Continuing Education Activity

Hormone replacement therapy (HRT) replenishes women with ovarian hormones diminished during the natural menopausal transition to alleviate associated symptoms, especially hot flashes and night sweats. Traditional HRT typically combines estrogen and progesterone to replicate ovarian hormones. HRT, approved by the Federal Drug Administration (FDA), treats severe vasomotor menopausal symptoms and prevents osteoporosis. Available estrogen therapies are ethinyl estradiol, conjugated equine estrogen (CEE), synthetic conjugated estrogens, and micronized 17β-estradiol. The addition of progesterone helps prevent endometrial hyperplasia in people with an intact uterus. Systemic HRT can be administered orally, vaginally, or transdermally, each with unique benefits and risks. This activity for healthcare professionals is designed to enhance the learner's understanding of HRT indications, risk-benefit ratios, individualized management, including estrogen and progesterone therapies and administration methods, and the implementation of an appropriate interprofessional management approach to improve patient outcomes.

Objectives:

• Identify the symptoms of menopause that are appropriate for treatment with hormone replacement therapy.

• Differentiate between the various types of estrogen and progesterone therapies available for hormone replacement therapy.

• Apply current clinical guidelines in managing menopausal symptoms using hormone replacement therapy.

• Apply interprofessional team strategies to improve care coordination and outcomes in patients using hormonal replacement therapy.

Indications

Various guidelines influence the recommendations regarding the use and risks of hormone replacement therapy (HRT), including those from the Menopause Society, The American College of Obstetricians and Gynecologists (ACOG), The National Institute for Health and Care Excellence (NICE), and The US Preventive Services Task Force (USPSTF).[1] 

Menopausal Transition

HRT is a treatment approach used to manage moderate-to-severe vasomotor symptoms that women frequently experience during the menopausal transition into the early postmenopausal timeframe. Vasomotor symptoms include hot flashes, flushing, and diaphoresis that can occur during the day or night.[1] The Postmenopausal Estrogen/Progestin Interventions trial, a large randomized controlled trial with 875 women, examined the impact of oral hormone therapy on vasomotor symptoms. The study compared oral conjugated equine estrogen alone, estrogen combined with continuous or cyclic progestin, and placebo. Results showed a significant reduction in vasomotor symptoms for the estrogen-alone (OR, 0.42; 95% CI, 0.28–0.62) and estrogen-plus-progestin groups (OR, 0.38; 95% CI, 0.25–0.58) compared to placebo.[2] HRT is not supported for use in preventing cardiovascular disease, cancer, stroke, dementia, or other chronic diseases.[3] To relieve vasomotor symptoms associated with menopause, conventional HRT includes an estrogen component to mimic hormones created by the human ovary and progesterone for those with an intact uterus. See our companion StatPearls reference article on "Male Hypogonadism" for male HRT.[4]

After 2002, the use of menopausal HRT declined sharply due to the Women's Health Initiative (WHI) reported safety concerns from conjugated equine estrogen (CEE) and medroxyprogesterone acetate, which resulted in premature discontinuation of this arm of the study. Following this WHI announcement, menopausal HRT initiation rates significantly declined. Before the WHI, HRT initiation was at 8.6%, but it dropped to 2.8% following the WHI (P < .001) and then to 1.9% 2 years later. The results from the WHI report focused on treating an older, asymptomatic group but have been falsely generalized over the past 21 years to include all estrogen products, all ages of menopausal women, and all methods of delivery.[5] Since then, new WHI study information has allowed HRT recommendations to be modified, allowing for greater individualization and flexibility.[6] The modifications include that conjugated equine estrogen (CEE) alone reduces breast cancer risk by 23%, decreases breast cancer deaths by 40%, and decreases all-cause deaths. The remaining WHI study concern, which has since been refuted, includes a possible slight increase in breast cancer incidence with CEE and medroxyprogesterone acetate, with no added risk of breast cancer mortality.[7]

The natural decline in estradiol during menopause leads to several adverse metabolic and health effects. Approximately 40% to 60% of women seek treatment, while 20% may delay treatment for over a year. Even among older women, 42% of those aged 60 to 64 and 33% aged 65 to 79 still report vasomotor symptoms (VMS). Australian studies show that 74% of postmenopausal women younger than 55 experience VMS, with 28% reporting moderate or severe symptoms. These symptoms may significantly affect quality of life, with an impact comparable to the stress of insecure housing.[8] Metabolically, the decline in estrogen levels causes increased central abdominal fat deposition even in slim women and contributes to insulin resistance, raising the risk of type 2 diabetes. Cardiovascular health is impacted through impaired endothelial function and a more adverse lipid profile. Skeletal effects include accelerated bone loss, starting before the final menstrual period, which increases the risk of fractures and can contribute to sarcopenia, the age-related decline in muscle mass and strength. Neurologically, some women may experience difficulties with verbal memory during perimenopause, which may improve after menopause.[8]

Premature Ovarian Insufficiency

A practical definition of menopause is the irreversible end of ovarian activity. This is seen with natural menopause but can also be seen with premature ovarian insufficiency (POI), which occurs in women younger than 40 and results in reduced ovarian function, leading to similar menopausal symptoms as natural menopause. POI affects 1% of patients younger than 40 and 0.1% younger than 30.[9] Management typically involves HRT or combined hormonal contraceptives until the average natural age of menopause (ie, 51) to alleviate symptoms and minimize long-term risks. Women experiencing POI due to medical therapy (eg, gonadotoxic chemotherapy with alkylating cancer treatment agents), radiation therapy to the pelvis, or surgical removal of both ovaries should also be offered similar management, including HRT until the age of natural menopause, based on individualized risks and benefits.[8][10] Long-term risks of low estrogen status before age 45 may include an increase in cardiovascular disease, osteoporotic fracture risk, and a potential increase in cognitive impairment.[9] 

Hormone Replacement Therapy Indications

The primary indication of HRT is the treatment of moderate-to-severe bothersome vasomotor symptoms in the perimenopausal and early menopausal years. HRT with estrogen is FDA-approved for first-line treatment of moderate-to-severe vasomotor symptoms due to menopause. A variety of estrogens are available for use in HRT. Conjugated equine estrogen is a mixture of conjugated estrogens. Synthetic conjugated estrogens are a blend of substances, including estrone sulfate, estradiol sulfate, and equilin sulfate. Micronized 17β-estradiol is identical to the estradiol produced from the ovaries. Ethinyl estradiol is a synthetic estrogen used primarily in contraceptive preparations.[11] 

A woman with an intact uterus who desires estrogen HRT must have a progestogen in addition to estrogen therapy for endometrial protection to prevent endometrial hyperplasia or malignancy, as estrogen therapy alone will cause the endometrial lining to grow unopposed. Progesterone prevents the lining from proliferating abnormally. If a woman has had a hysterectomy, progesterone is unnecessary. Progesterone can help with sleep disturbances and mood instability and is frequently given before bedtime.[12][13][14] 

Some regimens of HRT are also approved for the prevention, not treatment, of osteoporosis.[3] The USPSTF recommends against the use of HRT solely for osteoporosis prevention.[15] FDA-approved treatments for osteoporosis prevention include:

• Norethindrone acetate and ethinyl estradiol tablets
• Conjugated estrogen tablets
• Estradiol tablets
• Estradiol patches
• Estradiol and norgestimate tablets
• Estradiol and norethindrone acetate tablets
• Estradiol and levonorgestrel patches
• Conjugated estrogens and medroxyprogesterone acetate tablets
• Conjugated estrogens and bazedoxifene tablets [15]

Testosterone therapy indications

The addition of testosterone supplementation to menopausal HRT can be beneficial for women with female sexual interest and arousal disorder after other causes have been excluded and a trial of conventional HRT has been given. Currently, no FDA-approved testosterone product for women in the US is available. However, transdermal testosterone therapy at a dose suitable for postmenopausal women may enhance sexual desire, arousal, orgasm, and overall pleasure, keeping in mind that no specific level of any androgen is diagnostic of hypoactive sexual desire disorder (HSDD). Per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), published in 2022, HSDD is included in and referred to as female sexual arousal and interest disorder (FSAID).[16] Testosterone gel or cream formulations should be applied to clean, dry skin on the lower abdomen or upper thighs. The hands should be washed immediately after application, and contact with others should be avoided until the product is completely dry. The area should not be washed for 2 to 3 hours postapplication.[8][17]

In 2019, a global consensus position statement regarding testosterone therapy in women was made after a collaboration between many international societies to provide clearer guidelines for healthcare workers who prescribe testosterone to women. Some of these recommendations include that total testosterone and sex hormone binding globulin levels should be checked before treatment to establish a baseline and ensure that elevated testosterone levels are not present before therapy is begun. ACOG recommends testing testosterone levels at baseline, 3 months, and 6 months after the start of treatment to ensure that testosterone levels are not higher than normal values for premenopausal women.[5] However, clinicians should remember that no specific testosterone level is predictive of treatment efficacy.[16]

Placebo-controlled randomized clinical trials consistently show that testosterone therapy is more effective than placebo in treating hypoactive sexual desire disorder in postmenopausal women. Studies using transdermal testosterone patches delivering 300 μg/day or creams providing 5 mg daily have demonstrated that these treatments maintain total testosterone levels within the normal premenopausal range. However, while these outcomes are promising, safety data for testosterone therapy in physiological doses is limited to 24 months, and long-term safety, particularly regarding risks of breast cancer and cardiovascular events such as heart attack, stroke, and deep vein thrombosis, remains uncertain and inconclusive.[16] Compounded testosterone, testosterone pellets, injections, and oral formulations are not recommended for use in women. Male formulations can be down-titrated, however, this is an off-label use and not FDA-approved. Currently, no other evidence-based uses beyond female sexual arousal and interest disorder have been established for the use of testosterone therapy in women.[8][17]

Mechanism of Action

HRT with estrogen is thought to affect the hypothalamus by influencing the neurokinin B signaling pathway, which plays a key role in regulating reproductive and thermoregulatory responses. This pathway interacts closely with the median preoptic nucleus, which helps regulate body temperature. By modulating this system, estrogen therapy may help alleviate vasomotor symptoms commonly experienced during menopause.[18] Serotonin may also play a role in hot flashes and body temperature regulation during menopause, but the actual mechanism of action is not well understood. Nonetheless, HRT will reduce vasomotor symptoms by 85%, and this, in turn, results in a better quality of life as well as sleep.[19] 

Low-dose systemic estrogen therapies, including oral and transdermal options, have been shown to relieve vasomotor symptoms in postmenopausal women effectively. These regimens include 0.3 to 0.45 mg/day of oral conjugated equine estrogen, 0.5 mg/day of oral micronized estradiol, 5 µg/day of ethinyl estradiol, and 0.025 to 0.0375 mg/week of transdermal estradiol. A large trial with over 2500 postmenopausal women demonstrated that a daily dose of 0.625 mg of conjugated equine estrogen, as well as lower doses, significantly reduced bothersome vasomotor symptoms.[20] Another randomized placebo-controlled study found that 0.5 mg/day of oral estradiol was also effective for treating hot flashes.[21] 

Administration

Numerous estrogen and progesterone formulations are available for treating menopausal vasomotor symptoms with comparable efficacy. Medications may be administrated orally, transdermally through creams, injections, sprays, patches, gels, subdermal pellets, or with vaginal rings. Available dosages vary based on the route and formulation. Furthermore, the dosage used should be individualized according to the lowest effective dose.[22] Each route of administration has unique benefits and risks.[11] HRT management individualized to the lowest effective dose that relieves symptoms is recommended. If progesterone causes intolerable adverse effects, including fatigue, mood disturbances, and fluid retention, a combination of estrogen and a selective estrogen receptor modulator (SERM), eg, bazedoxifene, may serve as a suitable alternative for endometrial protection.[1] In October 2013, the FDA approved conjugated estrogens plus bazedoxifene for the treatment of moderate or severe vasomotor symptoms associated with menopause and for the prevention of postmenopausal osteoporosis.

Estrogen Formulations 

Oral formulations

The most common side effects of estrogen are weight gain, nausea, vomiting, breast tenderness, and headaches.[1] Additionally, oral estrogen increases activated protein-C resistance, increasing the risk of a blood clot. Oral estradiol also induces the hepatic formation of matrix metalloprotease 9, which decreases the formation and rupture of atherosclerotic plaque. Oral estrogen is convenient and typically has reliable absorption. However, it carries risks, including a higher chance of venous thromboembolism (VTE) and gallstones, as well as raising thyroid-binding globulin, which may require adjusting thyroid and other medication dosages. Additionally, estrogen can lead to significantly higher triglyceride levels in the blood.[8]

Transdermal formulations

Conversely, transdermal estrogen bypasses the hepatic metabolism that produces activated protein-C resistance, negating the risk of blood clotting seen with oral formulations.[11] Transdermal estradiol offers several benefits, including avoiding the digestive system and liver metabolism, resulting in no changes to thyroid-binding globulin or hepatic coagulation proteins at standard doses. Transdermal delivery has minimal impact on the risk of VTE and is convenient, typically requiring application once or twice a week. This makes transdermal estrogen a better choice than oral estrogen for most women, especially patients who smoke cigarettes or have migraines. Additionally, transdermal estrogen has a neutral effect on blood lipids. However, topical forms may cause skin irritation or, rarely, allergic reactions, though this is less common with gels. Some women may experience poor absorption or forget to change the patch regularly.[8]

Estrogen dosages

To reduce the risks of HRT, initiating the lowest effective dose with adjustments to balance the efficacy is recommended to minimize risks and side effects. The starting dose varies by formulation. For the treatment of moderate or severe vasomotor symptoms, a dose of 0.0375 mg per day of estradiol in a transdermal system is an excellent starting point. Some experts recommend starting with lower doses and increasing if needed, based on symptomatology. Available estrogen dosages include:

• Ultra-low dose
  • Conjugated estrogen 0.3 mg/day
  • Micronized estradiol 0.25 mg/day 
  • Transdermal estradiol 0.014 mg/day
• Low dose
  • Conjugated estrogen 0.45 mg/day
  • Micronized estradiol 0.5 mg/day
  • Transdermal estradiol 0.025 mg/day
• Standard dose
  • Conjugated estrogen 0.625 mg/day
  • Micronized estradiol 1 mg/day 
  • Transdermal estradiol 0.0375 to 0.05 mg/day

Estrogen pharmacokinetics likely vary between individuals, and estrogen levels in tissue are not predictable based on the estrogen dose used for treatment. Similarly, the actions of estrogen on different tissues vary as well.[23] Practitioners should note that monitoring hormone or drug levels does not correlate with the effectiveness or safety of HRT for managing vasomotor symptoms. Instead, clinicians should focus on assessing symptom relief and potential adverse effects. Relief of symptoms is often noticeable within a few weeks, but the full effects of HRT may take several weeks to months to manifest.[1]

Progestogen Formulations 

Progestin administration is usually via the oral route, although a few products are available in combination with estrogen in patch forms. Progesterone is available in an oral form that can also be used vaginally for non–FDA-approved uses.[11] Progestogens, such as micronized progesterone and synthetic progestins, can be combined with estradiol in tablets or patches or taken alongside estrogen therapy. The 52 mg levonorgestrel intrauterine device (LNG-IUD) offers an alternative to systemic progestogen therapy and may be used for 5 years for this indication; this regimen is considered off-label use due to limited study data. The LNG-IUD delivers 20 µg of levonorgestrel per day.[11][9] Compounded progesterone is not recommended due to insufficient evidence of endometrial protection.[8] Micronized progesterone 100 mg to 200 mg orally nightly is an excellent starting point. With a standard dose of 0.05 mg estradiol daily in patch form, 200 mg of daily micronized progesterone protects the endometrium. With lower doses of estrogen, lower doses of progesterone may be adequate.

According to Cochrane evidence, a minimum of 0.5 mg/day norethisterone or 2.5 mg/day medroxyprogesterone acetate is recommended for continuous combined HRT. For low-dose sequential regimens, options include 1 mg/day norethisterone for 10 days a month, 200 mg/day oral micronized progesterone for 12 days a month, 10 mg/day medroxyprogesterone acetate for 10 to 14 days, or 10 mg/day dydrogesterone for 14 days. The progestogen dose should align with the estrogen dose. In cases of high-dose estrogen use, an increased progestogen dose may be necessary to ensure adequate endometrial protection, such as 300 mg of micronized progesterone for 12 days in cyclical regimens or 200 mg daily in continuous regimens.

Cyclic HRT, as opposed to daily continuous use, may follow various schedules. For example, estrogen can be taken daily throughout the month, and progesterone can be added for 10 to 14 days of the month. This method may be more suitable for patients who have recently transitioned into menopause, perhaps within the previous 2 years, as continuous HRT during this period can lead to a higher risk of irregular or unscheduled breakthrough bleeding.[1]

Compounded Formulations

Specialized pharmacies make compounded estrogen and progesterone creams, sublingual troches, and vaginal inserts, but these are not FDA-approved and are not included in this discussion. ACOG, the Menopause Society, and the National Academies of Sciences, Engineering, and Medicine do not support the use of compounded hormonal therapy unless no other options exist.[5] These compounded therapies are minimally regulated, may easily be under- or overdosed, and lack safety and efficacy data. Additional concerns include variability in purity, potency, and quality.[15][24][25][11] 

Bioidentical Formulations

Bioidentical hormones are derived from plants, animals, or chemical synthesis and closely mimic the hormones naturally produced by the body. FDA-approved bioidentical hormones include products like micronized progesterone and estradiol.[15]

Vulvovaginal Therapy 

Estrogen is FDA-approved for the treatment of moderate to severe symptoms of genitourinary syndrome of menopause (GSM) and dyspareunia, but local estrogen is preferred over systemic therapy for this treatment. FDA-approved therapies for genitourinary syndrome of menopause include local estrogen, vaginal dehydroepiandrosterone, and an oral selective estrogen receptor modulator called ospimiphene.[11] Because estrogen has a strong affinity for its receptors, only a low dose is required to benefit the urogenital tissues. Vaginal hormone therapies for GSM include estrogen creams (eg, conjugated equine estrogens and estradiol), vaginal estradiol tablets, soft gel estradiol inserts, and a low-dose 2 mg estradiol ring, which should not be confused with the higher-dose systemic vaginal ring. Estriol vaginal suppositories are another option, though they are not available in the United States. Low-dose vaginal estradiol is available as an insert, cream, and ring, but conjugated equine vaginal estrogen only comes as a cream.[26]

All FDA-approved low-dose systemic estrogen formulations, including oral conjugated equine estrogen (0.3 mg/day) and transdermal estradiol (12.5 µg/day), can improve symptoms of GSM; however, they are not as effective as local estrogen therapy. For women with only vaginal symptoms, local estrogen therapy is recommended. Randomized controlled trials have shown that even low-dose vaginal estradiol tablets (10 µg) improve symptoms. Typically, local estrogen is initially used nightly for 2 weeks and then less frequently (eg, 2 to 3 times per week) for maintenance. Sexual intercourse should be avoided immediately after the use of intravaginal estrogen cream. The 3-month estradiol-releasing vaginal ring is often preferred over cream for its comfort, ease of use, and patient satisfaction; the cost may be prohibitive.[27] For a more comprehensive discussion of the evaluation and management of GSM, please see StatPearls' companion reference, "Genitourinary Syndrome of Menopause."

Adverse Effects

Women's Health Initiative Trial

When studying the potential adverse events of HRT, the most referenced information in the United States comes from the WHI.[28][29][30] The WHI was a multifaceted trial, including 2 double-blind, placebo-controlled, randomized trials of postmenopausal HRT.[31] The first arm included oral conjugated equine estrogens (CEE) at 0.625 mg daily and medroxyprogesterone acetate (MPA) at 2.5 mg oral daily versus placebo. The second arm studied patients with prior hysterectomies and only treated with oral CEE 0.625 mg per day. These 2 trials studied the risks and benefits of the patients on HRT intervention compared to placebo groups.[3]

Initially, the 2002 WHI trial reported that menopausal estrogen-progesterone therapy increased the risk of breast cancer, stroke, and coronary heart disease in women. These findings were widely publicized, contributing to the fear of HRT, despite most negative outcomes losing significance when adjusted with multiple statistical analyses, as per the review by Hodis and Sarrel published in 2018.[32] Hodis and Sarrel reported that the unusually low breast cancer incidence in the placebo group was what skewed the outcomes, making the results controversial. Clinicians should also remember that the WHI trial patients were not randomized according to baseline breast cancer risk, as this was not intended to be a breast cancer risk trial.[5]

The oral CEE-only group of the WHI trial with over 10,000 women was allowed to continue, and in 2004, an additional WHI report on estrogen HRT in women who have undergone hysterectomy showed an initial near-significant reduction in breast cancer. Later, in 2020, Chlebowski et al published a 20-year follow-up from the estrogen-only arm of the WHI study, confirming that this group had a significantly decreased incidence and mortality from breast cancer.[5] A substantial 23% reduction in breast cancer incidence was noted with long-term follow-up. However, this positive finding regarding HRT with estrogen received little media attention. Because of these long-term results, the Menopause Society now advises that continuing HRT beyond age 65 is reasonable for healthy women with persistent symptoms, with careful consideration of lower doses, non-oral routes, and different hormone formulations to mitigate risks.[32]

Hormone Replacement Therapy and Breast Cancer Risk

The conjugated equine estrogen plus provera (CEE/MPA) arm of the WHI trial was discontinued 3.3 years earlier than expected due to an increased incidence of invasive breast cancer of 24% at 5.6 years (hazard ratio [HR], 1.24). The CEE-only arm of the WHI trial was not discontinued early; it was completed in 2004, and extended follow-up of patients continued for 11.8 years. Results indicated that CEE use for 5 to 9 years was associated with a statistically significant reduction in breast cancer by 23% (HR, 0.77), as noted above. Those in the CEE-only arm also had decreased mortality from breast cancer by 63% compared to those not on CEE, and 38% fewer died from all other causes after breast cancer was diagnosed.[7] 

Whether breast cancer risk differs between oral and non-oral hormone therapy regimens is unclear.[8] The conclusions from the WHI trials are vastly different and unequal compared to evidence from European studies, which usually use estradiol derivatives rather than CEE and non-MPA progesterone. For example, the results from a large observational study, The Nationwide Finnish Comparative Study, found that estrogen was safe for the breast and also found a significant reduction in mortality up to 50% after 10 years of use of estradiol, including both transdermal and oral formulations.[5] Additional trials are needed to compare the safety and efficacy of other HRT regimens besides those used in the WHI trials.

From these clinical trial conclusions, it was thought that the medroxyprogesterone acetate component of combined HRT was what increased the risk of breast cancer for women. Observational studies suggest that micronized progesterone may be safer than synthetic progestins regarding breast cancer risk, although long-term data is limited, and no randomized trial evidence confirms this. Expert opinion favors micronized progesterone, presenting a lower breast cancer risk than the medroxyprogesterone acetate that was used in the WHI trials.[8] Any potential increase in the risk of breast cancer is related to treatment duration and reduces after stopping HRT. Breast cancer risk associated with HRT is a significant concern for many patients, but placing this risk in the context of lifestyle factors can be beneficial. Lifestyle changes, including quitting smoking, reducing alcohol consumption, losing weight, and maintaining regular exercise, can have a more substantial impact on overall health than medications alone.[9]

Hormone Replacement Therapy and the Heart

In the WHI trial's CEE/MPA arm, the overall incidence of coronary heart disease increased by 18% compared to the placebo group, though this increase was not statistically significant. After the intervention ended, the risk of cardiovascular disease returned to baseline levels. In the CEE-only trial, coronary heart disease risk decreased by 6% in the treatment group, with myocardial infarction rates decreasing by 3%, but these reductions were also not statistically significant. A more favorable interaction was observed for myocardial infarction in women aged 50 to 59 compared to older women, and this benefit persisted after the intervention. Therefore, the "timing hypothesis" was suggested in which early HRT at the time of menopause for only 10 years or less and not starting HRT in those older than 60 was recommended. This hypothesis has since been refuted. Additionally, 7.4 years after treatment, women who received estrogen therapy alone had significantly lower coronary artery calcium levels. The cardiovascular risks returned to baseline at a cumulative follow-up of 13 years.[3]

In contrast to CEE, endogenous estradiol is known to be cardioprotective. The ELITE (Early Versus Late Postmenopausal Treatment With Estradiol) was a randomized, double-blind, placebo-controlled trial that found a benefit to cardiac health with estradiol. This study suggests that the cardiovascular risks identified in the WHI trial may be specific to conjugated equine estrogen (CEE) and are not linked to transdermal estradiol or the timing of estrogen replacement therapy, as was previously believed.[5][33]

Hormone Replacement Therapy and Osteoporosis

The United Kingdom NICE Guidelines and other reputable sources endorse HRT for preventing osteoporosis and fractures, which is approved for this use in many countries. Eighteen articles have shown a reduction in fractures with HRT.[5] However, guidance is lacking on whether asymptomatic postmenopausal women with osteopenia who do not need HRT for vasomotor symptoms should use HRT to prevent fractures. Fracture risk depends on several factors, including bone geometry, mineralization, age, body mass index (BMI), mobility, balance, and various iatrogenic factors.[8] The USPSTF recommends against the use of HRT for the sole purpose of osteoporosis prevention.[15]

Currently, no studies provide a definitive t-score threshold for starting hormone therapy solely for fracture prevention in postmenopausal women not deemed high-risk by the Fracture Risk Assessment Tool (FRAX). HRT should be considered for women with osteopenia under age 65, taking other risk factors into account. A pragmatic cut-off for considering HRT is a T-score of -1.8 or lower, particularly in women under 65. This threshold, along with factors like BMI and time since menopause, should help guide treatment decisions. HRT can prevent bone loss and fractures in postmenopausal women and for those with a T-score of -1.8 or lower, with benefits likely outweighing the risks.[8]

Hormone Replacement Therapy and Risk of Stroke

Stroke incidence increased in both arms of the WHI trial. During the intervention, there were significantly increased rates of stroke of 11 per 10,000 person-years (HR 1.35) in the CEE alone group as compared to placebo, prompting the National Institutes of Health to stop the study in 2004. The CEE/MPA trial was stopped 3.3 years early, in 2002. The risk of stroke in the CEE/MPA group was increased by 9 per 10,000 person-years (HR 1.37).[3] This increased risk of stroke with oral estrogen is not seen with transdermal methods of estrogen replacement. 

Hormone Replacement Therapy and the Risk of Venous Thromboembolism

VTE, comprised of deep venous thrombosis and pulmonary embolism, was increased by 2-fold (HR, 2.06) in the WHI CEE/MPA arm. However, numerous European studies have evidence that transdermal estradiol does not confer the same thromboembolic risk. The ESTHER study from France showed an overall risk of 0.9 for a blood clot, which is a decreased risk.[34] Menopausal hormone therapy (MHT) likely increases the risk of VTE, including deep vein thrombosis and pulmonary embolism, though the absolute risk for individuals is low. Studies indicate a 2- to 3-fold higher VTE risk with oral MHT, with estrogen-progestin combinations posing more significant risks than estrogen-only therapies. Additionally, oral MHT is associated with higher VTE risk compared to transdermal therapy.[35] Subsequent studies looking at other transdermal estradiol doses and routes confirm these findings, with a null effect on blood clotting risk with transdermal estrogen, likely due to bypassing liver metabolism with this delivery route.

The ESTHER (Estrogen and Thromboembolism Risk) trial was a case-cohort study performed at multiple centers. This study found that there was no increased risk of VTE with transdermal estrogen and micronized progesterone as compared to oral estrogen and norpregnane formulations.[34][5]

Hormone Replacement Therapy after Cancer Diagnosis

In 2024, a published study examined the safety of HRT in women diagnosed with 17 different types of cancer, excluding breast cancer, due to its contraindication. Among 182,589 women across Scotland, Wales, and England, 7% used systemic HRT after their cancer diagnosis. The results showed no evidence of increased cancer-specific mortality in HRT users compared to non-users, including for common cancers like lung, colorectal, and melanoma. The findings suggest that HRT does not increase cancer-specific mortality in women with various cancer types, excluding breast cancer.[36] Since transdermal estrogen does not seem to raise the risk of VTE—a condition to which many cancer patients are already vulnerable—this formulation is recommended over oral estrogen formulations for HRT.[19] Because uterine sarcomas, low-grade serous epithelial, sex cord-stromal, and granulosa cell ovarian cancers may be estrogen-sensitive, European guidelines suggest the avoidance of HRT in these populations. However, this recommendation is based on very low levels of evidence.[19] 

Hormone Replacement Therapy after Breast Cancer

Given the increased risk of breast cancer recurrence, especially for those with estrogen-receptor-positive disease, most experts would generally advise against using systemic HRT in breast cancer survivors. However, with shared decision-making, exceptions may be made after careful consideration of whether the patient's quality of life is significantly affected or if the risk of recurrence is low.[19] Recent studies and reviews have indicated that systemic HRT may be safe for breast cancer survivors who have finished their treatment with tamoxifen or aromatase inhibitors.[5]

Local estrogen therapy to the vulvovaginal tissue, particularly in low doses, may be used for the genitourinary syndrome of menopause, again weighing risks and benefits for the individual circumstances. After prophylactic mastectomy or in patients with triple-negative breast cancers who have failed other management, HRT may be considered on an individualized risk-benefit basis. ACOG supports this notion that local estrogen to the vulva and vagina may also be considered in patients with hormone-sensitive cancers, again on an individualized basis.[19][37]

Hormone Replacement Therapy and Gene Mutations

Women with BRCA1 or BRCA2 mutations face a significantly higher lifetime risk of developing breast and ovarian cancer compared to the general population. BRCA1 mutation carriers have a 57% to 72% risk of breast cancer and a 39% to 59% risk of ovarian cancer, while BRCA2 carriers have a 45% to 69% breast cancer risk and an 11% to 20% ovarian cancer risk. To reduce cancer risk, strategies like risk-reducing salpingo-oophorectomy (RRSO) are recommended, especially after childbearing. However, decisions about accompanying procedures like hysterectomy and the use of HRT can be complex. There is widespread misinformation about the safety of HRT for BRCA mutation carriers without a cancer diagnosis, leading to hesitancy from both patients and clinicians. Education and shared decision-making are critical, particularly regarding the use of estrogen-only or combination HRT, which carries different risks depending on whether a hysterectomy is performed. Many BRCA mutation carriers are poorly informed about HRT, often overstating its risks and underestimating its benefits.[38]

Hormone Replacement Therapy and Migraines

Migraines are a known neurovascular disease, and migraines with aura are a risk factor for cerebrovascular diseases, like ischemic stroke. Estrogen may enhance the hypercoagulable state seen in patients with migraines. However, migraine with or without aura is not a contraindication to HRT for symptomatic menopausal patients. Non-oral routes and the lowest dose necessary to control menopausal symptoms should be recommended. The onset of new migraines or the increase in the incidence of migraines with the start of menopausal HRT should be investigated.[39] 

Hormone Replacement Therapy and Diabetes

In 2024, a retrospective cohort study, which included 6,566 participants (both HRT users and non-users) with matched cohorts, found that HRT was associated with a lower incidence of diabetes mellitus over a 20-year follow-up, with a hazard ratio of 0.693. The protective effect of HRT was more pronounced in individuals aged 46 to 50 and 55 to 60, as well as in White individuals, but not in Black or Asian populations. Additionally, HRT significantly reduced diabetes risk in those with a BMI of 24.9 or lower and 25 to 29.9 kg/m², but not in those with a BMI of 30 kg/m² or higher. The study concluded that HRT reduces long-term diabetes risk in premenopausal individuals with prediabetes.[40]

Hormone Replacement Therapy in Women Older than 65

In May of 2024, an updated study published in Menopause, The Journal of the Menopause Society, looked at 13 different outcomes using 40 different hormonal therapies that were started or continued in women older than 65. They found that the use of estrogen-only HRT for those older than 65 was linked to significant reductions in mortality (19%) and risks for several conditions, including breast, lung, and colorectal cancer, congestive heart failure, VTE, atrial fibrillation, myocardial infarction, and dementia. The risk reduction seen with estradiol was more significant than that seen with conjugated estrogens. Marginal risk reductions were seen with endometrial and ovarian cancers, ischemic heart disease, congestive heart failure, and VTE with the use of estrogen plus natural progestin. The only risk reduction seen with estrogen plus progesterone was in congestive heart failure. The study suggested that low-dose, transdermal, or vaginal hormone therapies generally offer greater benefits and lower risks compared to medium or high doses or oral preparations, with estradiol showing more favorable outcomes than conjugated estrogen. The conclusion of this study, recommending risk mitigation with low dose and non-oral formulations as well as varying types of estrogen and progestogen, was in line with The Menopause Society's 2022 position statement.[32]

Discontinuing HRT can lead to a recurrence of vasomotor symptoms in about 50% of women, regardless of age or duration of use. No clear evidence suggests whether abrupt or gradual discontinuation is better for preventing these symptoms. Decisions about continuing HT should be tailored to each woman's symptoms and risk-benefit profile. ACOG advises against routinely stopping systemic estrogen at age 65, as some older women may still benefit from it for managing vasomotor symptoms. As with younger women, HRT decisions should be individualized based on each woman's specific needs and clinical situation.[27]

Contraindications

Contraindications for oral or transdermal estrogen-based therapies include:

• Known, suspected, or history of estrogen-sensitive breast cancer (individualized risk/benefit should be analyzed)
• Known or suspected history of other estrogen-based cancer (ie, uterine cancer); women who have had a hysterectomy and have no remaining evidence of disease are still candidates for HRT
• Unexplained vaginal bleeding
• History of or an active deep venous thrombosis (DVT) or pulmonary embolism 
• History of blood clotting disorder, the most common being Factor V Leiden mutation carriers (may consider transdermal estrogen)
• Active or history of cerebrovascular accident (stroke) [22]

Conditions that increase the risk of stroke, including uncontrolled blood pressure (≥180/110) and triglycerides (>400 mg/dL), are relative contraindications for HRT.[22] These contraindications do not apply to transvaginal-based local estrogen therapies, as the serum concentration of estrogen from this route is extremely low. The Menopause Society has recommended that the black-box warning that applies to conventional HRT not be applied to transvaginal estrogen treatments.

Monitoring

Routine testing of follicle-stimulating hormone levels, estradiol levels, or progesterone levels is not traditionally recommended or supported by ACOG for monitoring, directing therapy, or diagnosing menopause.[5] Instead, the relief of menopausal symptoms and the absence of adverse effects signify an adequate medical response to therapy. Adverse effects may include:

• Abnormal uterine bleeding
• Fluid retention
• Nausea (with oral estrogen)
• Breast tenderness
• Headaches
• Bloating
• Mood changes [22]

Continuous-combined HRT leads to no vaginal bleeding in 90% of women after 12 months. Breakthrough bleeding is common during the initial months, but persistent or new bleeding after several (6) months should be investigated.[8] No scientific evidence links HRT with significant weight gain. Additionally, androgen therapies (eg, testosterone) are not considered conventional HRT.

Women on systemic HRT should have a medical review at 3 months to assess symptom relief, adverse effects, and ensure proper use. Long-term follow-up should be annual, including a medical examination, updated history, and breast assessment. Any unscheduled or prolonged bleeding after 3 to 6 months requires investigation.[8]

Enhancing Healthcare Team Outcomes

Misapplying the results of a well-designed clinical trial (the WHI trial) to populations and hormone formulations not included in the study has led to many women experiencing untreated menopausal symptoms and widespread confusion among clinicians about the actual risks and benefits of different hormone therapies. Awareness and adequate training for healthcare professionals are lacking regarding the menopausal transition, and this issue remains largely unaddressed today.

Enhancing patient-centered care, outcomes, safety, and team performance in menopausal HRT requires a collaborative, multidisciplinary approach. Physicians, advanced practitioners, nurses, pharmacists, and other health professionals must work together to deliver comprehensive care that addresses the unique needs of each patient. Physicians and advanced practitioners play a critical role in clinical decision-making, leveraging their expertise in menopausal management to tailor treatment plans based on the patient’s medical history, symptoms, and preferences. Nurses are essential for patient education, ensuring women understand their HRT options, potential side effects, and the importance of follow-up care. Pharmacists contribute by ensuring accurate medication dispensing, managing drug interactions, and counseling patients on adherence to their HRT regimen. Other health professionals, such as dietitians and mental health clinicians, address lifestyle changes, nutrition, and emotional well-being, which are critical components of holistic menopausal care.

A patient-centered strategy is vital, with individualized treatment plans that consider each woman’s risk factors. Shared decision-making between the patient and the healthcare team ensures that the patient’s values and preferences are central to the treatment process. Regular monitoring and follow-up allow for therapy adjustments, optimizing safety and effectiveness. Ethical considerations are also paramount, including informed consent, where patients receive clear, unbiased information about the risks and benefits of HRT. Equitable care must be prioritized, ensuring that all women, regardless of background, have access to appropriate menopausal care.

Interprofessional communication and care coordination are critical to maintaining continuity of care. Regular team discussions, clear protocols, and unified care plans allow clinicians to swiftly address any issues, such as adverse effects or medication interactions, ensuring patient safety. By working as a cohesive team and involving the patient in every step of the decision-making process, outcomes are improved, care is safer, and the overall patient experience is enhanced.