The Menopausal Transition and HRT: What Women Need To Know.

For many women, the transition through perimenopause and menopause brings a host of physical, cognitive, and emotional changes. These are often driven by the natural decline in estrogen levels. While this hormone is commonly known for its role in reproduction, researchers have uncovered its far-reaching impact on brain, bone, and cardiovascular health as well.

Estrogen’s Role in the Body

Estrogen plays an important role in various bodily functions, including cognition, bone density, mood regulation, and cardiovascular health. Starting with cognition, in the 1980s scientists began exploring estrogen’s role in brain function. Studies using mice have indicated that estrogen enhances neural connectivity in the hippocampus, a critical area for learning and memory, and modulates neurotransmitter levels, leading to improved cognitive performance.

The decline of estrogen during menopause is associated with an increased vulnerability to neurodegenerative diseases such as Alzheimer’s, suggesting a neuroprotective role of the hormone.

Women in perimenopause and menopause also often report symptoms such as brain fog, mood swings, forgetfulness, and disrupted sleep. Estrogen fluctuations—not just declines—can affect mood and cognitive function as well.  It’s no surprise that many women can experience depression during the menopausal transition, even if they have never had a history of depression.

On a physical level, the loss of estrogen contributes to decreased bone density and increased cardiovascular risk. Menopausal patients also may report urinary tract symptoms (urinary frequency), vaginal dryness, and hot flashes.

Considering Hormone Replacement Therapy (HRT)

Given these impacts, many women consider hormone replacement therapy (HRT) to help manage symptoms and reduce health risks. HRT is a treatment that replaces the estrogen (and sometimes progesterone) that the body stops producing.

There are two main types of HRT:

• Estrogen-only HRT, typically used for women who have had a hysterectomy.

• Combination HRT, which includes both estrogen and progesterone and is used for women who still have a uterus, to prevent endometrial cancer.

HRT can be delivered systemically (pills, patches, gels) or locally (vaginal creams for dryness). While systemic HRT addresses broad menopausal symptoms like hot flashes, night sweats, and brain fog, localized HRT mainly targets vaginal symptoms.

What About Breast Cancer Risk?

In 2002, the Women’s Health Initiative (WHI) study raised alarms by linking HRT to increased risks of cardiovascular disease and breast cancer. As a result, HRT use declined considerably. However, later analyses revealed key limitations: the study involved women who were, on average, over 60 and many years past menopause, not the typical candidates for initiating HRT.

Recent findings offer a more nuanced picture:

• The Timing Hypothesis proposes that there is a critical window around the onset of menopause when initiating HRT may offer the greatest benefits with relatively lower risks, especially when compared to starting HRT later in life such as over 60.

• Estrogen-only HRT has been found to reduce breast cancer risk in women with prior hysterectomies.

• Combination HRT may slightly increase breast cancer risk, particularly with long-term use, but the absolute risk remains low for women starting HRT in their 50s.

The benefits of HRT, including relief from distressing symptoms and protection against bone density loss, may outweigh the risks for many women, especially those without a personal or family history of breast cancer. That said, systemic HRT is not recommended for women with a history of hormone receptor-positive breast cancer, due to the risk of recurrence.

What about other risks of HRT?

HRT carries other potential risks that vary depending on your individual risk factors (age, smoking status, etc), how the hormones are administered (oral, transdermal, etc), and the dose used.

• Blood Clots: Oral forms of HRT, especially combination therapies, are linked with a higher risk of blood clots (venous thromboembolism). However, transdermal (through the skin) estrogen therapy does not appear to carry this risk based on current studies and may be an option for women at higher risk, such as those with obesity or high triglycerides.

• Cardiovascular Risk: Earlier WHI data showed increased heart risks with oral HRT, especially when started more than 10 years after menopause. However, newer research supports the “timing hypothesis” — starting HRT before age 60 or within 10 years of menopause is associated with better cardiovascular outcomes. Transdermal estrogen bypasses the liver, reducing the effect on blood markers that can influence heart health.

• Stroke: Oral estrogen is also linked to an increased risk of stroke, but again, transdermal estrogen appears to carry a much lower risk when compared to oral estrogen in recent observational studies.

In short, there are many factors that affect risk of HRT including how HRT is used, when it is initiated, and on your individual medical history.

Alternatives to HRT

If HRT isn’t an option, there are alternatives for women who are experiencing perimenopausal symptoms. It is important to discuss all your options with your doctor to determine what is recommended for you.

• Lifestyle modifications: weight bearing exercise, maintaining a healthy weight, reducing alcohol and caffeine, and avoiding triggers like spicy foods can ease vasomotor symptoms.

• Non-hormonal medications: Options like Fezolinetant (Veozah®), gabapentin, clonidine, and certain antidepressants may reduce hot flashes and mood changes.

• Complementary therapies: CBT, acupuncture, yoga, and mindfulness have shown benefit in managing symptoms.

• Topical therapies: Vaginal estrogen creams and moisturizers can help with dryness and discomfort.

• Regular Medical Check-ups: Routine health screenings and discussions with healthcare providers are crucial to monitor and manage the risks associated with menopause, including osteoporosis and cardiovascular disease.

Conclusion

There is “no one size fits all” approach to managing menopause. The decision to use HRT, or any treatment, should be made in collaboration with a knowledgeable healthcare provider who understands your individual health history and needs. Ongoing research continues to shed light on how best to support women through this transition. With growing awareness and personalized care, women can navigate menopause with more options and better outcomes than ever before.

Selected references:

Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;288(3):321–333. doi:10.1001/jama.288.3.321

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Oliver-Williams C, Glisic M, Shahzad S, Brown E, Pellegrino Baena C, Chadni M, Chowdhury R, Franco OH, Muka T. The route of administration, timing, duration and dose of postmenopausal hormone therapy and cardiovascular outcomes in women: a systematic review. Hum Reprod Update. 2019 Mar 1;25(2):257-271. doi: 10.1093/humupd/dmy039. PMID: 30508190.

Hodis HN, Mack WJ, Henderson VW, et al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. The New England Journal of Medicine. 2016;374(13):1221-1231. doi:10.1056/NEJMoa1505241.

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