Hormone replacement therapy (HRT) has been surrounded by controversy for decades, largely due to misinterpretations of early research. The Women's Health Initiative (WHI) study, one of the most influential trials on HRT, significantly shaped public and medical opinion. However, a closer examination of its findings, alongside more recent research, reveals a nuanced picture of HRT’s risks and benefits.
The WHI Study and Breast Cancer Risk
The WHI study, initiated in the 1990s, was a large, randomized clinical trial designed to assess the risks and benefits of HRT in postmenopausal women. The study consisted of two primary arms: one focused on oestrogen-only therapy for women who had undergone a hysterectomy, while the other examined oestrogen plus progestogen therapy for women with an intact uterus. Initially, the study reported an increased risk of breast cancer, which caused widespread concern and a reduction in HRT usage. However, further analysis revealed key distinctions. Oestrogen-only therapy appeared to be associated with a reduced risk of breast cancer, while combined oestrogen plus progestogen therapy showed a small increase in breast cancer risk, later attributed to synthetic progestins used in the study. It is also important to note that this small increased risk equates to approximately 4 extra cases of breast cancer per 1000 women after 5 years of HRT use, an incidence lower than that caused by other modifiable cancer risk factors such as obesity and smoking.
HRT’s Protective Benefits: Fracture Risk, Cardiovascular Health, and Cognitive Function
Fracture Prevention & Osteoporosis:
HRT can reduce fracture risk and protect against osteoporosis by maintaining bone density.
Cardiovascular Health:
Contrary to initial fears, follow-up analyses indicated that women who started HRT before the age of 60 or within 10 years of menopause onset experienced a reduced risk of cardiovascular disease (CVD). However, this benefit does not appear to extend to women who initiate HRT later in their menopause journey.
Cognitive Function:
Early initiation of HRT appeared to reduce the risk of dementia and cognitive decline, particularly in women using oestrogen-only therapy.
All-Cause Mortality:
Meta-analyses of randomised controlled trials conducted in 2023 have reported that HRT is associated with a reduction in all-cause mortality.
Why Topical Oestrogens Are Preferred
Conjugated equine oestrogens, once the standard in HRT, have fallen out of favour due to their less predictable metabolism and increased thrombotic risk. Studies now support the use of transdermal oestradiol, which:
Avoids first-pass metabolism in the liver, reducing the risk of clotting and stroke.
Provides more stable hormone levels, leading to better symptom control.
While HRT is contraindicated in individuals with a recent cardiac event or stroke, having risk factors alone is not a contraindication. In such cases, transdermal oestrogen is considered the safest option.
Micronised Progesterone vs. Synthetic Progestins
Observational research has highlighted the advantages of micronised progesterone over synthetic progestins (e.g. medroxyprogesterone acetate). Studies have found that:
Micronised progesterone has a neutral or even beneficial effect on breast tissue, unlike synthetic progestins, which were implicated in the increased breast cancer risk seen in the WHI study.
It may have a better cardiovascular profile, with less impact on blood pressure and clotting factors.
It may be better tolerated, with fewer side effects such as mood disturbances and bloating.
Additionally, oral micronised progesterone and the intrauterine progestogen are often preferred over topical and troche preparations due to superior symptom management and safety profiles. Oral progesterone brings a favourable impact on sleep, reduced risk of endometrial hyperplasia (thickening of the lining of the uterus), and ease of use. Oral micronised progesterone has demonstrated sedative properties, which can be beneficial for women experiencing sleep disturbances during menopause. Both intrauterine and oral forms are also more effective in protecting the endometrium when used in conjunction with oestrogen therapy.
Importantly, there are now FDA and TGA-approved forms of micronised progesterone, offering a regulated and reliable option for patients seeking safer hormone therapy with standardised dosing.
The Safety Profile and Benefits of the Mirena
The Mirena intrauterine system (IUS) is a progestogen-releasing device that provides a localised form of progesterone delivery, reducing systemic side effects commonly associated with oral progestins. Recent research, including a January 2024 study, has highlighted several key benefits:
Endometrial Protection: Mirena effectively prevents endometrial hyperplasia when used in combination with oestrogen therapy, making it a reliable option for women requiring endometrial protection in HRT.
Convenience and Long-Term Use: It provides up to eight years of continuous progesterone release, eliminating the need for daily oral progesterone intake.
Reduction in Heavy Menstrual Bleeding: Women transitioning into menopause often experience erratic bleeding patterns, and the Mirena helps significantly reduce or stop heavy periods.
Minimal Systemic Absorption: Because the Mirena delivers progesterone directly to the uterus, it bypasses systemic circulation, reducing the risk of progestogen-related side effects like bloating and mood changes.
Implications for HRT: Despite its benefits, it is important to note that the Mirena contains a synthetic progestogen, which has been associated with a slight increase in breast cancer risk. Although a very recent study highlights an increased relative risk associated with the Mirena, the absolute risk remains low. Its localised effect may make it a safer alternative compared to systemic progestins. Ongoing research continues to evaluate its long-term impact on breast tissue.
Overall, the Mirena offers a safe and effective alternative to oral progestins in HRT, particularly for women seeking low-maintenance and localised progestogen therapy while benefiting from transdermal oestrogen.
Bioidentical Hormone Therapy and the Role of Oestradiol and Oestriol
Bioidentical HT (bHT) formulations often contain a combination of oestradiol (E2) and oestriol (E3) in topical forms. These different oestrogen types provide distinct advantages:
Oestradiol (E2): The most potent oestrogen, primarily responsible for alleviating hot flushes, night sweats, and vaginal dryness.
Oestriol (E3): A weaker oestrogen, beneficial for urogenital health without stimulating breast tissue as strongly as oestradiol.
By tailoring the ratio of these oestrogens, treatment can be optimised for specific symptoms, improving outcomes for women experiencing menopause-related discomfort.
The Future of HRT: Individualised and Evidence-Based Care
The misconceptions surrounding HRT, primarily stemming from outdated interpretations of the WHI study, have resulted in significant hesitancy among women to pursue treatment. Consequently, many women have endured debilitating symptoms and a diminished quality of life throughout their menopause years as a result of this misinformation.
As awareness of menopause increases, an increasing number of individuals are actively seeking information and guidance on hormone replacement therapy options. This trend brings a more informed approach to managing menopause. While oestrogen and progesterone are the primary hormones replaced in conventional HRT, they are not the only hormones that decline during perimenopause. Women also produce testosterone, and its decline can significantly affect various aspects of health, including sexual function, muscle mass, basal metabolic rate, and weight management, to name a few. Dr. Danielle will be discussing how and when testosterone replacement can be safely incorporated into HRT and the broader implications for women's health in an article coming soon.
Dr. Danielle understands that when it comes to HRT, a one-size-fits-all approach does not work, and a comprehensive approach to menopause management that considers all hormonal changes. It is essential to understand that Hormone Replacement Therapy is a journey that may necessitate dose adjustments or modifications to treatments in order to meet individual needs.
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Disclaimer: The information provided in this article is for educational purposes only and should not be considered medical advice. Always consult a qualified healthcare professional before making decisions regarding hormone replacement therapy or any other medical treatment.
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