Hormone Replacement Therapy in Menopause: Why Don’t Everyone Agree?

Contents

The Effectiveness of Hormone Replacement Therapy (HRT) in Menopausal Symptoms
Important Risks of Treatment
Methods of Reducing Risks
The Hormone Replacement Debate in Menopause Treatment
📚 References

The Effectiveness of Hormone Replacement Therapy (HRT) in Menopausal Symptoms

Hormone therapy during menopause is a treatment approach that aims to improve quality of life and reduce long-term health risks by replacing depleted female hormones in a controlled manner.

It is most effective for the following complaints:

Hot flashes, night sweats, sleep disturbances

While hot flashes are tolerable for some women, for others they can severely disrupt sleep, work, social life, and mental health, making daily life impossible. This is where the risk-benefit balance of hormone therapy (HRT) comes into play. HRT eliminates these symptoms in 80-90% of cases, rapidly improving quality of life.

Osteoporosis and bone fractures

The prevalence of osteoporosis in postmenopausal women is around 25–30%, while osteopenia is seen in 40–50%.

Why does the risk increase after menopause?

Decreased estrogen: Osteoclast activity increases → bone breakdown accelerates.
Calcium and vitamin D deficiency: Bone mineral density decreases.
Aging: Muscle strength decreases, risk of falls increases.
Lifestyle factors: Smoking, alcohol, and inactivity increase the risk.

HRT compensates for estrogen deficiency after menopause, reducing bone breakdown and supporting bone formation. Thus, it provides a protective effect against osteoporosis and fracture risk. However, this protective effect disappears when HRT treatment is discontinued. Furthermore, it does not eliminate risk factors such as nutritional deficiencies, decreased muscle strength, and lifestyle; these factors must be considered in long-term treatment.

Urogenital atrophy (vaginal dryness, urinary tract infections, incontinence)

Postmenopausal urogenital atrophy occurs due to estrogen deficiency, resulting in thinning, dryness, and weakening of the vaginal tissues’ defense mechanisms. Local or systemic estrogen therapy activates receptors in these tissues, increasing epithelial thickness, moisture, and microbial resistance; thus, reducing symptoms such as dryness, infection, and incontinence.

Important Risks of Treatment

Breast cancer: In hormone therapy, estrogen alone is not given. This is because estrogen alone increases the risk of uterine cancer. When progesterone is added to the treatment, the uterus is preserved, but this increases cell proliferation in the breast tissue, ultimately raising the risk of breast cancer. In women who have had a hystectomy, estrogen alone can be used, in which case the risk of breast cancer is lower or neutral.

Thrombosis/embolism: Estrogen and progesterone increase the risk of thrombosis because they affect the blood clotting system; estrogen increases clotting factors in the liver, while progesterone causes additional changes in the vessel wall and coagulation balance. This combination, especially when taken orally, significantly increases the risk of venous thrombosis (deep vein thrombosis, pulmonary embolism).

Methods of Reducing Risks

Hormone replacement therapy (HRT) during menopause is one of the most effective methods for reducing vasomotor symptoms, particularly hot flashes and night sweats; it also plays a significant role in preserving bone mineral density, thereby reducing the risk of osteoporosis and fractures.
However, certain strategies should be implemented before and during treatment to minimize risks:

1. Personal Risk Profile

• Contraindications: HRT is not recommended for women with a history of breast cancer, BRCA mutation, or a strong family history.

• Those at risk of thrombosis: If there are risk factors such as obesity, smoking, or hypertension, oral HRT should be avoided, and transdermal administration should be preferred.

2. Choosing the Right Form

• Micronized progesterone: Has the same structure as the ovaries’ natural progesterone. It carries a lower risk of breast cancer compared to synthetic progestins.

• Transdermal estradiol (patch/gel): Safer than oral estrogen. Because it does not undergo first-pass metabolism in the liver, it has a lower risk of blood clots.

3. Age and Menopause Duration

• Starting early is safer: Starting HRT before age 60 or within the first 10 years after menopause carries a lower risk.

• Late initiation is risky: HRT started after age 60 or 10 years after menopause may increase the risk of cardiovascular disease and thrombosis.

4. Dosage and Duration

• The lowest effective dose should be used.

• The shortest possible term (usually 5 years or less) should be preferred.

• If long-term use is required, the risk-benefit balance should be reviewed regularly.

5. Monitoring and Screening

• Mammography: Should be done every 2 years or annually depending on risk factors.

• Cardiovascular screening: Blood pressure measurement and lipid profile assessment should be performed regularly.

• Thrombosis risk factors: Conditions such as obesity, smoking, and hypertension should be monitored regularly.

The Hormone Replacement Debate in Menopause Treatment

Large clinical trials have shown that hormone replacement therapy (HRT) increases the risk of breast cancer and blood clots.

However, there are differing opinions among experts regarding the magnitude of this risk and how it should be interpreted.

Some experts argue that the risks are exaggerated and that the benefits should not be overlooked, especially in women with severe symptoms. For example, the increased risk seen with birth control pills is much higher compared to HRT.

Some experts point out that clinical studies proving the risks have been conducted specifically with synthetic hormones. Therefore, they emphasize that the results cannot be generalized to all HRT options.

Indeed, large, evidence-based experimental studies such as the WHI (Women’s Health Initiative) have found an average 27% increase in the risk of breast cancer, stroke, and blood clots with synthetic hormones, but subsequent observational studies have presented a different picture. Specifically, bioequivalent combinations such as estradiol + micronized progesterone have been found to significantly lower the risk of breast cancer compared to synthetic hormones.

General Clinical Approach:

• For mild symptoms: HRT is not necessary; lifestyle changes and medications and supplements as recommended by your doctor may be preferred.

• For moderate to severe symptoms: If you experience symptoms such as hot flashes, night sweats, or vaginal dryness, short-term and effective low-dose HRT may be considered.

• In women at risk of osteoporosis: HRT may contribute to bone health, but first-line treatment is bisphosphonates.

Make decisions together with your doctor throughout your treatment journey; ask the right questions and be a part of the process.

Observational studies have shown the increase in risk more clearly according to hormone type and duration of use: while the increase is generally low (around 0–10%) with bioequivalent combinations, the risk is more pronounced and higher (between 20–70%) with synthetic progestins.

Bioequivalent hormones:
<5 years of use: Low risk (around 0–10%)
≥5 years of use: Moderate increase in risk (around 20%)

Synthetic hormones :
<5 years of use: Increased risk (20–40%)
≥5–10 years of use: Much higher risk (50–70%)

📚 References

• North American Menopause Society (NAMS). The 2022 Hormone Therapy Position Statement. menopause 2022.

• European Menopause and Andropause Society (EMAS). Guideline on menopausal hormone therapy. Maturitas. 2020.

• Endocrine Society Clinical Practice Guideline. Treatment of Symptoms of the Menopause. J Clin Endocrinol Metab. 2015.

• International Menopause Society. Recommendations on screening and monitoring during HRT. Climacteric. 2021.

• Chlebowski, R. T., Anderson, G. L., Aragaki, A. K., Manson, J. E., Stefanick, M. L., Pan, K., … Prentice, R. L. (2020). Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA, 324(4), 369–380. https://doi.org/10.1001/jama.2020.9482 (doi.org in Bing)

• Fournier, A., Berrino, F., & Clavel-Chapelon, F. (2005). Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N cohort study. International Journal of Cancer, 114(3), 448–454. https://doi.org/10.1002/ijc.20710

• Fornili, M., Baglietto, L., Dossus, L., Fagherazzi, G., Mancini, F. R., Mesrine, S., … Clavel-Chapelon, F. (2021). Association between menopausal hormone therapy, mammographic density and breast cancer risk: Results from the E3N cohort study. Breast Cancer Research, 23(1), 47. https://doi.org/10.1186/s13058-021-01436-2 (doi.org in Bing)

• Million Women Study Collaborators. (2003). Breast cancer and hormone-replacement therapy in the Million Women Study. The Lancet, 362(9382), 419–427. https://doi.org/10.1016/S0140-6736(03)14065-2 (doi.org in Bing)