AM, Faubion SS, et al. Rethinking Menopausal Hormone Therapy: For Whom, What, When, and How Long? Circulation. 2023;147(7):597–610.
52. Morris G, Talaulikar V. Hormone replacement therapy in women with history of thrombosis. Post Reprod Health. 2023;29(1):33–41.
53. Prabakaran S, Schwartz A, Lundberg G, et al. Cardiovascular risk in menopausal women. Ther Adv Endocrinol Metab. 2021;12:20420188211013917.
54. Xiang H, Wang L, Sun L, et al. The risk of ovarian cancer in hormone replacement therapy users. Front Endocrinol (Lausanne). 2024;15:1414968.
55. Lee SR, Cho MK, Cho YJ, et al. The 2020 Menopausal Hormone Therapy Guidelines. J Menopausal Med. 2020;26(2):69–98.
56. Vigneswaran K, Hamoda H. Hormone replacement therapy - Current recommendations. Best Pract Res Clin Obstet Gynaecol. 2022;81:8–21.
57. Xiang H, Wang L, Sun L, et al. Hormone replacement therapy and risk of ovarian cancer: A review. Front Endocrinol (Lausanne). 2024;15:1414968.