Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:
1. Identify the pathophysiology and risk factors associated with menopausal vasomotor symptoms.
2. Explain the risks and benefits of menopausal hormone therapy (MHT).
3. Plan MHT treatment options for postmenopausal patients experiencing symptoms caused by estrogen deprivation.
The use of hormone replacement therapy (HRT) for menopausal women has been debated since long before the 2002 Women's Health Initiative (WHI) study.1 This study resulted in a paradigm shift away from HRT use for prevention of chronic disease.2 In the almost 20 years since publication, many studies have reexamined the original WHI data and added new information to support the safe use of menopausal hormone therapy (MHT) to treat vasomotor symptoms (VMS) of menopause and provide substantial relief to patients. This article updates physicians who use MHT for menopausal VMS while summarizing practice guidelines, therapies, and contraindications to medical therapies.
Menopause is defined as 12 months of amenorrhea. The average age of menopause onset in the United States is 51 years. As ovarian follicular volume decreases, resultant hormonal changes including low estradiol and high follicular-stimulating hormone (FSH) levels may cause unpleasant to debilitating symptoms including hot flashes, mood changes, urogenital changes, and sleep disturbances.3
The physiologic mechanism of VMS remains uncertain. An accepted thought model attributes menopausal hormonal changes to a narrowed thermoregulatory zone; this lowers the threshold to trigger hot flashes to dissipate heat. Hot flashes are the most commonly reported symptom, affecting up to 80% of perimenopausal women, and are often described as the sudden sensation of heat in the upper body, face, neck, and chest.4 Other symptoms include perspiration, chills, anxiety, clamminess, or palpitations.3 These episodes may interfere with sleep or work and negatively impact quality of life. The overall duration and frequency of episodes is not well defined, with median duration reported from 6 months to 10 years. Most women report daily symptoms, with some patients having up to 20 episodes per day.4
Paradigm Shift: Then and Now
In 2002, the WHI estrogen-progestin arm was stopped early after an average of 5.2 years secondary to an increased risk of breast cancer, heart disease, stroke, venous thromboembolism (VTE), and overall harm.1 The original goal of the study was to evaluate the use of HRT for primary prevention of chronic disease including coronary heart disease (CHD), breast cancer, and colorectal cancer. The adverse findings resulted in a dramatic decrease in prescriber use and patient interest in HRT.1
Multiple studies have since been published with updated analyses and interpretations of the original findings and have produced new data to support the use of MHT for treatment of menopausal symptoms in specific populations. Most of the WHI study participants were older and further from menopause than the population for which MHT has been shown to be both safe and effective. Furthermore, WHI participants did not have significant VMS; therefore, the benefits of hormone therapy (HT) for VMS treatment could not be adequately assessed.5
The North American Menopause Society (NAMS) released a position statement in 2017 to address conflicting information. This statement supports the use of HT for the treatment of VMS but not for the prevention of disease. Additionally, the United States Preventive Services Task Force similarly rejected the use of HRT for primary prevention of chronic conditions.6 NAMS data further demonstrate that HT can be an effective option for management of the genitourinary syndrome of menopause (GSM) and osteoporosis prevention in menopausal patients.7
Epidemiology of VMS
Analyses of epidemiologic data from the longitudinal Study of Women's Health Across the Nation (SWAN) illustrate racial and ethnic differences in the way women experience and report their symptoms: African American women reported the most symptoms, followed by White and Hispanic women, followed finally by Asian women.4 These variations are attributed to differences in temperature perception or cultural variation of symptom severity. Dietary soy levels are also postulated to play a role. Differences in cultural perceptions of health, medicine, and menopause may influence how women experience and perceive these symptoms. Low socioeconomic status, high body mass index (BMI), history of tobacco use, mood disorders, and reduced physical activity are other factors that contribute to the duration and severity of VMS.3,4
Menopausal Hormone Therapy
MHT is the most effective treatment for VMS and severe GSM, with beneficial effects on bone loss and fracture prevention. Many factors must be considered when deciding route of administration, dose, and timing of initiation and discontinuation. Shared decision-making between patients and physicians is crucial to ensure maximum benefit and least harm of MHT.
FDA-Approved Indications
MHT has 4 FDA-approved indications, which include VMS management, bone loss prevention, genitourinary symptom treatment, and premature hypoestrogenism.7 MHT is the first-line therapy for VMS in menopausal patients who do not have contraindications for use. Appropriate therapy can reduce frequency and severity of weekly VMS by 75% including common hot flash symptoms, mood disturbances, difficulty with concentration, and forgetfulness.3 Several randomized clinical trials (RCTs) have demonstrated prevention of bone loss and fracture risk reduction by 24% for menopausal patients with the use of MHT in a dose-dependent manner.1,7 MHT should be considered in patients in early menopause with low bone mineral density, particularly if a patient cannot take bisphosphonates.8 Vulvovaginal symptoms such as dyspareunia, dryness, irritation, and urinary symptoms can be successfully treated with MHT by restoring genitourinary anatomy and improving vulvovaginal atrophy.7 MHT is FDA-approved for symptom management in patients with premature menopause due to iatrogenic or natural causes.
MHT Preparations
Systemic Estrogen Preparations
Systemic estrogen is the gold standard treatment for VMS. Progestogen is routinely recommended for women with a uterus to avoid the adverse effects of unopposed estrogen including endometrial hyperplasia and carcinoma. The most commonly used estrogen-based hormones are 17[beta]-estradiol and conjugated equine estrogen (CEE). Estradiol and other synthetic estrogens (esterified estrogen, estrone sulfate, and the more potent ethinyl estradiol) are derived from plant sources. CEE is formulated from pregnant mares' urine and contains primarily estrone sulfate. A meta-analysis of RCTs demonstrated no difference in FDA-approved estrogens in the management of VMS.7
Systemic estrogen therapy is available in a variety of doses and preparations (Tables 1 and 2). Oral CEE ranges in dosing from 0.3 to 0.625 mg daily and micronized oral 17[beta]-estradiol ranges from 0.25 to 1 mg daily. Transdermal therapy has no increased risk of VTE compared with women not on estrogen and is often the preferred route of administration.3,7,9 Transdermal estrogen bypasses the liver and is ideal in patients with well-controlled liver disease, hypertriglyceridemia, or diabetes mellitus.5,10 Transdermal dosing of 17[beta]-estradiol ranges from 0.014 to 0.1 mg/d from patches or gel that vary in frequency based on dose.
Low-dose estrogen is preferred due to a more favorable side effect profile with maintained efficacy. An RCT showed lower-dose combination therapies containing 0.45- and 0.3-mg CEE plus medroxyprogesterone acetate (MPA) are equally effective as 0.625-mg CEE plus MPA for the treatment of VMS.3,11 Ultra-low doses are not yet FDA-approved for VMS treatment; however, they have been offered to patients who experience predominantly vaginal symptoms. Women have reported VMS symptomatic relief with these formulations.3
Bazedoxifene (BZA), a synthetic estrogen receptor modulator, combined with CEE has been FDA-approved for VMS treatment and osteoporosis prevention.7 The SMART (Selective Estrogen Menopause And Response to Therapy 3) trials demonstrated that BZA/CEE reduced the number and severity of daily hot flashes compared with placebo, and improved symptoms of vulvovaginal atrophy including improved subjective lubrication and decreased dyspareunia.12 BZA/CEE has the additional benefit as a progestogen-free alternative for postmenopausal patients with an intact uterus to avoid the risk of endometrial hyperplasia.7,12 In 2014, the FDA-approved once-daily dosing of 20-mg BZA/0.45-mg CEE for the treatment of moderate to severe VMS associated with menopause and the prevention of postmenopausal osteoporosis.9
Local Estrogen Preparations
Low-dose vaginal therapy is preferred for patients with only vulvovaginal symptoms and can be continued indefinitely if symptoms persist.5,7Table 1 includes vaginal estrogens commonly prescribed for GSM and includes tablets (10 [mu]g daily for 14 days and then twice weekly), creams (0.5 g daily up to 14 days and then twice weekly), or rings (replace every 90 days). For patients on low-dose vaginal estrogen for GSM, progestogen therapy is not typically prescribed, although long-term RCT data are lacking.7 Periodic endometrial surveillance is not advised, but a thorough investigation is required for women who develop concerning symptoms such as vaginal bleeding.3,5
Progestogen Preparations
The term "progestogen" generally refers to any progestational agent including synthetic progestins and bioidentical progesterones. Progestogen is added to MHT to protect the endometrium from the effect of unopposed estrogen.10 Many formulations combine estrogen and progestogen for ease of use and cost-effectiveness (See Supplemental Digital Content 1, published online, http://links.lww.com/PGO/A9). Progestogen can be given daily (combined-continuous) or cyclically for 14 days per month. Combined-continuous regimens are often preferred given they can cause amenorrhea, whereas cyclic regimens may induce withdrawal bleeding.9 Combined-continuous regimens are also associated with a lower risk of endometrial carcinoma.10 (See Supplemental Digital Content 2, published online, http://links.lww.com/PGO/A10.)
The WHI trials suggest progestin may carry an increased risk of breast cancer.1,7 Observational studies have demonstrated that micronized progesterone may not carry this increased risk of breast cancer and is therefore used more often in clinical practice.5,7 Progestogens are not recommended alone as first-line treatment for VMS.3
A levonorgestrel intrauterine system (LNG-IUS) may have local efficacy and safety, although it is not yet FDA-approved for endometrial protection during VMS management. LNG-IUS is particularly useful for women beginning the menopausal transition who have minimal VMS and are still menstruating.9,10 Combined oral contraceptive pills are also useful for VMS relief in perimenopausal women because they offer the added utility of menstrual cycle control and pregnancy prevention.9
MHT Initiation, Duration, and Discontinuation
Initiation
Analyses of data from 30 pooled trials and various RCTs indicate that the optimal time for initiating MHT is within the first 10 years of menopausal onset up to 60 years of age. This "window of opportunity" reflects the increased risk of cardiovascular events and negative cognitive impact that MHT has on older postmenopausal women as noted in various observational studies.7,10 A meta-analysis has also shown a reduction in all-cause mortality for patients who initiate MHT before the age of 60 years and/or within 10 years of menopause onset.10 Women outside this time frame should participate in shared decision-making with their physicians because the risk-benefit ratio becomes less favorable due to an increased risk of CHD, stroke, VTE, and cognitive impairment.5
Duration and Monitoring
It is imperative for providers to establish expectations for MHT use including duration and monitoring. For many years, the guiding principle for MHT was to keep patients on the lowest dose for the shortest duration. However, updated NAMS guidelines have relaxed this rule, and instead report that there is no proven reason to discontinue MHT after 5 to 7 years and/or at the age of 65 years.7 This allows for greater flexibility especially considering the average menopausal woman experiences VMS for 7.4 years. Therapy can be continued as long as a patient requires symptomatic management for VMS or bone loss prevention.7,10 Annual monitoring for continuation of symptoms and for developing contraindications to MHT is recommended. Due to the increased risk of breast cancer with combined MHT, women should receive annual mammograms, although MHT may reduce the sensitivity of such testing.8 Patients on combined MHT may experience vaginal bleeding, which warrants further investigation with vaginal ultrasound and/or endometrial biopsy, particularly if bleeding continues for more than 6 months.5,7
Discontinuation
There is no defined age at which a patient is required to stop taking MHT; however, most patients will discontinue within 10 years. Women who develop a contraindication must discontinue MHT. Approximately 50% of patients will experience a return of their VMS upon discontinuation.3,7 For bothersome VMS, restarting MHT can provide relief of recurrent symptoms. There are no data to prove that tapering is superior to abrupt discontinuation in preventing rebound symptoms.3 Bone protection afforded by MHT rapidly diminishes after discontinuation of use; however, there is no evidence that patients are at increased risk of fractures after discontinuation.7 Low-dose vaginal therapies do not need to be discontinued as long as bothersome vulvovaginal symptoms persist.5
Benefits
Systemic
MHT provides benefits beyond the treatment of VMS and osteoporosis prevention. The WHI study reported that the risk of colorectal cancer was decreased by 37% in the combined HT arm (CEE+MPA) compared with placebo.1 Sleep disturbances caused by VMS are reduced with MHT due to the reduction of nighttime awakenings. Evidence from WHI shows a significant reduction in type 2 diabetes mellitus across both the CEE+MPA arm and the CEE-only arm; however, MHT is not FDA-approved for the prevention of diabetes. NAMS data report 4 observational studies that showed a potential decreased risk of Alzheimer disease when MHT is initiated early in menopause.7
Several studies suggest MHT started early in menopause decreases the risk of CHD and all-cause mortality. Observational data from the Early versus Late Intervention Postmenopausal Treatment with Estradiol (ELITE) trial show that estradiol is associated with decreased progression of atherosclerosis when initiated within 6 years of menopausal onset, therefore correlating to a protection from CHD.13 This is in contrast to the findings presented by WHI, which demonstrated a significantly increased risk of CHD in women who initiated replacement therapy around 10 to 20 years after menopause onset.1 Meta-analyses of pooled data from 30 trials demonstrated a significant reduction in all-cause mortality for women age 50 to 59 years.5 When data from WHI are stratified by age, there is a clear all-cause mortality benefit for women who start treatment before age 60.10
Vaginal
The benefits of vaginal MHT are largely attributed to relief of GSM. These therapies increase lubrication, blood flow and sensation, and improve sexual function. Many patients will also experience improvement in urinary symptoms and improved quality of life, including a reduction in urinary tract infections and improvement in incontinence symptoms.7
Risks
Systemic MHT carries a different risk profile than vaginal therapy due to variation in dosage, route of administration, and metabolism. Individual comorbidities and familial risks must be evaluated before initiating MHT.
VTE and Stroke
VTE is the most common adverse effect observed in patients taking MHT. A meta-analysis of women who initiated MHT within 10 years of menopause onset demonstrated a significant increase in the risk of VTE for patients in the MHT group compared with placebo (RR, 1.74).7 This risk is highest within the first 2 years of initiation and diminishes over time with continued use.8 Data from WHI showed an age-dependent risk for VTE, with a higher risk with initiation for patients in the 70- to 79-year age group [relative risk (RR), 7.46] compared with the 50- to 59-year age group (RR, 2.27). A meta-analysis of 31 RCTs showed that the risk of a thrombotic event is doubled in patients on combined MHT compared with estrogen only.10 Patients with thrombotic risk factors such as obesity, personal or family history of coagulopathy, and cardiovascular disease are more susceptible to VTE with MHT.
The increased risk of VTE with MHT is primarily attributed to the prothrombotic effects of oral systemic estrogen and progestogen. These hormones undergo first-pass metabolism in the liver, which induces the release of coagulation factors.10 This effect can be mitigated by electing transdermal preparations, which bypass liver metabolism and avoid the increased risk of VTE even in patients who are at higher risk for coagulopathies.3,7,9 These data have been consistently supported in multiple observational studies, but have not yet been confirmed in RCTs.10 In observational studies, lower-dose oral estrogen-containing MHT including 0.3- to 0.45-mg CEE daily, 0.5-mg oral 17[beta]-estradiol daily, or 0.025-mg ethinyl estradiol daily seems to confer a smaller risk of VTE compared with high-dose therapies (Table 2). Micronized progesterone may be linked to lower risk of VTE than other progestogens. There is no VTE risk associated with vaginally dosed MHT.7
Results from the WHI study demonstrated an increased risk of stroke in both the CEE+MPA arm [hazard ratio (HR), 1.37] and the CEE-only arm (HR, 1.35). This increased risk seems to be only during the intervention phase, and does not remain statistically significant during postintervention follow-up analyses.6,8 A meta-analysis of RCTs that included a total of 43,637 women of an average age of 63 years showed an increased risk of stroke after 3 years of continuous estrogen and progestogen therapy and after 7 years of continuous estrogen-only treatment.8 There is no significant increase in mortality risk from stroke for patients on MHT in either the intervention or postintervention as evidenced by follow-up phase data from WHI and a meta-analysis of 4 RCTs.8,14 Studies demonstrate that the increased risk of stroke occurs in patients who initiate MHT (estrogen and progestogen) when 60 years or older and/or beyond 10 years after menopause. Furthermore, various observational studies link standard-dose oral therapies to an increase in stroke risk compared with other systemic options such as low-dose oral or transdermal therapies.7
Breast Cancer
WHI data indicated that the risk of invasive breast cancer was elevated with combined MHT after a mean follow-up of 5.2 years.7 With estrogen-only preparations, there seemed to be a slight decrease in risk of breast cancer; however, the results were statistically insignificant.1,10 The risk does not appear to arise until after 4 to 5 years of combined therapy or after 7 years of estrogen-only therapy.9,15 The increased risk of breast cancer may be attributed to the increased breast tissue density that occurs with MHT.6 Whether this increase is secondary to the addition of a progestin remains unclear.3
Women who have had estrogen-positive breast cancer are not recommended to use systemic MHT, given the lack of strong safety evidence. Various observational studies and RCTs have shown both no harm and increased risk of cancer relapse.7 Therefore, patients should work closely with their oncologists to determine the most appropriate treatment plan. The American College of Obstetricians and Gynecologists (ACOG) and the NAMS recommend shared decision-making for survivors of breast cancer who experience bothersome GSM. These patients should be managed first with nonhormonal therapies, then consider the addition of vaginal estrogen if symptoms persist.7,16
Adverse Effects and Contraindications
Adverse effects are common for patients taking MHT and are often the primary reason patients discontinue use.4 The most common side effects are vaginal bleeding, bloating, headaches, nausea, fluid retention, mood swings, and breast tenderness.3,7 Breakthrough bleeding can be the most disruptive side effect and is often the main cause for discontinuation. Biliary disease and adverse effects on lipid profiles have also been reported.8 Post-WHI, the rate of patients discontinuing use due to an actual adverse event was surpassed by discontinuation out of fear of adverse effects.2 There is evidence that low and ultra-low doses are associated with fewer side effects, and patients should be periodically reassessed to ensure their risk-benefit profiles are maximized.3
There are few contraindications to systemic MHT including a history of a known estrogen-dependent breast or endometrial carcinoma, current liver disease, abnormal uterine bleeding, cardiovascular disease, thromboembolic disease (family or personal history), or severe hypertriglyceridemia.7-9 Porphyria cutanea tarda is an absolute contraindication to MHT. Patients with endometriosis, leiomyomas, and migraines should be counseled that their symptoms may worsen on MHT.7 For patients receiving vaginal therapy, vaginal bleeding and estrogen-dependent cancers are contraindications. Before initiation and at each annual visit, patients should be assessed for existing or newly acquired contraindications to ensure safety of treatment continuation.
Alternatives to MHT
Many women desire nonhormonal methods for VMS control including prescription medications, herbal remedies, and behavioral interventions. Compounded bioidentical hormones are another common alternative.
Nonestrogen Prescriptions
Nonhormonal prescription alternatives include selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin, and clonidine. An RCT demonstrated 62% reduction in daily hot flashes with SNRI administration, and a meta-analysis of RCTs using SSRIs/SNRIs for VMS showed a significant reduction compared with placebo. Paroxetine (an SSRI) is the only nonhormonal medication FDA-approved for the treatment of VMS.3 Other FDA-approved nonestrogen options for dyspareunia include intravaginal dehydroepiandrosterone or oral ospemifene.5,7
Herbal Remedies
There is insufficient evidence that herbal remedies are superior to placebo in treating VMS. Eastern medicine treatments, gingko biloba, St John's wort, and ginseng have no proven superiority compared with placebo.3
Lifestyle and Behavioral Changes
Lifestyle interventions are often initially recommended to patients for mild VMS management. Temperature regulation through layered clothing, drinking cool beverages, and avoiding caffeine has been shown to be effective for some patients.3 Psychological interventions have gained popularity, particularly among women for whom MHT is contraindicated. A meta-analysis of 12 RCTs analyzed the effect of mindfulness and cognitive-behavioral therapy for treatment of VMS. The data showed that short-term psychological interventions reduced symptom severity for patients and longer duration therapies reduced VMS frequency.17 Other activities known to improve mood in menopausal patients such as exercise have been studied with no evidence that these interventions improve VMS.3
Compounded Bioidenticals
Many patients express a preference for compounded bioidentical hormones rather than FDA-approved pharmaceutical, presumably as a result of marketing. Bioidentical hormones are typically advertised as plant-derived, naturally occurring hormones.3 However, given the lack of government regulation and assurance of safety, organizations such as the ACOG and the NAMS have recommended against the use of these compounded therapies primarily due to the inconsistency between preparations and the concern regarding variability in potency. Uncertainty regarding safety in producing these bioidentical hormones also prompts some physicians to recommend against their use.3,7,18 Perhaps most importantly, a majority of these hormones lack clinical trial data to support the claims that these treatments are safe or efficacious.9,18
In 2018, the FDA approved a bioidentical hormone consisting of single-capsule 17[beta]-estradiol-progesterone therapy (TX-001HR) for the treatment of VMS after the conclusion of the study known as the REPLENISH trial, which evaluated the safety and efficacy of different MHT. One of the concerns with compounded hormones is endometrial hyperplasia and increased cancer risk, but the results of REPLENISH indicated that this formulation did not induce endometrial hyperplasia and was still effective for the treatment of moderate to severe VMS.19
Conclusion
MHT is the best treatment for VMS such as hot flashes, mood changes, vaginal dryness, and sleep disturbances that arise in the menopausal period. Estrogen is the primary hormone that provides symptomatic relief. In women with a uterus, progestogen is added to prevent endometrial hyperplasia. Therapies come in a wide range of doses and routes of administration, which allows for easy titration and patient preference in regimen selection.
Although systemic MHT has a relatively favorable side effect profile, it does carry a risk for adverse events such as breast cancer, VTE, and CHD. These side effects can be mitigated by initiating MHT before the age of 60 or within 10 years of menopause onset. Routine screening and monitoring for development of concerning symptoms aids in the prevention of undesirable outcomes. Transdermal and vaginal preparations have been shown to be safe and effective in treating VMS and GSM with limited side effects.
The WHI prompted some providers and a huge number of patients to avoid MHT for treatment of VMS, but multiple clinical trials have repeatedly demonstrated the efficacy and safety of MHT in the appropriate circumstance. Physicians should be encouraged to counsel postmenopausal patients experiencing VMS on the appropriate and safe use of MHT for symptomatic relief.
Practice Pearls
* MHT is the most effective treatment for menopausal VMS and should be offered unless contraindicated.
* MHT is safest for women age 50-59 who initiate use within 10 years of menopause.
* Patients outside this age window can take MHT after shared decision-making around risks and benefits.
* Estrogen-only and combined estrogen-progestogen preparations relieve VMS. Combined MHT should be used in patients with an intact uterus.
* RCTs have demonstrated increased risk of breast cancer with combination preparations after 5 years of use. Estrogen-only therapy is associated with lower risk.
* Oral, but not transdermal, therapies are associated with increased risk of VTE.
REFERENCES