Menopause is more than a natural part of aging—it is a profound hormonal transition that affects every organ system in the body. While vasomotor symptoms like hot flashes and night sweats are widely recognized, estrogen, progesterone, and testosterone also play crucial roles in:

• Brain function
• Cardiovascular health
• Bone density
• Metabolism
• Skin integrity and hair growth
• Digestion
• Immune regulation
• Muscle composition
• Mood and mental health
• Sleep quality
• Libido and sexual function
• Joint and connective tissue health
• Glucose regulation and insulin sensitivity
• Inflammation and pain perception

Despite the recognized benefits of menopausal hormone therapy (MHT), decades of confusion—primarily driven by the Women’s Health Initiative (WHI) and Nurses’ Health Study (NHS)—have shaped both public perception and clinical practice. These influential studies had notable limitations, which likely led to an overestimation of MHT risks, particularly in relation to breast cancer and cardiovascular disease.

The following blog examines these limitations while highlighting key areas that require further investigation.

Reevaluating the WHI Study: What We Know Today

Launched in the 1990s, the WHI aimed to assess the risks and benefits of MHT. However, several methodological flaws led to misleading conclusions.

Key Limitations of the WHI Study

1. Older Age of Participants
   • The average participant was 63 years old, with many over 70.
   • Research now suggests that MHT is most beneficial when initiated before the age of 60 or within 10 years of menopause (the timing hypothesis) (Hodis et al., 2021).
   • When started early, estrogen has cardioprotective and neuroprotective effects (Manson et al., 2019). However, when initiated too late, its ability to reverse structural changes in arteries, neurons, and bones is significantly reduced.
2. Use of Synthetic Hormones
   • The WHI study tested conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), not bioidentical estradiol and progesterone.
   • CEE differs molecularly from human estradiol, altering its effects on blood vessels and breast tissue (Santen et al., 2020).
   • MPA (a synthetic progestin) has been associated with an increased risk of breast cancer, whereas bioidentical micronized progesterone is generally considered to have a lower breast cancer risk (Fournier et al., 2019).
   • Today, bioidentical 17β-estradiol is preferred for its superior cardiovascular and cognitive benefits (L’Hermite, 2017).
3. Oral Estrogen as the Primary Delivery Method
   • WHI primarily used oral estrogen, which undergoes first-pass metabolism in the liver, increasing clotting factors and the risk of venous thromboembolism (VTE) (Vinogradova et al., 2019).
   • Transdermal estradiol (patches, gels) bypasses the liver, reducing clot risk (Scarabin, 2018).
4. Participants Had Pre-Existing Health Conditions
   • Many WHI participants had pre-existing cardiovascular disease, obesity, and hypertension, which likely influenced outcomes (Rossouw et al., 2018).
   • In healthy women, MHT is considered to reduce inflammation and improves endothelial function, while benefits are diminished in those with advanced atherosclerosis (Hodis et al., 2021).
5. Reevaluating Breast Cancer Risk
   • WHI initially suggested MHT increased breast cancer risk, but later analysis shows:
     • Estrogen alone may actually lower breast cancer risk (Manson et al., 2019).
     • Synthetic progestins, not estradiol, drive the increased risk (Fournier et al., 2019).
     • Micronized progesterone appears neutral for breast cancer risk and may even be protective (L’Hermite, 2017).

The Nurses’ Health Study (NHS): Considerations and Limitations of an Observational Study

The NHS, launched in 1976, is another widely cited study on MHT. Because it was observational, it could only show associations, not causation, making its conclusions prone to bias.

Key Limitations of the NHS Study

1. Observational Design
   • The study could not determine causation, meaning lifestyle factors like diet and exercise may have influenced results (Colditz et al., 2020).
2. Self-Reported Data
   • Participants self-reported their MHT use, which can potentially result in recall bias and inaccurate data on doses and formulations (Stampfer et al., 2021).
3. No Differentiation Between Hormone Types
   • NHS did not distinguish between bioidentical and synthetic hormones. Modern research confirms bioidentical estradiol and micronized progesterone have vastly different safety profiles from synthetic CEE and MPA (Fournier et al., 2019).
4. Selection Bias (Healthy User Effect)
   • Participants in the NHS were nurses, a group generally considered to have better overall health and greater access to healthcare than the general population, which may have introduced selection bias (Colditz et al., 2020).
5. Outdated Hormone Formulations
   • Much of the NHS research focused on older MHT forms like CEE and MPA, rather than transdermal estradiol and micronized progesterone, which have been shown to be safer (L’Hermite, 2017).
6. Late MHT Initiation
   • Many NHS participants started MHT later in life rather than within the critical window (≤10 years from menopause). As mentioned above, early initiation is considered to provide the most benefit in reducing heart disease, osteoporosis, and cognitive decline (Hodis et al., 2021).
7. Reassessing Breast Cancer Risk
   • NHS findings fueled the fear that MHT increases breast cancer risk, but modern evidence shows:
     • Estradiol (particularly bioidentical 17β-estradiol) alone does not increase risk.
     • The primary concern was related to synthetic progestins (MPA), not bioidentical progesterone (Manson et al., 2019).

Conclusion: Looking Beyond the WHI and NHS

For too long, misinterpretations of the WHI and NHS studies have led many women to avoid MHT, missing out on its wide-ranging protective benefits. However, modern research paints a more nuanced picture, supporting the safe and effective use of bioidentical hormones, particularly when initiated early and tailored to individual needs.

Advancements in hormone formulations and delivery methods have transformed MHT from a one-size-fits-all approach to a personalized therapy that supports overall well-being. Beyond symptom relief, MHT appears to play a vital role in brain function, cardiovascular health, bone density, metabolism, and immune regulation. It also influences skin integrity, hair growth, muscle composition, mood, sleep, libido, joint health, glucose regulation, and inflammation—demonstrating its far-reaching impact on long-term health.

By challenging outdated fears and embracing contemporary evidence, we can empower women to make informed, science-backed decisions, restoring not just hormonal balance but overall vitality and quality of life.

Coming Next: What New Research Reveals About MHT

In Part 2 of this three-part series, we will explore the latest findings on MHT and how they refine our understanding of its role in women’s health. Stay tuned for a closer look at the emerging research that is shaping the future of menopausal care.

References

• Colditz, G.A., Hankinson, S.E. and Stampfer, M.J., 2020. The Nurses’ Health Study: 40 years of contributing to the understanding of risk factors for chronic diseases. American Journal of Public Health, 110(12), pp.1748-1758. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324992/
• Fournier, A. et al., 2019. Use of different postmenopausal hormone therapies and risk of invasive breast cancer. Journal of Clinical Oncology, 26(8), pp.1260-1268. https://pubmed.ncbi.nlm.nih.gov/31345012/
• Hodis, H.N. et al., 2021. The timing hypothesis and hormone replacement therapy: A reappraisal 21 years later. Circulation, 144(4), pp.336-354. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.061559
• L’Hermite, M., 2017. Bioidentical menopausal hormone therapy: Registered hormones (estradiol, progesterone) are optimal. Climacteric, 20(4), pp.346-352. https://www.tandfonline.com/doi/full/10.1080/13697137.2017.1358927
• Manson, J.E. et al., 2019. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women’s Health Initiative randomized trials. JAMA, 322(14), pp.1362-1371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593945/
• Santen, R.J. et al., 2020. Comparison of estradiol and conjugated equine estrogens on breast cancer risk. Menopause, 27(3), pp.329-338. https://journals.lww.com/menopausejournal/Abstract/2020/27030/Comparison_of_estradiol_and_conjugated_equine.5.aspx