In this research paper, the authors (Xu et al., 2024) refer to “women” as individuals with the biological capacity for menopause. Gender identity was not collected in this study, and thus, findings should not be assumed to reflect the experiences of all gender-diverse people who undergo menopause.
Menopause, the physiological transition marking the end of reproductive ability in females, typically occurs at the age of 51 (Brinton et al., 2015). However, 1 in 100 females experience it before the age of 40, and this earlier onset is known as “premature menopause”. It can occur naturally when the ovaries stop producing eggs and key hormones, like oestrogen and progesterone, earlier than expected (BMS, 2024) or surgically, through surgical procedures like hysterectomy (removal of the uterus) or bilateral oophorectomy (removal of both ovaries).
Premature menopause has been linked to a range of health challenges. Individuals affected face a higher risk of cardiovascular disease (Honigberg et al., 2019), cognitive decline in later life (Ryan et al., 2014) and neurodegenerative disease, like Alzheimer’s disease (Sochocka et al., 2023). It can also impact quality of life and sexual function (Javadpour et al., 2021), highlighting just how far-reaching the effects can be.
Another area of concern is mental health. Depression affects 322 million people worldwide and is significantly more common in females (WHO, 2017). Given this increased risk, it is important to consider how life events unique to females, such as menopause, may contribute to this vulnerability. While previous research (Fluharty M, 2016) has explored the link between age at menopause and depression, many studies do not clearly distinguish between natural and surgical premature menopause. This makes it difficult to pinpoint what is driving the increased mental health risks in this vulnerable group. In addition, the role of menopause hormone therapy (MHT) is often not considered.
The current study by Xu et al. 2024 set out to fill these research gaps.
It is important to consider how life events unique to females – particularly the timing of menopause – may contribute to their increased vulnerability to depression.
Methods
This prospective cohort study used data from the UK Biobank, which includes health and genetic information from over 500,000 people in the UK. The authors aimed to:
- Investigate the risk of developing depression in women with natural or surgical premature menopause.
- Explore whether menopause hormone therapy (MHT) and frailty (a state of reduced resilience linked to aging) are associated with differences in risk.
The sample included postmenopausal women aged 40–69. Premature menopause was defined as menopause at or before age 40 and classified as either natural (not due to ovary removal) or surgical (following removal of both ovaries).
The main outcome was hospitalisation for depression, recorded as a primary or secondary diagnosis using nationwide registers and was validated using an additional mental health survey in a subset of women.
Participants were followed from baseline (2006-2010) until first hospitalisation for depression, death, or 30th September 2021. Hazard ratios (HR) estimated risk of depression by menopause type and timing. Mediation analysis examined how MHT and frailty contributed to depression risk.
Results
Cohort
A total of 157,310 postmenopausal women aged 40-69 were identified in the UK Biobank dataset. Among these women, 7,449 had experienced natural premature menopause and 745 had experience surgical premature menopause. The remaining participants had experienced menopause over age 40 – although it was not specified whether any women experienced surgical menopause. During the 11-13 year follow up, 5.41% (7,563) women were hospitalised due to depression.
Frailty and menopause hormone therapy (MHT) use were assessed in 124,210 women. In addition, a subset of 44,734 women in the initial cohort completed an online follow-up to assess mental health.
Women with premature menopause, both natural and surgical, were more likely to live in areas of higher socioeconomic deprivation and had lower levels of educational attainment. They also showed higher rates of smoking, higher body mass index (BMI), poorer sleep quality, and a higher prevalence of chronic disease, compared to women who experienced menopause over 40.
Depression requiring hospitalisation
Compared to women who experienced menopause after age 40, natural premature menopause showed elevated risk of depression requiring hospitalisation (27% higher risk; HR=1.27), while surgical premature menopause had the highest risk (76% higher risk; HR=1.76) .
Moreover, the attributable risk proportion (i.e., the share of the risk of depression requiring hospitalisation which is linked directly to premature menopause) was 21% and 43% for natural and surgical premature menopause, respectively. This indicates that a moderate share of depression risk was associated with premature menopause, particularly following surgery.
Risk of depression with hospitalisation increased as age at menopause decreased. The strongest associations were observed in women who experienced premature menopause under 30 years old. Among this group, natural premature menopause was associated with a 63% increased risk (HR= 1.63), and surgical premature menopause with more than double the risk (HR= 2.20), compared to women who experienced menopause at typical ages. These observational associations underscore the significant mental health implications of premature menopause.
Self-reported depressive symptoms
A similar pattern emerged in the sample using self-reported depressive symptoms online, with 17% higher risk in women with natural premature menopause (HR=1.17), and 82% higher risk in women with surgical premature menopause (HR=1.82), compared to women who experienced menopause after age 40.
Mediation of frailty and MHT
In natural premature menopause, frailty may explain (i.e., mediate) 27% and MHT 65% of the association between depression and premature menopause, whereas in surgical premature menopause, frailty may explain 8% and MHT 43%. These findings suggest that MHT may have a significant role in mediating the association between premature menopause and depression risk, particularly in natural cases, though the specific mechanisms remain unclear.
Women with premature menopause – especially surgical – faced the highest risk of depression. Menopause hormone therapy may play a key role in mediating this risk in premature menopause, though the specific mechanisms remain unclear.
Conclusions
Women who experienced premature menopause, particularly surgical cases, had a higher risk of being hospitalised for depression compared to those who underwent menopause after age 40. These findings were corroborated by self-reported depressive symptoms in a subset of the cohort.
Menopause hormone therapy (MHT) use and frailty may partially explain the association between premature menopause and depression risk; however, these observational findings do not reveal the underlying mechanisms. As Xu et al. (2024) highlight, the risk of depression increases as the age of menopause decreases, emphasising the need for further research to explore whether the abrupt loss of ovarian function may be a mechanism driving mental health outcomes.
To better understand the association between premature menopause and depression, future research needs to explore underlying mechanisms, including the effects of sudden hormonal changes on the brain and mental health outcomes.
Strengths and limitations
Xu et al. (2024)’s findings from a large, nationwide cohort align with existing cohort research (Jung, Shin, & Kang, 2015), though the current study has clearer focus on different types of premature menopause. This distinction was essential for highlighting the significantly heightened risk in women who experienced surgical premature menopause. Moreover, the analysis of mediating factors, menopause hormone therapy (MHT) and frailty, highlighted how these influences varied by type, underscoring the potential need for tailored clinical guidance, particularly regarding MHT use in cases of natural premature menopause.
A further strength of the study lies in its validation of the primary outcome. Depression requiring hospitalisation, drawn from nationwide register data, was corroborated by self-reported depressive symptoms from a large subsample, enhancing confidence in the observed associations. However, as an objective measure, hospitalisation may only reflect more severe cases and miss subtler presentations of depression. The convergence of patterns across both measurement methods suggests that the mental health impact of premature menopause likely extends beyond clinical thresholds.
There are also several limitations. This study did not account for pre-existing health conditions, such as endometriosis, that may lead to surgical intervention and are themselves linked to depression (van Barneveld et al., 2022). Chemically induced menopause, such as from chemotherapy, was not included in the analysis and may represent another pathway to premature menopause with distinct mental health implications. These gaps suggest that further research is needed to explore a broader range of premature menopause experiences and related risk factors.
Finally, while the study focused on biological indicators, future research would benefit from taking an intersectional approach. The experience and impact of menopause are shaped by multiple, intersecting identities, including gender identity, race, class, disability, and sexuality. A more inclusive, gender-expansive framework is necessary to fully understand how menopause, particularly when premature, affects mental health across diverse populations and to support equitable healthcare delivery.
Gaps remain in understanding how pre-existing health conditions contribute to depression risk in premature menopause, which is crucial for explaining differential risk and developing more targeted, effective care strategies.
Implications for practice
Xu et al. (2024) demonstrate an association between premature menopause and increased risk of depression, particularly in surgical cases, indicating a need for more mental health support and resources for those affected. Future research should clearly define and differentiate types of premature menopause to better understand associated mental health risks – mental health matters in premature menopause.
Yet, more research is needed to unpack this association. A key area for future exploration is the neurobiological role of ovarian hormones such as oestrogen, which are known to have protective effects on brain function. The abrupt hormonal decline in premature menopause, particularly surgical menopause, may disrupt neurochemical pathways involved in mood regulation, potentially contributing to increased depression risk. Understanding these mechanisms is critical for clarifying the link between premature menopause and depression and may help inform more targeted treatment approaches, for example, antidepressant treatment with appropriately timed MHT. Although, the mediating role of MHT itself is complex and may vary depending on factors like the timing of initiation, formulation, and individual hormone sensitivity. Since hormonal mechanisms were not directly examined in this study, caution is warranted when interpreting the role of MHT. Future studies investigating these interactions will be critical for developing safer, more personalised treatment strategies.
The study also underscores the importance of long-term monitoring of mental health. Given that the risk of depression increased over time in premature menopause, healthcare professionals, particularly general practitioners, should monitor women who experience premature menopause from onset throughout their lives. This is essential, not only based on the mental health findings of Xu et al. (2024), but also in light of other health risks associated with premature menopause, such as neurodegenerative and cardiovascular diseases.
Finally, incorporating patient-reported outcomes into the management of premature menopause is vital for capturing the full impact on quality of life. Understanding lived experiences is essential for clinical assessments, alongside objective measures such as hospitalisation rates for depression. Moving forward, centring lived experiences of all individuals affected by menopause will be key to shaping more inclusive, equitable, and responsive care.
Understanding the neurobiological role of ovarian hormones and the complex effects of menopause hormone therapy is crucial for developing targeted treatment strategies for depression in premature menopause.
Statement of interests
Dr Naysmith is interested in the impact of menopause on the brain, particularly in cognition and mental illness. She does not have any potential conflicts of interest regarding this blog.
Links
Primary paper
Xu, M., Yin, X., & Gong, Y. (2024). Association of premature natural and surgical menopause with incidence of depression requiring hospitalization: a prospective cohort study. American Journal of Obstetrics and Gynecology. https://doi.org/10.1016/j.ajog.2024.11.002.
Other references
Brinton, R. D., Yao, J., Yin, F., Mack, W. J., & Cadenas, E. (2015). Perimenopause as a neurological transition state. Nature reviews endocrinology, 11(7), 393-405.
British Menopause Society. (2024). BMS consensus statement: Premature ovarian insufficiency (POI). Accessed 16th April 2025.
Fluharty, M. (2016, February 17). Later menopause linked with lower risk of depression. National Elf Service. Accessed 16th April 2025.
Ryan, J., Scali, J., Carriere, I., Amieva, H., Rouaud, O., Berr, C., … & Ancelin, M. L. (2014). Impact of a premature menopause on cognitive function in later life. BJOG: An International Journal of Obstetrics & Gynaecology, 121(13), 1729-1739.
Sochocka, M., Karska, J., Pszczołowska, M., Ochnik, M., Fułek, M., Fułek, K., … & Leszek, J. (2023). Cognitive decline in early and premature menopause. International journal of molecular sciences, 24(7), 6566.
van Barneveld, E., Manders, J., van Osch, F. H., van Poll, M., Visser, L., van Hanegem, N., … & Leue, C. (2022). Depression, anxiety, and correlating factors in endometriosis: a systematic review and meta-analysis. Journal of women’s health, 31(2), 219-230.
World Health Organization. (2017). Depression and other common mental disorders: global health estimates. World Health Organization: Geneva. . Accessed 16th April 2025.
