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52-59         Annals of Applied Psychophysiology December 2024 Volume 11 

Hormone Replacement Therapy and Mood Disorders During 

Menopause 
Monica Persson1, 
Published online: December 2024 

  © The Author(s) 2024 

 

Abstract 

Background: Menopause is a significant transitional phase for women, marked by hormonal changes that 

profoundly affect physical and mental health. This paper examines the intricate relationship between 

menopause, hormonal fluctuations, and mood disorders, emphasizing the challenges of treatment. The 

depletion of ovarian follicles and the resulting decline in estrogen, progesterone, and other hormones disrupt 

the hypothalamic-pituitary-gonadal axis and neurotransmitter pathways, leading to increased rates of 

depression, anxiety, and other mood disorders in middle-aged women. Conventional treatments, such as 

selective serotonin reuptake inhibitors (SSRIs), are often less effective for menopausal-related mood 

disorders, underscoring the need for alternative approaches. 

Methodology: A targeted review of current literature explores conventional and alternative treatment 

approaches for menopausal mood disorders. This includes a review of pharmacological therapies, such as 

selective serotonin reuptake inhibitors (SSRIs), and the potential efficacy of hormone replacement therapy 

(HRT) in mitigating mood-related symptoms. 

Results: Conventional treatments like SSRIs are often less effective for menopausal mood disorders, 

underscoring the need for alternative approaches. HRT emerges as a viable option, offering symptom relief 

from vasomotor and genitourinary syndromes, improved cardiovascular and bone health, and potential 

mitigation of mood disorders. However, the controversial results of the 2002 Women’s Health Initiative 

(WHI) study raised concerns about risks, resulting in reduced usage. Recent studies support the “critical 

window” hypothesis, suggesting that initiating HRT early in menopause enhances safety and efficacy. 

Conclusion: This paper highlights the importance of personalized and integrative strategies for managing 

menopause and mood disorders. Although HRT shows promise, further research is essential to clarify its 

influence on inflammatory pathways and neuroinflammatory mechanisms. Understanding the long-term 

effects of HRT and addressing the unique hormonal and neurobiological dynamics of menopausal women 

are critical for developing targeted interventions and improving outcomes for this underserved 

demographic. 

Keywords: Estrogen, Progesterone, Reproductive Hormones, Hormone Replacement Therapy, Mood 

Disorders, Depression, Anxiety. 

1. Monica Persson mpersson@saybrook.edu 

   Saybrook University, Pasadena, CA, USA 

 

 

mailto:mpersson@saybrook.edu


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Hormone Replacement Therapy and Mood Disorders During Menopause 

All human females with ovaries who reach puberty will ultimately experience menopause, 

provided they live long enough. Menopause consists of three main stages: perimenopause, 

menopause, and post menopause, generally occurring between the ages of 40 and 60.  At this stage, 

the ovaries begin to atrophy, decreasing the production of the main hormones that regulate the 

menstrual cycle: estrogen and progesterone. Most women experience vasomotor (hot flashes, 

excessive sweating, sleep disturbance) and genitourinary (vaginal dryness, pain during intercourse, 

urinary incontinence, decreased libido) symptoms during this period (Jin, 2017). Middle-aged 

women also experience significant increases in depression, anxiety, post-traumatic stress disorder, 

and substance abuse compared to other age groups. As a demographic cohort, women in this age 

range have a high suicide rate (Maki et al., 2019, as cited by Kulkarni et al., 2024).  Cultural, 

genetic, and environmental factors influence the menopause journey and subsequent treatment 

efficacy.  

During the feminist movement of the 1960s, there was a significant shift in the promotion 

of menopausal therapy, especially in European countries, with the concept of "feminine forever" 

(Wilson, 1968). A book by the same title became a bestseller, claiming that “menopause is a 

hormone deficiency disease, curable and totally preventable, just take estrogen” (Wilson, 1968, as 

cited in Cagnacci & Venier, 2019, p. 602). Since that time, women have had a complex relationship 

with hormone replacement, alternately viewing it as a panacea or risk too hazardous to employ. 

Menopause is a complex biological process characterized by hormonal changes that can 

significantly impact mental health, creating challenges for effective treatment. Pre-menopausal 

women without a history of mood disorders are nearly twice as likely to develop symptoms of 

anxiety and depression during menopause compared to those with no prior mood disorder history 

(Cohen et al., 2006, as cited in Alblooshi et al., 2023). As ovarian follicles deplete, ovarian function 

declines, leading to a reduction in mood-regulating hormones. This shift disrupts the 

hypothalamic-pituitary-gonadal axis, influencing mood regulation and stress responses. Life 

stages with low estrogen levels (premenstrual, postpartum, menopause) are linked to increased 

depressive symptoms. Additionally, between 15% to 50% of women report experiencing 

depression during the menopause transition (Toffol et al., 2015, as cited by Wieczorek et al., 2023). 

Fluctuations in estrogen, progesterone, testosterone, cortisol, triiodothyronine (T3), thyroxine 

(T4), dehydroepiandrosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) 

affect multiple systems, with estrogen, progesterone, and cortisol playing key roles in mood 

regulation. Understanding these hormonal changes is critical for addressing menopausal mood 

disorders effectively. 

Standard mental health interventions, such as lifestyle modification and antidepressants, 

are often insufficient in addressing menopausal mood disorders. Healthcare providers often 



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recommend stress reduction techniques and psychotherapies, like cognitive-behavioral therapy, as 

the first intervention. Antidepressants, particularly SSRIs, are usually the next treatment option. 

However, many medications that had previously helped are no longer effective, or a much higher 

dose is required to have the same effect (Worley et al., 2012; Grigoriadis et al., 2006, as cited by 

Behrman & Crockett, 2023). Current guidelines are to treat menopausal depression as any other 

depressive episode. However, it is known that peri- and postmenopausal people do not respond to 

SSRIs as effectively as other demographics, and rates of discontinuation due to adverse events are 

significant (Wu et al., 2020, as cited by Behrman & Crockett, 2023). Hormonal therapies may be 

more effective but remain underutilized due to safety concerns and a lack of sufficient knowledge 

among mental health professionals about their use in treating mood disorders (Behrman & 

Crockett, 2023). The interplay between hormonal shifts and mental health challenges underscores 

the necessity for a nuanced understanding of menopause in clinical settings. Conventional mental 

health treatments fail to account for the unique physiological changes during menopause, 

highlighting a critical gap in care. Integrative approaches and targeted interventions are needed to 

support women during this critical stage of life. 

Neuroscience of Hormonal Influence on Mental Health During Menopause 

Neurotransmitters such as serotonin, norepinephrine, and dopamine play a crucial role in 

modulating both vasomotor and mood disorders. Dysregulation of these pathways, particularly in 

the prefrontal cortex and limbic system, key regions of the central nervous system involved in 

mood control, can contribute to the onset of depression (Giannini et al., 2021). Estrogen has a role 

in the modulation of serotonin and the serotonergic pathways, considered a root neurobiological 

cause of depression (Herson & Kulkarni, 2022, as cited in Behrman & Crockett, 2023). Estrogen 

affects the concentration of serotonin by increasing the rate of monoamine oxidase (MAO), an 

enzyme responsible for serotonin catabolism. Estrogen is also linked to neuron activity due to its 

ability to affect cerebral blood flow, glucose levels, neuronal growth, and synaptic activity 

(Giannini et al., 2021). Other neurotransmitter pathways linked to changes in mood, such as 

dehydroepiandrosterone sulfate and gamma-aminobutyric acid (GABA), are also affected by the 

menopausal transition (Behrman & Crockett, 2023). Estrogen significantly affects mood-

regulating brain areas such as the hippocampus and amygdala by enhancing synaptic plasticity, 

promoting neuronal growth, and modulating neurotransmitter systems, collectively contributing to 

improved mood regulation and stress resilience (Behrman & Crockett, 2023). The progesterone 

derivative allopregnanolone “interacts with gamma-aminobutyric acid type A (GABA-A) 

receptors even at nanomolar concentrations and induces significant anti-depressant, anti-stress, 

sedative, and anxiolytic effects” (Stefaniak et al., 2023, p. 520). Low to moderate concentrations 

of allopregnanolone increase amygdala activity as measured by functional magnetic resonance 

imaging (fMRI), similar to changes experienced during heightened anxiety. When concentrations 

increased, amygdala activity slowed, resembling the effect of sedatives like benzodiazepines 

(Stefaniak et al., 2023). 



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Hormone Replacement Therapy 

HRT is an effective treatment for various adverse symptoms associated with menopause, 

including vasomotor symptoms (such as intense heat, sweating, and flushing) and genitourinary 

syndrome (characterized by vaginal dryness, irritation, burning, painful intercourse, recurrent 

urinary tract infections, and urinary incontinence). Additionally, multiple randomized trials have 

demonstrated HRT's positive effects on cardiovascular, endocrine, and bone health, with evidence 

suggesting a reduction in all-cause mortality among recently menopausal women (Flores et al., 

2021). However, the 2002 WHI report delivered transformative findings into HRT risks of breast 

cancer and cardiovascular disease in older postmenopausal women, driving a “seismic shift” in 

menopause management and influencing perspectives that persist today (Flores et al., 2021, p. 

720). The WHI study included a large population of older postmenopausal women more than 10 

years after the cessation of menses. These women were more likely to have pre-existing conditions, 

such as cardiovascular disease, making them more prone to adverse outcomes. The study also used 

a combination of estrogen and medroxyprogesterone acetate (MPA), a synthetic progestin. Unlike 

natural progesterone, MPA has been associated with an increased risk of breast cancer and 

cardiovascular disease (Manson et al., 2024). These issues led to misunderstandings about the 

safety of HRT, resulting in significant declines in prescribing, even for women not at significant 

risk. New formulations and updated research have clarified these findings, highlighting the 

significance of bio-identical progesterone, personalized treatment, and timing in hormone therapy 

choices. Although HRT is safe for many women, it still poses certain risks. Prolonged use can 

increase the chances of breast and endometrial cancer, blood clots, and stroke and may impair 

cognitive function (Marsden, 2022). The benefits and risks of taking HRT depend on an 

individual's age, menopause stage, and any pre-existing risk factors they may have.  

The aftermath of the WHI study has led to the “critical window” or “timing hypothesis,” 

which states estrogen can be neuroprotective only if HRT is started shortly after the onset of 

menopause. Some studies indicate that using HRT in the early postmenopausal phase is associated 

with improved well-being, while its use at later stages does not show the same benefits. According 

to Flores et al. (2021), HRT is a valuable option for symptomatic, healthy menopausal women who 

are under 60 years old and have been menopausal for less than 10 years. This applies as long as 

they do not have any contraindications, such as cardiovascular disease, poorly controlled diabetes, 

or high blood pressure, as well as no risk factors for venous thromboembolism, including obesity, 

smoking, or clotting disorders.   

While the number of hormones that shift during menopause is significant, only estrogen 

and progesterone are used in HRT for this cohort. Estrogen-only formulations for HRT include 

conjugated equine estrogens, 17β- E2, and esterified estrogens; they are typically used for women 

without a uterus (Flores et al., 2021). In addition to oral routes of administration, estrogen-only 

formulations such as injection, subdermal implant, and transdermal formulations are available. 



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Progesterone can be used alone or in combination with estrogen. Available routes of administration 

include oral, injection, implants, transdermal (via vaginal application), and intrauterine systems. 

Formulations containing progesterone are used more commonly in women with a uterus. Selective 

estrogen receptor modulators are a newer treatment option that targets specific estrogen receptors 

to exert agonist or antagonist actions on the estrogen receptors in various estrogen-target tissues 

(Flores et al., 2021). 

Women randomized to oral estrogen in the Kronos Early Estrogen Prevention Cognitive 

and Affective Ancillary Study showed greater benefit on affective mood states than women 

randomized to transdermal 17β-estradiol or placebo (Raz et al., 2016). However, after a systematic 

review of the literature comparing the transdermal and oral administration routes of estrogens for 

menopausal women, Goldštajn et al. (2023) determined that available evidence is limited and low 

quality. The authors indicate that until more research is available, the main clinical difference 

between the two administration routes is the reduced risk of venous thromboembolism, which 

suggests that transdermal HRT is safer than the oral administration route. 

Perceived and Actual Risk Factors of HRT 

Similarly, like all pharmaceutical interventions, HRT is not without risk. Depending on 

formulation and individual patient profile, physical risks include increased prevalence of breast 

and uterine cancer, cardiovascular disease, gallbladder disease, and urinary incontinence. While 

research does not indicate that HRT directly decreases emotional well-being, there may be indirect 

risk. Even in the absence of physical risk factors, there is the possibility of a toll on mental health 

. Hearing about others experiencing negative outcomes can amplify concerns and lead to anxiety 

or worsening mental health. According to Bagarić et al. (2022), the phenomenon known as the 

vicarious nocebo effect refers to the psychological impact of learning about the adverse effects 

experienced by others who are using the same medical intervention. This may decrease as 

erroneous media reports about the WHI study claiming that hormone therapy causes breast cancer 

and cardiovascular disease fade from the memories of healthcare providers and the general public. 

Emerging Research on HRT’s Role in Inflammatory Pathways 

In recent years, researchers have hypothesized that mood disorders may result from an 

inflammatory response. Evidence supporting this hypothesis was presented by Ye et al. (2023), 

who identified low-grade systemic inflammation in patients with depression. Their findings 

included elevated concentrations of C-reactive protein in 21% to 34% of patients, as well as 

increased levels of interleukin-6 (IL-6) and other inflammatory cytokines in both blood and 

cerebrospinal fluid. This inflammatory activity is believed to impact neural circuits in the brain 

related to mood regulation, such as the hippocampus and the prefrontal cortex (Ye et al., 2023). 

Autoimmune diseases often worsen during menopause due to increased inflammation, 

highlighting the complex interplay between physical health and mood disorders during this 



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transition. These links suggest that targeting inflammation could be a viable approach to managing 

mental health symptoms.  

HRT, particularly estrogen-based therapies, may help modulate inflammatory responses in 

menopausal women. Estrogen has anti-inflammatory properties that can reduce levels of pro-

inflammatory cytokines like IL-6. By potentially lowering systemic inflammation, HRT could 

alleviate some of the depressive and anxiety symptoms that are exacerbated by these inflammatory 

processes. Slavich and Sacher (2019) describe how estrogen modulates the hypothalamic-

pituitary-adrenal (HPA) axis and its implications for stress-related disorders. Researchers note that 

estrogen can attenuate HPA axis responses to stress, which may be beneficial in reducing anxiety 

and depression symptoms (Slavich & Sacher, 2019). These findings suggest a promising role for 

HRT not only in alleviating physical symptoms of menopause but also in addressing the 

neuroinflammatory mechanisms that contribute to mood disorders. While these studies are 

promising, they are limited in scope, and more research is needed to determine the underlying 

mechanisms of HRT in relation to inflammation-related mental health outcomes. Large-scale, 

randomized controlled trials are necessary to confirm conclusions and identify the most effective 

treatment protocols. 

Conclusion 

  Given the complex interplay between hormones and mental health, there is a need for 

personalized treatment approaches when it comes to treatment. There is an understanding that HRT 

may mitigate mood disorders. However, it may be most efficacious for a narrow subset of 

individuals during a specific stage of menopause or used in conjunction with antidepressants. All 

women, but especially older women, do not have equal representation in health research. Further 

investigation is needed to deepen our understanding of the complex relationship between hormonal 

transitions and mood disorders in women. 

References 

Alblooshi, S., Taylor, M., & Gill, N. (2023). Does menopause elevate the risk for developing 

depression and anxiety? Results from a systematic review. Australasian Psychiatry, 31(2), 

165-173. https://doi.org/10.1177/10398562231165439 

Bagarić, B., Jokić-Begić, N., & Sangster Jokić, C. (2022). The nocebo effect: A review of 

contemporary experimental research. International Journal of Behavioral Medicine, 29(3), 

255-265. https://doi.org/10.1007/s12529-021-10016-y 

Behrman, S., & Crockett, C. (2023). Severe mental illness and the perimenopause. BJPsych 

Bulletin, 1–7. doi:10.1192/bjp.2023.89 



58 
 

Cagnacci, A., & Venier, M. (2019). The controversial history of hormone replacement therapy. 

Medicina, 55(9), 602. https://doi.org/10.3390/medicina55090602 

Flores, V. A., Pal, L., & Manson, J. E. (2021). Hormone therapy in menopause: Concepts, 

controversies, and approach to treatment. Endocrine Reviews, 42(6), 720-752. 

https://doi.org/10.1210/endrev/bnab011 

Giannini, A., Caretto, M., Genazzani, A. R., & Simoncini, T. (2021). Neuroendocrine changes 

during menopausal transition. Endocrines, 2(4), 405-416. 

https://doi.org/10.3390/endocrines2040036 

Goldštajn, M. Š., Mikuš, M., Ferrari, F. A., Bosco, M., Uccella, S., Noventa, M., ... & Garzon, S. 

(2023). Effects of transdermal versus oral hormone replacement therapy in postmenopause: 

a systematic review. Archives of Gynecology and Obstetrics, 307(6), 1727-1745. 

https://doi.org/10.1007/s00404-022-06647-5 

Jin, J. (2017). Vaginal and urinary symptoms of menopause. JAMA, 317(13), 1388-1388. 

Kulkarni, J., Gurvich, C., Mu, E., Molloy, G., Lovell, S., Mansberg, G., ... & Szoeke, C. (2024). 

Menopause depression: Under recognised and poorly treated. Australian & New Zealand 

Journal of Psychiatry, 58(8), 636-640. 

Manson, J. E., Crandall, C. J., Rossouw, J. E., Chlebowski, R. T., Anderson, G. L., Stefanick, M. 

L., ... & Prentice, R. L. (2024). The Women’s Health Initiative randomized trials and 

clinical practice: A review. JAMA, 331(20):1748-1760. 

https://doi:10.1001/jama.2024.6542 

Marsden, J. (2022). The British menopause society consensus statement on the management of 

estrogen deficiency symptoms, arthralgia and menopause diagnosis in women with treated 

for early breast cancer. Post Reproductive Health, 28(4), 199-210. 

Raz, L., Hunter, L. V., Dowling, N. M., Wharton, W., Gleason, C. E., Jayachandran, M., Anderson, 

L., Asthana, S. & Miller, V. M. (2016). Differential effects of hormone therapy on 

serotonin, vascular function and mood in the KEEPS. Climacteric, 19(1), 49-59. 

https://doi.org/10.3109/13697137.2015.1116504 

Slavich, G. M., & Sacher, J. (2019). Stress, sex hormones, inflammation, and major depressive 

disorder: Extending social signal transduction theory of depression to account for sex 

differences in mood disorders. Psychopharmacology, 236(10), 3063-3079. 

Stefaniak, M., Dmoch-Gajzlerska, E., Jankowska, K., Rogowski, A., Kajdy, A., & Maksym, R. B. 

(2023). Progesterone and its metabolites play a beneficial role in affect regulation in the 

female brain. Pharmaceuticals, 16(4), 520.  https://doi.org/10.3390/ph16040520 



59 
 

Wieczorek, K., Targonskaya, A., & Maslowski, K. (2023). Reproductive hormones and female 

mental wellbeing. Women, 3(3), 432-444.  

Wilson, R. A. (1968). Feminine forever. Pocket Books. 

Ye, Z., Kappelmann, N., Moser, S., Smith, G. D., Burgess, S., Jones, P. B., & Khandaker, G. M. 

(2021). Role of inflammation in depression and anxiety: Tests for disorder specificity, 

linearity and potential causality of association in the UK Biobank. EClinicalMedicine, 38. 

https://doi.org/10.1016/j.eclinm.2021.100992 


