When Hormone Replacement Therapy Doesn't Resolve All the Symptoms

About 85% of women will experience perimenopause symptoms that significantly impact daily functioning (Santoro et al., 2021). That's millions of women every year enduring hot flashes, night sweats, brain fog, muscle aches, and mood symptoms due to declining endogenous estradiol levels. Recent months have witnessed growing interest in discussing perimenopause and specifically accessing hormone replacement therapy (HRT). As more women learn about the safety and efficacy of treatment, we're gaining greater understanding of access challenges—and those barriers are improving.

Though I am a strong advocate for HRT and regularly refer female patients to OB/GYN specialists for treatment, I want to acknowledge an important clinical reality: HRT doesn't always successfully treat mood symptoms. Research indicates that 20-30% of women who receive HRT continue experiencing perimenopausal mood symptoms even into menopause (Schmidt et al., 2020). For many women, this represents a disheartening reality, especially after fighting battles to access HRT and having their hopes elevated for complete symptom resolution. These persistent symptoms involve complex neurobiological changes beyond simple hormone deficiency, though we remain in the early stages of understanding due to limited research on women's mental health.

Understanding the Hormonal Foundation

There's considerable discussion about estrogen, but three different forms predominate at various life stages. Estradiol, the most potent form produced by the ovaries, is predominant during the premenopausal period and is the type used in transdermal HRT. Estrone becomes the predominant form during menopause, converted to estradiol by adipose tissue. Estriol is produced by the placenta during pregnancy.

Fluctuating estrogen levels directly impact crucial neurotransmitters—serotonin, dopamine, and GABA—that regulate mood (Gordon et al., 2018). This mechanism underlies conditions like PMDD and explains why mood symptoms emerge when estrogen levels decrease. By menopause, estradiol levels drop to 10% of previous levels, yet HRT doesn't always restore optimal neurotransmitter function for every woman.

Recent research has identified cyclical patterns in ADHD symptoms, with women experiencing significant increases in inattention and hyperactivity-impulsivity just before and during menstruation due to estrogen withdrawal (Eng et al., 2023). This helps explain why many women first recognize ADHD during perimenopause, when declining estrogen can unmask previously manageable symptoms. However, our understanding of these patterns remains limited and warrants continued research.

When HRT Needs Reinforcement: A Comprehensive Approach

In my practice, I've observed that women who thrive during perimenopause combine HRT with strategic lifestyle interventions. Research supports this approach, demonstrating that lifestyle interventions can significantly improve mental health symptoms (Rosenbaum et al., 2014). This isn't about wellness trends or supplement regimens—this is comprehensive health care built on a foundation of community, purpose, and movement.

The Power of Strength Training

Strength training emerges as particularly crucial. Women with greater lean body mass experience fewer vasomotor symptoms and tend to have better mood regulation. Exercise increases beneficial neurobiological factors through multiple pathways, potentially providing neuroprotective effects during the hormonal fluctuations of perimenopause (Sleiman et al., 2016). When the brain faces hormonal volatility, the cognitive and emotional benefits of regular exercise become especially important for maintaining stability and function.

Reclaiming Your Time and Energy

Managing time effectively becomes essential during this life stage—making space for social connections that allow us to thrive while setting boundaries that protect our energy for what matters most. Many women discover that perimenopause brings an unexpected gift: caring less about others' opinions. This natural shift can make boundary-setting easier, though some struggle with releasing the "superwoman" persona that may have served them in earlier life stages.

This transition often requires therapeutic support, especially when facing the reality that this life phase frequently brings increasing demands at work, family relationship changes, significant losses, and external stressors. The challenge lies in creating space for yourself amid competing priorities—a skill that becomes not just helpful, but essential.

Nourishing Your Body Through Change

Nutrition during perimenopause focuses on supporting your body through hormonal fluctuations. A whole food approach works best: emphasizing leafy greens and colorful vegetables, fruits, legumes and lentils, and healthy fats while limiting added sugars and refined carbohydrates. Prioritizing fiber-rich foods and balanced macronutrients supports both metabolism and gut health, which can positively impact mood regulation.

I emphasize adding healthy foods rather than eliminating favorites, especially when starting this journey. The goal is feeling supported and nourished, not burdened by restrictive rules during an already challenging time.

Psychiatric Interventions: Specialized Care When Needed

When symptoms persist despite optimized HRT, psychiatric consultation becomes essential. Early research suggests perimenopausal mood disorders may require specialized approaches, though clinical guidelines remain limited and represent another area where women's health research lags behind our clinical needs.

For women with new symptoms, HRT should be the first intervention, but if symptoms persist after 6-8 weeks or are severe, specialized psychiatric care is indicated. Women with pre-existing psychiatric disorders will likely benefit from providers who understand hormone-disorder interactions—a specialized knowledge base that unfortunately remains uncommon in clinical practice.

Treatment Options

Available medications include SSRIs and SNRIs selected based on individual symptom profiles and potential HRT interactions, mood stabilizers when appropriate, and ADHD medications for women experiencing symptom exacerbation during hormonal transitions.

For sleep disturbances, both estrogen and progesterone in HRT are crucial, as progesterone significantly impacts sleep quality. Additional interventions include targeted sleep medications and evidence-based nutraceuticals like magnesium glycinate.

For persistent vasomotor symptoms, SSRIs, SNRIs, and gabapentin can provide significant relief in conjunction with HRT. Many women can be weaned off these medications once symptoms stabilize as they transition closer to menopause and experience less estrogen variability.

The Research Reality: We're Just Getting Started

Current perimenopause research represents only the beginning of understanding women's health complexity during this transition. We are genuinely in the infancy of knowledge regarding women's health during menopause and perimenopause, with profound research gaps that limit our ability to provide optimal, personalized care.

The most glaring limitation involves biomarker interpretation. Current studies examining neurobiological markers in perimenopausal women haven't assessed physical activity levels, exercise habits, or lean body mass—variables that could fundamentally change how we understand and respond to research findings. We don't know if exercise-induced neurobiological changes produce different outcomes than stress-response changes, yet this distinction could be crucial for treatment decisions.

Personalized treatment approaches remain largely unexplored. We lack understanding of how cultural factors, socioeconomic status, and individual circumstances influence treatment response. We know that Black and Latina women experience more severe symptoms yet receive HRT at lower rates (Gold et al., 2006), but we have minimal understanding of the mechanisms behind these disparities or how to address them effectively.

The scope of what we don't know is staggering—optimal intervention timing and combinations, individual prediction models for treatment response, long-term outcomes across different approaches, and cultural factors influencing both symptom expression and treatment effectiveness.

Comprehensive Care in an Evidence-Limited Field

Despite these limitations, we must provide the best available care while honestly acknowledging knowledge gaps. I recommend comprehensive perimenopause mental health support when women experience:

• Persistent symptoms despite 3-6 months of optimized HRT

• New or worsening ADHD, anxiety, or depression interfering with daily functioning

• Concerns about medication interactions between HRT and psychiatric treatments

Optimal care requires comprehensive assessment including lifestyle, stress, exercise, and cultural factors; individualized treatment plans that acknowledge research limitations; and collaborative care integrating reproductive psychiatry with lifestyle medicine and therapeutic support.

Moving Forward Together

At Bloom & Build Integrative Psychiatry, we integrate the highest quality evidence-based treatments while maintaining clinical humility about how much we still need to learn about women's health during this transition. We recognize that some women achieve excellent outcomes with HRT alone, while others require comprehensive interventions addressing the multifaceted nature of perimenopausal challenges.

Rather than viewing persistent symptoms as treatment failure, we see them as both a clinical opportunity and a call for the research advancement that women urgently need and deserve. Every woman who seeks comprehensive care contributes to our understanding of how to better serve all women during this critical life transition.

Ready to explore comprehensive perimenopause care that honors both current evidence and your individual complexity? Schedule your consultation today to discuss a personalized treatment plan that integrates the best available knowledge while advocating for the research progress that will benefit all women.

Disclaimer: This content is for educational purposes only and does not constitute medical advice. Always consult qualified healthcare providers before making treatment changes.

About The Author:

Dr. Alecia Greenlee is a Harvard and UCSF-trained psychiatrist specializing in reproductive psychiatry and lifestyle medicine for high functioning women. Dr. Greenlee provides evidence-based, culturally responsive care while advocating for the research advancement that women's health urgently requires.

References

Eng, A. G., Nirjar, U., Elkins, A. R., Sizemore, Y. J., Monticello, K. N., Petersen, M. K., Miller, S. A., Barone, J., Eisenlohr-Moul, T. A., & Martel, M. M. (2023). Attention-deficit/hyperactivity disorder and the menstrual cycle: Theory and evidence. Hormones and Behavior, 152, 105364.

Gold, E. B., Colvin, A., Avis, N., Bromberger, J., Greendale, G. A., Powell, L., Sternfeld, B., & Matthews, K. (2006). Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: Study of Women's Health Across the Nation. American Journal of Public Health, 96(7), 1226-1235.

Gordon, J. L., Girdler, S. S., Meltzer-Brody, S. E., Stika, C. S., Thurston, R. C., Clark, C. T., Prairie, B. A., Moses-Kolko, E., Joffe, H., & Wisner, K. L. (2018). Ovarian hormone fluctuation, neurosteroids, and HPA axis dysregulation in perimenopausal depression: A novel heuristic model. American Journal of Psychiatry, 172(3), 227-236.

Rosenbaum, S., Tiedemann, A., Sherrington, C., Curtis, J., & Ward, P. B. (2014). Physical activity interventions for people with mental illness: A systematic review and meta-analysis. Journal of Clinical Psychiatry, 75(9), 964-974.

Santoro, N., Epperson, C. N., & Mathews, S. B. (2021). Menopausal symptoms and their management. Endocrinology and Metabolism Clinics of North America, 50(4), 684-694.

Schmidt, P. J., Ben Dor, R., Martinez, P. E., Guerrieri, G. M., Harsh, V. L., Thompson, K., Koziol, D. E., Nieman, L. K., & Rubinow, D. R. (2020). Effects of estradiol withdrawal on mood in women with past perimenopausal depression: A randomized clinical trial. JAMA Psychiatry, 72(7), 714-726.

Sleiman, S. F., Henry, J., Al-Haddad, R., El Hayek, L., Abou Haidar, E., Stringer, T., Ulja, D., Karuppagounder, S. S., Holson, E. B., Ratan, R. R., Ninan, I., & Chao, M. V. (2016). Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. eLife, 5, e15092.