TY - JOUR
AU1 - Stuenkel, Cynthia, A.
AU2 - Davis, Susan, R.
AU3 - Gompel,, Anne
AU4 - Lumsden, Mary, Ann
AU5 - Murad, M., Hassan
AU6 - Pinkerton, JoAnn, V.
AU7 - Santen, Richard, J.
AB - Objective: The objective of this document is to generate a practice guideline for the management and treatment of symptoms of the menopause. Participants: The Treatment of Symptoms of the Menopause Task Force included six experts, a methodologist, and a medical writer, all appointed by The Endocrine Society. Evidence: The Task Force developed this evidenced-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews of published data and considered several other existing meta-analyses and trials. Consensus Process: Multiple e-mail communications, conference calls, and one face-to-face meeting determined consensus. Committees of The Endocrine Society, representatives from endorsing societies, and members of The Endocrine Society reviewed and commented on the drafts of the guidelines. The Australasian Menopause Society, the British Menopause Society, European Menopause and Andropause Society, the European Society of Endocrinology, and the International Menopause Society (co-sponsors of the guideline) reviewed and commented on the draft. Conclusions: Menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms and other symptoms of the climacteric. Benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of menopause. Health care professionals should individualize therapy based on clinical factors and patient preference. They should screen women before initiating MHT for cardiovascular and breast cancer risk and recommend the most appropriate therapy depending on risk/benefit considerations. Current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia. Other options are available for those with vasomotor symptoms who prefer not to use MHT or who have contraindications because these patients should not use MHT. Low-dose vaginal estrogen and ospemifene provide effective therapy for the genitourinary syndrome of menopause, and vaginal moisturizers and lubricants are available for those not choosing hormonal therapy. All postmenopausal women should embrace appropriate lifestyle measures. Summary of Recommendations 1.0 Diagnosis and symptoms of menopause 1.1 We suggest diagnosing menopause based on the clinical criteria of the menstrual cycle. (2|⊕⊕○○) 1.2 If establishing a diagnosis of menopause is necessary for patient management in women having undergone a hysterectomy without bilateral oophorectomy or presenting with a menstrual history that is inadequate to ascertain menopausal status, we suggest making a presumptive diagnosis of menopause based on the presence of vasomotor symptoms (VMS) and, when indicated, laboratory testing that includes replicate measures of FSH and serum estradiol. (2|⊕⊕○○) 2.0 Health considerations for all menopausal women 2.1 When women present during the menopausal transition, we suggest using this opportunity to address bone health, smoking cessation, alcohol use, cardiovascular risk assessment and management, and cancer screening and prevention. (Ungraded best practice statement) 3.0 Hormone therapy for menopausal symptom relief 3.1 Estrogen and progestogen therapy 3.1a For menopausal women < 60 years of age or < 10 years past menopause with bothersome VMS (with or without additional climacteric symptoms) who do not have contraindications or excess cardiovascular or breast cancer risks and are willing to take menopausal hormone therapy (MHT), we suggest initiating estrogen therapy (ET) for those without a uterus and estrogen plus progestogen therapy (EPT) for those with a uterus. (2|⊕⊕○○) Cardiovascular risk 3.1b For women < age 60 or < 10 years past menopause onset considering MHT for menopausal symptom relief, we suggest evaluating the baseline risk of cardiovascular disease (CVD) and taking this risk into consideration when advising for or against MHT and when selecting type, dose, and route of administration. (2|⊕⊕○○) 3.1c For women at high risk of CVD, we suggest initiating nonhormonal therapies to alleviate bothersome VMS (with or without climacteric symptoms) over MHT. (2|⊕⊕○○) 3.1d For women with moderate risk of CVD, we suggest transdermal estradiol as first-line treatment, alone for women without a uterus or combined with micronized progesterone (or another progestogen that does not adversely modify metabolic parameters) for women with a uterus, because these preparations have less untoward effect on blood pressure, triglycerides, and carbohydrate metabolism. (2|⊕⊕○○) Venous thromboembolic events 3.1e For women at increased risk of venous thromboembolism (VTE) who request MHT, we recommend a nonoral route of ET at the lowest effective dose, if not contraindicated (1|⊕⊕○○); for women with a uterus, we recommend a progestogen (for example, progesterone and dydrogestone) that is neutral on coagulation parameters. (1|⊕⊕⊕○) Breast cancer 3.1f For women considering MHT for menopausal symptom relief, we suggest evaluating the baseline risk of breast cancer and taking this risk into consideration when advising for or against MHT and when selecting type, dose, and route of administration. (2|⊕⊕○○) 3.1g For women at high or intermediate risk of breast cancer considering MHT for menopausal symptom relief, we suggest nonhormonal therapies over MHT to alleviate bothersome VMS. (2|⊕⊕○○) Tailoring MHT 3.1h We suggest a shared decision-making approach to decide about the choice of formulation, starting dose, the route of administration of MHT, and how to tailor MHT to each woman's individual situation, risks, and treatment goals. (Ungraded best practice statement) Custom-compounded hormones 3.1i We recommend using MHT preparations approved by the US Food and Drug Administration (FDA) and comparable regulating bodies outside the United States and recommend against the use of custom-compounded hormones. (Ungraded best practice statement) 3.2 Conjugated equine estrogens with bazedoxifene 3.2 For symptomatic postmenopausal women with a uterus and without contraindications, we suggest the combination of conjugated equine estrogens (CEE)/bazedoxifene (BZA) (where available) as an option for relief of VMS and prevention of bone loss. (2|⊕⊕⊕○) 3.3 Tibolone 3.3a For women with bothersome VMS and climacteric symptoms and without contraindications, we suggest tibolone (in countries where available) as an alternative to MHT. (2|⊕⊕○○) 3.3b We recommend against adding tibolone to other forms of MHT. (1|⊕⊕○○) 3.3c We recommend against using tibolone in women with a history of breast cancer. (1|⊕⊕○○) 3.4 Clinical management of patients taking hormone therapies Monitoring during therapy 3.4a For women with persistent unscheduled bleeding while taking MHT, we recommend evaluation to rule out pelvic pathology, most importantly, endometrial hyperplasia and cancer. (1|⊕⊕⊕○) 3.4b We recommend informing women about the possible increased risk of breast cancer during and after discontinuing EPT and emphasizing the importance of adhering to age-appropriate breast cancer screening. (1|⊕⊕⊕○) 3.4c We suggest that the decision to continue MHT be revisited at least annually, targeting the shortest total duration of MHT consistent with the treatment goals and evolving risk assessment of the individual woman. (Ungraded best practice statement) 3.4d For young women with primary ovarian insufficiency (POI), premature or early menopause, without contraindications, we suggest taking MHT until the time of anticipated natural menopause, when the advisability of continuing MHT can be reassessed. (2|⊕⊕○○) Stopping considerations 3.4e For women preparing to discontinue MHT, we suggest a shared decision-making approach to elicit individual preference about adopting a gradual taper vs abrupt discontinuation. (2|⊕⊕○○) 4.0 Nonhormonal therapies for VMS 4.0 For postmenopausal women with mild or less bothersome hot flashes, we suggest a series of steps that do not involve medication, such as turning down the thermostat, dressing in layers, avoiding alcohol and spicy foods, and reducing obesity and stress. (2|⊕⊕○○) 4.1 Nonhormonal prescription therapies for VMS 4.1a For women seeking pharmacological management for moderate to severe VMS for whom MHT is contraindicated, or who choose not to take MHT, we recommend selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) or gabapentin or pregabalin (if there are no contraindications). (1|⊕⊕⊕○) 4.1b For those women seeking relief of moderate to severe VMS who are not responding to or tolerating the nonhormonal prescription therapies, SSRIs/SNRIs or gabapentin or pregabalin, we suggest a trial of clonidine (if there are no contraindications). (2|⊕⊕○○) 4.2 Over-the-counter and alternative nonhormonal therapies for VMS 4.2 For women seeking relief of VMS with over-the-counter (OTC) or complementary medicine therapies, we suggest counseling regarding the lack of consistent evidence for benefit for botanicals, black cohosh, omega-3-fatty acids, red clover, vitamin E, and mind/body alternatives including anxiety control, acupuncture, paced breathing, and hypnosis. (2|⊕⊕○○) 5.0 Treatment of genitourinary syndrome of menopause 5.1 Vaginal moisturizers and lubricants 5.1a For postmenopausal women with symptoms of vulvovaginal atrophy (VVA), we suggest a trial of vaginal moisturizers to be used at least twice weekly. (2|⊕⊕○○) 5.1b For women who do not produce sufficient vaginal secretions for comfortable sexual activity, we suggest vaginal lubricants. (2|⊕⊕○○) 5.2 Vaginal estrogen therapies 5.2a For women without a history of hormone- (estrogen) dependent cancers who are seeking relief from symptoms of genitourinary syndrome of menopause (GSM) (including VVA) that persist despite using vaginal lubricants and moisturizers, we recommend low-dose vaginal ET. (1|⊕⊕⊕○) Practice statement 5.2b In women with a history of breast or endometrial cancer, who present with symptomatic GSM (including VVA), that does not respond to nonhormonal therapies, we suggest a shared decision-making approach that includes the treating oncologist to discuss using low-dose vaginal ET. (Ungraded best practice statement) 5.2c For women taking raloxifene, without a history of hormone- (estrogen) dependent cancers, who develop symptoms of GSM (including VVA) that do not respond to nonhormonal therapies, we suggest adding low-dose vaginal ET. (2|⊕⊕○○) 5.2d For women using low-dose vaginal ET, we suggest against adding a progestogen (ie, no need for adding progestogen to prevent endometrial hyperplasia). (2|⊕○○○) 5.2e For women using vaginal ET who report postmenopausal bleeding or spotting, we recommend prompt evaluation for endometrial pathology. (1|⊕⊕○○) 5.3 Ospemifene 5.3a For treatment of moderate to severe dyspareunia associated with vaginal atrophy in postmenopausal women without contraindications, we suggest a trial of ospemifene. (2|⊕⊕⊕○) 5.3b For women with a history of breast cancer presenting with dyspareunia, we recommend against ospemifene. (1|⊕○○○) Method of Development of Evidence-based Clinical Practice Guidelines The Clinical Guidelines Subcommittee (CGS) of The Endocrine Society deemed management of menopause a priority area in need of a practice guideline and appointed a Task Force to formulate evidence-based recommendations. The Task Force followed the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group, an international group with expertise in development and implementation of evidence-based guidelines (1). A detailed description of the grading scheme has been published elsewhere (2). The Task Force used the best available research evidence to develop the recommendations. The Task Force commissioned three systematic reviews of the literature to inform its key recommendations. The Task Force used consistent language and graphical descriptions of both the strength of a recommendation and the quality of evidence using the recommendations of the GRADE system. In terms of the strength of the recommendation, strong recommendations use the phrase “we recommend” or “we recommend against” and the number 1, and weak recommendations use the phrase “we suggest” or “we suggest against” and the number 2. Cross-filled circles indicate the quality of the evidence, such that ⊕○○○ denotes very low quality evidence; ⊕⊕○○, low quality; ⊕⊕⊕○, moderate quality; and ⊕⊕⊕⊕, high quality. The Task Force has confidence that persons who receive care according to the strong recommendations will derive, on average, more good than harm. Weak recommendations require more careful consideration of the person's circumstances, values, and preferences to determine the best course of action. Linked to each recommendation is a description of the evidence and the values the panelists considered when making the recommendation. In some instances, there are remarks, a section in which panelists offer technical suggestions for testing conditions, dosing, and monitoring. These technical comments reflect the best available evidence applied to a typical person being treated. Often this evidence comes from the unsystematic observations of the panelists and their values and preferences; therefore, these remarks should be considered suggestions. In this guideline, the Task Force made several statements to emphasize the importance of shared decision making, general preventive care measures, and basic principles of women's health. These were labeled as ungraded best practice statements. Direct evidence for these statements was either unavailable or not systematically appraised and was considered out of the scope of this guideline. The intention of these statements is to draw attention and remind providers of these principles, and these statements should not be considered as graded recommendations (3). The 2013 Appraisal of Guidelines for Research and Evaluation II (AGREEII) criteria (23 items) were satisfied, with three exceptions. Item 5 stipulates that the views and preferences of the target population (patients, public, etc) have been sought. The Task Force did not conduct specific polling/outreach to the public in anticipation of this guideline. Item 14 states that a procedure for updating the guideline is provided. This process has not been formalized. Item 20 suggests that the potential resource implications of applying the recommendations have been considered. The Task Force did not include cost analysis of risk assessment tools or prescription drug therapies. The Endocrine Society maintains a rigorous conflict-of-interest review process for the development of clinical practice guidelines. All Task Force members must declare any potential conflicts of interest, which are reviewed before the members are approved to serve on the Task Force and periodically during the development of the guideline. The conflict-of-interest forms are vetted by the CGS before the members are approved by the Society's Council to participate on the guideline Task Force. Participants in the guideline development must include a majority of individuals without conflict of interest in the matter under study. Participants with conflicts of interest may participate in the development of the guideline, but they must have disclosed all conflicts. The CGS and the Task Force have reviewed all disclosures for this guideline and resolved or managed all identified conflicts of interest. Conflicts of interest are defined by remuneration in any amount from the commercial interest(s) in the form of grants; research support; consulting fees; salary; ownership interest (eg, stocks, stock options, or ownership interest excluding diversified mutual funds); honoraria or other payments for participation in speakers' bureaus, advisory boards, or boards of directors; or other financial benefits. Completed forms are available through the Endocrine Society office. Funding for this guideline was derived solely from the Endocrine Society, and thus the Task Force received no funding or remuneration from commercial or other entities. Commissioned systematic reviews The Task Force formulated three questions for systematic reviews to provide evidence supporting this guideline. The first compared the effect of oral vs transdermal estrogens on the risk of venous and arterial thrombotic events. Low-quality evidence derived from 15 observational studies suggested that, compared with transdermal MHT, oral MHT was associated with increased risk of VTE, deep vein thrombosis (DVT), and possibly stroke, but not myocardial infarction (MI) (4). The second question evaluated the effect of MHT on mortality. Data from 43 randomized controlled trials (RCTs) demonstrated no association between all-cause mortality, regardless of hormone type, the presence of pre-existing heart disease, or length of follow-up (5). Meta-analysis of 2 RCTs in which MHT was started at a mean age less than 60 and 3 RCTs in which MHT was started less than10 years after menopause suggested possible reduction of mortality with MHT. The third question compared the effect of MHT with natural progesterone vs synthetic progestins on breast cancer risk. Low-quality evidence from two observational studies suggested that natural progesterone may be associated with a reduced risk for breast cancer compared with synthetic progestins, but data were insufficient to draw a firm conclusion. Introduction and background VMS, hot flashes, and night sweats, are the hallmarks of menopause, although not all women experience these symptoms. Other climacteric symptoms include sleep disturbance (6, 7), arthralgia (7–9), and vaginal dryness and dyspareunia (7, 10, 11). It is less clear whether anxiety, irritability, depression, palpitations, skin dryness, loss of libido, and fatigue can be attributed to menopause (7, 9, 12). Symptoms frequently start in the years before the final menstrual period and can last, with unpredictable duration, from a few years to more than 13 years (13–16). ET has long been recognized as the most effective treatment for the relief of bothersome vasomotor and vaginal symptoms associated with menopause. However, prescriptions for MHT declined considerably after the 2002 publication of the Women's Health Initiative (WHI) RCT. This study determined that for postmenopausal women (average age, 63 y), oral CEE alone after hysterectomy (17), or coupled with daily medroxyprogesterone acetate (MPA) in women with a uterus (18), was associated with risks disproportionate to preventive benefits (17, 18). During ensuing years, a consensus arose that most healthy symptomatic women, without contraindications and closer to the time of menopause (<10 y after menopause onset or age <60 y), were appropriate candidates for MHT for symptom relief (19, 20). Post hoc WHI analyses and observational data suggest that benefits exceed risks in most of these women. At this juncture, women in the United States and some other countries have a broader range of therapeutic choices than ever before, including: MHT dose, type, and route of administration; new selective estrogen receptor modulators (SERMs) as solo or combination therapies; and expanded choices of nonhormonal prescription medications. In this guideline, we emphasize safety in identifying which late perimenopausal and recently postmenopausal women are candidates for various therapeutic agents. Considerations include the risks and benefits of each available therapy, the expected duration of treatment, the intensity of monitoring during therapy, and most importantly, individualizing the course of therapy to reflect the specific characteristics of the patient who is making decisions regarding symptom management. This guideline covers the full spectrum of therapies for relief of the most common and bothersome menopausal symptoms (Figure 1). (The detailed management of early menopause transition, primary ovarian insufficiency, and prevention of osteoporosis and fracture are considered beyond the current scope.) Choice of therapy is ideally based on available evidence regarding safety and efficacy and is generally a shared decision including both patient and provider. The treatment selected should be tailored to the individual patient and will vary according to each woman's symptom severity, age, medical profile, personal preference, and estimated benefit/risk ratio. The impact of severe menopausal symptoms on quality of life (QOL) can be substantial, and there are instances in which a woman with a history of coronary heart disease (CHD) or breast cancer, for example, will choose to accept a degree of risk that might otherwise be considered to outweigh the benefits of MHT. An accepted philosophy is that a fully informed patient should be empowered to make a decision that best balances individual QOL benefits against potential health risks (21). Figure 1. Open in new tabDownload slide Approach to menopause guideline. Numbers correspond to section of text addressing selected clinical issue. Figure 1. Open in new tabDownload slide Approach to menopause guideline. Numbers correspond to section of text addressing selected clinical issue. 1.0 Diagnosis and symptoms of menopause 1.1 We suggest diagnosing menopause based on the clinical criteria of the menstrual cycle. (2|⊕⊕○○) 1.2 If establishing a diagnosis of menopause is necessary for patient management in women having undergone a hysterectomy without bilateral oophorectomy or presenting with a menstrual history that is inadequate to ascertain menopausal status, we suggest making a presumptive diagnosis of menopause based on the presence of VMS and, when indicated, laboratory testing that includes replicate measures of FSH and serum estradiol. (2|⊕⊕○○) Technical remark Table 1 summarizes other etiologies of secondary amenorrhea to be considered in the differential diagnosis. Table 1. Definitions of Spectrum of Menopause Menopause     Clinical status after the final menstrual period, diagnosed retrospectively after cessation of menses for 12 mo in a previously cycling woman and reflecting complete or nearly complete permanent cessation of ovarian function and fertility. Spontaneous menopause     Cessation of menses that occurs at an average age of 51 y in the absence of surgery or medication (316–318). Menopausal transition (or perimenopause)     An interval preceding the menopause characterized by variations in menstrual cycle length and bleeding pattern, mood shifts, vasomotor, and vaginal symptoms and with rising FSH levels and falling anti-Mullerian hormone and inhibin B levels, which starts during the late reproductive stage and progresses during the menopause transition (15, 319). Climacteric     The phase in the aging of women marking the transition from the reproductive phase to the nonreproductive state. This phase incorporates the perimenopause by extending for a longer variable period before and after the perimenopause. Climacteric syndrome     When the climacteric is associated with symptomatology. Menopause after hysterectomy without oophorectomy     Spontaneous cessation of ovarian function without the clinical signal of cessation of menses. Induced menopause     Cessation of ovarian function induced by chemotherapy, radiotherapy, or bilateral oophorectomy. Early menopause     Cessation of ovarian function occurring between ages 40 and 45 in the absence of other etiologies for secondary amenorrhea (pregnancy, hyperprolactinemia, and thyroid disorders). POI     Loss of ovarian function before the age of 40 y with waxing and waning course and potential resumption of menses, conception, and pregnancy (320). The prevalence of POI is approximately 1% (321) and is differentiated into idiopathic, autoimmune (associated with polyglandular autoimmune syndromes), metabolic disorders, and genetic abnormalities (including fragile X premutation). Menopause     Clinical status after the final menstrual period, diagnosed retrospectively after cessation of menses for 12 mo in a previously cycling woman and reflecting complete or nearly complete permanent cessation of ovarian function and fertility. Spontaneous menopause     Cessation of menses that occurs at an average age of 51 y in the absence of surgery or medication (316–318). Menopausal transition (or perimenopause)     An interval preceding the menopause characterized by variations in menstrual cycle length and bleeding pattern, mood shifts, vasomotor, and vaginal symptoms and with rising FSH levels and falling anti-Mullerian hormone and inhibin B levels, which starts during the late reproductive stage and progresses during the menopause transition (15, 319). Climacteric     The phase in the aging of women marking the transition from the reproductive phase to the nonreproductive state. This phase incorporates the perimenopause by extending for a longer variable period before and after the perimenopause. Climacteric syndrome     When the climacteric is associated with symptomatology. Menopause after hysterectomy without oophorectomy     Spontaneous cessation of ovarian function without the clinical signal of cessation of menses. Induced menopause     Cessation of ovarian function induced by chemotherapy, radiotherapy, or bilateral oophorectomy. Early menopause     Cessation of ovarian function occurring between ages 40 and 45 in the absence of other etiologies for secondary amenorrhea (pregnancy, hyperprolactinemia, and thyroid disorders). POI     Loss of ovarian function before the age of 40 y with waxing and waning course and potential resumption of menses, conception, and pregnancy (320). The prevalence of POI is approximately 1% (321) and is differentiated into idiopathic, autoimmune (associated with polyglandular autoimmune syndromes), metabolic disorders, and genetic abnormalities (including fragile X premutation). Open in new tab Table 1. Definitions of Spectrum of Menopause Menopause     Clinical status after the final menstrual period, diagnosed retrospectively after cessation of menses for 12 mo in a previously cycling woman and reflecting complete or nearly complete permanent cessation of ovarian function and fertility. Spontaneous menopause     Cessation of menses that occurs at an average age of 51 y in the absence of surgery or medication (316–318). Menopausal transition (or perimenopause)     An interval preceding the menopause characterized by variations in menstrual cycle length and bleeding pattern, mood shifts, vasomotor, and vaginal symptoms and with rising FSH levels and falling anti-Mullerian hormone and inhibin B levels, which starts during the late reproductive stage and progresses during the menopause transition (15, 319). Climacteric     The phase in the aging of women marking the transition from the reproductive phase to the nonreproductive state. This phase incorporates the perimenopause by extending for a longer variable period before and after the perimenopause. Climacteric syndrome     When the climacteric is associated with symptomatology. Menopause after hysterectomy without oophorectomy     Spontaneous cessation of ovarian function without the clinical signal of cessation of menses. Induced menopause     Cessation of ovarian function induced by chemotherapy, radiotherapy, or bilateral oophorectomy. Early menopause     Cessation of ovarian function occurring between ages 40 and 45 in the absence of other etiologies for secondary amenorrhea (pregnancy, hyperprolactinemia, and thyroid disorders). POI     Loss of ovarian function before the age of 40 y with waxing and waning course and potential resumption of menses, conception, and pregnancy (320). The prevalence of POI is approximately 1% (321) and is differentiated into idiopathic, autoimmune (associated with polyglandular autoimmune syndromes), metabolic disorders, and genetic abnormalities (including fragile X premutation). Menopause     Clinical status after the final menstrual period, diagnosed retrospectively after cessation of menses for 12 mo in a previously cycling woman and reflecting complete or nearly complete permanent cessation of ovarian function and fertility. Spontaneous menopause     Cessation of menses that occurs at an average age of 51 y in the absence of surgery or medication (316–318). Menopausal transition (or perimenopause)     An interval preceding the menopause characterized by variations in menstrual cycle length and bleeding pattern, mood shifts, vasomotor, and vaginal symptoms and with rising FSH levels and falling anti-Mullerian hormone and inhibin B levels, which starts during the late reproductive stage and progresses during the menopause transition (15, 319). Climacteric     The phase in the aging of women marking the transition from the reproductive phase to the nonreproductive state. This phase incorporates the perimenopause by extending for a longer variable period before and after the perimenopause. Climacteric syndrome     When the climacteric is associated with symptomatology. Menopause after hysterectomy without oophorectomy     Spontaneous cessation of ovarian function without the clinical signal of cessation of menses. Induced menopause     Cessation of ovarian function induced by chemotherapy, radiotherapy, or bilateral oophorectomy. Early menopause     Cessation of ovarian function occurring between ages 40 and 45 in the absence of other etiologies for secondary amenorrhea (pregnancy, hyperprolactinemia, and thyroid disorders). POI     Loss of ovarian function before the age of 40 y with waxing and waning course and potential resumption of menses, conception, and pregnancy (320). The prevalence of POI is approximately 1% (321) and is differentiated into idiopathic, autoimmune (associated with polyglandular autoimmune syndromes), metabolic disorders, and genetic abnormalities (including fragile X premutation). Open in new tab Diagnosis Table 1 lists definitions of the clinical spectrum of menopause. In a woman with an intact uterus, menopause is a clinical diagnosis based upon cessation of menses for at least 12 months. Sex steroids, gonadotropins, inhibin B, or anti-Mullerian hormone measurements do not further inform the diagnosis, do not indicate precisely when the final menstrual period will occur, and will not influence management unless a woman is seeking fertility. In women having undergone a hysterectomy but not bilateral oophorectomy, elevated FSH levels and estradiol concentrations < 20 pg/mL on several occasions support but do not confirm the diagnosis. A distinction between the late perimenopause transition, marked by episodes of > 60 days of amenorrhea and increasing severity of VMS (15), and early postmenopause cannot be made on the sole basis of hormone measurements. With radiotherapy- or chemotherapy-induced menopause, it is important to recognize that ovarian function may resume after 12 months of amenorrhea (22), depending on the age of the woman and the dose and duration of treatment (22). For POI, persistent FSH elevation in women < age 40 provides a tentative diagnosis (Table 1). Signs and symptoms Vasomotor symptoms Prevalence. Hot flashes (also called hot flushes) occur in approximately 75% of postmenopausal women in the United States (23). In the Study of Women Across the Nation (SWAN), after controlling for age, education, health, and economic strain, researchers found that US Caucasian women report more psychosomatic symptoms, African American and Hispanic women report more VMS, and Asian women report more somatic complaints (16, 24). Notably, across countries and ethnic backgrounds, the percentage of women reporting hot flashes varies (25–27). In a cross-sectional study of premenopausal women (mean age, 48 y), one-third reported “ever” experiencing hot flashes (28). A comparison between VMS experienced during the premenopause vs the postmenopause may be informative when counseling a postmenopausal woman regarding symptom relief, although to our knowledge, the presence and frequency of premenopausal hot flashes have not been studied as being predictive of response to therapy in the postmenopause. Persistence of hot flashes may also vary depending upon when in the menopausal transition VMS were first noted. In SWAN, earlier onset of VMS was associated with longer postmenopausal duration (16). Clinical manifestations. Hot flashes typically begin as the sudden sensation of heat centered on the upper chest and face. When moderate or severe, the hot flash rapidly becomes generalized, lasts from 2 to 4 minutes, and can be associated with profuse perspiration, palpitations, or anxiety. Triggers include spicy food or alcohol. At night, vasomotor instability manifests as hot flashes or night sweats, which may represent different physiological mechanisms. The differential diagnosis includes several entities distinguishable by clinical features (Table 2). New-onset VMS in older (age, ≥ 65 y) postmenopausal women may be associated with, but not necessarily causally related to, increased risk of major CHD and all-cause mortality (29). Table 2. Conditions That May Cause or Mimic Vasomotor Events and That Can Be Distinguished From Menopausal Symptoms by History, Examination, and Investigations, as Indicated Hormone excess     Thyroid hormone excess     Carcinoid syndrome (flushing without sweating)     Pheochromocytoma (hypertension, flushing, and profuse sweating) Dietary factors     Alcohol     Spicy food     Food additives (eg, monosodium glutamate, sulfites) Pharmaceuticals     Chronic opioid use     Opiate withdrawal     SSRIs (may cause sweats)     Nicotinic acid (intense warmth, itching lasting up to 30 min)     Calcium channel blockers     Medications that block estrogen action or biosynthesis Chronic infection (increased body temperature) Other medical conditions     Postgastric surgery dumping syndrome     Mastocytosis and mast cell disorders (usually with gastrointestinal symptoms)     Some cancers: medullary carcinoma of the thyroid, pancreatic islet-cell tumors, renal cell carcinoma, lymphoma     Anxiety disorders Hormone excess     Thyroid hormone excess     Carcinoid syndrome (flushing without sweating)     Pheochromocytoma (hypertension, flushing, and profuse sweating) Dietary factors     Alcohol     Spicy food     Food additives (eg, monosodium glutamate, sulfites) Pharmaceuticals     Chronic opioid use     Opiate withdrawal     SSRIs (may cause sweats)     Nicotinic acid (intense warmth, itching lasting up to 30 min)     Calcium channel blockers     Medications that block estrogen action or biosynthesis Chronic infection (increased body temperature) Other medical conditions     Postgastric surgery dumping syndrome     Mastocytosis and mast cell disorders (usually with gastrointestinal symptoms)     Some cancers: medullary carcinoma of the thyroid, pancreatic islet-cell tumors, renal cell carcinoma, lymphoma     Anxiety disorders Open in new tab Table 2. Conditions That May Cause or Mimic Vasomotor Events and That Can Be Distinguished From Menopausal Symptoms by History, Examination, and Investigations, as Indicated Hormone excess     Thyroid hormone excess     Carcinoid syndrome (flushing without sweating)     Pheochromocytoma (hypertension, flushing, and profuse sweating) Dietary factors     Alcohol     Spicy food     Food additives (eg, monosodium glutamate, sulfites) Pharmaceuticals     Chronic opioid use     Opiate withdrawal     SSRIs (may cause sweats)     Nicotinic acid (intense warmth, itching lasting up to 30 min)     Calcium channel blockers     Medications that block estrogen action or biosynthesis Chronic infection (increased body temperature) Other medical conditions     Postgastric surgery dumping syndrome     Mastocytosis and mast cell disorders (usually with gastrointestinal symptoms)     Some cancers: medullary carcinoma of the thyroid, pancreatic islet-cell tumors, renal cell carcinoma, lymphoma     Anxiety disorders Hormone excess     Thyroid hormone excess     Carcinoid syndrome (flushing without sweating)     Pheochromocytoma (hypertension, flushing, and profuse sweating) Dietary factors     Alcohol     Spicy food     Food additives (eg, monosodium glutamate, sulfites) Pharmaceuticals     Chronic opioid use     Opiate withdrawal     SSRIs (may cause sweats)     Nicotinic acid (intense warmth, itching lasting up to 30 min)     Calcium channel blockers     Medications that block estrogen action or biosynthesis Chronic infection (increased body temperature) Other medical conditions     Postgastric surgery dumping syndrome     Mastocytosis and mast cell disorders (usually with gastrointestinal symptoms)     Some cancers: medullary carcinoma of the thyroid, pancreatic islet-cell tumors, renal cell carcinoma, lymphoma     Anxiety disorders Open in new tab Association with sleep. In polysomnography studies, nocturnal hot flashes are more common during the first 4 hours of sleep, whereas subsequent rapid eye movement sleep suppresses hot flashes, arousals, and awakenings (30). A recent study that induced estrogen deficiency in healthy premenopausal women with a GnRH agonist directly demonstrated that hot flashes are associated with three factors: 1) an increase in episodes of waking after sleep-onset; 2) a decrease in perceived sleep efficiency; and 3) a statistically significant correlation between nocturnal VMS and sleep disruption (31). Although these data are informative, it has not been substantiated whether they apply in naturally postmenopausal women with continuously high gonadotropins. An important contributing factor is aging, which likely is also involved in sleep disturbances in menopausal women. Mechanisms. VMS appear to involve the central nervous system (32) because: 1) hot flashes occur simultaneously with, but are not caused by, LH pulses (33, 34); and 2) research has shown an association with the neuroregulators kisspeptin, neurokinin B, and dynorphin (35). Alterations of thermoregulatory systems are mechanistically involved because women with hot flashes exhibit a narrowing of the thermoregulatory-neutral zone (32). Whereas premenopausal women initiate mechanisms to dissipate heat when the core body temperature increases by 0.4°C, this happens with much lower increases in temperature in menopausal women (36). Core body temperature is usually still within the normal range at the onset of the flash, but inappropriate peripheral vasodilatation with increased digital and cutaneous blood flow and perspiration results in rapid heat loss and a fall in core body temperature (32). Shivering may occur to restore the core temperature (36). Genitourinary syndrome of menopause This new term “genitourinary syndrome of menopause” (GSM) combines the conditions of VVA and urinary tract dysfunction (Table 3) (37). VVA most often presents in the late postmenopausal stage, when VMS may have abated (15). When VVA is severe, women may have discomfort wearing tight-fitting clothing or while sitting or exercising. Sexual activity is not required for patients to experience vaginal or genital discomfort. Urinary symptoms—dysuria, urinary frequency, and recurrent urinary tract infections—increase in severity with time since menopause. Table 3. Genitourinary Syndrome of Menopause Symptoms     Vulvar pain, burning, or itching     Vaginal dryness     Vaginal discharge     Dyspareunia     Spotting or bleeding after intercourse     Dysuria, urinary frequency, urgency     Recurrent urinary tract infections Signs, external genitalia     Decreased labial size     Loss of vulvar fat pads     Vulvar fissures     Receded or phimotic clitoris     Prominent urethra with mucosal eversion or prolapse Signs, vagina     Introital narrowing     Loss of elasticity with constriction     Thin vaginal epithelial lining     Loss of mature squamous epithelium     Pale or erythematous appearance     Petechiae, ulcerations, or tears     Alkaline pH (>5.5)     Infection (yellow or greenish discharge) Symptoms     Vulvar pain, burning, or itching     Vaginal dryness     Vaginal discharge     Dyspareunia     Spotting or bleeding after intercourse     Dysuria, urinary frequency, urgency     Recurrent urinary tract infections Signs, external genitalia     Decreased labial size     Loss of vulvar fat pads     Vulvar fissures     Receded or phimotic clitoris     Prominent urethra with mucosal eversion or prolapse Signs, vagina     Introital narrowing     Loss of elasticity with constriction     Thin vaginal epithelial lining     Loss of mature squamous epithelium     Pale or erythematous appearance     Petechiae, ulcerations, or tears     Alkaline pH (>5.5)     Infection (yellow or greenish discharge) Derived from D. J. Portman et al: Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society. Menopause. 2014;21:1063–1068 (37), with permission. Open in new tab Table 3. Genitourinary Syndrome of Menopause Symptoms     Vulvar pain, burning, or itching     Vaginal dryness     Vaginal discharge     Dyspareunia     Spotting or bleeding after intercourse     Dysuria, urinary frequency, urgency     Recurrent urinary tract infections Signs, external genitalia     Decreased labial size     Loss of vulvar fat pads     Vulvar fissures     Receded or phimotic clitoris     Prominent urethra with mucosal eversion or prolapse Signs, vagina     Introital narrowing     Loss of elasticity with constriction     Thin vaginal epithelial lining     Loss of mature squamous epithelium     Pale or erythematous appearance     Petechiae, ulcerations, or tears     Alkaline pH (>5.5)     Infection (yellow or greenish discharge) Symptoms     Vulvar pain, burning, or itching     Vaginal dryness     Vaginal discharge     Dyspareunia     Spotting or bleeding after intercourse     Dysuria, urinary frequency, urgency     Recurrent urinary tract infections Signs, external genitalia     Decreased labial size     Loss of vulvar fat pads     Vulvar fissures     Receded or phimotic clitoris     Prominent urethra with mucosal eversion or prolapse Signs, vagina     Introital narrowing     Loss of elasticity with constriction     Thin vaginal epithelial lining     Loss of mature squamous epithelium     Pale or erythematous appearance     Petechiae, ulcerations, or tears     Alkaline pH (>5.5)     Infection (yellow or greenish discharge) Derived from D. J. Portman et al: Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society. Menopause. 2014;21:1063–1068 (37), with permission. Open in new tab Other signs and symptoms The menopausal decline of estradiol increases bone resorption and contributes to fractures (38). Possible related signs and symptoms Research has suggested (but not proven) a direct relationship between menopause and mood changes, mild depressive symptoms, anxiety, irritability, arthralgias, loss of libido, palpitations, skin dryness, fatigue, and reduction in QOL (38, 39). As opposed to the conclusions in the 2005 National Institutes of Health State of the Science consensus regarding the uncertain relationship between mood and menopause, more recent longitudinal studies now support an association of the menopause transition with depressed mood, major depressive episodes, and anxiety. 2.0 Health considerations for all menopausal women 2.1 When women present during the menopausal transition, we suggest using this opportunity to address bone health, smoking cessation, alcohol use, cardiovascular risk assessment and management, and cancer screening and prevention. (Ungraded best practice statement) Evidence The menopause transition, a portal to the second half of life, is a critical window to reassess lifestyle, recognize ongoing and potential health concerns, and encourage a proactive approach to future well-being, regardless of menopausal symptoms. To decrease morbidity and mortality from CVD and cancer and maintain QOL, optimizing diet and exercise to maintain healthy weight are important measures, as are counseling regarding alcohol use and smoking cessation and identifying and treating hypertension, glucose intolerance, and dyslipidemias (40, 41). Adequate intake of calcium and vitamin D, along with limiting alcohol consumption will minimize bone loss and reduce the risk of falls and fractures (42). For postmenopausal women < 65 years of age and at high risk of osteoporosis, dual-energy x-ray absorptiometry assessment of bone mineral density contributes to risk assessment. ET for the relief of menopausal symptoms prevents bone loss and reduces fracture risk (43). Women without VMS and at significant risk of osteoporosis can discuss the merits of ET for bone preservation. Recent guidelines address bone-specific therapies (43). 3.0 Hormone therapy for menopausal symptom relief 3.1 Estrogen and progestogen therapy 3.1a For menopausal women < 60 years of age or < 10 years past menopause with bothersome VMS (with or without additional climacteric symptoms) who do not have contraindications or excess cardiovascular or breast cancer risks and are willing to take MHT, we suggest initiating ET for those without a uterus and EPT for those with a uterus. (2|⊕⊕○○) Evidence In postmenopausal women, ET improves menopause-associated (climacteric) symptoms (eg, VMS, genitourinary symptoms, sleep disturbance, menopause-associated anxiety and depressive symptoms, and arthralgias). ET also reduces menopause-related bone loss, lowers the risk of fragility fractures in older women, and reduces the incidence of self-reported diabetes. In addition, combined EPT reduced the risk of colorectal cancer and, in cumulative follow-up of the WHI, endometrial cancer (38, 44). MHT is not appropriate for all symptomatic menopausal women (Figure 2). There are no commonly recognized lists of absolute or relative contraindications to MHT as published in professional society guidelines. And whereas US product labeling (regulated by the FDA) does include contraindications to MHT (Table 4), caution is also advised for women with certain additional medical conditions (Table 4). Risk/benefit assessment is the most important consideration, and QOL may be an important issue in a decision to recommend MHT. Women with conditions precluding MHT (Table 4) who are unwilling to take MHT, or at substantial risk for breast cancer or CVD, can consider nonhormonal options for symptom relief (Section 4.0). Figure 2. Open in new tabDownload slide Approach to the patient with VMS contemplating MHT. TIA, transient ischemic attack. Figure 2. Open in new tabDownload slide Approach to the patient with VMS contemplating MHT. TIA, transient ischemic attack. Table 4. Specific Cautions to Use of Systemic MHT or SERMsa,b for Treatment of Menopausal Symptoms In general, ET should not be used in women with any of the following conditions:     Undiagnosed abnormal genital bleeding     Known, suspected, or history of cancer of the breast     Known or suspected estrogen-dependent neoplasia including endometrial cancer     Active DVT, pulmonary embolism, or history of these conditions     Active arterial thromboembolic disease (for example, stroke, MI) or a history of these conditions     Known anaphylactic reaction or angioedema in response to any ingredient in the medicationc     Known liver impairment or disease     Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disordersc     Known or suspected pregnancy Caution should also be exercised in women with:     Gallbladder disease (oral ET)     Hypertriglyceridemia (>400 mg/d) (oral ET)     Diabetes     Hypoparathyroidism (risk of hypocalcemia)     Benign meningioma     Intermediate or high risk of breast cancer     High risk of heart disease     Migraine with aura (oral ET)     Other conditionsd In general, ET should not be used in women with any of the following conditions:     Undiagnosed abnormal genital bleeding     Known, suspected, or history of cancer of the breast     Known or suspected estrogen-dependent neoplasia including endometrial cancer     Active DVT, pulmonary embolism, or history of these conditions     Active arterial thromboembolic disease (for example, stroke, MI) or a history of these conditions     Known anaphylactic reaction or angioedema in response to any ingredient in the medicationc     Known liver impairment or disease     Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disordersc     Known or suspected pregnancy Caution should also be exercised in women with:     Gallbladder disease (oral ET)     Hypertriglyceridemia (>400 mg/d) (oral ET)     Diabetes     Hypoparathyroidism (risk of hypocalcemia)     Benign meningioma     Intermediate or high risk of breast cancer     High risk of heart disease     Migraine with aura (oral ET)     Other conditionsd a Also apply to conjugated estrogens/BZA, ospemifene, and tibolone therapies. b Advice not to use estrogens in the specific conditions listed is based on FDA recommendations and package labeling in the United States. The advice to exercise caution is based on a review of the literature (including package labeling) and not dictums generally included in various Menopause Society guidelines. Because these guidelines are meant to be used internationally, it should be noted that these considerations may vary from country to country. c Specific to CEE ± combination with BZA. d Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Open in new tab Table 4. Specific Cautions to Use of Systemic MHT or SERMsa,b for Treatment of Menopausal Symptoms In general, ET should not be used in women with any of the following conditions:     Undiagnosed abnormal genital bleeding     Known, suspected, or history of cancer of the breast     Known or suspected estrogen-dependent neoplasia including endometrial cancer     Active DVT, pulmonary embolism, or history of these conditions     Active arterial thromboembolic disease (for example, stroke, MI) or a history of these conditions     Known anaphylactic reaction or angioedema in response to any ingredient in the medicationc     Known liver impairment or disease     Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disordersc     Known or suspected pregnancy Caution should also be exercised in women with:     Gallbladder disease (oral ET)     Hypertriglyceridemia (>400 mg/d) (oral ET)     Diabetes     Hypoparathyroidism (risk of hypocalcemia)     Benign meningioma     Intermediate or high risk of breast cancer     High risk of heart disease     Migraine with aura (oral ET)     Other conditionsd In general, ET should not be used in women with any of the following conditions:     Undiagnosed abnormal genital bleeding     Known, suspected, or history of cancer of the breast     Known or suspected estrogen-dependent neoplasia including endometrial cancer     Active DVT, pulmonary embolism, or history of these conditions     Active arterial thromboembolic disease (for example, stroke, MI) or a history of these conditions     Known anaphylactic reaction or angioedema in response to any ingredient in the medicationc     Known liver impairment or disease     Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disordersc     Known or suspected pregnancy Caution should also be exercised in women with:     Gallbladder disease (oral ET)     Hypertriglyceridemia (>400 mg/d) (oral ET)     Diabetes     Hypoparathyroidism (risk of hypocalcemia)     Benign meningioma     Intermediate or high risk of breast cancer     High risk of heart disease     Migraine with aura (oral ET)     Other conditionsd a Also apply to conjugated estrogens/BZA, ospemifene, and tibolone therapies. b Advice not to use estrogens in the specific conditions listed is based on FDA recommendations and package labeling in the United States. The advice to exercise caution is based on a review of the literature (including package labeling) and not dictums generally included in various Menopause Society guidelines. Because these guidelines are meant to be used internationally, it should be noted that these considerations may vary from country to country. c Specific to CEE ± combination with BZA. d Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Open in new tab Risks and benefit overview Healthcare providers and patients should choose MHT based on individual risks and benefits utilizing a shared decision-making approach. Current recommendations suggest that the initiation of MHT should generally be limited to women < 60 years of age or < 10 years after menopause onset. Accordingly, data are needed to estimate risks and benefits in this specific population. No adequately powered RCTs with clinical outcomes have been specifically conducted with younger, symptomatic women, however, and data for women < 50 years old are limited. The best available evidence comes from subgroup analyses of WHI data, which provide information specifically in women 50 to 59 years of age or < 10 years since menopause onset. Because of the number of women participants ages 50 to 59 (5520 in the combined therapy arm and 3313 in the estrogen-alone arm), and the low event rate for MI and stroke in this age group, such data provide trends but few statistically significant differences. Findings from observational studies, case reports, and clinical expertise, both from the United States and other countries, provide additional sources of evidence regarding younger postmenopausal women. Estimations of risks and benefits previously published in The Endocrine Society's 2010 Scientific Statement utilized both observational and RCT data. However, updated outcomes from the WHI are now available. Accordingly, the updated reanalysis of the WHI (44) is considered by many to provide the best available data on risks and benefits in women ages 50 to 59, but not in those younger than age 50. The 2010 Statement expresses attributable (excess) benefits and risks as the number of affected women/1000 users/5 years of therapy, assuming that most women initiating MHT will consider therapy for 5 years. Maintaining this format, the risks and benefits (as reported in the WHI and reflecting the specific oral therapies studied) are presented in Figure 3 and are not repeated in the text of this guideline. These data, representing the effects of CEE with or without MPA, cannot be extrapolated to other MHT regimens. However, in the absence of RCTs with other specific agents, they provide the most conservative estimates. Notably, the baseline risk of most adverse events is lower in younger vs older women and results in lower attributable risk although relative risks may be similar among various age groups. The converse is also true for benefits, such as fracture reduction. Figure 3. Open in new tabDownload slide Updated summary of the effects of orally administered CEE alone or combined with MPA in women ages 50–59 years during intervention phase of WHI. One set of analyses examined the risks and benefits of these agents in women ages 50–59 years. This figure plots these data, which are expressed here as excess risks and benefits per 1000 women using MHT for 5 years. Because women deciding to use MHT are more likely to continue this for a period of years rather than 1 year, this figure is constructed according to that assumption. WHI studies were not powered for age-related subset analyses, and none of the data presented in the figure are statistically significant. Nonetheless, this figure represents the best estimates that are available at the present time and are likely more reliable than similar estimates based on observational studies as reported previously in The Endocrine Society Scientific Statement (38). The HR (95% CI) values for the bars in the figure are listed here with reference to the alphabetical designations shown next to the bars: a, HR, 0.60 (0.35–1.04); b, HR, 1.34 (0.82–2.19); c, HR, 0.82 (0.50–1.34); d, HR, 1.21 (0.81–1.80); e, HR, 0.99 (0.53–1.85); f, HR, 1.51 (0.81–2.82); g, HR, 1.53 (0.63–3.75); h, HR, 2.05 (0.89–4.71); i, HR, 1.66 (0.76–3.67); j, HR, 3.01 (1.36–6.66); k, HR, 0.71 (0.30–1.67); l, HR, 0.79 (0.29–2.18); m, HR, 1.00 (ns-ns); n, HR, 1.12 (0.45–2.75); o, HR, 0.62 (0.30–1.29); p, HR, 0.90 (0.72–1.11); q, HR, 0.82 (0.68–1.00); r, HR, 5.01 (0.59–42.9); s, HR, 0.17 (0.02–1.45); t, HR, 0.70 (0.46–1.09); u, HR, 0.67 (0.43–1.04); v, HR, 0.83 (0.67–1.04); and w, HR, 0.85 (0.66–1.09). [RJ Santen, et al: Competency in menopause management: whither goest the internist? J Womens Health (Larchmt). 2014;23(4):281–285, courtesy of Mary Ann Liebert, Inc]. Figure 3. Open in new tabDownload slide Updated summary of the effects of orally administered CEE alone or combined with MPA in women ages 50–59 years during intervention phase of WHI. One set of analyses examined the risks and benefits of these agents in women ages 50–59 years. This figure plots these data, which are expressed here as excess risks and benefits per 1000 women using MHT for 5 years. Because women deciding to use MHT are more likely to continue this for a period of years rather than 1 year, this figure is constructed according to that assumption. WHI studies were not powered for age-related subset analyses, and none of the data presented in the figure are statistically significant. Nonetheless, this figure represents the best estimates that are available at the present time and are likely more reliable than similar estimates based on observational studies as reported previously in The Endocrine Society Scientific Statement (38). The HR (95% CI) values for the bars in the figure are listed here with reference to the alphabetical designations shown next to the bars: a, HR, 0.60 (0.35–1.04); b, HR, 1.34 (0.82–2.19); c, HR, 0.82 (0.50–1.34); d, HR, 1.21 (0.81–1.80); e, HR, 0.99 (0.53–1.85); f, HR, 1.51 (0.81–2.82); g, HR, 1.53 (0.63–3.75); h, HR, 2.05 (0.89–4.71); i, HR, 1.66 (0.76–3.67); j, HR, 3.01 (1.36–6.66); k, HR, 0.71 (0.30–1.67); l, HR, 0.79 (0.29–2.18); m, HR, 1.00 (ns-ns); n, HR, 1.12 (0.45–2.75); o, HR, 0.62 (0.30–1.29); p, HR, 0.90 (0.72–1.11); q, HR, 0.82 (0.68–1.00); r, HR, 5.01 (0.59–42.9); s, HR, 0.17 (0.02–1.45); t, HR, 0.70 (0.46–1.09); u, HR, 0.67 (0.43–1.04); v, HR, 0.83 (0.67–1.04); and w, HR, 0.85 (0.66–1.09). [RJ Santen, et al: Competency in menopause management: whither goest the internist? J Womens Health (Larchmt). 2014;23(4):281–285, courtesy of Mary Ann Liebert, Inc]. Benefits of MHT Vasomotor symptoms ET is the most effective treatment for VMS and improving QOL in symptomatic women (38). In a dose-dependent manner, MHT reduces hot flash frequency by approximately 75% and severity by 87%, compared with 50% with placebo (38, 45, 46). Genitourinary syndrome of menopause Systemic estrogen administration effectively treats VVA and improves symptoms of overactive bladder and recurrent urinary tract infections (47, 48). With lower doses of systemic MHT, vaginal symptoms may persist and local therapy may be needed (Section 5). Sleep disruption Large placebo-controlled trials reported significantly fewer sleep disturbances with MHT use (44), but additional data are required for definitive conclusions. Anxiety and depressive symptoms Anxiety symptoms increase during the menopause transition and are associated with an increased likelihood of a major depressive disorder (49). ET may improve mild-to-moderate depressive symptoms during or shortly after the menopause transition, whereas antidepressant therapy remains appropriate treatment for major depression (50, 51). Arthralgia Joint pain or stiffness and general aches or pains were improved in women receiving EPT (38, 44, 52). Joint pain increased slightly after discontinuation of treatment (44). Potential preventive benefits of menopausal hormone therapy Although studies have suggested certain preventive benefits, the U.S. Preventive Services Task Force (53) and many expert groups (40, 54–56) recommend against MHT for primary or secondary disease prevention, whereas other experts disagree (57). Bone loss and fracture. RCTs, observational studies, and meta-analyses consistently report reduction in bone loss with ET (38). The updated WHI analysis reports a significant reduction in vertebral fractures and a borderline significant reduction for all fractures with EPT in women ages 50 to 59 years (Figure 3); this effect was greater than with ET (44). Benefit may also be dose-related (38). Type 2 diabetes. RCTs (58–60) and large observational studies (61, 62) reported that MHT reduced the prevalence of self-reported diabetes by 14 to 19% (44), an effect that did not persist after therapy was discontinued (44). Colorectal cancer. In clinical trials, EPT was associated with a nonsignificant lower incidence of colorectal cancer in women ages 50 to 59 (44). Cancers that did occur in women receiving EPT, however, were diagnosed at a more advanced stage when all age groups were considered (64). The reduction in cancer during active therapy did not persist after discontinuation (44). Endometrial cancer. During 13 years of cumulative follow-up of the WHI, combined CEE and MPA was associated with a 35% reduction in endometrial cancer in women ages 50 to 59 years (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.37–1.12) (44). This finding may be unique to the specific type, dose, and regimen utilized. Risks of MHT Endometrial cancer Unopposed ET increases the risk of endometrial hyperplasia and cancer (38, 65, 66), whereas concurrent progestogen therapy (Table 5) for at least 12 days per month reduces this risk (18, 44, 67) and is recommended for all women with a uterus. Continuous combined CEE and MPA was associated with a reduced risk of endometrial cancer over 13 years of cumulative follow-up (44). After 6 to 10 years, sequential regimens may be associated with a 2-fold increased risk of endometrial cancer, particularly in thin women (38). Micronized progesterone and dydrogesterone, in combination with estrogen, have been associated with an approximate 2-fold increase in endometrial cancer when continued beyond 5 years in a large observational study (68). In contrast, one RCT comparing micronized progesterone with MPA (3 y) (69), a second RCT comparing micronized progesterone with chlormadinone acetate (18 mo) (70), and a third trial of single-tablet formulation of cyclical estradiol-dydrogesterone (2 y) (71) each demonstrated endometrial safety. The difference in outcome may reflect enhanced patient compliance with progestogen therapies when formulated in combination. Limited information is available about the safety of long cycle intermittent use of progestogens, but concern has been raised about increased risk of endometrial cancer (72, 73). Table 5. Commonly Prescribed Hormone Therapies Preparation . Doses . Comments . Systemic estrogen therapiesa     Oral estrogen tablets         Micronized E2 0.5, 1.0, 2.0 mg/d         Estradiol valerateb 1.5 mg/d         CEE 0.3, 0.45, 0.625 mg/d Higher doses available Preparation used in WHI     Transdermal estrogens         Estradiol patch 0.025 to 0.1 mg once or twice weekly depending on preparation Corresponds to 0.5 to 2.0 mg estradiol tablets Diffusion can be different from one patch to another 0.014 mg/wk Preserved bone in women >60 y old         Estradiol percutaneous gel 0.25–1.5 mg qd Corresponds to 0.5 to 2.0 mg estradiol tablets Can be transferred to persons and pets by skin contact         Estradiol transdermal spray 1.5 mg qd Estradiol via spray Can be transferred to persons and pets by skin contact     Vaginal ring         Estradiol acetate 0.05–0.10 mg/d Systemic levels of estradiol provide relief of VMS; 90-d duration/ring Progestogen therapies     Oral progestin tablets         Medroxyprogesterone acetate 2.5, 5, 10 mg/d Utilized in WHI         Norethindrone 0.35 mg/d         Neta 5.0 mg/d         Megestrol acetate 20, 40 mg/d         Dydrogesteroneb 10 mg/d         Chlormadinone acetateb 5, 10 mg/d         Medrogestoneb 5 mg/d         Nomegestrol acetateb 3.75, 5 mg/d         Promegestoneb 0.125, 0.25, 0.5 mg/d     Oral progesterone capsule         Micronized progesterone 100, 200 mg/d In peanut oil; avoid if peanut allergy. May cause drowsiness and should be taken at bedtime     Intrauterine system progestinc         LNorg 20 μg released/d IUD for 5-y use 6 μg/d IUD for 3-y use     Vaginal gel progesteronec 4%, 8% 45- or 90-mg applicator Combination hormone therapies     Oral         CEE + MPA 0.3–0.625 mg/1.5–5 mg/d Cyclic or continuous         E2 + Neta 0.5–1 mg/0.1–0.5 mg/d Continuous         E2 + drospirenone 0.5–1 mg/0.25–1 mg/d Continuous         E2 + norgestimate 1 mg/0.09 mg/d Cycle 3 d E alone, 3 d E + progesterone         E2 + dydrogesteroneb 1–2 mg/5–10 mg/d Cyclic and continuous         E2 + cyproterone acetateb 2 mg/1 mg/d Continuous         E2 + MPAb 1–2 mg/2–10 mg/d Continuous         CEE + BZAd 0.45 mg/20 mg/d Continuous     Transdermal         E2 + Neta 50 μg/0.14–0.25 mg/patch Twice weekly         E2 + LNorg 45 μg/0.015 mg/patch Once weekly Preparation . Doses . Comments . Systemic estrogen therapiesa     Oral estrogen tablets         Micronized E2 0.5, 1.0, 2.0 mg/d         Estradiol valerateb 1.5 mg/d         CEE 0.3, 0.45, 0.625 mg/d Higher doses available Preparation used in WHI     Transdermal estrogens         Estradiol patch 0.025 to 0.1 mg once or twice weekly depending on preparation Corresponds to 0.5 to 2.0 mg estradiol tablets Diffusion can be different from one patch to another 0.014 mg/wk Preserved bone in women >60 y old         Estradiol percutaneous gel 0.25–1.5 mg qd Corresponds to 0.5 to 2.0 mg estradiol tablets Can be transferred to persons and pets by skin contact         Estradiol transdermal spray 1.5 mg qd Estradiol via spray Can be transferred to persons and pets by skin contact     Vaginal ring         Estradiol acetate 0.05–0.10 mg/d Systemic levels of estradiol provide relief of VMS; 90-d duration/ring Progestogen therapies     Oral progestin tablets         Medroxyprogesterone acetate 2.5, 5, 10 mg/d Utilized in WHI         Norethindrone 0.35 mg/d         Neta 5.0 mg/d         Megestrol acetate 20, 40 mg/d         Dydrogesteroneb 10 mg/d         Chlormadinone acetateb 5, 10 mg/d         Medrogestoneb 5 mg/d         Nomegestrol acetateb 3.75, 5 mg/d         Promegestoneb 0.125, 0.25, 0.5 mg/d     Oral progesterone capsule         Micronized progesterone 100, 200 mg/d In peanut oil; avoid if peanut allergy. May cause drowsiness and should be taken at bedtime     Intrauterine system progestinc         LNorg 20 μg released/d IUD for 5-y use 6 μg/d IUD for 3-y use     Vaginal gel progesteronec 4%, 8% 45- or 90-mg applicator Combination hormone therapies     Oral         CEE + MPA 0.3–0.625 mg/1.5–5 mg/d Cyclic or continuous         E2 + Neta 0.5–1 mg/0.1–0.5 mg/d Continuous         E2 + drospirenone 0.5–1 mg/0.25–1 mg/d Continuous         E2 + norgestimate 1 mg/0.09 mg/d Cycle 3 d E alone, 3 d E + progesterone         E2 + dydrogesteroneb 1–2 mg/5–10 mg/d Cyclic and continuous         E2 + cyproterone acetateb 2 mg/1 mg/d Continuous         E2 + MPAb 1–2 mg/2–10 mg/d Continuous         CEE + BZAd 0.45 mg/20 mg/d Continuous     Transdermal         E2 + Neta 50 μg/0.14–0.25 mg/patch Twice weekly         E2 + LNorg 45 μg/0.015 mg/patch Once weekly Abbreviations: IUD, intrauterine device; E, estrogen; E2, 17-β estradiol; LNorg, levonorgestrel; Neta, norethindrone acetate or norethisterone acetate; qd, once daily. a Not all preparations and doses are available in all countries. b Only available outside the United States. c Not approved in the United States for endometrial protection when administered with postmenopausal estrogen. d Approved indications in the United States include treatment of moderate to severe VMS associated with menopause and prevention of postmenopausal osteoporosis. In the European Union, the indications state: treatment of estrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 mo since the last menses) for whom treatment with progestin-containing therapy is not appropriate. The experience treating women older than 65 years is limited. Open in new tab Table 5. Commonly Prescribed Hormone Therapies Preparation . Doses . Comments . Systemic estrogen therapiesa     Oral estrogen tablets         Micronized E2 0.5, 1.0, 2.0 mg/d         Estradiol valerateb 1.5 mg/d         CEE 0.3, 0.45, 0.625 mg/d Higher doses available Preparation used in WHI     Transdermal estrogens         Estradiol patch 0.025 to 0.1 mg once or twice weekly depending on preparation Corresponds to 0.5 to 2.0 mg estradiol tablets Diffusion can be different from one patch to another 0.014 mg/wk Preserved bone in women >60 y old         Estradiol percutaneous gel 0.25–1.5 mg qd Corresponds to 0.5 to 2.0 mg estradiol tablets Can be transferred to persons and pets by skin contact         Estradiol transdermal spray 1.5 mg qd Estradiol via spray Can be transferred to persons and pets by skin contact     Vaginal ring         Estradiol acetate 0.05–0.10 mg/d Systemic levels of estradiol provide relief of VMS; 90-d duration/ring Progestogen therapies     Oral progestin tablets         Medroxyprogesterone acetate 2.5, 5, 10 mg/d Utilized in WHI         Norethindrone 0.35 mg/d         Neta 5.0 mg/d         Megestrol acetate 20, 40 mg/d         Dydrogesteroneb 10 mg/d         Chlormadinone acetateb 5, 10 mg/d         Medrogestoneb 5 mg/d         Nomegestrol acetateb 3.75, 5 mg/d         Promegestoneb 0.125, 0.25, 0.5 mg/d     Oral progesterone capsule         Micronized progesterone 100, 200 mg/d In peanut oil; avoid if peanut allergy. May cause drowsiness and should be taken at bedtime     Intrauterine system progestinc         LNorg 20 μg released/d IUD for 5-y use 6 μg/d IUD for 3-y use     Vaginal gel progesteronec 4%, 8% 45- or 90-mg applicator Combination hormone therapies     Oral         CEE + MPA 0.3–0.625 mg/1.5–5 mg/d Cyclic or continuous         E2 + Neta 0.5–1 mg/0.1–0.5 mg/d Continuous         E2 + drospirenone 0.5–1 mg/0.25–1 mg/d Continuous         E2 + norgestimate 1 mg/0.09 mg/d Cycle 3 d E alone, 3 d E + progesterone         E2 + dydrogesteroneb 1–2 mg/5–10 mg/d Cyclic and continuous         E2 + cyproterone acetateb 2 mg/1 mg/d Continuous         E2 + MPAb 1–2 mg/2–10 mg/d Continuous         CEE + BZAd 0.45 mg/20 mg/d Continuous     Transdermal         E2 + Neta 50 μg/0.14–0.25 mg/patch Twice weekly         E2 + LNorg 45 μg/0.015 mg/patch Once weekly Preparation . Doses . Comments . Systemic estrogen therapiesa     Oral estrogen tablets         Micronized E2 0.5, 1.0, 2.0 mg/d         Estradiol valerateb 1.5 mg/d         CEE 0.3, 0.45, 0.625 mg/d Higher doses available Preparation used in WHI     Transdermal estrogens         Estradiol patch 0.025 to 0.1 mg once or twice weekly depending on preparation Corresponds to 0.5 to 2.0 mg estradiol tablets Diffusion can be different from one patch to another 0.014 mg/wk Preserved bone in women >60 y old         Estradiol percutaneous gel 0.25–1.5 mg qd Corresponds to 0.5 to 2.0 mg estradiol tablets Can be transferred to persons and pets by skin contact         Estradiol transdermal spray 1.5 mg qd Estradiol via spray Can be transferred to persons and pets by skin contact     Vaginal ring         Estradiol acetate 0.05–0.10 mg/d Systemic levels of estradiol provide relief of VMS; 90-d duration/ring Progestogen therapies     Oral progestin tablets         Medroxyprogesterone acetate 2.5, 5, 10 mg/d Utilized in WHI         Norethindrone 0.35 mg/d         Neta 5.0 mg/d         Megestrol acetate 20, 40 mg/d         Dydrogesteroneb 10 mg/d         Chlormadinone acetateb 5, 10 mg/d         Medrogestoneb 5 mg/d         Nomegestrol acetateb 3.75, 5 mg/d         Promegestoneb 0.125, 0.25, 0.5 mg/d     Oral progesterone capsule         Micronized progesterone 100, 200 mg/d In peanut oil; avoid if peanut allergy. May cause drowsiness and should be taken at bedtime     Intrauterine system progestinc         LNorg 20 μg released/d IUD for 5-y use 6 μg/d IUD for 3-y use     Vaginal gel progesteronec 4%, 8% 45- or 90-mg applicator Combination hormone therapies     Oral         CEE + MPA 0.3–0.625 mg/1.5–5 mg/d Cyclic or continuous         E2 + Neta 0.5–1 mg/0.1–0.5 mg/d Continuous         E2 + drospirenone 0.5–1 mg/0.25–1 mg/d Continuous         E2 + norgestimate 1 mg/0.09 mg/d Cycle 3 d E alone, 3 d E + progesterone         E2 + dydrogesteroneb 1–2 mg/5–10 mg/d Cyclic and continuous         E2 + cyproterone acetateb 2 mg/1 mg/d Continuous         E2 + MPAb 1–2 mg/2–10 mg/d Continuous         CEE + BZAd 0.45 mg/20 mg/d Continuous     Transdermal         E2 + Neta 50 μg/0.14–0.25 mg/patch Twice weekly         E2 + LNorg 45 μg/0.015 mg/patch Once weekly Abbreviations: IUD, intrauterine device; E, estrogen; E2, 17-β estradiol; LNorg, levonorgestrel; Neta, norethindrone acetate or norethisterone acetate; qd, once daily. a Not all preparations and doses are available in all countries. b Only available outside the United States. c Not approved in the United States for endometrial protection when administered with postmenopausal estrogen. d Approved indications in the United States include treatment of moderate to severe VMS associated with menopause and prevention of postmenopausal osteoporosis. In the European Union, the indications state: treatment of estrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 mo since the last menses) for whom treatment with progestin-containing therapy is not appropriate. The experience treating women older than 65 years is limited. Open in new tab The levonorgestrel intrauterine device (not approved for a postmenopausal indication in the United States, but widely used in other countries and, increasingly, off-label in United States) appears effective at minimizing hyperplasia and endometrial cancer risk, especially in obese women (74–76). Breast cancer Estrogen therapy. Most, but not all, observational studies report an increased breast cancer risk with oral or transdermal estradiol when initiated in recently menopausal women (77–79). This increase occurs as a function of duration of ET (38, 80–82) with a linear trend in the largest study (83). Insufficient numbers of patients may confound the interpretation of these data on ET alone (ie, type II statistical error). It is possible that in observational studies mammographic surveillance differed between users and nonusers of MHT. The finding of increased risk in recently menopausal women is controversial, however. In women in the WHI ages 50 to 59 or < 10 years after menopause onset, CEE did not increase risk (44, 84). The statistically significant 21% reduction of invasive breast cancer in the 13-year cumulative follow-up of all women in the estrogen-alone arm of the WHI was of similar magnitude in each age group (44), but some analyses have suggested less reduction or an increase in risk among women starting ET close to menopause (77, 85). The presence or absence of obesity confounds the interpretation of existing data. The aromatase enzyme, which increases with obesity, results in enhanced endogenous estrogen production, which may minimize the additional effects of exogenous ET. The insulin resistance associated with obesity also confounds the relationship between obesity and breast cancer risk (86). Therefore, increased breast cancer risk with ET in non-US studies might reflect differing levels of obesity between US and European populations. CEE and estradiol may also have differential effects as suggested by in vitro (87) and primate (88) studies. In summary, the risk of breast cancer from estrogen alone, taken for 5 years, appears to be small. Combined EPT. Studies examining the effects of combined therapy report a consistent increase in breast cancer risk (38, 89, 90). It should be noted that the original WHI study did not report any increase overall in women who had not previously used MHT (hormone naive), but data on this issue are not available for women ages 50 to 59 or < 10 years postmenopausal (18, 91), and there are no reported follow-up data for the hormone-naive women. In women ages 50 to 59 in the WHI, the excess risk of invasive breast cancer during the intervention phase persisted 7 years after the cessation of EPT, with 4.5 excess cases/1000 over 5 years (HR, 1.34; 95% CI, 1.03–1.75) (44). Studies have reported similar findings with most other estrogen/progestogen combinations (38, 89, 92). However, observational data suggest that progesterone or dydrogesterone (5, 89) may be associated with a lower risk, but further studies are required to confirm this. Observational studies also report a greater risk when EPT is started close to menopause (79, 85, 93) and with continuous rather than with cyclic regimens (78, 82, 94). Lung cancer In the 50- to 59-year age group in the WHI study, the incidence of lung cancer was not significantly increased or decreased in either treatment arm (44). Ovarian cancer In the 50- to 59-year age group of the WHI, the HR of ovarian cancer with EPT was 0.30 (two vs six cases; 95% CI, 0.06–1.47), with 1.5 fewer cases/1000 per 5 years of treatment (44). No data have been reported for ET. A controversial meta-analysis of 52 observational studies (95–97) showed an increase of 0.52 cases/1000 in women starting MHT (no difference in risk between ET and EPT) at age 50 and continuing therapy for 5 years. Risk persisted 5 years after stopping MHT, with 0.37 cases/1000 in the same women when ages 55 to 59 (95). Of note, the overall risk of ovarian cancer with EPT in the WHI (HR, 1.41), although not statistically significant, was comparable to findings in the meta-analysis, as was the rate in the cumulative follow-up (HR, 1.24). Based on current data, adequately powered RCTs are needed to fully ascertain ovarian cancer risk in symptomatic, recently postmenopausal women. Coronary heart disease Estrogen therapy. The age at initiation of ET influences risk. In the WHI, there was a trend toward a reduction in CHD and total MI in women aged 50 to 59 years at trial enrollment (44). Composite outcomes, including revascularization (98) and coronary artery calcium scores (99), were lower with ET than with placebo. Observational studies of ET suggest the potential for CHD benefit in some women, although a number of biases might have contributed to those conclusions (100). In summary, ET does not increase CHD risk in women starting therapy at ages < 60 years and may possibly reduce this risk. Although observational studies suggest that a dermal route of ET may carry a lower risk of MI (101, 102), a meta-analysis reported no significant difference in CHD outcomes between oral and transdermal MHT (4). No associations with estrogen dose were reported (101, 102). Combined EPT. Age at initiation of EPT does not appear to influence the relative risk of CHD, based on the most recent WHI data (44) and a meta-analysis (4). In women in the WHI aged 50 to 59, there was a trend toward excess risk of CHD, but no increased risk was apparent in women < 10 years since menopause onset (44). These findings and those of several recent studies have been controversial. A randomized osteoporosis trial that did not have CHD as a predefined primary endpoint reported that 10 years of MHT treatment in women < 50 years old at study onset was associated with the reduction of a composite safety endpoint (death, hospital admission for MI, or heart failure) (103). This study has been criticized for its composite index and nonblinded nature. A primary prevention RCT of recently (< 3 y) postmenopausal women ages 42 to 58 failed to detect a difference in progression of atherosclerosis (as assessed by carotid intima-medial thickness and coronary artery calcium determinations) after 4 years of therapy (104) but may have been underpowered to detect significant differences (ie, type II error). In summary, EPT does not appear to be associated with an increased risk of CHD among women close to the onset of menopause, and if any risk elevation is present in women younger than 60 years, its magnitude is small. A definitive conclusion regarding CHD risk requires an appropriately powered RCT. Stroke Researchers reported a nonsignificant trend toward an increase in stroke risk with EPT in women ages 50 to 59 in the WHI (44) but did not report an adverse effect with ET. When examined by years since menopause, ET increased stroke risk in women < 10 years since menopause (6.5 women/1000 over 5 y) (44). The differences between these two groups might reflect the difficulty in establishing time of menopause in women with a hysterectomy. No RCTs have evaluated stroke risk according to estrogen type, dose, or route of administration. Some observational studies suggest that transdermal estradiol in doses ≤ 50 μg may confer a lower risk compared with higher dose transdermal or oral therapies (4, 105). Other studies are conflicting regarding effects of estrogen type (102, 106) and dose (101, 105, 107). In summary, MHT may confer a small risk of stroke. Venous thromboembolic events Estrogen therapy. RCTs demonstrate that oral ET increases VTE risk in women ages 50 to 59 (44). These data are supported by observational studies (106, 108, 109). Risk declined after discontinuing therapy (44). Observational studies (108–112) and meta-analyses (4, 113) suggest that transdermal ET does not increase VTE risk, even in women with thrombophilia or obesity (114–117). In an observational study, oral CEE was associated with a 2-fold increase in VTE compared with oral estradiol (106). Combined EPT. The WHI trial found an association between EPT and both DVT and pulmonary embolism (PE) in women ages 50 to 59 (44). Risks resolved when therapy was discontinued. Observational studies suggest that formulations containing MPA and normethytestosterone derivatives appear to be associated with greater risk than other progestogens (108, 109, 111). A recent meta-analysis comparing ET and EPT did not report any statistically significant differences in risk (4). Gallbladder disease No data are available specifically for women ages 50 to 59; conclusions regarding gallbladder disease rely on overall findings of the WHI. ET resulted in 29 excess cases/1000 women over 5 years (44). This risk did not persist after discontinuation (44, 118). With EPT, the excess risk was 23 women/1000 (44), similar to another trial (119). Risk persisted at least 5 years after cessation of EPT (44, 120). Observational studies report increased risk with oral, but not transdermal, estradiol (121, 122) and increased dose and duration (120, 123). Incontinence Stress urinary incontinence, urge urinary incontinence, and mixed urinary incontinence increase in women taking oral ET and EPT (124, 125). An increased risk may persist after discontinuation (44). Uncertain benefits of hormone therapy Mortality A meta-analysis of RCTs demonstrated no significant effect on all-cause mortality with MHT use, but these data included women < and > 60 years of age (5). A recent Cochrane collaboration review reported a 30% relative risk reduction (HR, 0.70; 95% CI, 0.52–0.95) of all-cause mortality in women starting MHT < 10 years since menopause (or < age 60) (127). Comparison of the ET and EPT groups in the WHI suggested a stronger trend by age group among those on ET, with a statistically significant trend by age in the ET trial but not in the EPT trial (44). Observational studies (128–130) reported a reduction in mortality with MHT, as did one small RCT with composite endpoints (103). This is consistent with meta-analyses that reported a 30–40% mortality reduction (131, 132). In summary, further data are required for definitive conclusions about mortality in younger women. Dementia Observational studies suggest a possible benefit of MHT if started in younger women closer to menopause (133), as opposed to the detrimental effects reported in clinical trials when MHT is initiated in women > 65 years old (134). Some studies of postmenopausal women treated with estradiol reported an improvement in verbal memory and executive function (135–138), whereas other studies did not associate CEE therapy with cognitive improvement (139, 140). Definitive conclusions about MHT in women < age 60, therefore, are lacking. Individual baseline risk assessment and therapeutic decisions Evaluating risk facilitates individual counseling and decisions regarding MHT for symptom relief (Figure 2). However, no clinical trial evidence is available to support the practice of incorporating risk assessment instruments for quantifying cardiovascular (CHD, stroke, and VTE) and breast cancer risks among women considering MHT. Nevertheless, we feel that risk assessment instruments are useful to facilitate decision-making regarding MHT. Cardiovascular risk 3.1b For women < age 60 or < 10 years past menopause onset considering MHT for menopausal symptom relief, we suggest evaluating the baseline risk of CVD and taking this risk into consideration when advising for or against MHT and when selecting type, dose, and route of administration. (2|⊕⊕○○) 3.1c For women at high risk of CVD, we suggest initiating nonhormonal therapies to alleviate bothersome VMS (with or without climacteric symptoms) over MHT. (2|⊕⊕○○) Technical remarks High risk includes known MI, cerebrovascular disease, and peripheral arterial disease, abdominal aortic aneurysm, diabetes mellitus, chronic kidney disease, and 10-year CVD risk > 10% (40). 3.1d For women with moderate risk of CVD, we suggest transdermal estradiol as first-line treatment, alone for women without a uterus or combined with micronized progesterone (or another progestogen that does not adversely modify metabolic parameters) for women with a uterus because these preparations have less untoward effect on blood pressure, triglycerides, and carbohydrate metabolism. (2|⊕⊕○○) Evidence Cardiovascular risk Results showing fewer excess CHD and stroke events when MHT was initiated in younger rather than older study participants in the WHI (141) provide the foundation for the widely accepted consensus that MHT should be initiated primarily in younger women (age < 60 y) close in time (< 10 y) to menopause onset, when women likely have less baseline atherosclerosis (19, 20). The population prevalence of obesity, hypertension, dyslipidemia, and diabetes continues to increase. Accordingly, baseline CVD risk evaluation is important in women considering MHT. As reviewed in recent statements, CHD and stroke are associated with a wide range of risk factors, many unique to women (40, 41). Notably, a prior history of CHD conveys the highest risk of subsequent MI and stroke (142). We feel that methods to integrate these factors to categorize individual risk as minimal, moderate, and high are useful and can be accomplished qualitatively by clinical judgment or quantitatively by risk assessment tools. Country- and population-specific CVD risk calculators are available to quantify individual risk per local guidelines (143). However, specific cutoffs for the safe use of MHT have not been formally validated, and practice differs from country to country. The Menopause Decision-Support Algorithm (63) starts with calculating the American College of Cardiology (ACC)/American Heart Association (AHA) 10-year CVD risk (144), then stratifies by years since menopause to suggest appropriateness of MHT (Table 6) (63). For a woman at intermediate risk, family history, coronary artery calcium score, C-reactive protein, and ankle-brachial index can further stratify risk (144); inflammatory markers and lipid ratios predict treatment-related CHD events (145). Table 6. Evaluating CVD Risk in Women Contemplating MHT 10-y CVD Risk . Years Since Menopause Onset . <5 y . 6 to 10 y . Low (<5%) MHT ok MHT ok Moderate (5–10%) MHT ok (choose transdermal) MHT ok (choose transdermal) High (>10%)a Avoid MHT Avoid MHT 10-y CVD Risk . Years Since Menopause Onset . <5 y . 6 to 10 y . Low (<5%) MHT ok MHT ok Moderate (5–10%) MHT ok (choose transdermal) MHT ok (choose transdermal) High (>10%)a Avoid MHT Avoid MHT CVD risk calculated by ACC/AHA Cardiovascular Risk Calculator (144). Methods to calculate risk and risk stratification vary among countries. Derived from J. E. Manson: Current recommendations: what is the clinician to do? Fertil Steril. 2014;101:916–921 (63), with permission. © Elsevier Inc. a High risk includes known MI, stroke, peripheral artery disease, etc. Open in new tab Table 6. Evaluating CVD Risk in Women Contemplating MHT 10-y CVD Risk . Years Since Menopause Onset . <5 y . 6 to 10 y . Low (<5%) MHT ok MHT ok Moderate (5–10%) MHT ok (choose transdermal) MHT ok (choose transdermal) High (>10%)a Avoid MHT Avoid MHT 10-y CVD Risk . Years Since Menopause Onset . <5 y . 6 to 10 y . Low (<5%) MHT ok MHT ok Moderate (5–10%) MHT ok (choose transdermal) MHT ok (choose transdermal) High (>10%)a Avoid MHT Avoid MHT CVD risk calculated by ACC/AHA Cardiovascular Risk Calculator (144). Methods to calculate risk and risk stratification vary among countries. Derived from J. E. Manson: Current recommendations: what is the clinician to do? Fertil Steril. 2014;101:916–921 (63), with permission. © Elsevier Inc. a High risk includes known MI, stroke, peripheral artery disease, etc. Open in new tab Metabolic syndrome. The metabolic syndrome (MetS) is associated with higher risk of cardiovascular events and breast and colon cancers (146). In a nested case-control study in the WHI, women with MetS at baseline were twice as likely to have CHD events while taking oral MHT as with placebo (147). In contrast, women without MetS had no increase in CHD risk on MHT. Transdermal estradiol with micronized progesterone might have less deleterious metabolic effects than oral therapies, but there are no RCTs that have evaluated the safety of these preparations in women with MetS. Diabetes. Diabetes is considered by the AHA to be a CHD risk equivalent (40), which would suggest that women with diabetes should not take MHT. However, clinical trial evidence of CVD outcomes associated with MHT in women with diabetes is mostly lacking. Some diabetic women were included in RCTs (Heart and Estrogen/Progestin Replacement Study [19%]; WHI [4.4–7.7%]), but these trials were not powered to assess differences in CVD outcomes. A few short-term RCTs have evaluated glucose control in diabetic women taking a variety of MHT preparations and showed either no effect or improved control (148). The evidence at this time is inadequate to make firm recommendations. An individualized approach to treating menopausal symptoms could be considered, with a low threshold to recommend nonhormonal therapies, particularly in women with concurrent CVD. However, some diabetic women, after careful evaluation of cardiovascular risk, may be candidates for MHT, preferably transdermal estrogen and micronized progesterone or another less metabolically active progestogen. Venous thromboembolic events 3.1e For women at increased risk of VTE who request MHT, we recommend a nonoral route of ET at the lowest effective dose, if not contraindicated (1|⊕⊕○○); for women with a uterus, we recommend a progestogen (for example, progesterone and dydrogestone) that is neutral on coagulation parameters. (1|⊕⊕⊕○) Evidence Obesity, age, and thrombophilia are associated with increased risk of VTE. An approximately 2-fold increased risk of VTE (both DVT and PE) with oral MHT is similar among women at low, intermediate, or high risk (149, 150). Accordingly, the attributable risk of MHT will be higher in those at high or intermediate baseline risk. A prior history of VTE confers the highest risk. If the patient has a known inherited coagulation defect, such as Factor V Leiden, oral ET or EPT should be avoided because research has shown a high risk of VTE recurrence (114). A history of VTE due to pregnancy, oral contraceptives, unknown etiology, or blood clotting disorders poses a contraindication to any ET, whereas VTE due to past immobility, surgery, or bone fracture would be a contraindication to oral but not necessarily transdermal MHT (151). In some countries, a history of any VTE is a contraindication to oral but not low-dose transdermal ET. Breast cancer 3.1f For women considering MHT for menopausal symptom relief, we suggest evaluating the baseline risk of breast cancer and taking this risk into consideration when advising for or against MHT and when selecting type, dose, and route of administration. (2|⊕⊕○○) 3.1g For women at high or intermediate risk of breast cancer considering MHT for menopausal symptom relief, we suggest nonhormonal therapies over MHT to alleviate bothersome VMS. (2|⊕⊕○○) Technical remarks High or intermediate risk includes calculated level of risk that would qualify for risk-reducing medications. Evidence There are no established clear criteria for recommending (or avoiding) MHT based on a woman's risk of breast cancer. Nonsignificant trends from the WHI suggest that the relative risk of breast cancer in association with MHT remains stable or increases in the 5-year Gail model breast risk categories of < 1.25 vs ≥ 1.75. On this basis, the excess or attributable risk should increase in women at higher categories of risk (90, 152). As another consideration, it seems prudent not to recommend MHT for women whose risk meets the criteria for breast cancer prevention with SERMs or aromatase inhibitors. The U.S. Preventive Services 2013 Task Force recommends that women with a 5-year risk of ≥ 3% should be considered for preventive therapy with tamoxifen or raloxifene (126), whereas the American Society of Clinical Oncology guidelines suggest discussing such therapy in women with a risk of ≥ 1.67% (153), consistent with enrollment criteria of breast cancer prevention trials. Prevention recommendations differ outside the United States. Another consideration is to take into account the data suggesting that breast cancer risk is associated with combined estrogen/progestogen use, but less so, if at all, with CEE alone. We suggest one potential algorithm for MHT counseling, extrapolated from breast cancer prevention trial enrollment criteria (Table 7); however, it is not validated in clinical trials or widely utilized. This algorithm requires the assessment of breast cancer risk, which can be accomplished by qualitative methods or preferably with readily available quantitative risk assessment tools. The National Cancer Institute Breast Cancer Risk Assessment Tool provides a standardized online risk calculator for 5-year risk of invasive breast cancer (154). The International Breast Intervention Study calculator predicts 10-year and lifetime risk (155, 156). For women with strong family histories of breast cancer, several other methods are available (155). Although these provide useful predictive information, all are limited by only moderate discriminatory accuracy (155). Mammographic breast density, when added to these methods, may emerge as an important objective risk for women contemplating MHT (157–159). Table 7. Breast Cancer Risk Cutoffs for Counseling Before Recommending MHTa Risk Categorya . 5-y NCI or IBIS Breast Cancer Risk Assessment, % . Suggested Approach . Low <1.67 MHT ok Intermediate 1.67–5 Cautionb High >5 Avoid Risk Categorya . 5-y NCI or IBIS Breast Cancer Risk Assessment, % . Suggested Approach . Low <1.67 MHT ok Intermediate 1.67–5 Cautionb High >5 Avoid Abbreviations: IBIS, International Breast Intervention Study; NCI, National Cancer Institute. a Categories here are newly defined for these guidelines and based on recommendations published for use of antiestrogens for breast cancer prevention (126, 153, 322, 323). The assumption is that candidates for breast cancer prevention with antiestrogens should not be candidates for initiating MHT. Method to calculate risk varies among countries. b Caution indicates need for detailed counseling regarding anticipated benefits and risks of MHT with strong consideration of nonhormonal therapies for symptom relief, and possible consideration of chemopreventive strategies for women who meet suggested criteria. Open in new tab Table 7. Breast Cancer Risk Cutoffs for Counseling Before Recommending MHTa Risk Categorya . 5-y NCI or IBIS Breast Cancer Risk Assessment, % . Suggested Approach . Low <1.67 MHT ok Intermediate 1.67–5 Cautionb High >5 Avoid Risk Categorya . 5-y NCI or IBIS Breast Cancer Risk Assessment, % . Suggested Approach . Low <1.67 MHT ok Intermediate 1.67–5 Cautionb High >5 Avoid Abbreviations: IBIS, International Breast Intervention Study; NCI, National Cancer Institute. a Categories here are newly defined for these guidelines and based on recommendations published for use of antiestrogens for breast cancer prevention (126, 153, 322, 323). The assumption is that candidates for breast cancer prevention with antiestrogens should not be candidates for initiating MHT. Method to calculate risk varies among countries. b Caution indicates need for detailed counseling regarding anticipated benefits and risks of MHT with strong consideration of nonhormonal therapies for symptom relief, and possible consideration of chemopreventive strategies for women who meet suggested criteria. Open in new tab Although a history of breast cancer is considered by most to be a contraindication to MHT, the severity of menopausal symptoms, the compromise in QOL experienced by breast cancer survivors, and limitations of nonhormonal therapies for relief of VMS present a persistent clinical challenge. As recently summarized, it is not possible from currently available studies to draw firm conclusions regarding the risks of MHT in this population (38), but adding estrogen seems counterintuitive when current breast cancer therapies interrupt or decrease estrogen levels. Future studies taking into account estrogen receptor status, time since diagnosis and therapy, mastectomy status, and risks for breast cancer recurrence might better inform decision-making. Tailoring menopausal hormone therapy 3.1h We suggest a shared decision-making approach to decide about the choice of formulation, starting dose, the route of administration of MHT, and how to tailor MHT to each woman's individual situation, risks, and treatment goals. (Ungraded best practice statement) Clinicians prescribe estrogen alone for women without a uterus. Starting dosages are generally lower than those in the WHI (Table 5), and the overarching principle is to use the lowest effective dose with upward titration based on clinical response. Clinicians usually do not measure estradiol levels to monitor therapy except when symptoms do not improve with escalating doses, particularly after changing the mode of administration from oral to transdermal. For younger women with surgical menopause or those with POI who are accustomed to higher baseline endogenous estradiol levels, clinicians often prescribe higher starting doses of ET (eg, transdermal estradiol, 100 μg), and then slowly lower the dose as tolerated. When women with premature menopause approach the age of natural menopause, the reassessment and tapering of MHT dose seems reasonable. Estrogen preparations Oral estrogens. Estradiol tablets or conjugated estrogens (synthetic or equine) are convenient, are studied most extensively, and alleviate climacteric symptoms in a dose-dependent fashion. CEE, derived from pregnant mares' urine and used for decades, contain more than 200 compounds with varying estrogenic potency (160). Oral micronized estradiol and other oral estrogen preparations may result in up to 5-fold higher levels of circulating estrone and 10- to 20-fold higher estrone sulfate than transdermally administered estradiol at comparable or even higher doses. The biological effects of these estrone and estrone-sulfate increments are unknown (161–163). Cutaneous and transdermal estradiol. Cutaneous and transdermal estradiol, administered via percutaneous gels, sprays, emulsions, or transdermal patches, have a similar efficacy as oral ET in reducing climacteric symptoms and are easily tailored to the individual (164, 165). The primary advantage of transdermal ET is to alleviate the first-pass hepatic metabolic effect (166) of oral estrogens resulting in a procoagulant effect and increases in SHBG, thyroid-binding globulin, cortisol-binding globulin (167, 168), triglycerides, and markers of inflammation such as C-reactive protein (167, 169). Transdermal therapies, at low doses, are preferable for women with a VTE risk, as evidenced by a recent meta-analysis commissioned for these guidelines (4), and they may also be preferable in patients with hypertension, hypertriglyceridemia, obesity, MetS, diabetes, or a history of gallbladder disease. Clinicians should keep in mind that there are no existing head-to-head RCTs with clinical outcomes that compare transdermal with oral therapies. Vaginal delivery of systemic estrogens. Estradiol acetate vaginal rings, delivering 50 or 100 μg of estradiol daily (Table 5), provide consistent systemic estradiol levels for 3 months per ring insertion. They are indicated for treatment of moderate to severe VMS and VVA due to menopause (170, 171). High-dose vaginal creams containing estradiol or CEE (ie, 1–2 g) also result in systemic estrogen levels. Concomitant progestogen is needed with these preparations to abrogate endometrial stimulation. We discuss low-dose vaginal ETs for the specific treatment of GSM in Section 5.0. Progestogen administration In women with a uterus, a progestogen must be added to prevent endometrial hyperplasia and cancer. The various formulations (Table 5) are administered in two regimens. The combined sequential regimen includes estrogen for 20 to 25 days and a progestogen for 12 to 15 days each month. This approach is preferred for recently menopausal woman who are prone to breakthrough bleeding during the first year or two of therapy. The combined continuous regimen utilizes both an estrogen and progestogen daily on a continuous basis. Clinicians can administer progestogen orally, transdermally by patch, vaginally, or by intrauterine administration (172). The levonorgestrel intrauterine device minimizes systemic progestogen absorption, but increased blood levels do occur, and one observational study reported higher breast cancer incidence (173). Progestogen alone. For those who do not tolerate ET, progestogens can relieve VMS. In RCTs, oral synthetic progestogens (Table 5) (174, 175) and micronized progesterone (176) were effective. Clinical outcome trials are lacking in women with breast cancer; thus, progestogen therapy is best avoided, except under limited circumstances in these patients, because the effect on recurrence is unclear (80). Custom-compounded hormones 3.1i We recommend using MHT preparations approved by the FDA and comparable regulating bodies outside the United States and recommend against the use of custom-compounded hormones. (Ungraded best practice statement) Evidence A number of FDA-approved hormonal therapies are “biochemically identical” to endogenous estradiol and progesterone and are preferred to custom-compounded options. Custom-compounded hormone therapies have become increasingly popular but are not recommended because the manufacturing process lacks FDA oversight (177). Clinical trials documenting the efficacy and safety of compounded progesterone for endometrial protection are lacking. Proponents of custom-compounded hormone therapies often advise measuring salivary hormone levels to monitor therapy. However, scientific evidence is lacking to justify salivary measurements due to inter- and intra-assay variability, variable salivary flow rates dependent upon hydration, food intake, and other factors, and the inability to predict the pharmacokinetics of a custom-compounded hormone dose in a manner that would allow for valid salivary sampling. 3.2 Conjugated equine estrogens with bazedoxifene 3.2 For symptomatic postmenopausal women with a uterus and without contraindications, we suggest the combination of CEE/BZA (where available) as an option for relief of VMS and prevention of bone loss. (2|⊕⊕⊕○) Evidence The combination of CEE with the SERM/BZA (available in the United States and licensed in the European Union) relieves VMS and vaginal atrophy and reduces bone resorption in women with a uterus; it provides an alternative to progestogen therapy for women averse to vaginal bleeding, breast tenderness, or altered mood. A series of RCTs up to 2 years in duration evaluated effects of CEE/BZA (0.45 mg/20 mg, the approved dose) compared with MHT (CEE 0.45 mg/MPA 1.5 mg) (178–180). Benefits Vasomotor symptoms. The number and severity of moderate-to-severe VMS were significantly decreased at 12 weeks; hot flash frequency was reduced by 74% compared with 51% for placebo, and hot flash severity was reduced up to 54%. Hot flash reduction was sustained at 12 months (P < .05) (181). Bone loss. Bone loss at the lumbar spine and hip was prevented in postmenopausal women at risk for osteoporosis (182), as reflected by reduction of serum bone turnover markers and enhancement of bone mineral density vs placebo (180, 181). At 12 months, CEE/BZA was less effective at the lumbar spine than CEE/MPA (180). Fracture data are lacking. Vaginal effects. Treating postmenopausal women ages 40 to 65 with VVA at baseline (183) improved vaginal maturation at 12 weeks (181). Women reported a lower incidence of dyspareunia. Quality of life. Secondary endpoints included improvements in sleep, health-related QOL, and improved treatment satisfaction (184, 185). In RCTs, both CEE/BZA and CEE/MPA improved sleep disturbance and time to fall asleep (185). Safety considerations Breast. The incidence of breast pain and tenderness was similar for CEE/BZA and placebo (185–187) and was less than with CEE/MPA. After 1 year of therapy with CEE/BZA, mammographic breast density was not appreciably different than with placebo, whereas it increased with CEE/MPA (184). In trials up to 2 years, the rates of breast cancer (reported as adverse events, not clinical outcomes) were not sufficient to assess risk or benefit (186, 187). Endometrium. Cumulative amenorrhea rates for CEE/BZA were comparable with placebo and greater than for CEE/MPA (188). At 2 years, the incidence of neither endometrial hyperplasia nor endometrial cancer was increased (180, 189). Potential risks Adverse events. Although an osteoporosis trial found a 2-fold risk of VTE with BZA 20-mg therapy alone (190), there was no additive effect on VTE when BZA was combined with CEE, although adequately powered studies are necessary (181). In trials of up to 2 years in women ages 40 to 65, rates of cardiovascular events, cancers (breast, endometrial, ovarian), and mortality were similar to placebo (191), but studies were underpowered to draw firm conclusions regarding these endpoints. 3.3 Tibolone 3.3a For women with bothersome VMS and climacteric symptoms and without contraindications, we suggest tibolone (in countries where available) as an alternative to MHT. (2|⊕⊕○○) 3.3b We recommend against adding tibolone to other forms of MHT. (1|⊕⊕○○) 3.3c We recommend against using tibolone in women with a history of breast cancer. (1|⊕⊕○○) Evidence Tibolone belongs to the group of normethyltestosterone progestogen derivatives and has metabolites that exhibit estrogenic, progestogenic, and androgenic effects (192). This agent (193) is available in many countries outside of the United States at doses of 1.25–2.5 mg/d. Benefits Menopausal symptoms. Tibolone alleviates VMS with equivalent or lesser potency than conventional MHT. Tibolone also improves sleep, mood, and urogenital atrophy and may improve libido (194–197). Bone loss and fracture. Tibolone prevents postmenopausal bone loss and osteoporotic fractures in women with osteoporosis (198, 199), but is not approved for this purpose because of the increased risk of stroke in older women with osteoporosis initiating therapy at ages ≥ 60 years (199). Possible risks Endometrium. There is no endometrial thickening (197) or increase in myoma with tibolone (200). A Cochrane analysis concluded that there was no clear evidence of endometrial cancer with tibolone therapy (seven RCTs, n = 8152; odds ratio, 1.98; 95% CI, 0.73–5.32) (194). Thrombosis and CVD. In an observational study (110), tibolone did not increase the risk of thrombosis. In an RCT of older women with osteoporosis, tibolone increased stroke (199). Breast and colon cancers. The incidence of breast tenderness is low (around 3%), (201, 202), and neither mammographic density nor invasive breast cancer was increased; however, the risk of colon cancer was decreased (199, 201). An RCT of women with a history of breast cancer, after a median follow-up of 3.1 years, reported a higher rate of breast cancer recurrence with tibolone (HR, 1.40; 95% CI, 1.14–1.70) (203). The study reported the greatest increase for women taking an aromatase inhibitor (HR, 2.42; 95% CI, 1.01–5.79). 3.4 Clinical management of patients taking hormone therapies Monitoring during therapy 3.4a For women with persistent unscheduled bleeding while taking MHT, we recommend evaluation to rule out pelvic pathology, most importantly, endometrial hyperplasia and cancer. (1|⊕⊕⊕○) 3.4b We recommend informing women about the possible increased risk of breast cancer during and after discontinuing EPT and emphasizing the importance of adhering to age-appropriate breast cancer screening. (1|⊕⊕⊕○) Technical remarks Regular clinical follow-up, initially, within 1 to 3 months after starting MHT, and then every 6 to 12 months, depending upon the individual (and health care system), allows for monitoring efficacy and side effects (abdominal/pelvic pain, mastalgia, metrorrhagia, weight gain, mood changes, blood pressure), and if necessary, making treatment adjustments (Table 8). Table 8. Clinical Caveats During Treatment With MHT Symptom/Condition When MHT Started . Approach to Resolution . Persistent, intolerable VMS Switch mode of administration or adjust dose of estrogen and/or progestogen. Hot flashes that persist after treatment adjustment Consider another etiology of flashes (Table 2). Ensure absorption: if transdermal, consider serum estradiol determination. Bleeding: approach depends on time since menopause, MHT regimen, duration of therapy, duration and character of bleeding Sequential regimen may be more appropriate for recently menopausal (<2 y), because unscheduled bleeding with continuous combined MHT can be problematic. Persistent irregular bleeding (>6 mo) should be evaluated for endometrial pathology; if obese, diabetic, or having family history for endometrial cancer, evaluate sooner. Atrophic endometrium in women more remote from menopause may respond to increased estrogen dose if otherwise appropriate. Breast tenderness Usually responds to a reduction in estrogen dose or change in progestogen preparation. CEE/BZA may improve symptoms. Changing to tibolone may be helpful in women who develop mastalgia on conventional MHT. Baseline TG level >200 mg/dL Review family history and seek contributing factors. Transdermal ET is preferred. If oral estrogen is selected, monitor serum TG levels 2 wk after starting therapy. Hypothyroid on thyroid replacement Monitor TSH 6 to 12 wk after starting oral MHT; T4 dose may need to be increased (209). Symptom/Condition When MHT Started . Approach to Resolution . Persistent, intolerable VMS Switch mode of administration or adjust dose of estrogen and/or progestogen. Hot flashes that persist after treatment adjustment Consider another etiology of flashes (Table 2). Ensure absorption: if transdermal, consider serum estradiol determination. Bleeding: approach depends on time since menopause, MHT regimen, duration of therapy, duration and character of bleeding Sequential regimen may be more appropriate for recently menopausal (<2 y), because unscheduled bleeding with continuous combined MHT can be problematic. Persistent irregular bleeding (>6 mo) should be evaluated for endometrial pathology; if obese, diabetic, or having family history for endometrial cancer, evaluate sooner. Atrophic endometrium in women more remote from menopause may respond to increased estrogen dose if otherwise appropriate. Breast tenderness Usually responds to a reduction in estrogen dose or change in progestogen preparation. CEE/BZA may improve symptoms. Changing to tibolone may be helpful in women who develop mastalgia on conventional MHT. Baseline TG level >200 mg/dL Review family history and seek contributing factors. Transdermal ET is preferred. If oral estrogen is selected, monitor serum TG levels 2 wk after starting therapy. Hypothyroid on thyroid replacement Monitor TSH 6 to 12 wk after starting oral MHT; T4 dose may need to be increased (209). Abbreviation: TG, triglycerides. Open in new tab Table 8. Clinical Caveats During Treatment With MHT Symptom/Condition When MHT Started . Approach to Resolution . Persistent, intolerable VMS Switch mode of administration or adjust dose of estrogen and/or progestogen. Hot flashes that persist after treatment adjustment Consider another etiology of flashes (Table 2). Ensure absorption: if transdermal, consider serum estradiol determination. Bleeding: approach depends on time since menopause, MHT regimen, duration of therapy, duration and character of bleeding Sequential regimen may be more appropriate for recently menopausal (<2 y), because unscheduled bleeding with continuous combined MHT can be problematic. Persistent irregular bleeding (>6 mo) should be evaluated for endometrial pathology; if obese, diabetic, or having family history for endometrial cancer, evaluate sooner. Atrophic endometrium in women more remote from menopause may respond to increased estrogen dose if otherwise appropriate. Breast tenderness Usually responds to a reduction in estrogen dose or change in progestogen preparation. CEE/BZA may improve symptoms. Changing to tibolone may be helpful in women who develop mastalgia on conventional MHT. Baseline TG level >200 mg/dL Review family history and seek contributing factors. Transdermal ET is preferred. If oral estrogen is selected, monitor serum TG levels 2 wk after starting therapy. Hypothyroid on thyroid replacement Monitor TSH 6 to 12 wk after starting oral MHT; T4 dose may need to be increased (209). Symptom/Condition When MHT Started . Approach to Resolution . Persistent, intolerable VMS Switch mode of administration or adjust dose of estrogen and/or progestogen. Hot flashes that persist after treatment adjustment Consider another etiology of flashes (Table 2). Ensure absorption: if transdermal, consider serum estradiol determination. Bleeding: approach depends on time since menopause, MHT regimen, duration of therapy, duration and character of bleeding Sequential regimen may be more appropriate for recently menopausal (<2 y), because unscheduled bleeding with continuous combined MHT can be problematic. Persistent irregular bleeding (>6 mo) should be evaluated for endometrial pathology; if obese, diabetic, or having family history for endometrial cancer, evaluate sooner. Atrophic endometrium in women more remote from menopause may respond to increased estrogen dose if otherwise appropriate. Breast tenderness Usually responds to a reduction in estrogen dose or change in progestogen preparation. CEE/BZA may improve symptoms. Changing to tibolone may be helpful in women who develop mastalgia on conventional MHT. Baseline TG level >200 mg/dL Review family history and seek contributing factors. Transdermal ET is preferred. If oral estrogen is selected, monitor serum TG levels 2 wk after starting therapy. Hypothyroid on thyroid replacement Monitor TSH 6 to 12 wk after starting oral MHT; T4 dose may need to be increased (209). Abbreviation: TG, triglycerides. Open in new tab Duration of therapy 3.4c We suggest that the decision to continue MHT be revisited at least annually, targeting the shortest total duration of MHT consistent with the treatment goals and evolving risk assessment of the individual woman. (Ungraded best practice statement) Technical remarks Most published recommendations suggest using MHT for the shortest duration possible, but strong evidence is lacking to support this recommendation. Current proposed limits on duration of therapy are informed by large intervention trials (5 to 7 y) with extended follow-up for 13 years (44). Regarding duration of use, these data suggest that risk rates for breast cancer and CVD increase with age and time since menopause, although the risks with ET appear to be less than with EPT. Ovarian cancer risk may also increase relative to duration of MHT (95). We conclude, and guidelines from other societies concur, that clinicians and patients should reassess MHT continuation yearly and discuss the risks (and individual benefits) beyond 5 years (55, 56). Patients likely to consider continuing therapy include those who fail an attempt to stop EPT, who are at high risk for fracture, or for whom alternative therapies are not appropriate. 3.4d For young women with POI, premature, or early menopause, without contraindications, we suggest taking MHT until the time of anticipated natural menopause, when the advisability of continuing MHT can be reassessed. (2|⊕⊕○○) Stopping considerations 3.4e For women preparing to discontinue MHT, we suggest a shared decision-making approach to elicit individual preference about adopting a gradual taper vs abrupt discontinuation. (2|⊕⊕○○) Evidence A number of studies have compared methods (ie, taper protocols vs abrupt cessation) to facilitate the discontinuation of MHT (204–207) and have detected no differences. Therefore, the approach to discontinuation is an individual choice. Anecdotally, some women find that a very low dose of ET maintains adequate symptom relief and well-being and prefer that to complete discontinuation. Menopausal symptoms and joint pain can recur when MHT is discontinued (44). Depending on the severity of the symptoms, women may elect to restart MHT, perhaps at a lower dose, or seek relief with nonhormonal therapies. Accelerated bone loss was reported after the discontinuation of MHT, whereas in contrast, bone density is stable for some years after discontinuing bisphosphonate therapy. Bisphosphonates, however, remain in bone indefinitely, and most expert groups do not recommend initiating bisphosphonate therapy for osteoporosis prevention in women aged 50 to 59. Adverse effects such as osteonecrosis of the jaw and atypical femur fractures, while rare, increase with the duration of therapy. Furthermore, as opposed to reports from observational studies (208), in the long-term follow-up of the WHI, hip fracture rates did not increase during 5 to 7 years of observation after MHT was discontinued (44). Breast cancer risk after 5 years of EPT in the WHI persisted 7 years after discontinuation. A large meta-analysis of observational studies found a persistent risk of ovarian cancer up to a decade after discontinuing MHT (95). Urinary incontinence persisted after oral MHT was discontinued; however, the percentage of affected women was approximately one-third less than during active treatment (44). MHT discontinuation may result in symptoms of VVA (Section 5.0), and when oral therapy is discontinued, glucose, cholesterol, triglycerides, calcium, and TSH (209) levels may change. 4.0 Nonhormonal therapies for VMS 4.0 For postmenopausal women with mild or less bothersome hot flashes, we suggest a series of steps that do not involve medication, such as turning down the thermostat, dressing in layers, avoiding alcohol and spicy foods, and reducing obesity and stress. (2|⊕⊕○○) Evidence As hot flashes result from alterations of the thermoregulatory neutral zone, shedding layers of clothing, using fans, keeping the bedroom cool (30), avoiding alcohol and spicy foods, and reducing stress may be effective. Being overweight or obese is a risk factor for VMS (26, 210, 211), and weight loss may reduce hot flash frequency (212, 214). 4.1 Nonhormonal prescription therapies for VMS 4.1a For women seeking pharmacological management for moderate to severe VMS for whom MHT is contraindicated, or who choose not to take MHT, we recommend SSRIs/SNRIs or gabapentin or pregabalin (if there are no contraindications). (1|⊕⊕⊕○) Evidence The interpretation of hot flash efficacy studies requires an appreciation of an important confounding factor. There is a strong, consistently reported placebo effect, which averages 30% (range, 4–57%; Figure 4) and occurs more often in women with high anxiety and stress scores (215–220). Clinical trials of paroxetine, venlafaxine, desvenlafaxine, citalopram, and escitalopram demonstrate statistically significant efficacy with a reduction of frequency of hot flashes ranging from 25 to 69% (Figure 4). The composite score of hot flash frequency and severity is reduced by 27–61%. Other agents such as sertraline and fluoxetine are associated with non-statistically significant trends toward the reduction of hot flashes and inconsistent results (221–223). Figure 4. Open in new tabDownload slide Hot flash frequency and composite score with nonhormonal prescription therapies for relief of VMS. Upper panel, Effect on frequency of VMS; lower panel, effect on composite score (severity times frequency; best representation of effect); open bars, placebo; colored bars, therapies; length of bars, ranges in studies; horizontal bar, means. All of these agents are generally well tolerated (226). Hypersensitivity or prior adverse drug reactions to each of these agents represent contraindications. For the SSRI/SNRIs, prior neuroleptic syndrome, serotonin syndrome, and concurrent use of monoamine oxidase inhibitors are also contraindications. SSRI/SNRIs should be used with caution in patients with bipolar disease, uncontrolled seizures, hepatic or renal insufficiency, uncontrolled hyponatremia, concurrent use of other SSRI/SNRIs, or poorly controlled hypertension. These agents uncommonly induce suicidal thoughts within the first few months of treatment. Preliminary evidence suggests a possible increase in risk of bone fracture. Gabapentin and pregabalin may increase suicidal thoughts and behaviors, cause drowsiness or dizziness, and impair balance and coordination. Pregabalin may impair memory and concentration. Clonidine is contraindicated in patients with low blood pressure and may cause lightheadedness, hypotension, headache, and constipation; sudden cessation of treatment can be associated with significant increments in blood pressure (63). Figure 4. Open in new tabDownload slide Hot flash frequency and composite score with nonhormonal prescription therapies for relief of VMS. Upper panel, Effect on frequency of VMS; lower panel, effect on composite score (severity times frequency; best representation of effect); open bars, placebo; colored bars, therapies; length of bars, ranges in studies; horizontal bar, means. All of these agents are generally well tolerated (226). Hypersensitivity or prior adverse drug reactions to each of these agents represent contraindications. For the SSRI/SNRIs, prior neuroleptic syndrome, serotonin syndrome, and concurrent use of monoamine oxidase inhibitors are also contraindications. SSRI/SNRIs should be used with caution in patients with bipolar disease, uncontrolled seizures, hepatic or renal insufficiency, uncontrolled hyponatremia, concurrent use of other SSRI/SNRIs, or poorly controlled hypertension. These agents uncommonly induce suicidal thoughts within the first few months of treatment. Preliminary evidence suggests a possible increase in risk of bone fracture. Gabapentin and pregabalin may increase suicidal thoughts and behaviors, cause drowsiness or dizziness, and impair balance and coordination. Pregabalin may impair memory and concentration. Clonidine is contraindicated in patients with low blood pressure and may cause lightheadedness, hypotension, headache, and constipation; sudden cessation of treatment can be associated with significant increments in blood pressure (63). Meta-analyses and a Cochrane review concluded that SSRIs and SNRIs exert mild-to-moderate effects to reduce hot flashes in women with a history of breast cancer (217, 224–227). Each of these agents appears to have similar efficacy in breast cancer survivors as in healthy menopausal women, although studies are small (213, 217, 228–234). Caution is advised in the use of paroxetine in patients taking tamoxifen because paroxetine markedly interferes with the metabolism of tamoxifen to its metabolite, endoxifen (221, 222, 224, 235–237). The only FDA-approved agent in this class is low-dose paroxetine mesylate, but others have been used off-label in the United States. No direct trials are available to determine the relative efficacy of one over another. We describe suggested daily doses, efficacy, side effects, and contraindications in Figure 4. In general, the evidence suggests that these agents are effective and well tolerated. Gabapentin Four RCTs confirmed moderate efficacy in relieving hot flashes (238–241). On the basis of clinical experience, women whose hot flashes occur primarily at night respond well to a single bedtime dose. Individual dose requirements vary widely, as determined by empiric dose escalation, and range from 300 to 1200 mg. Gabapentin effects as a sedative and a reducer of vasomotor instability work well together when used at bedtime because sedating side effects dissipate by morning. However, when used during the day, gabapentin may result in a level of lethargy that is not tolerable. Pregabalin In one 6-week RCT, pregabalin (75–150 mg twice daily) decreased mean hot flash scores by 65 and 71%, compared with 50% by placebo (242), and was reasonably well tolerated. Choice of SSRI/SNRI vs gabapentin/pregabalin A randomized, crossover, multicenter trial that compared recommended doses of venlafaxine vs gabapentin, 300 mg three times a day (243), reported that both agents reduced hot flash scores by 66%, but two-thirds of patients preferred venlafaxine over gabapentin. The quality of this comparative evidence is low due to imprecision. Relative efficacy of nonhormonal prescription therapies vs estrogens A limited number of head-to-head RCTs have compared varying estrogen doses, preparations, and routes of administration with nonhormonal agents (213, 240, 244). None of the RCTs established statistically significant superiority of one treatment regimen over another. However, when these and other published data are taken into account (213, 217, 236, 245), the limited evidence available suggests that standard-dose MHT is more effective than nonhormonal agents. 4.1b For those women seeking relief of moderate to severe VMS who are not responding to or tolerating the nonhormonal prescription therapies SSRIs/SNRIs or gabapentin or pregabalin, we suggest a trial of clonidine (if there are no contraindications). (2|⊕⊕○○) Evidence Clonidine Several RCTs demonstrated that this α-2-adrenergic receptor agonist reduced hot flashes, but less effectively than the SSRI/SNRIs, gabapentin, and pregabalin, and with more side effects (Figure 4) (217, 236). Clonidine transdermal patches are preferred over tablets because of more stable blood levels. 4.2 OTC and alternative nonhormonal therapies for VMS 4.2 For women seeking relief of VMS with OTC or complementary medicine therapies, we suggest counseling regarding the lack of consistent evidence for benefit for botanicals, black cohosh, omega-3 fatty acids, red clover, vitamin E, and mind/body alternatives including anxiety control, acupuncture, paced breathing, and hypnosis. (2|⊕⊕○○) Evidence Clinical trials with these agents have reported inconsistent efficacy over placebo, but individual patients may experience benefit (Table 9). The MSFLASH trial showed that omega-3 fatty acids do not improve VMS (246). In a randomized trial of 187 symptomatic menopausal women, clinical hypnosis was associated with a 74.2% reduction in hot flashes compared with a 17.1% reduction in women randomized to structured attention control (P < .001) (247). The phytoestrogens are nonsteroidal compounds that have both estrogenic and antiestrogenic properties. Caution is advised because some of these agents, when consumed as supplements, can exert estrogenic effects, a concern in breast cancer survivors although dietary soy appears to have no adverse effects on breast cancer prognosis (248). Table 9. Alternative Therapies for Treatment of VMS Agents . Comments . Refs. . Agents with inconsistent reports of benefit     Genistein Purified isoflavone 324–336 ±Estrogenically active Breast safety not established     Daidzein Purified isoflavone 324–336 ±Estrogenically active Breast safety not established     S-equol Metabolite of daidzein 337     Nonpurified isoflavones Breast safety not established 338     Flaxseed 225, 236, 328, 339–341     Red clover Breast safety not established 225, 236, 328, 339–341     High-dose extracted or synthesized phytoestrogen 225, 236, 328, 339–341     Dietary soy Agreement about breast safety 248     Vitamin E 10% benefit in some studies 217, 342, 343 Reports with predominantly no benefit     Black cohosh Some short-term trials report benefit, most report no benefit 225, 344–352 Breast safety not established Reports of liver toxicity     Omega-3 fatty acids No benefit in MSFLASH trial 246     Acupuncture Not effective when compared to “sham acupuncture” controls 353–356     Exercise Exercise with sweating may increase hot flashes 357     Other complementary approaches Ginseng, dong quai, wild yam, progesterone creams, traditional Chinese herbs, reflexology, magnetic devices 225, 332 Agents requiring further study     Stellate ganglion block Need further RCTs to establish lack of complications 358     Guided relaxation Stress management, deep breathing, paced respiration, guided imagery, mindfulness training 217, 225, 247, 359–365     Hypnosis Recent studies suggest efficacy 247     Cognitive behavior modification Recent studies suggest efficacy with trained practitioners 366, 367 Agents . Comments . Refs. . Agents with inconsistent reports of benefit     Genistein Purified isoflavone 324–336 ±Estrogenically active Breast safety not established     Daidzein Purified isoflavone 324–336 ±Estrogenically active Breast safety not established     S-equol Metabolite of daidzein 337     Nonpurified isoflavones Breast safety not established 338     Flaxseed 225, 236, 328, 339–341     Red clover Breast safety not established 225, 236, 328, 339–341     High-dose extracted or synthesized phytoestrogen 225, 236, 328, 339–341     Dietary soy Agreement about breast safety 248     Vitamin E 10% benefit in some studies 217, 342, 343 Reports with predominantly no benefit     Black cohosh Some short-term trials report benefit, most report no benefit 225, 344–352 Breast safety not established Reports of liver toxicity     Omega-3 fatty acids No benefit in MSFLASH trial 246     Acupuncture Not effective when compared to “sham acupuncture” controls 353–356     Exercise Exercise with sweating may increase hot flashes 357     Other complementary approaches Ginseng, dong quai, wild yam, progesterone creams, traditional Chinese herbs, reflexology, magnetic devices 225, 332 Agents requiring further study     Stellate ganglion block Need further RCTs to establish lack of complications 358     Guided relaxation Stress management, deep breathing, paced respiration, guided imagery, mindfulness training 217, 225, 247, 359–365     Hypnosis Recent studies suggest efficacy 247     Cognitive behavior modification Recent studies suggest efficacy with trained practitioners 366, 367 Open in new tab Table 9. Alternative Therapies for Treatment of VMS Agents . Comments . Refs. . Agents with inconsistent reports of benefit     Genistein Purified isoflavone 324–336 ±Estrogenically active Breast safety not established     Daidzein Purified isoflavone 324–336 ±Estrogenically active Breast safety not established     S-equol Metabolite of daidzein 337     Nonpurified isoflavones Breast safety not established 338     Flaxseed 225, 236, 328, 339–341     Red clover Breast safety not established 225, 236, 328, 339–341     High-dose extracted or synthesized phytoestrogen 225, 236, 328, 339–341     Dietary soy Agreement about breast safety 248     Vitamin E 10% benefit in some studies 217, 342, 343 Reports with predominantly no benefit     Black cohosh Some short-term trials report benefit, most report no benefit 225, 344–352 Breast safety not established Reports of liver toxicity     Omega-3 fatty acids No benefit in MSFLASH trial 246     Acupuncture Not effective when compared to “sham acupuncture” controls 353–356     Exercise Exercise with sweating may increase hot flashes 357     Other complementary approaches Ginseng, dong quai, wild yam, progesterone creams, traditional Chinese herbs, reflexology, magnetic devices 225, 332 Agents requiring further study     Stellate ganglion block Need further RCTs to establish lack of complications 358     Guided relaxation Stress management, deep breathing, paced respiration, guided imagery, mindfulness training 217, 225, 247, 359–365     Hypnosis Recent studies suggest efficacy 247     Cognitive behavior modification Recent studies suggest efficacy with trained practitioners 366, 367 Agents . Comments . Refs. . Agents with inconsistent reports of benefit     Genistein Purified isoflavone 324–336 ±Estrogenically active Breast safety not established     Daidzein Purified isoflavone 324–336 ±Estrogenically active Breast safety not established     S-equol Metabolite of daidzein 337     Nonpurified isoflavones Breast safety not established 338     Flaxseed 225, 236, 328, 339–341     Red clover Breast safety not established 225, 236, 328, 339–341     High-dose extracted or synthesized phytoestrogen 225, 236, 328, 339–341     Dietary soy Agreement about breast safety 248     Vitamin E 10% benefit in some studies 217, 342, 343 Reports with predominantly no benefit     Black cohosh Some short-term trials report benefit, most report no benefit 225, 344–352 Breast safety not established Reports of liver toxicity     Omega-3 fatty acids No benefit in MSFLASH trial 246     Acupuncture Not effective when compared to “sham acupuncture” controls 353–356     Exercise Exercise with sweating may increase hot flashes 357     Other complementary approaches Ginseng, dong quai, wild yam, progesterone creams, traditional Chinese herbs, reflexology, magnetic devices 225, 332 Agents requiring further study     Stellate ganglion block Need further RCTs to establish lack of complications 358     Guided relaxation Stress management, deep breathing, paced respiration, guided imagery, mindfulness training 217, 225, 247, 359–365     Hypnosis Recent studies suggest efficacy 247     Cognitive behavior modification Recent studies suggest efficacy with trained practitioners 366, 367 Open in new tab 5.0 Treatment of genitourinary syndrome of menopause 5.1 Vaginal moisturizers and lubricants 5.1a For postmenopausal women with symptoms of VVA, we suggest a trial of vaginal moisturizers to be used at least twice weekly. (2|⊕⊕○○) Evidence Vaginal moisturizers (eg, polycarbophil-based moisturizer, hyaluronic acid-based preparations, and a pectin-based preparation), when used regularly (at least twice weekly), may provide an effective nonhormonal approach to alleviating symptoms of vaginal atrophy. However, studies have been small, mostly open-labeled, and limited to 12 weeks (249–257). Although helpful, these approaches are not likely as effective as vaginal ET. Vaginal moisturizers have not been shown to reduce urinary tract symptoms or asymptomatic bacteriuria. Use of a vaginal moisturizer may not eliminate the need for a vaginal lubricant during intercourse. 5.1b For women who do not produce sufficient vaginal secretions for comfortable sexual activity, we suggest vaginal lubricants. (2|⊕⊕○○) Evidence Vaginal lubricants are used to enhance the sexual experience in women with symptoms of VVA by alleviating vaginal dryness and preventing dyspareunia (258). Lubricants do not treat the underlying problem and only briefly alleviate symptoms. Several OTC options are available. Because data do not demonstrate the superiority of one to another, women can experiment with these products. Olive oil is also effective (259). Petroleum jelly has been associated with an increased rate of bacterial vaginosis (260). 5.2 Vaginal estrogen therapies 5.2a For women without a history of hormone- (estrogen) dependent cancers who are seeking relief from symptoms of GSM (including VVA) that persist despite using vaginal lubricants and moisturizers, we recommend low-dose vaginal ET. (1|⊕⊕⊕○) Evidence A 2006 Cochrane meta-analysis of vaginal estrogens (261) compared 19 efficacy trials and found that all products effectively alleviated symptoms, but study differences limited comparisons among agents. As a guiding principle, we recommend using the lowest effective dose. RCTs of low-dose vaginal estrogen products (262–267) report rapid improvement of vaginal symptoms (vaginal dryness or dyspareunia) and urinary symptoms (dysuria and urge incontinence) within 2 to 3 weeks. Objective improvements continue at 12 weeks and are maintained to 1 year. Limited evidence suggests that vaginal ET may prevent recurrent urinary tract infections (268, 269) and overactive bladder (270, 271). No clear proof exists that vaginal ET prevents or improves pelvic prolapse (272), but it may be advantageous preoperatively (273). Adverse effects include potential transfer to partner via penile or oral absorption and, with vaginal creams, residue on undergarments. Vaginal estrogens Vaginal estrogen preparations have been categorized as: 1) low, 2) intermediate, and 3) systemic doses (274) (Table 10). By using the lowest effective doses, systemic absorption is minimized. During the initiation of therapy, vaginal atrophy may enhance systemic absorption, although not all studies demonstrate this effect (267, 275). When vaginal epithelium is restored (after several weeks of ET), systemic absorption may decrease (276, 277). Table 10. Classification of Government-Approved Vaginal Estrogens Type . Dose . Serum Estradiol Level . Low dose <20 pg/mL     Silastic estradiol vaginal ring 7.5 μg     Estradiol vaginal tablet 10 μg     Promestriene (estradiol diether) ovulea 10 mg     Estriol ovulea 0.5 mg     Estriol + progesterone + Lactobacillus Doderleini ovulea 0.2 mg + 2 mg + 341 mg     Promestriene creama 3 mg     Estriol creama 0.015–0.03 mg Intermediate dose >20 pg/mL     CEE vaginal cream >0.3-mg dose 5–50 pg/mL     Estradiol vaginal tablet 25 μgb Some >20 pg/mL High dose (systemic) 35–200 pg/mL     Estradiol vaginal ring 50 and 100 μg     Vaginal estradiol >0.5 mg     Vaginal CEE >0.5 mgc Type . Dose . Serum Estradiol Level . Low dose <20 pg/mL     Silastic estradiol vaginal ring 7.5 μg     Estradiol vaginal tablet 10 μg     Promestriene (estradiol diether) ovulea 10 mg     Estriol ovulea 0.5 mg     Estriol + progesterone + Lactobacillus Doderleini ovulea 0.2 mg + 2 mg + 341 mg     Promestriene creama 3 mg     Estriol creama 0.015–0.03 mg Intermediate dose >20 pg/mL     CEE vaginal cream >0.3-mg dose 5–50 pg/mL     Estradiol vaginal tablet 25 μgb Some >20 pg/mL High dose (systemic) 35–200 pg/mL     Estradiol vaginal ring 50 and 100 μg     Vaginal estradiol >0.5 mg     Vaginal CEE >0.5 mgc a Not approved or recommended in United States. b No longer available in United States. c Predominantly estrone sulfate; LH suppression reflects systemic absorption. Open in new tab Table 10. Classification of Government-Approved Vaginal Estrogens Type . Dose . Serum Estradiol Level . Low dose <20 pg/mL     Silastic estradiol vaginal ring 7.5 μg     Estradiol vaginal tablet 10 μg     Promestriene (estradiol diether) ovulea 10 mg     Estriol ovulea 0.5 mg     Estriol + progesterone + Lactobacillus Doderleini ovulea 0.2 mg + 2 mg + 341 mg     Promestriene creama 3 mg     Estriol creama 0.015–0.03 mg Intermediate dose >20 pg/mL     CEE vaginal cream >0.3-mg dose 5–50 pg/mL     Estradiol vaginal tablet 25 μgb Some >20 pg/mL High dose (systemic) 35–200 pg/mL     Estradiol vaginal ring 50 and 100 μg     Vaginal estradiol >0.5 mg     Vaginal CEE >0.5 mgc Type . Dose . Serum Estradiol Level . Low dose <20 pg/mL     Silastic estradiol vaginal ring 7.5 μg     Estradiol vaginal tablet 10 μg     Promestriene (estradiol diether) ovulea 10 mg     Estriol ovulea 0.5 mg     Estriol + progesterone + Lactobacillus Doderleini ovulea 0.2 mg + 2 mg + 341 mg     Promestriene creama 3 mg     Estriol creama 0.015–0.03 mg Intermediate dose >20 pg/mL     CEE vaginal cream >0.3-mg dose 5–50 pg/mL     Estradiol vaginal tablet 25 μgb Some >20 pg/mL High dose (systemic) 35–200 pg/mL     Estradiol vaginal ring 50 and 100 μg     Vaginal estradiol >0.5 mg     Vaginal CEE >0.5 mgc a Not approved or recommended in United States. b No longer available in United States. c Predominantly estrone sulfate; LH suppression reflects systemic absorption. Open in new tab Low-dose therapies Low-dose vaginal ring. Low-dose vaginal rings result in estradiol levels that remain within the normal postmenopausal range; however, bone resorption and lipid levels decrease, suggesting possible systemic effects (278, 279). Insertion and removal at 3-month intervals may be difficult, the ring can be sensed during intercourse, and it can be expelled, particularly in women who have undergone a hysterectomy (265). Vaginal estradiol tablets. The 10-μg tablet provides standard twice weekly dosing, relieves vaginal symptoms by 8 weeks, and is effective for at least 52 weeks (263, 275, 280, 281). Therapy is initiated with daily administration for 2 weeks, and then twice weekly thereafter. Vaginal placement of the tablet may provide less introital benefit than creams. Promestriene (estradiol diether). This is a low-dose estrogen used outside the United States. Evidence is limited to studies of poor quality and very few RCTs (282). Intermediate-dose vaginal estrogen The 25-μg estradiol tablets increase plasma estradiol from 3.1 ± 0.83 to 19.8 ± 6.1 pg/mL by 7 days (283). An RCT of CEE vaginal cream ≥ 0.3 mg applied daily or twice weekly reported an improvement in VVA by 12 weeks that was sustained for 52 weeks without reports of endometrial effects (266). Intermediate-dose estradiol and CEE creams provide flexibility of dosing, allow treatment from the introitus to the vaginal apex, and provide the emollient effect of vehicle. Some systemic absorption exists (284, 285). Systemic-dose vaginal estrogen CEE 0.625- to 2.5-mg vaginal cream, administered daily, results in systemic effects as evidenced by LH and FSH suppression (285). No RCT data are available regarding the FDA-approved dosing of estradiol 2- to 4-g vaginal cream, administered daily for 1 to 2 weeks, followed by a maintenance dosage of 1 g, one to three times a week. Other hormonal agents Estriol vaginal preparations (gels and suppositories) are manufactured and government regulated in a number of countries outside the United States. Estriol is considered a low-affinity estrogen and, despite increased plasma concentration after repeated vaginal administration, is not considered to have substantial systemic effects (286, 287). Adverse events Because serum estradiol levels during therapy usually fall within the normal postmenopausal range, the risk profile with low-dose vaginal ET is expected to be lower than with systemic ET (288). However, long-term endometrial safety data are lacking, and 1 year is the maximum duration of RCTs of vaginal ET (261). Side effects include vulvovaginal candidiasis (289, 290) and, with higher dosing and systemic absorption, vaginal bleeding and breast pain (289). Increased CVD or VTE risk has not been reported (261). This may reflect an actual neutral effect due to the absence of a first-pass hepatic effect by vaginal estrogens, or that studies of women at high CVD or VTE risk are lacking (281). Available evidence does not support the boxed warning on low-dose vaginal estrogen regarding an increased risk of CHD, stroke, VTE, dementia, and breast cancer, and efforts to modify the labeling of these products are in progress (288). Practice statement 5.2b In women with a history of breast or endometrial cancer, who present with symptomatic GSM (including VVA), that does not respond to nonhormonal therapies, we suggest a shared decision-making approach that includes the treating oncologist to discuss using low-dose vaginal ET. (Ungraded best practice statement) Evidence Breast cancer Whether small increases in circulating estrogens from low-dose vaginal estrogen can stimulate the growth of residual breast cancer cells (280, 291–293) remains an unanswered question. However, for women taking aromatase inhibitors, the effectiveness of which depends upon blocking up to 95% of estrogen synthesis and reducing circulating estradiol levels to < 1 pg/mL (250), caution is raised because minimal amounts of estrogen can be absorbed with low-dose vaginal ET. In a cohort case-control study of 13 479 breast cancer survivors taking adjuvant tamoxifen or aromatase inhibitor therapy for at least 1 year, after 3.5 years of concurrent administration of the low-dose estrogen ring or 10-μg vaginal tablet, breast cancer recurrence did not increase (relative risk, 0.78; 95% CI, 0.48–1.25) (294). These data are insufficient, however, to conclude safety and to recommend this approach. Endometrial cancer The effect of low-dose vaginal ET on endometrial cancer recurrence is unknown. The only RCT attempting to evaluate the effect of systemic ET on recurrence rate and survival in women after surgery for stage I or II endometrial cancer was closed prematurely without complete enrollment (295). In the absence of RCT findings to guide practice recommendations, the decision to use ET remains controversial and involves assessing the severity of postmenopausal symptoms and tumor characteristics (296, 297). 5.2c For women taking raloxifene, without a history of hormone- (estrogen) dependent cancers, who develop symptoms of GSM (including VVA) that do not respond to nonhormonal therapies, we suggest adding low-dose vaginal ET. (2|⊕⊕○○) Evidence Raloxifene has neutral vaginal effects (298–300). In two clinical trials, vaginal, but not oral (301) ET, was safely used to treat vaginal symptoms in women taking raloxifene without untoward endometrial effects (302, 303). 5.2d For women using low-dose vaginal ET, we suggest against adding a progestogen (ie, no need for adding progestogen to prevent endometrial hyperplasia). (2|⊕○○○) 5.2e For women using vaginal ET who report postmenopausal bleeding or spotting, we recommend prompt evaluation for endometrial pathology. (1|⊕⊕○○) Evidence Bleeding or spotting in a woman using only vaginal estrogens is uncommon in the absence of endometrial pathology. The 2006 Cochrane review of 19 studies found no significant difference among vaginal creams, tablets, or rings in terms of endometrial thickness or hyperplasia or in the proportion of women with adverse events (261). Recent 1-year-long studies of vaginal CEE cream and low-dose vaginal estradiol tablets revealed no cases of endometrial hyperplasia or cancer as determined by endometrial biopsy (263, 266, 304). Vaginal administration of estradiol tablets, when placed in the upper third of the vagina, may result in a uterine first-pass effect resulting in a higher degree of uterine stimulation (305–309). It is unknown whether endometrial proliferation, hyperplasia, or cancer can occur after long-duration treatment (> 1 y) or in women with risk factors (late menopause, higher body mass index, higher dosing). For women at higher risk of endometrial cancer, surveillance using transvaginal ultrasound, followed by endometrial biopsy if endometrial thickening is present, may be prudent. Intermittent (possibly annual) progestogen withdrawal may be considered to assess endometrial status (261, 280). 5.3 Ospemifene 5.3a For treatment of moderate to severe dyspareunia associated with vaginal atrophy in postmenopausal women without contraindications, we suggest a trial of ospemifene. (2|⊕⊕⊕○) 5.3b For women with a history of breast cancer presenting with dyspareunia, we recommend against ospemifene. (1|⊕○○○) Evidence Benefits Not all women are comfortable using vaginal ET, and women may prefer an oral medication specifically indicated for dyspareunia. Vaginal symptoms and sexual function. Two 12-week RCTs of ospemifene reported improvements in pH and vaginal maturation index, severity of dyspareunia (310, 311), and standardized measures of sexual function (including desire, arousal, orgasm, and satisfaction) (312). Two year-long studies (313, 314) demonstrated sustained vaginal benefits. Risks Vasomotor symptoms. The most common adverse effect was VMS (7.2% of women taking ospemifene compared with 2% taking placebo) (314). Cardiovascular. Ospemifene involves risk of VTE (315) and is contraindicated in women at risk for venous or arterial thrombosis or stroke. In safety studies, incidence rates for thromboembolic stroke, hemorrhagic stroke, and DVT were 0.72, 1.45, and 1.45/1000, respectively, in women receiving ospemifene 60 mg vs 1.04, 0, and 1.04/1000, respectively, in women assigned to placebo (310). Endometrium. No cases of endometrial carcinoma have been reported. Studies reported endometrial thickening of ≥ 5 mm at a rate of 60.1/1000 women per year of therapy with ospemifene vs 21.2/1000 women per year of therapy with placebo. The incidence of proliferative endometrium (weakly plus active plus disordered) was 86.1/1000 women with ospemifene vs 13.3/1000 with placebo (315). The incidence of uterine polyps was 5.9 cases/1000 women with ospemifene vs 1.8/1000 women with placebo (315). Breast. Data on breast density or breast cancer risk are lacking. Estrogen-dependent neoplasia is a contraindication. Future research There are numerous gaps in our knowledge regarding menopause symptoms. Some of these include a lack of the most basic understanding of what causes hot flashes, questions regarding the potential link between VMS and CVD in older vs younger postmenopausal women, and a poor understanding of the relationships between menopause and sleep and hormonal transitions and mood, which have significant social and economic implications. Given the uncertainties regarding the precise neuroendocrine events that cause VMS, developing specific targeted therapies is challenging. Establishing appropriate animal models and expanding recent research involving the neuroregulators kisspeptin, neurokinin B, and dynorphin may help develop new effective treatments (35). Management of the transition to menopause remains uncharted territory. The SWAN and the Melbourne Women's Midlife Health Project provide extensive epidemiological, physiological, and descriptive data characterizing reproductive changes that occur during the transition to menopause. However, clinical management decisions are often based on the extrapolation of observational data collected from studies conducted in younger, reproductive age women. RCTs of frequently prescribed therapies, such as oral contraceptives, MHT, and measures to control mood, with clinical outcomes relevant to women of relatively advanced age are sorely needed to confidently advise patients regarding the safest and most effective therapies to use during this transition. Managing the loss of ovarian function in premenopausal women due to surgery, the range of disorders manifesting as POI, or the sequelae of treatment for breast cancer and other malignancies remains challenging. This is due to a dearth of quality data assessing the long-term risks and benefits of MHT or other options for symptom relief and prevention of chronic diseases in these groups. Fertility issues can be managed with modern assisted reproductive technology, but we fall short on adequately managing estrogen deficiency. Pressing questions remain regarding optimal treatment preparation, dosing and regimens, and the merits of long-term MHT, even in women without menopausal symptoms. International registries and clinical trials are overdue to address the long-reaching implications of these important issues. The most persistent question for naturally postmenopausal women is how to balance menopausal symptom relief with the prevention of chronic diseases of aging such as CHD, osteoporotic fractures, and dementia. ET has long been hypothesized to meet this goal, although conclusive evidence remains elusive, and questions persist regarding the interaction between EPT and these outcomes, as well as breast cancer. Observational data suggesting differences in VTE risk and other CVD outcomes continue to accumulate, suggesting a significant need for adequately powered clinical trials comparing the safety and efficacy of oral with transdermal therapies in younger, recently postmenopausal women. Finally, new SERM therapies (alone and partnered with estrogens) are promising, but larger, longer trials are needed to fully characterize the benefit/risk profiles of these new treatments and inform the clinician as to which patients stand to benefit the most from their use. Financial Disclosures of the Task Force* Financial Disclosure of Task Force:* Cynthia A. Stuenkel, MD. (chair)—Financial or business/organizational interests: North American Menopause Society (Chair, Exam Committee), National Women's Law Center-Well Women's Project; Significant financial interest or leadership position: none declared. Susan R. Davis, MBBS, PhD—Financial or Business/Organizational Interests: International Menopause Society, North American Menopause Society, Menopause, Maturitas, Climacteric, Trimel Pharmaceuticals Canada, Lawley Pharmaceuticals Australia, Abbott Pharmaceuticals; Significant Financial Interest or Leadership Position: International Menopause Society, National Health and Medical Research Council, Australia, Bupa Health Foundation. Anne Gompel, MD, PhD—Financial or Business/Organizational Interests: European Society for Contraception, European Society of Endocrinology, Groupe d'Etude sur la Ménopause et le Vieillissement Hormonal, Société Française de Sénologie et Pathologie Mammaire; Significant financial interest or leadership position: none declared. Mary Ann Lumsden, MD, PhD—Financial or Business/Organizational Interests: —Financial or Business/Organizational Interests: International Menopause Society, British Menopause Society; Significant Financial Interest or Leadership Position: National Institute of Health and Clinical Excellence. M. Hassan Murad, M.D., M.P.H.** —Financial or business/organizational interests: Mayo Clinic, Division of Preventive Medicine; Significant financial interest or leadership position: none declared. JoAnn V. Pinkerton, MD—Financial or business/organizational interests: North American Menopause Society, Menopause Journal, OBG Management, Climacteric Journal, Journal of Women's Health, University of Virginia Board of Visitors (Noven Pharmaceuticals, Pfizer, Inc., Shionogi, Therapeutics MD), University of Virginia Clinical Trials (Therapeutics MD); Significant Financial Interest or Leadership Position: North American Menopause Society, Academy of Women's Health, South Atlantic Association of ObGyn. Richard J. Santen, MD—Financial or business/organizational interests: American Society of Clinical Oncology, Up-to-Date (Author/Honorarium); Significant Financial Interest or Leadership Position: Pfizer (Advisory Board, Research Grant). * Financial, business, and organizational disclosures of the Task Force cover the year prior to publication. Disclosures prior to this time period are archived. ** Evidence-based reviews for this guideline were prepared under contract with The Endocrine Society. Acknowledgments Special thanks are extended to Drs. David F. Archer, Gloria A. Bachmann, Henry Burger, Roger A. Lobo, Charles L. Loprinzi, JoAnn E. Manson, Kathryn A. Martin, Nanette F. Santoro, Hugh S. Taylor, and Nelson B. Watts for careful review and thoughtful suggestions. Cosponsoring Associations: The Australasian Menopause Society, the British Menopause Society, European Menopause and Andropause Society, the European Society of Endocrinology, and the International Menopause Society. Abbreviations BZA bazedoxifene CEE conjugated equine estrogens CHD coronary heart disease CI confidence interval CVD cardiovascular disease DVT deep vein thrombosis EPT estrogen plus progestogen therapy ET estrogen therapy GSM genitourinary syndrome of menopause HR hazard ratio MetS metabolic syndrome MHT menopausal hormone therapy MI myocardial infarction MPA medroxyprogesterone acetate OTC over the counter PE pulmonary embolism POI primary ovarian insufficiency QOL quality of life RCT randomized controlled trial SERM selective estrogen receptor modulator SSRI selective serotonin reuptake inhibitor SNRI serotonin-norepinephrine reuptake inhibitor VMS vasomotor symptoms VTE venous thromboembolism VVA vulvovaginal atrophy. References 1. Atkins D , Best D, Briss PA, et al. . Grading quality of evidence and strength of recommendations . BMJ . 2004 ; 328 : 1490 . Google Scholar Crossref Search ADS PubMed WorldCat 2. Swiglo BA , Murad MH, Schünemann HJ, et al. . A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system . J Clin Endocrinol Metab . 2008 ; 93 : 666 – 673 . Google Scholar Crossref Search ADS PubMed WorldCat 3. Guyatt GH , Schünemann HJ, Djulbegovic B, Akl EA. Guideline panels should not GRADE good practice statements . J Clin Epidemiol . 2015 ; 68 : 597 – 600 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Mohammed K , Benkhadra K, et al. . Oral vs. transdermal estrogen and the risk of venous and arterial thrombotic events: a systematic review and meta-analysis . J Clin Endocrinol Metab . (To be submitted 2015) . OpenURL Placeholder Text WorldCat 5. Benkhadra KM , Nofal AA, Carranza Leon BG, Alahdab F, Abu Dabrh AM. Menopausal hormonal therapy and mortality: a systematic review and meta-analysis . J Clin Endocrinol Metab (to be submitted 2015) . OpenURL Placeholder Text WorldCat 6. Tom SE , Kuh D, Guralnik JM, Mishra GD. Self-reported sleep difficulty during the menopausal transition: results from a prospective cohort study . Menopause . 2010 ; 17 : 1128 – 1135 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Mishra GD , Kuh D. Health symptoms during midlife in relation to menopausal transition: British prospective cohort study . BMJ . 2012 ; 344 : e402 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Syed Alwi SA , Lee PY, Awi I, Mallik PS, Md Haizal MN. The menopausal experience among indigenous women of Sarawak, Malaysia . Climacteric . 2009 ; 12 : 548 – 556 . Google Scholar Crossref Search ADS PubMed WorldCat 9. Liu M , Wang Y, Li X, et al. . A health survey of Beijing middle-aged registered nurses during menopause . Maturitas . 2013 ; 74 : 84 – 88 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Nappi RE , Davis SR. The use of hormone therapy for the maintenance of urogynecological and sexual health post WHI . Climacteric . 2012 ; 15 : 267 – 274 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Dennerstein L , Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms . Obstet Gynecol . 2000 ; 96 : 351 – 358 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 12. Freeman EW , Sammel MD, Lin H. Temporal associations of hot flashes and depression in the transition to menopause . Menopause . 2009 ; 16 : 728 – 734 . Google Scholar Crossref Search ADS PubMed WorldCat 13. Herber-Gast GC , Mishra GD, van der Schouw YT, Brown WJ, Dobson AJ. Risk factors for night sweats and hot flushes in midlife: results from a prospective cohort study . Menopause . 2013 ; 20 ( 9 ): 953 – 959 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Freeman EW . Hot flushes and the menopause: how long should they be expected to last? Maturitas . 2014 ; 78 : 153 – 154 . Google Scholar Crossref Search ADS PubMed WorldCat 15. Harlow SD , Gass M, Hall JE, et al. . Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging . J Clin Endocrinol Metab . 2012 ; 97 : 1159 – 1168 . Google Scholar Crossref Search ADS PubMed WorldCat 16. Avis NE , Crawford SL, Greendale G, et al. . Duration of menopausal vasomotor symptoms over the menopause transition . JAMA Intern Med . 2015 ; 175 : 531 – 539 . Google Scholar Crossref Search ADS PubMed WorldCat 17. Anderson GL , Limacher M, Assaf AR, et al. . Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial . JAMA . 2004 ; 291 : 1701 – 1712 . Google Scholar Crossref Search ADS PubMed WorldCat 18. Rossouw JE , Anderson GL, Prentice RL, et al. . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial . JAMA . 2002 ; 288 : 321 – 333 . Google Scholar Crossref Search ADS PubMed WorldCat 19. Stuenkel CA , Gass ML, Manson JE, et al. . A decade after the women's health initiative–the experts do agree . J Clin Endocrinol Metab . 2012 ; 97 : 2617 – 2618 . Google Scholar Crossref Search ADS PubMed WorldCat 20. de Villiers TJ , Gass ML, Haines CJ, et al. . Global consensus statement on menopausal hormone therapy . Maturitas . 2013 ; 74 : 391 – 392 . Google Scholar Crossref Search ADS PubMed WorldCat 21. Santen R , Pritchard K, Burger H. The consensus conference on treatment of estrogen deficiency symptoms in women surviving breast cancer . Obstet Gynecol Surv . 1998 ; 53 : S1 – S83 . Google Scholar Crossref Search ADS PubMed WorldCat 22. Goodwin PJ , Ennis M, Pritchard KI, Trudeau M, Hood N. Risk of menopause during the first year after breast cancer diagnosis . J Clin Oncol . 1999 ; 17 : 2365 – 2370 . Google Scholar Crossref Search ADS PubMed WorldCat 23. Woods NF , Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women's lives . Am J Med . 2005 ; 118 ( suppl 12B ): 14 – 24 . Google Scholar Crossref Search ADS PubMed WorldCat 24. Avis NE , Stellato R, Crawford S, et al. . Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic groups . Soc Sci Med . 2001 ; 52 : 345 – 356 . Google Scholar Crossref Search ADS PubMed WorldCat 25. Freeman EW , Sherif K. Prevalence of hot flushes and night sweats around the world: a systematic review . Climacteric . 2007 ; 10 : 197 – 214 . Google Scholar Crossref Search ADS PubMed WorldCat 26. Gartoulla P , Islam MR, Bell RJ, Davis SR. Prevalence of menopausal symptoms in Australian women at midlife: a systematic review . Climacteric . 2014 ; 17 : 529 – 539 . Google Scholar Crossref Search ADS PubMed WorldCat 27. Islam MR , Gartoulla P, Bell RJ, Fradkin P, Davis SR. Prevalence of menopausal symptoms in Asian midlife women: a systematic review . Climacteric . 2015 ; 18 : 157 – 176 . Google Scholar Crossref Search ADS PubMed WorldCat 28. Reed SD , Lampe JW, Qu C, et al. . Premenopausal vasomotor symptoms in an ethnically diverse population . Menopause . 2014 ; 21 : 153 – 158 . Google Scholar Crossref Search ADS PubMed WorldCat 29. Szmuilowicz ED , Manson JE, Rossouw JE, et al. . Vasomotor symptoms and cardiovascular events in postmenopausal women . Menopause . 2011 ; 18 : 603 – 610 . Google Scholar Crossref Search ADS PubMed WorldCat 30. Freedman RR , Roehrs TA. Effects of REM sleep and ambient temperature on hot flash-induced sleep disturbance . Menopause . 2006 ; 13 : 576 – 583 . Google Scholar Crossref Search ADS PubMed WorldCat 31. Joffe H , Crawford S, Economou N, et al. . A gonadotropin-releasing hormone agonist model demonstrates that nocturnal hot flashes interrupt objective sleep . Sleep . 2013 ; 36 : 1977 – 1985 . Google Scholar Crossref Search ADS PubMed WorldCat 32. Freedman RR . Hot flashes: behavioral treatments, mechanisms, and relation to sleep . Am J Med . 2005 ; 118 ( suppl 12B ): 124 – 130 . Google Scholar Crossref Search ADS PubMed WorldCat 33. Casper RF , Yen SS, Wilkes MM. Menopausal flushes: a neuroendocrine link with pulsatile luteinizing hormone secretion . Science . 1979 ; 205 : 823 – 825 . Google Scholar Crossref Search ADS PubMed WorldCat 34. Tataryn IV , Meldrum DR, Lu KH, Frumar AM, Judd HL. LH, FSH and skin temperature during the menopausal hot flash . J Clin Endocrinol Metab . 1979 ; 49 : 152 – 154 . Google Scholar Crossref Search ADS PubMed WorldCat 35. Rance NE , Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes . Front Neuroendocrinol . 2013 ; 34 : 211 – 227 . Google Scholar Crossref Search ADS PubMed WorldCat 36. Casper RF , Yen SS. Neuroendocrinology of menopausal flushes: an hypothesis of flush mechanism . Clin Endocrinol (Oxf) . 1985 ; 22 : 293 – 312 . Google Scholar Crossref Search ADS PubMed WorldCat 37. Portman DJ , Gass ML, Vulvovaginal Atrophy Terminology Consensus Conference Panel . Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society . Menopause . 2014 ; 21 : 1063 – 1068 . Google Scholar Crossref Search ADS PubMed WorldCat 38. Santen RJ , Allred DC, Ardoin SP, et al. . Postmenopausal hormone therapy: an Endocrine Society scientific statement . J Clin Endocrinol Metab . 2010 ; 95 : s1 – s66 . Google Scholar Crossref Search ADS PubMed WorldCat 39. The Study of Women's Health Across the Nation . SWAN Research Findings Publication List. Pages 1–37. Updated September 7, 2015 . http://www.swanstudy.org/publications/swan-research-findings/ . Accessed September 15, 2015 40. Mosca L , Benjamin EJ, Berra K, et al. . Effectiveness-based guidelines for the prevention of cardiovascular disease in women–2011 update: a guideline from the American Heart Association . Circulation . 2011 ; 123 : 1243 – 1262 . Google Scholar Crossref Search ADS PubMed WorldCat 41. Bushnell C , McCullough LD, Awad IA, et al. . Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association . Stroke . 2014 ; 45 : 1545 – 1588 . Google Scholar Crossref Search ADS PubMed WorldCat 42. National Osteoporosis Foundation . 2014 Clinician's Guide to Prevention and Treatment of Osteoporosis . http://nof.org/files/nof/public/content/file/2791/upload/919.pdf . Accessed April 12, 2014 43. Cosman F , de Beur SJ, LeBoff MS, et al. . Clinician's guide to prevention and treatment of osteoporosis . Osteoporos Int . 2014 ; 25 : 2359 – 2381 . Google Scholar Crossref Search ADS PubMed WorldCat 44. Manson JE , Chlebowski RT, Stefanick ML, et al. . Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials . JAMA . 2013 ; 310 : 1353 – 1368 . Google Scholar Crossref Search ADS PubMed WorldCat 45. Maclennan AH , Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes . Cochrane Database Syst Rev . 2004 ; 4 : CD002978 . OpenURL Placeholder Text WorldCat 46. Utian WH , Shoupe D, Bachmann G, Pinkerton JV, Pickar JH. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate . Fertil Steril . 2001 ; 75 : 1065 – 1079 . Google Scholar Crossref Search ADS PubMed WorldCat 47. Cardozo L , Bachmann G, McClish D, Fonda D, Birgerson L. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee . Obstet Gynecol . 1998 ; 92 : 722 – 727 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 48. Perrotta C , Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women . Cochrane Database Syst Rev . 2008 ; 2 : CD005131 . OpenURL Placeholder Text WorldCat 49. Kravitz HM , Schott LL, Joffe H, Cyranowski JM, Bromberger JT. Do anxiety symptoms predict major depressive disorder in midlife women? The Study of Women's Health Across the Nation (SWAN) Mental Health Study (MHS) . Psychol Med . 2014 ; 44 : 2593 – 2602 . Google Scholar Crossref Search ADS PubMed WorldCat 50. Soares CN . Mood disorders in midlife women: understanding the critical window and its clinical implications . Menopause . 2014 ; 21 : 198 – 206 . Google Scholar Crossref Search ADS PubMed WorldCat 51. Worsley R , Davis SR, Gavrilidis E, et al. . Hormonal therapies for new onset and relapsed depression during perimenopause . Maturitas . 2012 ; 73 : 127 – 133 . Google Scholar Crossref Search ADS PubMed WorldCat 52. Barnabei VM , Cochrane BB, Aragaki AK, et al. . Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative . Obstet Gynecol . 2005 ; 105 : 1063 – 1073 . Google Scholar Crossref Search ADS PubMed WorldCat 53. Moyer VA , U.S. Preventive Services Task Force . Menopausal hormone therapy for the primary prevention of chronic conditions: U.S. Preventive Services Task Force recommendation statement . Ann Intern Med . 2013 ; 158 : 47 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat 54. Marjoribanks J , Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women . Cochrane Database Syst Rev . 2012 ; 7 : CD004143 . OpenURL Placeholder Text WorldCat 55. North American Menopause Society . The 2012 hormone therapy position statement of: The North American Menopause Society . Menopause . 2012 ; 19 : 257 – 271 . Crossref Search ADS PubMed WorldCat 56. ACOG Practice Bulletin No. 141: management of menopausal symptoms . Obstet Gynecol . 2014 ; 123 : 202 – 216 . Crossref Search ADS PubMed WorldCat 57. Lobo RA , Davis SR, De Villiers TJ, et al. . Prevention of diseases after menopause . Climacteric . 2014 ; 17 : 540 – 556 . Google Scholar Crossref Search ADS PubMed WorldCat 58. Kanaya AM , Herrington D, Vittinghoff E, et al. . Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/Progestin Replacement Study. A randomized, double-blind, placebo-controlled trial . Ann Intern Med . 2003 ; 138 : 1 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 59. Margolis KL , Bonds DE, Rodabough RJ, et al. . Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial . Diabetologia . 2004 ; 47 : 1175 – 1187 . Google Scholar Crossref Search ADS PubMed WorldCat 60. Bonds DE , Lasser N, Qi L, et al. . The effect of conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomised trial . Diabetologia . 2006 ; 49 : 459 – 468 . Google Scholar Crossref Search ADS PubMed WorldCat 61. Manson JE , Rimm EB, Colditz GA, et al. . A prospective study of postmenopausal estrogen therapy and subsequent incidence of non-insulin-dependent diabetes mellitus . Ann Epidemiol . 1992 ; 2 : 665 – 673 . Google Scholar Crossref Search ADS PubMed WorldCat 62. de Lauzon-Guillain B , Fournier A, Fabre A, et al. . Menopausal hormone therapy and new-onset diabetes in the French Etude Epidemiologique de Femmes de la Mutuelle Générale de l'Education Nationale (E3N) cohort . Diabetologia . 2009 ; 52 : 2092 – 2100 . Google Scholar Crossref Search ADS PubMed WorldCat 63. Manson JE . Current recommendations: what is the clinician to do? Fertil Steril . 2014 ; 101 : 916 – 921 . Google Scholar Crossref Search ADS PubMed WorldCat 64. Chlebowski RT , Wactawski-Wende J, Ritenbaugh C, et al. . Estrogen plus progestin and colorectal cancer in postmenopausal women . N Engl J Med . 2004 ; 350 : 991 – 1004 . Google Scholar Crossref Search ADS PubMed WorldCat 65. Weiss NS , Szekely DR, Austin DF. Increasing incidence of endometrial cancer in the United States . N Engl J Med . 1976 ; 294 : 1259 – 1262 . Google Scholar Crossref Search ADS PubMed WorldCat 66. Mack TM , Pike MC, Henderson BE, et al. . Estrogens and endometrial cancer in a retirement community . N Engl J Med . 1976 ; 294 : 1262 – 1267 . Google Scholar Crossref Search ADS PubMed WorldCat 67. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial . JAMA . 1995 ; 273 : 199 – 208 . Crossref Search ADS PubMed WorldCat 68. Fournier A , Dossus L, Mesrine S, et al. . Risks of endometrial cancer associated with different hormone replacement therapies in the E3N cohort, 1992–2008 . Am J Epidemiol . 2014 ; 180 : 508 – 517 . Google Scholar Crossref Search ADS PubMed WorldCat 69. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial . JAMA . 1996 ; 275 : 370 – 375 . Crossref Search ADS PubMed WorldCat 70. Jondet M , Maroni M, Yaneva H, Brin S, Peltier-Pujol F, Pélissier C. Comparative endometrial histology in postmenopausal women with sequential hormone replacement therapy of estradiol and, either chlormadinone acetate or micronized progesterone . Maturitas . 2002 ; 41 : 115 – 121 . Google Scholar Crossref Search ADS PubMed WorldCat 71. Ferenczy A , Gelfand MM, van de Weijer PH, Rioux JE. Endometrial safety and bleeding patterns during a 2-year study of 1 or 2 mg 17 β-estradiol combined with sequential 5–20 mg dydrogesterone . Climacteric . 2002 ; 5 : 26 – 35 . Google Scholar Crossref Search ADS PubMed WorldCat 72. Pukkala E , Tulenheimo-Silfvast A, Leminen A. Incidence of cancer among women using long versus monthly cycle hormonal replacement therapy, Finland 1994–1997 . Cancer Causes Control . 2001 ; 12 : 111 – 115 . Google Scholar Crossref Search ADS PubMed WorldCat 73. Jaakkola S , Lyytinen HK, Dyba T, Ylikorkala O, Pukkala E. Endometrial cancer associated with various forms of postmenopausal hormone therapy: a case control study . Int J Cancer . 2011 ; 128 : 1644 – 1651 . Google Scholar Crossref Search ADS PubMed WorldCat 74. Wildemeersch D , Pylyser K, De Wever N, Pauwels P, Tjalma W. Endometrial safety after 5 years of continuous combined transdermal estrogen and intrauterine levonorgestrel delivery for postmenopausal hormone substitution . Maturitas . 2007 ; 57 : 205 – 209 . Google Scholar Crossref Search ADS PubMed WorldCat 75. Orbo A , Vereide A, Arnes M, Pettersen I, Straume B. Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial . BJOG . 2014 ; 121 : 477 – 486 . Google Scholar Crossref Search ADS PubMed WorldCat 76. Morelli M , Di Cello A, Venturella R, Mocciaro R, D'Alessandro P, Zullo F. Efficacy of the levonorgestrel intrauterine system (LNG-IUS) in the prevention of the atypical endometrial hyperplasia and endometrial cancer: retrospective data from selected obese menopausal symptomatic women . Gynecol Endocrinol . 2013 ; 29 : 156 – 159 . Google Scholar Crossref Search ADS PubMed WorldCat 77. Beral V , Reeves G, Bull D, Green J, Million Women Study Collaborators . Breast cancer risk in relation to the interval between menopause and starting hormone therapy . J Natl Cancer Inst . 2011 ; 103 : 296 – 305 . Google Scholar Crossref Search ADS PubMed WorldCat 78. Bakken K , Fournier A, Lund E, et al. . Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition . Int J Cancer . 2011 ; 128 : 144 – 156 . Google Scholar Crossref Search ADS PubMed WorldCat 79. Fournier A , Mesrine S, Boutron-Ruault MC, Clavel-Chapelon F. Estrogen-progestagen menopausal hormone therapy and breast cancer: does delay from menopause onset to treatment initiation influence risks? J Clin Oncol . 2009 ; 27 : 5138 – 5143 . Google Scholar Crossref Search ADS PubMed WorldCat 80. Beral V , Million Women Study Collaborators . Breast cancer and hormone-replacement therapy in the Million Women Study . Lancet . 2003 ; 362 : 419 – 427 . Google Scholar Crossref Search ADS PubMed WorldCat 81. Chen WY , Manson JE, Hankinson SE, et al. . Unopposed estrogen therapy and the risk of invasive breast cancer . Arch Intern Med . 2006 ; 166 : 1027 – 1032 . Google Scholar Crossref Search ADS PubMed WorldCat 82. Saxena T , Lee E, Henderson KD, et al. . Menopausal hormone therapy and subsequent risk of specific invasive breast cancer subtypes in the California Teachers Study . Cancer Epidemiol Biomarkers Prev . 2010 ; 19 : 2366 – 2378 . Google Scholar Crossref Search ADS PubMed WorldCat 83. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer . Lancet . 1997 ; 350 : 1047 – 1059 . Crossref Search ADS PubMed WorldCat 84. Anderson GL , Chlebowski RT, Aragaki AK, et al. . Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial . Lancet Oncol . 2012 ; 13 : 476 – 486 . Google Scholar Crossref Search ADS PubMed WorldCat 85. Prentice RL , Manson JE, Langer RD, et al. . Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause . Am J Epidemiol . 2009 ; 170 : 12 – 23 . Google Scholar Crossref Search ADS PubMed WorldCat 86. Goodwin PJ , Stambolic V. Obesity and insulin resistance in breast cancer–chemoprevention strategies with a focus on metformin . Breast . 2011 ; 20 ( suppl 3 ): S31 – S35 . Google Scholar Crossref Search ADS PubMed WorldCat 87. Song Y , Santen RJ, Wang JP, Yue W. Effects of the conjugated equine estrogen/bazedoxifene tissue-selective estrogen complex (TSEC) on mammary gland and breast cancer in mice . Endocrinology . 2012 ; 153 : 5706 – 5715 . Google Scholar Crossref Search ADS PubMed WorldCat 88. Wood CE , Clarkson TB, Chen H, et al. . Comparative effects of oral conjugated equine estrogens and micronized 17β-estradiol on breast proliferation: a retrospective analysis . Menopause . 2008 ; 15 : 890 – 898 . Google Scholar Crossref Search ADS PubMed WorldCat 89. Fournier A , Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study . Breast Cancer Res Treat . 2008 ; 107 : 103 – 111 . Google Scholar Crossref Search ADS PubMed WorldCat 90. Chlebowski RT , Anderson GL, Gass M, et al. . Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women . JAMA . 2010 ; 304 : 1684 – 1692 . Google Scholar Crossref Search ADS PubMed WorldCat 91. Anderson GL , Chlebowski RT, Rossouw JE, et al. . Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin . Maturitas . 2006 ; 55 : 103 – 115 . Google Scholar Crossref Search ADS PubMed WorldCat 92. Lyytinen H , Dyba T, Pukkala E, Ylikorkala O. Do the dose or route of administration of norethisterone acetate as a part of hormone therapy play a role in risk of breast cancer: national-wide case-control study from Finland . Int J Cancer . 2010 ; 127 : 185 – 189 . Google Scholar Crossref Search ADS PubMed WorldCat 93. Chlebowski RT , Manson JE, Anderson GL, et al. . Estrogen plus progestin and breast cancer incidence and mortality in the Women's Health Initiative Observational Study . J Natl Cancer Inst . 2013 ; 105 : 526 – 535 . Google Scholar Crossref Search ADS PubMed WorldCat 94. Cordina-Duverger E , Truong T, Anger A, et al. . Risk of breast cancer by type of menopausal hormone therapy: a case-control study among post-menopausal women in France . PLoS One . 2013 ; 8 : e78016 . Google Scholar Crossref Search ADS PubMed WorldCat 95. Collaborative Group On Epidemiological Studies Of Ovarian Cancer , Beral V, Gaitskell K, et al. . Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies . Lancet . 2015 ; 385 : 1835 – 1842 . Google Scholar Crossref Search ADS PubMed WorldCat 96. Gompel A , Burger H. A commentary on a recent update of the ovarian cancer risk attributable to menopausal hormone therapy . Climacteric . 2015 ; 18 : 376 – 378 . Google Scholar Crossref Search ADS PubMed WorldCat 97. Davis SR , Baber R. Reproductive endocrinology: menopausal hormone therapy-ovarian cancer risk revisited . Nat Rev Endocrinol . 2015 ; 11 : 322 – 323 . Google Scholar Crossref Search ADS PubMed WorldCat 98. Hsia J , Langer RD, Manson JE, et al. . Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative . Arch Intern Med . 2006 ; 166 : 357 – 365 . Google Scholar Crossref Search ADS PubMed WorldCat 99. Manson JE , Allison MA, Rossouw JE, et al. . Estrogen therapy and coronary-artery calcification . N Engl J Med . 2007 ; 356 : 2591 – 2602 . Google Scholar Crossref Search ADS PubMed WorldCat 100. Barrett-Connor E , Grady D. Hormone replacement therapy, heart disease, and other considerations . Annu Rev Public Health . 1998 ; 19 : 55 – 72 . Google Scholar Crossref Search ADS PubMed WorldCat 101. Løkkegaard E , Andreasen AH, Jacobsen RK, Nielsen LH, Agger C, Lidegaard Ø. Hormone therapy and risk of myocardial infarction: a national register study . Eur Heart J . 2008 ; 29 : 2660 – 2668 . Google Scholar Crossref Search ADS PubMed WorldCat 102. Shufelt CL , Merz CN, Prentice RL, et al. . Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women: findings from the Women's Health Initiative Observational Study . Menopause . 2014 ; 21 : 260 – 266 . Google Scholar Crossref Search ADS PubMed WorldCat 103. Schierbeck LL , Rejnmark L, Tofteng CL, et al. . Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial . BMJ . 2012 ; 345 : e6409 . Google Scholar Crossref Search ADS PubMed WorldCat 104. Harman SM , Black DM, Naftolin F, et al. . Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial . Ann Intern Med . 2014 ; 161 : 249 – 260 . Google Scholar Crossref Search ADS PubMed WorldCat 105. Renoux C , Dell'aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study . BMJ . 2010 ; 340 : c2519 . Google Scholar Crossref Search ADS PubMed WorldCat 106. Smith NL , Blondon M, Wiggins KL, et al. . Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens . JAMA Intern Med . 2014 ; 174 : 25 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat 107. Grodstein F , Manson JE, Stampfer MJ, Rexrode K. Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy . Arch Intern Med . 2008 ; 168 : 861 – 866 . Google Scholar Crossref Search ADS PubMed WorldCat 108. Canonico M , Oger E, Plu-Bureau G, et al. . Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study . Circulation . 2007 ; 115 : 840 – 845 . Google Scholar Crossref Search ADS PubMed WorldCat 109. Sweetland S , Beral V, Balkwill A, et al. . Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study . J Thromb Haemost . 2012 ; 10 : 2277 – 2286 . Google Scholar Crossref Search ADS PubMed WorldCat 110. Renoux C , Dell'Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: a population-based study . J Thromb Haemost . 2010 ; 8 : 979 – 986 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 111. Canonico M , Fournier A, Carcaillon L, et al. . Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study . Arterioscler Thromb Vasc Biol . 2010 ; 30 : 340 – 345 . Google Scholar Crossref Search ADS PubMed WorldCat 112. Roach RE , Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy . J Thromb Haemost . 2013 ; 11 : 124 – 131 . Google Scholar Crossref Search ADS PubMed WorldCat 113. Canonico M , Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis . BMJ . 2008 ; 336 : 1227 – 1231 . Google Scholar Crossref Search ADS PubMed WorldCat 114. Høibraaten E , Qvigstad E, Arnesen H, Larsen S, Wickstrøm E, Sandset PM. Increased risk of recurrent venous thromboembolism during hormone replacement therapy–results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET) . Thromb Haemost . 2000 ; 84 : 961 – 967 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 115. Olié V , Plu-Bureau G, Conard J, Horellou MH, Canonico M, Scarabin PY. Hormone therapy and recurrence of venous thromboembolism among postmenopausal women . Menopause . 2011 ; 18 : 488 – 493 . Google Scholar Crossref Search ADS PubMed WorldCat 116. Straczek C , Oger E, Yon de Jonage-Canonico MB, et al. . Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration . Circulation . 2005 ; 112 : 3495 – 3500 . Google Scholar Crossref Search ADS PubMed WorldCat 117. Canonico M , Oger E, Conard J, et al. . Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study . J Thromb Haemost . 2006 ; 4 : 1259 – 1265 . Google Scholar Crossref Search ADS PubMed WorldCat 118. Cirillo DJ , Wallace RB, Rodabough RJ, et al. . Effect of estrogen therapy on gallbladder disease . JAMA . 2005 ; 293 : 330 – 339 . Google Scholar Crossref Search ADS PubMed WorldCat 119. Simon JA , Hunninghake DB, Agarwal SK, et al. . Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease. The Heart and Estrogen/progestin Replacement Study . Ann Intern Med . 2001 ; 135 : 493 – 501 . Google Scholar Crossref Search ADS PubMed WorldCat 120. Grodstein F , Colditz GA, Stampfer MJ. Postmenopausal hormone use and cholecystectomy in a large prospective study . Obstet Gynecol . 1994 ; 83 : 5 – 11 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 121. Liu B , Beral V, Balkwill A, et al. . Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study . BMJ . 2008 ; 337 : a386 . Google Scholar Crossref Search ADS PubMed WorldCat 122. Racine A , Bijon A, Fournier A, et al. . Menopausal hormone therapy and risk of cholecystectomy: a prospective study based on the French E3N cohort . CMAJ . 2013 ; 185 : 555 – 561 . Google Scholar Crossref Search ADS PubMed WorldCat 123. Hart AR , Luben R, Welch A, Bingham S, Khaw KT. Hormone replacement therapy and symptomatic gallstones - a prospective population study in the EPIC-Norfolk cohort . Digestion . 2008 ; 77 : 4 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 124. Hendrix SL , Cochrane BB, Nygaard IE, et al. . Effects of estrogen with and without progestin on urinary incontinence . JAMA . 2005 ; 293 : 935 – 948 . Google Scholar Crossref Search ADS PubMed WorldCat 125. Steinauer JE , Waetjen LE, Vittinghoff E, et al. . Postmenopausal hormone therapy: does it cause incontinence? Obstet Gynecol . 2005 ; 106 : 940 – 945 . Google Scholar Crossref Search ADS PubMed WorldCat 126. Moyer VA , U.S, Preventive Services Task Force . Medications to decrease the risk for breast cancer in women: recommendations from the U.S. Preventive Task Force Recommendation Statement . Ann Intern Med . 2013 ; 159 ( 10 ): 698 – 708 . http://www.ncbi.nlm.nih.gov/pubmed/24061412 “Annals of internal medicine” 127. Boardman HM , Hartley L, Eisinga A, et al. . Hormone therapy for preventing cardiovascular disease in post-menopausal women . Cochrane Database Syst Rev . 2015 ; 3 : CD002229 . OpenURL Placeholder Text WorldCat 128. Grodstein F , Stampfer MJ, Colditz GA, et al. . Postmenopausal hormone therapy and mortality . N Engl J Med . 1997 ; 336 : 1769 – 1775 . Google Scholar Crossref Search ADS PubMed WorldCat 129. Berglind IA , Andersen M, Citarella A, Linder M, Sundström A, Kieler H. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins . Menopause . 2015 ; 22 : 369 – 376 . Google Scholar Crossref Search ADS PubMed WorldCat 130. Mikkola TS , Tuomikoski P, Lyytinen H, et al. . Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality . Menopause . 2015 ; 22 ( 9 ): 976 – 983 . Google Scholar Crossref Search ADS PubMed WorldCat 131. Salpeter SR , Cheng J, Thabane L, Buckley NS, Salpeter EE. Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women . Am J Med . 2009 ; 122 : 1016 – 1022.e1 . Google Scholar Crossref Search ADS PubMed WorldCat 132. Salpeter SR , Walsh JM, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis . J Gen Intern Med . 2004 ; 19 : 791 – 804 . Google Scholar Crossref Search ADS PubMed WorldCat 133. Maki PM . Critical window hypothesis of hormone therapy and cognition: a scientific update on clinical studies . Menopause . 2013 ; 20 : 695 – 709 . Google Scholar Crossref Search ADS PubMed WorldCat 134. Shumaker SA , Legault C, Rapp SR, et al. . Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial . JAMA . 2003 ; 289 : 2651 – 2662 . Google Scholar Crossref Search ADS PubMed WorldCat 135. Carlson MC , Zandi PP, Plassman BL, et al. . Hormone replacement therapy and reduced cognitive decline in older women: the Cache County Study . Neurology . 2001 ; 57 : 2210 – 2216 . Google Scholar Crossref Search ADS PubMed WorldCat 136. Jacobs DM , Tang MX, Stern Y, et al. . Cognitive function in nondemented older women who took estrogen after menopause . Neurology . 1998 ; 50 : 368 – 373 . Google Scholar Crossref Search ADS PubMed WorldCat 137. Sherwin BB , Tulandi T. “Add-back” estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri . J Clin Endocrinol Metab . 1996 ; 81 : 2545 – 2549 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 138. Phillips SM , Sherwin BB. Effects of estrogen on memory function in surgically menopausal women . Psychoneuroendocrinology . 1992 ; 17 : 485 – 495 . Google Scholar Crossref Search ADS PubMed WorldCat 139. Kang JH , Weuve J, Grodstein F. Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women . Neurology . 2004 ; 63 : 101 – 107 . Google Scholar Crossref Search ADS PubMed WorldCat 140. Espeland MA , Rapp SR, Shumaker SA, et al. . Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study . JAMA . 2004 ; 291 : 2959 – 2968 . Google Scholar Crossref Search ADS PubMed WorldCat 141. Rossouw JE , Prentice RL, Manson JE, et al. . Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause . JAMA . 2007 ; 297 : 1465 – 1477 . Google Scholar Crossref Search ADS PubMed WorldCat 142. Rosamond W , Flegal K, Furie K, et al. . Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee . Circulation . 2008 ; 117 : e25 – e146 . Google Scholar Crossref Search ADS PubMed WorldCat 143. Kariuki JK , Stuart-Shor EM, Leveille SG, Hayman LL. Evaluation of the performance of existing non-laboratory based cardiovascular risk assessment algorithms . BMC Cardiovasc Disord . 2013 ; 13 : 123 . Google Scholar Crossref Search ADS PubMed WorldCat 144. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. . 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines . Circulation . 2014 ; 129 : S49 – S73 . Google Scholar Crossref Search ADS PubMed WorldCat 145. Rossouw JE , Cushman M, Greenland P, et al. . Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the Women's Health Initiative trials of hormone therapy . Arch Intern Med . 2008 ; 168 : 2245 – 2253 . Google Scholar Crossref Search ADS PubMed WorldCat 146. Esposito K , Chiodini P, Colao A, Lenzi A, Giugliano D. Metabolic syndrome and risk of cancer: a systematic review and meta-analysis . Diabetes Care . 2012 ; 35 : 2402 – 2411 . Google Scholar Crossref Search ADS PubMed WorldCat 147. Wild RA , Wu C, Curb JD, et al. . Coronary heart disease events in the Women's Health Initiative hormone trials: effect modification by metabolic syndrome: a nested case-control study within the Women's Health Initiative randomized clinical trials . Menopause . 2013 ; 20 : 254 – 260 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 148. Szmuilowicz ED , Stuenkel CA, Seely EW. Influence of menopause on diabetes and diabetes risk . Nat Rev Endocrinol . 2009 ; 5 : 553 – 558 . Google Scholar Crossref Search ADS PubMed WorldCat 149. Curb JD , Prentice RL, Bray PF, et al. . Venous thrombosis and conjugated equine estrogen in women without a uterus . Arch Intern Med . 2006 ; 166 : 772 – 780 . Google Scholar Crossref Search ADS PubMed WorldCat 150. Cushman M , Kuller LH, Prentice R, et al. . Estrogen plus progestin and risk of venous thrombosis . JAMA . 2004 ; 292 : 1573 – 1580 . Google Scholar Crossref Search ADS PubMed WorldCat 151. Manson JE , Bassuk SS. The menopause transition and postmenopausal hormone therapy . In: Longo DL, Fauci AS, Kasper DL, et al. . Harrison's Principles of Internal Medicine . New York, NY : McGraw Hill ; 2012 ; 3040 – 3045 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 152. Stefanick ML , Anderson GL, Margolis KL, et al. . Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy . JAMA . 2006 ; 295 : 1647 – 1657 . Google Scholar Crossref Search ADS PubMed WorldCat 153. Visvanathan K , Hurley P, Bantug E, et al. . Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline . J Clin Oncol . 2013 ; 31 : 2942 – 2962 . Google Scholar Crossref Search ADS PubMed WorldCat 154. National Cancer Institute . Breast Cancer Risk Assessment Tool . http://www.cancer.gov/bcrisktool/ . Accessed April 12, 2015 155. Amir E , Freedman OC, Seruga B, Evans DG. Assessing women at high risk of breast cancer: a review of risk assessment models . J Natl Cancer Inst . 2010 ; 102 : 680 – 691 . Google Scholar Crossref Search ADS PubMed WorldCat 156. Tyrer J , Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors . Stat Med . 2004 ; 23 : 1111 – 1130 . Google Scholar Crossref Search ADS PubMed WorldCat 157. Kerlikowske K , Cook AJ, Buist DS, et al. . Breast cancer risk by breast density, menopause, and postmenopausal hormone therapy use . J Clin Oncol . 2010 ; 28 : 3830 – 3837 . Google Scholar Crossref Search ADS PubMed WorldCat 158. Hou N , Hong S, Wang W, Olopade OI, Dignam JJ, Huo D. Hormone replacement therapy and breast cancer: heterogeneous risks by race, weight, and breast density . J Natl Cancer Inst . 2013 ; 105 : 1365 – 1372 . Google Scholar Crossref Search ADS PubMed WorldCat 159. Chen J , Pee D, Ayyagari R, et al. . Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density . J Natl Cancer Inst . 2006 ; 98 : 1215 – 1226 . Google Scholar Crossref Search ADS PubMed WorldCat 160. Bhavnani BR . Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism . Proc Soc Exp Biol Med . 1998 ; 217 : 6 – 16 . Google Scholar Crossref Search ADS PubMed WorldCat 161. Torres-Santiago L , Mericq V, Taboada M, et al. . Metabolic effects of oral versus transdermal 17β-estradiol (E2): a randomized clinical trial in girls with Turner syndrome . J Clin Endocrinol Metab . 2013 ; 98 : 2716 – 2724 . Google Scholar Crossref Search ADS PubMed WorldCat 162. Slater CC , Hodis HN, Mack WJ, Shoupe D, Paulson RJ, Stanczyk FZ. Markedly elevated levels of estrone sulfate after long-term oral, but not transdermal, administration of estradiol in postmenopausal women . Menopause . 2001 ; 8 : 200 – 203 . Google Scholar Crossref Search ADS PubMed WorldCat 163. Nachtigall LE , Raju U, Banerjee S, Wan L, Levitz M. Serum estradiol-binding profiles in postmenopausal women undergoing three common estrogen replacement therapies: associations with sex hormone-binding globulin, estradiol, and estrone levels . Menopause . 2000 ; 7 : 243 – 250 . Google Scholar Crossref Search ADS PubMed WorldCat 164. Nelson HD . Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review . JAMA . 2004 ; 291 : 1610 – 1620 . Google Scholar Crossref Search ADS PubMed WorldCat 165. Crandall C . Low-dose estrogen therapy for menopausal women: a review of efficacy and safety . J Womens Health (Larchmt) . 2003 ; 12 : 723 – 747 . Google Scholar Crossref Search ADS PubMed WorldCat 166. Mauvais-Jarvis P , Bercovici JP. Hormone therapy by percutaneous route. Physiological bases. Clinical applications [in French] . Therapeutique . 1972 ; 48 : 403 – 406 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 167. Vehkavaara S , Silveira A, Hakala-Ala-Pietilä T, et al. . Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women . Thromb Haemost . 2001 ; 85 : 619 – 625 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 168. Scarabin PY , Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial . Arterioscler Thromb Vasc Biol . 1997 ; 17 : 3071 – 3078 . Google Scholar Crossref Search ADS PubMed WorldCat 169. Loeper J , Loeper MJ, Ohlghiesser C, de Lignières B, Mauvais-Jarvis P. The influence of estrogen therapy on triglycerides. Importance of the choice of substance and the route of administration (author's translation) [in French] . Nouv Presse Med . 1977 ; 6 : 2747 – 2750 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 170. Speroff L . Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal symptoms . Obstet Gynecol . 2003 ; 102 : 823 – 834 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 171. Al-Azzawi F , Buckler HM, United Kingdom Vaginal Ring Investigator Group . Comparison of a novel vaginal ring delivering estradiol acetate versus oral estradiol for relief of vasomotor menopausal symptoms . Climacteric . 2003 ; 6 : 118 – 127 . Google Scholar Crossref Search ADS PubMed WorldCat 172. Jaakkola S , Lyytinen H, Pukkala E, Ylikorkala O. Endometrial cancer in postmenopausal women using estradiol-progestin therapy . Obstet Gynecol . 2009 ; 114 : 1197 – 1204 . Google Scholar Crossref Search ADS PubMed WorldCat 173. Soini T , Hurskainen R, Grénman S, Mäenpää J, Paavonen J, Pukkala E. Cancer risk in women using the levonorgestrel-releasing intrauterine system in Finland . Obstet Gynecol . 2014 ; 124 : 292 – 299 . Google Scholar Crossref Search ADS PubMed WorldCat 174. Schiff I , Tulchinsky D, Cramer D, Ryan KJ. Oral medroxyprogesterone in the treatment of postmenopausal symptoms . JAMA . 1980 ; 244 : 1443 – 1445 . Google Scholar Crossref Search ADS PubMed WorldCat 175. Prior JC , Nielsen JD, Hitchcock CL, Williams LA, Vigna YM, Dean CB. Medroxyprogesterone and conjugated oestrogen are equivalent for hot flushes: a 1-year randomized double-blind trial following premenopausal ovariectomy . Clin Sci . 2007 ; 112 : 517 – 525 . Google Scholar Crossref Search ADS PubMed WorldCat 176. Hitchcock CL , Prior JC. Oral micronized progesterone for vasomotor symptoms–a placebo-controlled randomized trial in healthy postmenopausal women . Menopause . 2012 ; 19 : 886 – 893 . Google Scholar Crossref Search ADS PubMed WorldCat 177. The Endocrine Society . The Endocrine Society re-issues position statement on bioidentical hormones. Press release . https://www.endocrine.org/news-room/press-release-archives/2009/societyreissuespositionstatementonbioidenticalhormones. Published February 5, 2009 . Accessed February 13, 2015 178. Sharifi M , Lewiecki EM. Conjugated estrogens combined with bazedoxifene: the first approved tissue selective estrogen complex therapy . Expert Rev Clin Pharmacol . 2014 ; 7 : 281 – 291 . Google Scholar Crossref Search ADS PubMed WorldCat 179. Mirkin S , Komm BS, Pan K, Chines AA. Effects of bazedoxifene/conjugated estrogens on endometrial safety and bone in postmenopausal women . Climacteric . 2013 ; 16 : 338 – 346 . Google Scholar Crossref Search ADS PubMed WorldCat 180. Pinkerton JV , Harvey JA, Lindsay R, et al. . Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: a randomized trial . J Clin Endocrinol Metab . 2014 ; 99 : E189 – E198 . Google Scholar Crossref Search ADS PubMed WorldCat 181. Lobo RA , Pinkerton JV, Gass ML, et al. . Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile . Fertil Steril . 2009 ; 92 : 1025 – 1038 . Google Scholar Crossref Search ADS PubMed WorldCat 182. Lindsay R , Gallagher JC, Kagan R, Pickar JH, Constantine G. Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women . Fertil Steril . 2009 ; 92 : 1045 – 1052 . Google Scholar Crossref Search ADS PubMed WorldCat 183. Kagan R , Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women . Menopause . 2010 ; 17 : 281 – 289 . Google Scholar Crossref Search ADS PubMed WorldCat 184. Utian W , Yu H, Bobula J, Mirkin S, Olivier S, Pickar JH. Bazedoxifene/conjugated estrogens and quality of life in postmenopausal women . Maturitas . 2009 ; 63 : 329 – 335 . Google Scholar Crossref Search ADS PubMed WorldCat 185. Abraham L , Pinkerton JV, Messig M, Ryan KA, Komm BS, Mirkin S. Menopause-specific quality of life across varying menopausal populations with conjugated estrogens/bazedoxifene . Maturitas . 2014 ; 78 : 212 – 218 . Google Scholar Crossref Search ADS PubMed WorldCat 186. Pinkerton JV , Harvey JA, Pan K, et al. . Breast effects of bazedoxifene-conjugated estrogens: a randomized controlled trial . Obstet Gynecol . 2013 ; 121 : 959 – 968 . Google Scholar Crossref Search ADS PubMed WorldCat 187. Harvey JA , Pinkerton JV, Baracat EC, Shi H, Chines AA, Mirkin S. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens . Menopause . 2013 ; 20 : 138 – 145 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 188. Mirkin S , Archer DF, Taylor HS, Pickar JH, Komm BS. Differential effects of menopausal therapies on the endometrium . Menopause . 2014 ; 21 : 899 – 908 . Google Scholar Crossref Search ADS PubMed WorldCat 189. Pickar JH , Yeh IT, Bachmann G, Speroff L. Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy . Fertil Steril . 2009 ; 92 : 1018 – 1024 . Google Scholar Crossref Search ADS PubMed WorldCat 190. de Villiers TJ , Chines AA, Palacios S, et al. . Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial . Osteoporos Int . 2011 ; 22 : 567 – 576 . Google Scholar Crossref Search ADS PubMed WorldCat 191. Komm BS , Thompson JR, Mirkin S. Cardiovascular safety of conjugated estrogens plus bazedoxifene: meta-analysis of the SMART trials . Climacteric . 2015 ; 18 : 503 – 511 . Google Scholar Crossref Search ADS PubMed WorldCat 192. Kloosterboer HJ . Intracrinology: the secret of the tissue-specificity of tibolone . J Br Menopause Soc . 2000 ; 6 : 23 – 27 . OpenURL Placeholder Text WorldCat 193. Tiefert MA , Roy H, Moudrianakis EN. Binding of adenine nucleotides and pyrophosphate by the purified coupling factor of photophosphorylation . Biochemistry . 1977 ; 16 : 2396 – 2404 . Google Scholar Crossref Search ADS PubMed WorldCat 194. Formoso G , Perrone E, Maltoni S, et al. . Short and long term effects of tibolone in postmenopausal women . Cochrane Database Syst Rev . 2012 ; 2 : CD008536 . OpenURL Placeholder Text WorldCat 195. Davis SR . The effects of tibolone on mood and libido . Menopause . 2002 ; 9 : 153 – 155 . Google Scholar Crossref
TI - Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline
JF - Journal of Clinical Endocrinology and Metabolism
DO - 10.1210/jc.2015-2236
DA - 2015-11-01
UR - https://www.deepdyve.com/lp/oxford-university-press/treatment-of-symptoms-of-the-menopause-an-endocrine-society-clinical-CPirpQsJMg
SP - 3975
VL - 100
IS - 11
DP - DeepDyve
ER -