New Advances in Menopausal Hormone Replacement Therapy
Menopause marks a significant transition in a woman’s life and is often accompanied by a host of physical and emotional alterations, indicative of hormonal imbalance. As more than 50 million women enter menopause each year, the need for improved and efficient modalities to alleviate these symptoms is pivotal (1). While menopausal hormone replacement therapy (MHRT) has been a cornerstone of treatment for decades, recent advances in research and clinical practice are reshaping how hormone therapy is understood, prescribed, and monitored.
Reframing Menopause: A Shift in Perspective
Historically, menopause has been viewed through a medical lens as a disorder or deficiency requiring intervention. However, recent discussions in the medical community suggest it’s time to reconsider this perspective. A focal study published in The Lancet in 2024 argues that menopause should no longer be treated solely as a medical condition to be “fixed.” Rather, the article proposes a more holistic, evidence-based approach to addressing menopause that includes improved education, exploration of non-medical treatments, and a wider range of research beyond pharmaceuticals (2).
These findings highlight that while hormone therapy can effectively address menopause symptoms for many women, it should not be the sole focus of treatment. A broader, multidimensional view of addressing menopause should include lifestyle interventions, such as supporting the gut microbiome, detoxification, and methylation pathways, adequate nutrition, exercise, and sleep, as well as mitigating stress and engaging in activities that bring joy in conjunction with any treatment(s). As the research evolves, this shift in mindset empowers women to take a more active role in their health, bodies, and well-being during this marked transition.
Understanding the Benefits of MHRT
Hormones exist in a delicate balance in the body and are integral for modulating its systemic functions, including the metabolism of nearly all cells. Hormones also have important roles in regulating psychobiological aspects of health.
Menopause is associated with marked alterations in estrogen and other hormones necessary to modulate these functions. Imbalances in hormones can induce changes in metabolism, libido, sleep, cardiovascular, immune, bone, and mental health.
Menopausal hormone replacement therapy (MHRT) replenishes ovarian hormones that are reduced during the menopause transition (3). It is known for effectively alleviating common menopause symptoms, including mood and sleep disturbances, hot flashes, and vaginal dryness, by optimizing biochemical and hormonal pathways. Hormone replacement therapy can be administered orally, vaginally, or transdermally.
New research in 2024 has reaffirmed the safety and efficacy of hormone therapy, particularly for women who begin treatment prior to age 60. A study published in the Journal of the American Medical Association (JAMA) revealed that hormone therapy significantly reduces the severity of vasomotor symptoms and enhances overall quality of life (1). Beyond symptom relief, hormone therapy has been shown to improve bone health, cognitive function, and cardiovascular health, offering significant long-term benefits for women (4-6). Personalized treatment is key based on individual health needs and preferences.
Bioidentical Hormone Replacement Therapy
Bioidentical Hormone Replacement Therapy (BHRT) is a widely used treatment by functional medicine practitioners to support hormone levels during the rapid decline experienced in menopause (7). Bioidentical hormones, derived from plants or animals, are designed to closely match the structure of the hormones naturally produced by the body. In the context of menopause, practitioners may prescribe BHRT through compounding pharmacies, typically in the form of progesterone, estrogen, or androgen.
Transdermal Estradiol
Transdermal estradiol, absorbed through the skin, has become a preferred choice for many women undergoing MHRT. A 2024 randomized controlled trial (RCT) study published in Climacteric compared oral versus transdermal estradiol and found that both significantly alleviated menopause symptoms. However, transdermal estradiol was associated with fewer side effects, more stable estrogen levels, and a lower risk of thrombotic events, which can be a concern with oral estrogen due to liver metabolism (8). This method bypasses the liver’s first-pass effect, offering a safer and more physiological estrogen release, especially beneficial for women with liver concerns.
A 2024 observational study involving 451 postmenopausal women in Germany further confirmed the effectiveness of transdermal estradiol spray (EMDTS), noting significant improvements in menopause-related symptoms such as hot flashes and sweating. By 12 months, 81.4% of women reported improvement, and both patients and physicians expressed high satisfaction with the treatment. The study also highlighted the minimal side effects associated with transdermal estradiol, with the most common adverse events being mild headaches and nausea (9).
Oral Progesterone: Balancing Estrogen’s Effects
Progesterone is crucial for balancing estrogen during menopause, especially for women with an intact uterus. Without progesterone, unopposed estrogen can lead to endometrial hyperplasia and increase the risk of uterine cancer. While oral progesterone has been the standard, it is often associated with side effects like drowsiness and mood changes. A 2024 study published in BMC Complementary Medicine and Therapies found that micronized progesterone, which is better tolerated, improved mood and cognitive function without the sedative effects of traditional oral progesterone (10). Other delivery methods, including transdermal progesterone and IUDs, are also gaining popularity for their reduced side effects.
Cutting-Edge Estrogen Monitoring with Dried Urine Testing
Dried urine testing is emerging as a groundbreaking method for monitoring estrogen and progesterone levels. Unlike blood or saliva tests, dried urine provides a more comprehensive profile of hormone metabolites, offering deeper insights into how estrogen is processed in the body. This advanced testing method enables healthcare providers to personalize therapies and optimize hormone balance for women undergoing MHRT.
The Science Behind DIM: A Breakthrough in Estrogen Metabolism
Emerging research emphasizes the importance of monitoring estrogen metabolism, which can influence long-term health risks associated with hormone therapy. A recent study (Newman & Smeaton, 2024) examined the effects of 3′,3′-diindolylmethane (DIM) on estrogen metabolism patterns in premenopausal women (10). DIM, a compound found in cruciferous vegetables, has shown potential in optimizing estrogen metabolism by lowering estrogenic burden and promoting the breakdown of estrogen into protective metabolites.
Using the innovative DUTCH dried urine test, results demonstrated that DIM supplementation reduced levels of key estrogens—estradiol, estrone, and estriol—while increasing protective estrogen metabolites (10). These findings represent a significant step forward in understanding how DIM can optimize estrogen metabolism while mitigating risks associated with estrogen imbalance. This is particularly beneficial for women concerned with estrogen dominance or hormone-related conditions.
This landmark study analyzed the effects of DIM on the urinary estrogen profiles of 19,294 premenopausal women, some of whom were taking DIM supplements and others who were not. The findings were compelling and provided strong evidence of DIM’s impact on estrogen metabolism:
- Lower Levels of Estrogen. Women taking DIM had notably lower levels of estradiol, estrone, and estriol—the three primary forms of estrogen. This reduction in estrogen levels could be beneficial for women seeking to manage estrogen dominance or reduce their overall estrogenic burden.
- Reduced Estrogenic Proliferation. DIM supplementation lowered levels of 16-OHE1, an estrogen metabolite linked to increased cell proliferation and potential hormone-related risks, such as breast cancer. This reduction may help mitigate such risks.
- Increased Protective Metabolites. DIM users exhibited higher levels of 2-hydroxy estrogen metabolites (2-OHE1 and 2-OHE2), which are considered protective and less likely to promote cell proliferation, supporting a healthier estrogenic environment.
- Improved Metabolite Ratios. DIM supplementation led to a more favorable estrogen metabolite ratio, including increases in the 2-OHE1/16-OHE1 and 2-OHE1/4-OHE1 ratios. These ratios indicate a healthier, more beneficial estrogen breakdown.
The study’s results were consistent across both the larger cohort and a smaller subset of women analyzed before and after starting DIM supplementation, further underscoring DIM’s role in optimizing estrogen metabolism.
Implications – These findings suggest DIM could play a crucial role in balancing estrogen levels, reducing estrogen dominance, and promoting overall hormone health.
DIM has been a subject of growing interest due to its potential to support healthy estrogen metabolism. The recent study by Newman & Smeaton (2024) marks a significant milestone in the understanding of DIM, providing compelling evidence of its effects on estrogen metabolism. DIM influences not only individual components of estrogen metabolism, but the complete estrogen profile, including parent estrogens, estrogen metabolites, and their ratios. With lower levels of estrogen, reduced proliferative metabolites, and improved estrogen metabolite ratios, DIM supplementation offers a promising natural strategy for women seeking to support and modulate their estrogenic health.
The Future of MHRT
Advancements in MHRT, especially with transdermal estradiol and oral progesterone, are reshaping how we manage menopause symptoms. Personalized care based on individual hormonal profiles is at the forefront of treatment, allowing women to make informed decisions about their health. The ongoing research into DIM supplementation, dried urine testing, and other hormone monitoring techniques continues to optimize hormone therapy, ensuring its safety and efficacy for women transitioning through menopause. These findings call for a more nuanced, individualized, and empowered approach to treating menopause in women.
Functional Medicine & Women’s Health
A functional medicine approach to menopause goes beyond symptom management by targeting the root causes of discomfort. In addition to utilizing MHRT as necessary, this approach evaluates critical factors such as the microbiome, detoxification and methylation pathways, nutritional deficiencies, oxidative stress, inflammation, and key lifestyle elements like sleep, stress, and exercise.
A nutrient-dense diet plays a pivotal role in supporting women through menopause. Rich in phytoestrogens—found in foods like brussels sprouts, kale, broccoli, cabbage, fruits, and seeds—this diet helps balance hormones, enhance detoxification and methylation processes, and promote gut health while reducing inflammation. In addition to these plant-based foods, quality protein and anti-inflammatory fats are essential for overall well-being during this transition.
Complementing these nutritional strategies, practices such as yoga, meditation, and acupuncture have gained recognition for their effectiveness in alleviating menopause symptoms, making them invaluable components of a holistic, healthy lifestyle.
Join us on February 4th from 5-7 pm PST for a comprehensive webinar, Clinical Updates in Menopausal Hormone Replacement Therapy: Optimizing Treatment and Hormone Monitoring. Jeffrey Bland, PhD will kick off the session, followed by Jaclyn Smeaton, ND, who will provide an in-depth review of the latest MHRT research, focusing on transdermal estradiol and oral progesterone and the role of dried urine testing in monitoring estrogen metabolism. Mark Newman, MS, will debunk common myths around hormone monitoring and introduce the new DUTCH MHRT course, along with recent research on DIM’s impact on estrogen metabolism.
References:
- Manson JE, Crandall CJ, Rossouw JE, et al. The Women’s Health Initiative Randomized Trials and Clinical Practice: A Review. JAMA. 2024;331(20):1748–1760. doi:10.1001/jama.2024.6542
- Hickey, M; LaCroix, A Z; Doust, J; Mishra, Gita D; Sivakami, M; Garlick, D; Hunter, M S. The Lancet, 2024. doi: https://doi.org/10.1016/S0140-6736(23)02799-X
- Harper-Harrison G, Carlson K, Shanahan MM. Hormone Replacement Therapy. 2024 Oct 6. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 29630243.
- Taylor S, Davis SR. Is it time to revisit the recommendations for initiation of menopausal hormone therapy? Lancet Diabetes Endocrinol. 2025 Jan;13(1):69-74. doi: 10.1016/S2213-8587(24)00270-5. Epub 2024 Oct 14. PMID: 39419045.
- Andy C, Nerattini M, Jett S, Carlton C, Zarate C, Boneu C, Fauci F, Ajila T, Battista M, Pahlajani S, Christos P, Fink ME, Williams S, Brinton RD, Mosconi L. Systematic review and meta-analysis of the effects of menopause hormone therapy on cognition. Front Endocrinol (Lausanne). 2024 Mar 4;15:1350318. doi: 10.3389/fendo.2024.1350318. PMID: 38501109; PMCID: PMC10944893.
- Machuca JN, Rosales-Alvarez CP. Cardiovascular Disease in Women and the Role of Hormone Replacement Therapy. Cureus. 2024 Sep 19;16(9):e69752. doi: 10.7759/cureus.69752. PMID: 39429315; PMCID: PMC11490310.
- Santangelo G, Lagana AS, Giannini A, Murina F, Di Dio C, Ruggiero G, Di Donato V, Perniola G, Fischetti M, Casorelli A, Clemente F, Minnetti M, Lombardo F, Benedetti Panici P, Muzii L, Bogani G. Spotlight on Compounded Bioidentical Hormones. Gynecol Obstet Invest. 2024;89(1):31-40. doi: 10.1159/000535982. Epub 2023 Dec 27. PMID: 38151014.
- Tang R, Xie Z, Ruan X, Zhang Z, Ren M, Wu J, Shu K, Shi H, Xie M, Lv S, Yang X, Chen R, Yu Q. Changes in menopausal symptoms comparing oral estradiol versus transdermal estradiol. Climacteric. 2024 Apr;27(2):171-177. doi: 10.1080/13697137.2023.2273530. Epub 2023 Nov 9. PMID: 37942806
- Hadji P, Schmeißer JO, Peters K, Göckeler-Leopold E. Use of an estradiol transdermal spray in women with menopausal symptoms: a non-interventional study. Climacteric. 2024 Oct;27(5):473-481. doi: 10.1080/13697137.2024.2376185. Epub 2024 Jul 22. PMID: 39036835
- Newman, M., Smeaton, J. Exploring the impact of 3,3’-diindolylmethane on the urinary estrogen profile of premenopausal women. BMC Complement Med Ther 24, 405 (2024). https://doi.org/10.1186/s12906-024-04708-7