Abstract

Background & Objective: Hormonal instability during the menopausal transition negatively impacts the limbic and prefrontal circuits, heightening women’s vulnerability to depressive disorders and anxiety. This narrative review integrates basic-science and clinical evidence to clarify how perimenopausal endocrine disturbances increase vulnerability to depression and anxiety, and whether augmenting first-line antidepressants with hormone replacement therapy (HRT) offers superior relief. Methods: English-language literature between the years 1990 – 2024 was searched in PubMed and Google Scholar for studies on menopause, estradiol, depression, anxiety, selective-serotonin/-norepinephrine reuptake inhibitors (SSRI/SNRI), and HRT. Preference was given to randomised controlled trials (RCTs), meta-analyses, and extensive cohort studies; mechanistic papers were included when they provided insight into pathophysiology. Findings were collated qualitatively. Results & Conclusion: Estrogen withdrawal disrupts serotonergic concentration, upregulates HPA-axis reactivity, and alters ERα/ERβ signalling in limbic-cortical circuits, predisposing to mood lability, especially in late perimenopause. Multiple studies and a 2023 network meta-analysis demonstrate that adding systemic estradiol (with or without progesterone) to fluoxetine or similar agents yields higher response and symptomatic remission rates (up to 92% vs. 48%) than either modality alone.

However, systemic HRT also raises breast cancer, thromboembolic, and stroke risk, with the magnitude increasing over prolonged use.

References

1. Qi Y, Yin C-X, Hui Y, Yu J, He F-F, Wei J, ‭et al.‬ Comparison of the effect of fluoxetine‬ ‭combined with hormone replacement therapy (HRT) and single HRT in treating‬ ‭menopausal depression.‬ Zhonghua Fu Chan Ke Za Zhi.‬‭2004;39(7):461-4‬.‬‬‬‬‬‬‬‬‬‬
2. Parry‭ BL. Special issues in menopause and major depressive disorder.‬ Psychiatric‭ Times.‬ 2013;30(9)‬‭‬‬‬‬‬‬
3. ‭Foster TC. Role of estrogen receptor α and β expression and signaling on cognitive‬ ‭function during aging.‬ Hippocampus.‬‭2012;22(4):656-69.‬ doi:10.1002/hipo.20935‬.‬‬‬‬‬‬
4. Yang JL, Hodara E, Sriprasert I, Shoupe D, Stanczyk FZ. Estrogen deficiency in the‬ ‭menopause and the role of hormone therapy: integrating the findings of basic science‬ research‭ with clinical trials.‬ Menopause‭.‬2024;31(10):926‭-39.‬ doi:10‭.1097/GME.0000000000002407.‬‬‬‬‬‬‬‬‬‬
5. Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of‬ ‭depression during the menopausal transition: the Harvard Study of Moods and Cycles.‬ Arch‭ Gen Psychiatry. ‬2006; 63(4): 385‭-90. doi:10.1001/archpsyc.63.4.385‬‬‬‬‬‬‬
6. Tseng‭ P-T, Chiu H-J, Suen M-W, Zeng B-S, Wu M-K, Tu Y-K,‬ et‭ al.‬ Pharmacological‬‭ interventions‭ and hormonal therapies for depressive symptoms in peri- and‬ post‭-menopausal women: a network meta-analysis of randomized controlled trials.‬ Psychiatry‭ Res.‬2023;326:115316‭. doi:10.1016/j.psychres.2023.115316.‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬
7. Borozan S, Vujošević S, Mikhailidis DP, Muzurović E. Hormone replacement therapy for‬ menopausal‭ mood swings and sleep quality: the current evidence. ‬World‭ J Psychiatry.‬ 2024;14(10):1605‭-10. doi:10.5498/wjp.v14.i10.1605.‬‬‬‬‬‬‬
8. ‭Bustamante-Barrientos FA, Méndez-Ruette M, Ortloff A, ‭et al. ‭Impact of estrogen and‬ ‭estrogen-like molecules in neurogenesis and neurodegeneration: beneficial or harmful?‬ ‭Front Cell Neurosci.‬ 2021;15:636176. doi:10.3389/fncel.2021.636176.‬‬‬‬‬‬‬‬‬‬‬
9. Herson‭ M, Kulkarni J. Hormonal agents for the treatment of depression associated with‬ the‭ menopause.‬ Drugs‭ Aging.‬2022;39(8):607‭-18. doi:10.1007/s40266-022-00962-x.‬‬‬‬‬‬‬‬‬
10. ‭Gordon JL, Rubinow DR, Eisenlohr-Moul TA, Xia K, Schmidt PJ, Girdler SS. Efficacy‬ of‭ transdermal estradiol and micronized progesterone in the prevention of depressive‬ symptoms‭ in the menopause transition: a randomized clinical trial.‬ JAMA‭ Psychiatry.‬ ‭2018;75(2):149-57. doi:10.1001/jamapsychiatry.2017.3998.‬‬‬‬‬‬‬‬‬‬‬
11. ‭Sun Q, Li G, Zhao F, Dong M, Xie W, Liu Q, Yang W, Cui R. Role of estrogen in‬ treatment‭ of female depression.‬ Aging‭ (Albany NY).‬2024;16(3):3021‭-42.‬ doi:10‭.18632/aging.205507.‬‬‬‬‬‬‬‬‬‬‬
12. Genazzani AR, Bernardi F, Pluchino N, Begliuomini S, Lenzi E, Casarosa E, Luisi M.‬ ‭Endocrinology of menopausal transition and its brain implications.‬ CNS Spectr.‬ ‭2005;10(6):449-57. doi:10.1017/S1092852900023142.‬‬‬‬‬
13. Gnanasegar R, Wolfman W, Hernandez Galan L, Cullimore A, Shea AK. Does‬ menopause‭ hormone therapy improve symptoms of depression? Findings from a‬ specialized‭ menopause clinic. ‬Menopause‭.‬2024;31(4):320‭-5.‬ doi:10‭.1097/GME.0000000000002325.‬‬‬‬‬‬‬‬‬‬‬
14. Wium-Andersen MK, Østergaard SD, Nielsen JB,‬‭et al.‬ Association of hormone therapy‬ with‭ depression during menopause in a cohort of Danish women.‬ JAMA‭ Network Open.‬‭2022;5(11):e2243921. doi:10.1001/jamanetworkopen.2022.43921.‬‬‬‬‬‬‬‬‬
15. Psychiatric News. Discontinuing hormone therapy may increase risk of depression in‬ ‭some women. ‭Psychiatr News.‬ 2015;50(15):1. doi:10.1176/appi.pn.2015.7b29.‬‬‬‬‬
16. ‭Cagnacci A, Venier M. The controversial history of hormone replacement therapy.‬ Medicina‭ (Kaunas).‬2019;55(9):602‭. doi:10.3390/medicina55090602.‬‬‬‬‬‬‬
17. ‭Domingues RR, Wiltbank MC, Hernandez LL. The antidepressant fluoxetine (Prozac®)‬ modulates‭ estrogen signaling in the uterus and alters estrous cycles in mice.‬ Mol‭ Cell‬ ‭Endocrinol.‬ 2023;559:111783. doi:10.1016/j.mce.2022.111783.‬‬‬‬‬‬‬‬‬
18. Rybaczyk LA, Bashaw MJ, Pathak DR, Huang-Budin E, Dubrovsky YV. An overlooked‬ ‭connection: serotonergic mediation of estrogen-related physiology and pathology.‬ BMC‬ Womens‭ Health.‬2005;5:12‭. doi:10.1186/1472-6874-5-12.‬‬‬‬‬‬‬
19. Pop A, Lupu DI, Cherfan J, Kiss B, Loghin F. Estrogenic/antiestrogenic activity of‬ selected‭ selective serotonin reuptake inhibitors. ‬Clujul‭ Med.‬2015;88(3):381‭-7.‬ ‭doi:10.15386/cjmed-474.‬‬‬‬‬‬‬‬‬
20. Genazzani AR, Bernardi F, Pluchino N, Begliuomini S, Lenzi E, Casarosa E, Luisi M.‬ ‭Endocrinology of menopausal transition and its brain implications.‬ CNS Spectr.‬ 2005;10(6):449‭-57. doi:10.1017/S1092852900023142.‬‬‬‬‬
21. National Health Service (NHS). Benefits and risks of hormone replacement therapy‬ (HRT)‭ [Internet]. London: NHS; 2023 Feb 8 [cited 2025 Jun 24]. Available from:‬ ‭https://www.nhs.uk/medicines/hormone-replacement-therapy-hrt/benefits-and-risks-of-ho‬rmone‭-replacement-therapy-hrt/ nhs.uk‬‬‬‬‬‬‬
22. Eagle R. HRT after hysterectomy: recommendations, benefits, and risks. Medical News‬ Today‭ [Internet]. 2024 Nov 28 [cited 2025 Jun 24]. Available from:‬ ‭https://www.medicalnewstoday.com/articles/hrt-after-hysterectomy‬‬‬‬‬
23. Gersh F, O'Keefe JH, Elagizi A, Lavie CJ, Laukkanen JA. Estrogen and cardiovascular‬ ‭disease. Prog Cardiovasc Dis. 2024 May-Jun; 84:60-67. Epub 2024 Jan 24.‬ doi:10‭.1016/j.pcad.2024.01.015‬‬‬‬‬
24. LaCroix AZ, Burke W. Breast cancer and hormone replacement therapy.‬‭Lancet.‬ 1997‬ ‭Oct 11;350(9084):1042-3. doi:10.1016/S0140-6736(97)22041-6‬‬‬‬‬