MENOPAUSE AND HORMONE REPLACEMENT THERAPY: DO THE BENEFITS OUTWEIGH THE RISKS? (PART 2)

Medically Reviewed and Updated by Dr. Rosmy Barrios - September 30, 2024

The following article attempts to summarize what is currently known about HRT in the context of hormonal decline, menopause, and female aging:

• Part 1 discusses the causes of menopause, symptoms, the benefits of HRT and how it works, as well as synthetic forms of HRT.
• Part 2 below discusses natural forms of HRT, oral vs. transdermal administration, side effects, contraindications and the risks involved, as well as other treatment options for menopausal symptoms. Healthy diet and lifestyle considerations for optimal female aging are also briefly reviewed.

Natural Hormones

Natural hormones consist of conjugated equine estrogens, compounded bioidentical hormones, and phytoestrogens.

Conjugated Equine Estrogens are extracted from horses and are believed to be a very safe and effective alternative to synthetic estrogens. In spite of how it may seem, equine estrogens are not bioidentical and maintain a structure unique to the physiology of horses. By comparison to other natural hormones, equine estrogens have been the most extensively tested. Large scale trials have confirmed that equine estrogens have a similar efficacy and safety profile to bioidentical estrogens, with little to no risk of complications.

• More Effective Than Synthetic HRT. In one study, low-dose oral equine estrogens (450mcg) were superior to very low-dose transdermal estradiol (50mcg) plus micronized progesterone (200mg; only every 12 days of each month) in reducing menopausal symptoms over a 4-year period.^[1] Conjugated equine estrogens reduced the incidence of hot flashes from 44% to 4.2% and night sweats from 35% to 4.7%. By comparison, transdermal estrogen decreased the incidence of these symptoms to 7.4% and 5.3%, respectively. Despite a similar degree of efficacy, equine estrogens significantly improved insomnia and sleep quality at a faster rate than transdermal estrogen (3 years vs. 4 years).

Bioidentical Hormone Therapy. As the name suggests, bioidentical hormones are compounds that have the exact same structure as the natural hormones found in the body.^[2] Bioidentical hormones are generally extracted and compounded from natural plant-based sources that match our hormonal chemistry.

• Limited Evidence Suggests Enhanced Efficacy. Far fewer studies have been conducted on bioidentical hormones compared to equine estrogens and synthetic hormones. Preliminary studies have consistently revealed that properly formulated bioidentical hormones trump synthetic varieties in their efficacy, often yielding better results with lower risk^[3]. This is particularly true of bioidentical progesterone.
• Unlikely to Promote Breast Cancer at Low Doses. There is much debate over whether natural HRT is superior to synthetic HRT in terms of breast cancer risk. Experimental studies show that excessive levels of any female reproductive hormones will increase the growth of the breast cells as well as the risk for breast cancer. Some studies have highlighted that low doses of either equine estrogens or bioidentical estrogens are not associated with breast cancer risk, whereas synthetic hormones, particularly progestins, could increase the risk.^[4]
• Custom Compounded HRT is Not Standardized. Some select pharmacies around the globe offer custom compounded bioidentical HRT formulations that make use of a spectrum of bioidentical hormones at quantities that are tailored to the patient. Many of these formulas will contain other hormones not common to HRT, such as DHEA, androstenedione, testosterone and estriol (an estrogen produced only during pregnancy). Some include Chinese herbs and other potent ingredients that enhance their hormonal effects. These custom-made formulations have not been extensively tested for their safety and efficacy and may contribute to additional health problems. It is important to opt for legitimate products to avoid unwarranted side effects. A skilled healthcare provider should be able to offer safe, natural HRT alternatives to those who wish to avoid synthetic options.^{[5] [6]}

In spite of the higher risk profile of synthetic HRT, most healthcare practitioners will prescribe synthetic hormones unless the patient specifies otherwise. It is worth discussing bioidentical hormones with your doctor when considering HRT.

Oral vs. Transdermal Products

The main differences between oral and transdermal products are highlighted below.

Transdermal Vs. Oral HRT. Transdermal products have proven to be more effective than oral products for the majority of women undergoing HRT.^[7] Transdermal HRT does not interfere with liver metabolism as the hormones administered pass directly from the skin into the bloodstream. These products often make use of very low hormone doses, which reduces the risk of side effects and optimizes the benefits, as evidenced across studies^[8]. Additionally, they can offer immediate symptom relief by being applied directly to the reproductive area, allowing for more treatment flexibility. In addition to efficacy, there is evidence that transdermal HRT is safer than oral HRT due to the increased venous thromboembolism risk observed with the latter.^[9] All the other benefits and risks were found to be similar.

Types of Transdermal Products. Transdermal products consist of low-dose vaginal inserts such as pills, creams, or rings and are used to take away vaginal dryness, itchiness and pain. Other products, such as HRT patches, can immediately increase blood hormone levels. As with taking oral estrogen, transdermal products are typically safer when administered in a bioidentical form.

Oral HRT and Other HRT Types. For women with extreme menopausal symptoms, a physician will often recommend higher-dose products. These consist of hormone tablets and/or injections. Oral therapy has been associated with more side effects and complications on average due to its more pronounced impact on the liver. Synthetic versions, even if not taken orally, may also pose a higher risk of reproductive cancers, stroke, and thromboembolism. It is not advisable to opt for these therapies on a long-term basis. Bioidentical or equine hormone equivalents should be opted for where possible.

HRT Side Effects

According to the British NHS, side effects of HRT are transient and typically subside within the first 3 months of treatment.^[10] Side effects of HRT may include:

• Fluid retention
• Abdominal pains
• Cramps
• Indigestion
• Nausea
• Headaches
• Tenderness of the breasts
• Vaginal bleeding

HRT Risks and Complications

It is noteworthy that a higher risk for complications is indicated if HRT is started more than 10 years after menopause symptoms begin. Early initiation of HRT in postmenopausal women can be beneficial. Moreover, according to studies, taking HRT during the 40s or 50s is typically not associated with an increased risk of cardiovascular disease.^[11]

• Mild Pregnancy Risk. In spite of irregular or absent menstruation, there is a very small chance that one can get pregnant while undergoing HRT. Contraception is recommended for up to 2 years following your last period if below age 50 and up to 1 year for those who are older.
• Hormone-Positive Cancers. Hormone replacement therapy is one of the largest risk factors for hormone-positive breast cancer in susceptible women. In healthy women, HRT has only been associated with a 1% lifetime risk for breast cancer. This risk can be compounded by using oral products, taking higher doses of hormone supplements, obesity, giving birth at an advanced age, reaching puberty at an early age, excessive lifetime alcohol consumption,^[12] as well as menopause onset at an older age.^[13] Breast and ovarian cancer risk is also observed to be higher for those who were previously at risk, who opt for HRT after the age of 60, or who have used HRT for more than 10 years.^{[14] [15]} In addition, synthetic estrogens and progestins may substantially increase breast cancer risk. The risk can be reduced by stopping treatment before 60, making use of safer forms, and opting for low-dose transdermal products.
• Hypertension. Despite being known to decrease LDL and promote vasodilation, HRT can increase triglycerides and blood pressure. Conjugated equine estrogens with or without synthetic progestin have been shown to increase blood pressure in over 9000 women with hypertension. Results were worse for those on synthetic progestin than on equine estrogens alone.^[16]
• Strokes and Heart Attacks. High-dose oral estrogen formulations have been associated with heart attacks and strokes in some women due to promoting thrombosis. In a large-scale review assessing more than 40000 women, the risk for stroke was approximately 0.6% and only found to be associated with women using HRT 10 years or later after menopause. Venous thromboembolism risk was found to be at 0.8% and pulmonary embolism at 0.4% across all users.^[17] Risk has been noted to be highest in products containing medroxyprogesterone acetate, as well as in oral products containing high doses of estrogen. ^[18]
• Reproductive hyperplasia. Oral estrogen use, as well as high doses of estrogen in the absence of progesterone, may increase the risk of growth abnormalities in reproductive tissues. The risk is greatly reduced in low-dose products and likely only extends to women already at risk.
• Incontinence. HRT can both raise the risk for incontinence and increase the frequency of symptoms in women who are already incontinent, according to several large studies. These observations were shown for synthetic estrogen, progestins,^[19] and conjugated equine estrogens^[20]. Locally applied vaginal products, such as HRT creams and patches, were shown to reduce symptoms of incontinence.^[21] Incontinence has been associated with both estrogen decline as well as stress. Women who are at risk or who experience symptoms of incontinence after 4 months of therapy may wish to discontinue or switch to transdermal solutions.

Contraindications

HRT is not recommended for women with the following conditions*:

• Liver disease
• Gallbladder disease
• Blood clotting disorders
• Breast, uterine or ovarian cancers
• Endometriosis
• Hypertension or high blood pressure
• Thromboembolism or related diseases
• Pregnancy

*Excluding pregnancy, it is also important to consult with your doctor about proceeding with HRT if you have a past history or genetic risk pertaining to any of the above conditions.

Extreme Side Effects. If HRT induces extreme side effects, then it should be discontinued. Bleeding^[22] and severe breast tenderness in response to therapy could be a sign that the patient is at an increased risk for contracting endometrial and breast cancer.

Alcohol Consumption may be contraindicated while on HRT as it can triple E2 levels by comparison to those who do not consume alcohol and substantially increase the risk for breast cancer. Despite promoting estrogen elevations, women who drink are known to experience worse menopausal symptoms.^[23]

Current and Former Smoking. Oral estrogens may be contraindicated for those who smoke or who used to smoke in the decade prior to initiating HRT. Studies reveal that smokers tend to have lower levels of estrogen and that oral estrogens fail to be metabolized in the livers of smokers. The effects of smoking on the liver likely persist for many years after cessation of smoking, as former smokers have been shown to be non-responsive towards oral HRT as well. Transdermal HRT may be a better option for these women as it bypasses the liver and can therefore help to ease symptoms.^[24]

Various Medications. Some pharmaceuticals may interfere with the metabolism of hormones or promote their associated side effects. If on other prescription medications, it is best to check with a doctor beforehand whether they are compatible with HRT. If any medications are contraindicated, transdermal HRT may be a better option for those suffering severe menopausal symptoms.

Other Menopausal Treatments

Since the Women’s Health Initiative brought forth its results pertaining to HRT and the associated cancer risk, the use of the treatment has been on the decline worldwide.

Through the persistence of many women, doctors, and scientists, other treatments for managing menopausal symptoms have been formulated. Of these treatments, tailored nutrition, healthy lifestyle practices, and ovarian grafting appear to be the most promising options aside from HRT.

1. Bone Health Prescriptions. Osteoporosis is one of the main medical conditions associated with menopause, characterized by frailty, low bone mineral density, and joint stiffness.^[25] Estrogen plays an important role in maintaining sufficient calcium in the bones, and therefore, when it is on the decline, bone health gets compromised as well. In this respect, HRT largely tackles many of the osteoporotic symptoms menopausal women may experience.

For those who have more severe osteoporosis-like symptoms with less of the other classic menopausal manifestations, the following treatments may prove rather useful:

• Vitamin D3 and Vitamin K2. These are the precise nutrients the body uses (alongside estrogen) in order to maintain adequate bone mineral density – provided basic dietary nutritional requirements are met. Vitamin D3 is a bioactive form of calcium that may have further benefits for menopausal women, such as improved sleep quality; although reports are contradictory. Without K2, D3 does not remain in the bone matrix and the benefit of supplementation is reduced. Vitamin K2 alone has been shown to improve bone mineral density in postmenopausal women, yet more research is required before a firm conclusion can be made.^[26]
• Bisphosphonates. Phosphorus is a mineral that aids bone mineral metabolism and works closely together with calcium to ensure skeletal health. Bisphosphonates are synthetic phosphorus compounds that specifically target bone cells, preventing the resorption of bone and therefore improving bone integrity.^[27] Prolonged use of bisphosphonates ultimately contributes toward adynamic bone, a condition in which the body no longer replaces bone cells.

2. Antidepressants. For women suffering more from neurological menopause symptoms such as depression and increased anxiety, doctors may prescribe antidepressants. It ought to be noted that most antidepressants do not work in the long run for treating depression or anxiety. Prolonged use can promote worse symptoms and may even become addictive. In terms of menopause, certain antidepressants have been shown to decrease the frequency of hot flashes, and these include gabapentin, clonidine and paroxetine. However, long-term use of these antidepressants can substantially increase the risk for depression, suicidal ideation^[28] and even breast cancer^[29]. Caution is advised when considering antidepressants. Safe and effective alternatives include physical exercise and consuming a healthier diet that supports the microbiome.
3. Ovarian Grafting for Preventing Premature Menopause. Ovarian grafting has proven to be an effective option for restoring fertility in young women who suffer from ovarian insufficiency, cancer, or the devastating consequences of chemoradiotherapy. Through advanced cryogenic techniques, healthy ovarian tissue is removed from the recipient and saved aside for later use. When required, the healthy tissue can be regrafted, stimulated and made to regenerate ovarian function. Recipients tend to begin menstruating again within several weeks to months after the procedure.^[30] The effects have been shown to last between 1-10 years in younger women^[31]. This treatment is currently being offered by a few select clinics worldwide for fertility preservation.

• Cryopreservation and Premature Menopause. Despite its potential for prolonging fertility in younger women at risk for infertility, it is not likely to restore ovarian function in older women due to menopause. However, some studies show that ovarian tissue cryopreservation can potentially delay menopause and restore fertility^[32]. At present, many questions concerning the safety and efficacy of cryopreservation remain unclear with more clinical trials needed for definitive indications.

Dietary and Lifestyle Tips in Support of Graceful Aging

The following tips may enhance the effectiveness of HRT and promote healthier aging in the long run:

Consuming a “Rainbow” Diet that is rich in vitamins, minerals, water-soluble fiber, and other supportive nutrients is associated with reduced severity of menopausal symptoms and improved aging^[33]. Conversely, a diet high in processed foods that promote inflammation has been associated with both hormonal excesses and deficits in postmenopausal women.^[34] Nutrient-dense, plant-based diets, low in processed foods, have been shown to be the best for overall health and well-being.^[35]

Nutritional support has long been used in complementary medicine as a means to help improve the quality of life in menopausal women. This is likely due to the way in which antioxidants help to support the function of the mitochondria, both of which are known to decline with age and promote metabolic endocrine disruptions^[36]. Specific dietary nutrients that help support a smooth menopausal transition include:

• Foods Rich in Phytoestrogens. Phytoestrogens are plant-based nutrients that mimic the chemical structure of body-derived estrogens. Across studies, higher intake of phytoestrogens throughout the diet has been associated with overall better nutritional status and reduced incidence of hot flashes in menopausal women^[37]. While the evidence is contradictory^[38], some studies indicate that higher phytoestrogen consumption may protect against bone mineral density loss in the hips and spines of postmenopausal women^[39] when coupled with adequate calcium and other bone-supportive nutrients^[40]. There is also limited evidence to suggest phytoestrogens may help reduce side effects associated with HRT by improving the cardiovascular profile of postmenopausal women^[41] and potentially reducing the risk for reproductive cancer.^[42] Nuts, seeds, legumes, and some fruits, including pomegranates, have a relatively higher phytoestrogen content than other foods.
• Omega-3 Fats have been proven to help lower bodily inflammation and the incidence of depression in populations that consumed them in high quantities. While evidence regarding menopause is scarce, omega-3 fats may help to reduce body pain and associated depressive symptoms^[43]. A small review found that omega-3 supplementation helped to lower night sweats in menopausal women^[44].
• Vitamin E may be complementary to HRT treatment, particularly when combined with topical creams or in the diet alongside other anti-inflammatory nutrients such as vitamin C and omega-3 fats^[45]. Research has shown that supplementing with vitamin E can help to reduce hot flashes^[46] and lipid oxidation (and inflammation), thereby improving outcomes in HRT as well as the cardiovascular profile of postmenopausal women. It has been shown to help decrease symptoms related to vaginal atrophy in menopausal women when applied topically.^[47]
• Vitamin C. A few studies have revealed that vitamin C consumption is likely to be directly proportional to better bone health in menopausal women. Similar associations have been made regarding vitamin C status and menopausal cardiovascular and cognitive functioning.^[48]

For more information on menopausal nutritional support, it is advisable to consult with a nutritionist.

Smoking Cessation. Smoking has the propensity to increase the risk for premature menopause^[49] and increase the intensity of menopausal symptoms, particularly in women who have smoked for most of their lives^[50]. Through its effect on the liver, smoking results in lowering hormone levels and tends to reduce the efficacy of HRT as well. Smoking should be moderated or stopped in support of healthier aging.

Frequent Exercise has been shown to improve health outcomes for any person at any age, with an additive effect throughout one’s life. Women that exercise regularly prior to menopause tend to experience less severe symptoms, particularly with regard to urogenital symptoms and incontinence^[51]. In pre-menopausal women, exercise supports hormonal balance and regular menstruation, as well as lowers excessive testosterone levels^[52]. Moderately intensive physical activity helps to strengthen bones and muscles, which in turn protects against osteoporosis, falls, and fractures. Regular exercise may also have a positive effect on other aspects of menopause by improving mood, lowering cardiovascular disease risk, improving glycemic control, and helping to regulate overall metabolism. The anti-aging benefits of frequent physical activity are known to benefit postmenopausal women as well through promoting longevity, reducing the number of senescent cells, and reducing the risk of acquiring age-related diseases.

Stress Management. Stress is known to increase the severity of menopausal symptoms by as much as 21%^[53]. Keeping one’s stress levels under control is important for healthy aging and less severe menopausal symptoms. Studies show that while social support is usually key for coping with stressful life events, it does not appear to reduce stress levels in menopausal women. Healthy lifestyle interventions, such as consuming a more nutrient-dense diet, making time for recreational activities, and engaging in regular physical activity, can help to manage stress.

In order to get results from healthier lifestyle changes, one ought to consult with a relevant healthcare provider, such as a nutritionist, functional medical doctor or similar specialist.

Conclusion

Hormone replacement therapy remains the gold standard for treating symptoms of menopause. The benefits of remedying hormonal decline in females appear to extend beyond treating menopausal symptoms, with the potential for prolonging the onset of age-related diseases such as osteoporosis and dementia. The risks associated with HRT use are minimal for healthy women aged between 45 and 60, especially when opting for low-dose products that are free of synthetic progestins. HRT is contraindicated for smokers, those who drink excessively, those with a history of various diseases and pregnant women. Leading a healthier lifestyle can enhance the anti-aging benefits associated with HRT, including consuming a nutrient-dense diet, engaging in adequate physical activity and managing stress effectively.

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