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Treatment of menopausal symptoms with hormone therapy
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Treatment of menopausal symptoms with hormone therapy
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Jun 08, 2016.

INTRODUCTION — Normal women have menopause at a mean age of 51 years, with 95 percent becoming menopausal between the ages of 45 to 55 years. Estrogen is the most effective treatment available for relief of menopausal symptoms, most importantly hot flashes. Menopausal hormone therapy (MHT; estrogen alone or combined with a progestin) is currently indicated for management of menopausal symptoms. Long-term use for prevention of disease is no longer recommended. The treatment of menopausal symptoms with MHT (estrogen alone or combined with progestin) will be reviewed here. An overview of the risks and benefits of estrogen, available hormone preparations, and an overview of menopausal therapies for women who choose not to or cannot take estrogen are discussed separately. (See "Menopausal hormone therapy: Benefits and risks" and "Preparations for menopausal hormone therapy" and "Menopausal hot flashes".)

GENERAL PRINCIPLES — Menopausal hormone therapy (MHT) is the broad term used to describe unopposed estrogen use for women who have undergone hysterectomy or combined estrogen-progestin therapy (EPT) for women with an intact uterus who need a progestin to prevent estrogen-associated endometrial hyperplasia. By convention, unopposed estrogen therapy is known as ET, combined estrogen-progestin therapy as EPT, and menopausal hormone therapy as MHT [1].

Goals of therapy — The goal of MHT is to relieve menopausal symptoms, most importantly hot flashes (vasomotor symptoms). Other symptoms associated with perimenopause and menopause that respond to ET include mood lability/depression, vaginal atrophy, sleep disturbances (when related to hot flashes), and in some cases, joint aches and pains. The management of vasomotor symptoms and the use of vaginal estrogen for vaginal atrophy are reviewed in greater detail separately. (See "Menopausal hot flashes" and "Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)".)

Women being treated for menopausal symptoms such as hot flashes require systemic estrogen; women being treated only for vulvovaginal atrophy (now referred to as “genitourinary syndrome of menopause” [GSM]) should be treated with low-dose vaginal estrogen rather than systemic estrogen. (See "Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)".)

In the past, MHT was also used by some clinicians to prevent coronary heart disease [CHD] and osteoporosis. However, we do not recommend MHT for prevention of disease given the results of the Women’s Health Initiative (WHI), a set of two large randomized trials that demonstrated an unfavorable risk-benefit profile of MHT. (See "Menopausal hormone therapy: Benefits and risks", section on 'Overview'.)

Importance of patient age — While the WHI clearly demonstrated adverse effects of MHT in older postmenopausal women (over age 60 years), this is not the age group that presents with new onset of menopausal symptoms. Almost all women who seek medical therapy for menopausal symptoms do so in their late 40s or 50s. Women in this age group should be reassured that the absolute risk of complications for healthy, young postmenopausal women taking MHT for five years is very low (figure 1). (See "Menopausal hormone therapy: Benefits and risks", section on 'Estimates of risk in women 50 to 59 years'.)

Indications — The most common indication for MHT is vasomotor symptoms (or hot flashes). Vasomotor symptoms occur most often in the late menopausal transition and early postmenopause (figure 2). Although there are alternative therapies for vasomotor symptoms, none are as effective as estrogen. The physiology, clinical manifestations (including insomnia), and treatment of hot flashes (including intractable hot flashes) are discussed in detail elsewhere (see "Menopausal hot flashes"). An overview of the clinical manifestations of the menopausal transition and menopause are found separately. (See "Clinical manifestations and diagnosis of menopause".)

In addition to hot flashes, other potential indications for MHT include:

Mood lability/depression – MHT, alone or in combination with an antidepressant such as a selective serotonin reuptake inhibitor (SSRI), is effective for women who experience mood lability or depression during the menopausal transition. (See 'Depression in perimenopausal women' below.)

Joint aches and pains – It is unclear if the pain is related to estrogen deficiency or a rheumatologic disorder, but in the WHI, women with joint pain or stiffness at baseline were more likely to get relief with either combined EPT or unopposed ET than with placebo [2,3]. (See "Clinical manifestations and diagnosis of menopause", section on 'Joint pain'.)

Genitourinary symptoms of menopause (GSM) – The epithelial linings of the vagina and urethra are very sensitive to estrogen, and estrogen deficiency leads to thinning of the vaginal epithelium. This results in GSM (also called vaginal atrophy or atrophic vaginitis), causing symptoms of vaginal dryness, itching, dyspareunia, and sometimes urinary symptoms. Both systemic and vaginal estrogen are effective for genitourinary atrophy symptoms, but we suggest vaginal rather than systemic estrogen for women who have only GSM without other menopausal symptoms such as hot flashes. (See "Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)", section on 'Vaginal estrogen therapy'.)

MHT is no longer recommended for prevention of chronic disease (CHD or osteoporosis) [4]. In addition, we do not suggest its use for cognitive function or prevention of dementia (See "Menopausal hormone therapy: Benefits and risks".)

CHD - We suggest not using MHT for the prevention of CHD, even in young postmenopausal women. Although the risk profile appears to be more favorable in young women taking unopposed estrogen, use for prevention is still not warranted [1,5-7]. The hormone regimen studied in the WHI was conjugated estrogens and medroxyprogesterone acetate (MPA). While it is possible that other estrogen or progestin formulations or doses might not have the same negative cardiovascular effects as conjugated estrogen and MPA, data to support their use for prevention are not available. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Timing of exposure'.)

Osteoporosis - Although we previously recommended estrogen as a first-line choice for prevention and treatment of osteoporosis, we now recommend bisphosphonates. However, in the occasional patient with persistent menopausal symptoms who cannot tolerate first and second-line therapies for osteoporosis, estrogen may be a reasonable option. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Estrogen/progestin therapy'.)

Cognitive function and dementia – We currently do not suggest the routine use of MHT for peri- and postmenopausal women who are experiencing cognitive symptoms (memory loss and difficulty concentrating). Although substantial biologic evidence supports the importance of estrogen to cognitive function, clinical trial evidence has generally ruled out any global (but not domain-specific) cognitive benefits. (See "Estrogen and cognitive function", section on 'Clinical trial evidence'.)

In addition, we suggest not using MHT to prevent dementia. Although some epidemiologic data suggest that estrogen may be beneficial, clinical trials of MHT administered to women over age 65 years showed harm. Strong evidence of cognitive benefits for women taking MHT at younger ages (eg, near menopause) is also lacking, and thus MHT should not be prescribed for preservation of cognitive function in younger women. (See "Estrogen and cognitive function", section on 'Clinical trial data'.)

Contraindications — Contraindications to MHT include a history of breast cancer, CHD, a previous venous thromboembolic event or stroke, active liver disease, unexplained vaginal bleeding, high-risk endometrial cancer, or transient ischemic attack [8].

Oral estrogens should be avoided in women with hypertriglyceridemia, active gallbladder disease, or known thrombophilias such as factor V Leiden (without a personal history of venous thromboembolism [VTE]). Transdermal estrogen is also preferred for women with migraine headaches with auras.

OVERVIEW OF APPROACH

Choosing candidates — We consider the initiation of menopausal hormone therapy (MHT) to be a safe option for healthy, symptomatic women who are within 10 years of menopause or younger than age 60 years and who do not have contraindications to MHT (such as a history of breast cancer, coronary heart disease [CHD], a previous venous thromboembolic event or stroke, or active liver disease) [1,5,8,9]. (See 'Contraindications' above.)

The 2015 clinical practice guideline published by the Endocrine Society presents an individualized approach to treatment based upon calculating a woman’s baseline cardiovascular and breast cancer risks prior to initiating therapy [8]. Similar to most other guidelines, the Endocrine Society agrees that MHT is indicated for the management of menopausal symptoms but not for the prevention of cardiovascular disease (CVD), osteoporosis, or dementia.

Calculating risks — The Endocrine Society guideline suggests calculating cardiovascular and breast cancer risks before initiating MHT [8]. They suggest nonhormonal therapies for symptomatic women who are at high risk (>10 percent 10-year risk) for CVD (table 1) or moderate (1.67 to 5 percent five-year risk) to high risk (>5 percent) for breast cancer. For women at moderate risk of CVD (5 to 10 percent 10-year risk), they suggest transdermal rather than oral estrogen, with micronized progesterone for those with a uterus (table 1). They note that a population-based CVD risk calculator should be used to estimate CVD risk (calculator 1). An online tool such as the National Cancer Institute Breast Cancer Risk Assessment Tool can be used to assess five-year breast cancer risk [10].

Although this represents the ideal approach, a formal CVD calculation may not be necessary in a thin, healthy, nonhypertensive patient who is well known to the clinician. For women at increased risk of venous thromboembolism (VTE), they also suggest transdermal estrogen with a progestin that has a neutral effect on coagulation parameters (eg, micronized progesterone).

Starting estrogen — Once a decision has been made to treat a postmenopausal woman with estrogen, consideration should be given to the type of estrogen and the route by which it is to be given, as well as the need for progestin and the most appropriate progestin regimen. Estrogen is available in many forms: oral, transdermal, topical gels and lotions, intravaginal creams and tablets, and vaginal rings. In some countries, estrogen can also be given as a subcutaneous implant (table 2).

The potency and therefore the doses of these estrogen preparations differ, but they differ little in efficacy [11]. Vaginal estrogen is most commonly used in very low doses for the management of genitourinary syndrome of menopause (GSM), also known as vaginal atrophy. However, high doses of vaginal estrogen can also be used to treat vasomotor symptoms, much like a transdermal preparation [12]. We do not recommend these high doses, ie, systemic estrogen doses, in women who need therapy for genitourinary symptoms only. (See "Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)", section on 'Vaginal estrogen therapy'.)

Estrogen therapy (ET) remains the gold standard for relief of menopausal symptoms, in particular, hot flashes.

Route — We start many women on transdermal 17-beta estradiol because it is associated with a lower risk of VTE, stroke, and hypertriglyceridemia than oral estrogens. The transdermal route is particularly important in women with hypertriglyceridemia or risk factors for thromboembolism.

However, the baseline risk of both VTE and stroke is very low in otherwise healthy, young postmenopausal women. Therefore, if a patient prefers an oral preparation over a transdermal one (cost or personal preference), we consider oral estrogen to be safe. We typically choose oral 17-beta estradiol preparations although some clinicians prefer conjugated estrogens, a preparation that has been popular historically (and the preparation studied in the Women’s Health Initiative [WHI]). Details on the types of estrogen preparations are reviewed separately. (See "Preparations for menopausal hormone therapy", section on 'Estrogen preparations'.)

All routes of estrogen administration appear to be equally effective for symptom relief (and bone density), but their metabolic effects differ:

Oral estrogen has more favorable effects on lipid profiles, but there is no evidence that this results in long-term clinical benefit. On the other hand, oral estrogens are associated with increases in serum triglycerides and C-reactive protein. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Lipids'.)

Oral estrogens increase sex hormone-binding globulin (SHBG) more than transdermal preparations, which results in lower free testosterone concentrations. In theory, this could result in a negative impact on libido and sexual function, but this has not been proven. Similar effects on thyroxine-binding globulin (TBG) and bioavailable thyroxine (T4) occur with oral estrogen (increased TBG and lower bioavailable T4). Oral estrogens also increase cortisol-binding globulin (CBG), resulting in an increase in total serum cortisol. Interpreting serum cortisol values in a woman taking oral estrogen can therefore be misleading. (See 'Factors affecting oral estrogen metabolism' below.)

The risks of VTE and stroke appear to be higher with oral when compared with transdermal estrogen. (See "Menopausal hormone therapy and cardiovascular risk" and 'Factors affecting oral estrogen metabolism' below.)

In addition to oral and transdermal estrogen preparations, estrogen is available as a vaginal ring and as a topical spray, cream, or gel. The topical spray (Evamist) has been linked to adverse effects in children and pets exposed to the drug via skin contact. (See "Preparations for menopausal hormone therapy", section on 'Topical estradiol'.)

The US Food and Drug Administration (FDA) now requires the adding of labels to all estrogen and estrogen-progestin products warning of the possible risk of heart disease, stroke, and cancer [13].

Dose — All types and routes of estrogen are effective for relieving menopausal symptoms, particularly, hot flashes. (See "Menopausal hot flashes", section on 'Menopausal hormone therapy'.)

In a meta-analysis of 24 trials of MHT in 3329 women, the frequency of hot flashes decreased more in those receiving MHT (weighted mean difference -18 hot flashes per week compared with placebo; 95% CI -22.86 to -12.99; 75 percent reduction) [14]. The severity of hot flashes also decreased more with MHT compared with placebo.

In a second meta-analysis, conjugated estrogen 0.625 mg/day and 17-beta estradiol (oral 1 mg/day or transdermal 0.05 mg/day) appeared to be equally effective for the treatment of hot flashes [15]. These doses eliminate hot flashes completely in about 80 percent of women and reduce the frequency and severity in the remainder [14].

In the past, a “one-size-fits-all” approach to estrogen dosing was used, with oral conjugated estrogen (0.625 mg/day) or its equivalent oral 17-beta estradiol (1 mg/day), or transdermal 17-beta estradiol (0.05 mg [50 mcg]), prescribed to most women. If symptoms were relieved, the same dose was continued indefinitely. However, the current approach is to start with lower doses, such as transdermal estradiol (0.025 mg) or oral estradiol (0.5 mg/day), and titrate up to relieve symptoms. Lower doses are associated with less vaginal bleeding and breast tenderness [16].

Lower doses are also associated with fewer effects on coagulation and inflammatory markers, and a possible lower risk of stroke and VTE than standard-dose therapy [17,18].

Based upon available data, we suggest starting with lower doses of estrogen (oral 17-beta estradiol [0.5 mg/day] or 0.025 mg of transdermal estradiol) unless the patient has severe symptoms. If hot flashes are still present after one month, we increase transdermal estradiol to 0.0375 mg and reassess one month later. If symptoms are still not relieved, we increase further to 0.05 mg. An exception to this approach is the patient with severe symptoms; we start with a transdermal dose of 0.05 mg to achieve more rapid relief of symptoms.

“Standard” doses of estrogen given daily (conjugated estrogen 0.625 mg or its equivalent) are adequate for symptom relief in the majority of women [14,15,19]. An exception is younger women after bilateral oophorectomy. They often require higher doses (eg, up to 0.1 mg transdermal estradiol) for the first two to three years after surgery; the dose can subsequently be tapered down.

The lowest available transdermal estradiol dose is 0.014 mg; it is approved for prevention of bone loss. However, about 50 percent of women derive some benefit for hot flashes. [20]. Progestin doses may be lowered with low-dose estrogen, but there is no consensus on optimal regimens. (See 'Adding a progestin' below.)

Estrogen should be administered continuously; past regimens where estrogen was administered days 1 to 25 of the calendar month are considered to be obsolete. Women will often get hot flashes during the days off, and there is no known advantage to stopping for several days each month.

Side effects — Common side effects of estrogen include breast soreness, which can often be minimized by using lower doses. As noted above, some women experience mood symptoms and bloating with progestin therapy. Vaginal bleeding occurs in almost all women receiving cyclic estrogen-progestin regimens and is common in the early months of a continuous estrogen-progestin regimen. (See 'Adding a progestin' below.)

Factors affecting oral estrogen metabolism — There are several situations in which the metabolism of exogenous estrogen is altered and therefore a change in the dose may be needed. Increased metabolism may result in lower serum estrogen concentrations, while decreased metabolism can result in higher serum concentrations.

The above dosing suggestions (see 'Dose' above) may need to be increased in women taking anticonvulsant drugs (phenytoin, carbamazepine), which increase the hepatic clearance of estrogens and other steroid hormones. However, there is no way to predict how much more estrogen is needed [21]. In this situation, a transdermal estrogen may be better than oral estrogen since it avoids the first-pass hepatic metabolism. (See "Overview of the use of estrogen-progestin contraceptives", section on 'Drug interactions'.)

Oral estrogens increase TBG more than transdermal preparations, which results in lower bioavailable T4. Therefore, in women receiving T4 replacement therapy, the addition of oral ET may increase T4 requirements. (See "Treatment of hypothyroidism".)

Concurrent acute alcohol ingestion with oral estradiol has been found to cause a threefold rise in serum estradiol concentrations, apparently by slowing the metabolism of estradiol [22]. While it would be difficult to alter the medication dose based upon these findings, women taking exogenous estrogen should be encouraged to limit alcohol intake.

Women with end-stage renal disease have higher serum estradiol concentrations after an oral dose of estrogen than do normal women [23].

Adding a progestin — We suggest oral micronized progesterone as our first-line progestin. All women with an intact uterus need a progestin in addition to estrogen to prevent endometrial hyperplasia, which can occur after as little as six months of unopposed ET. Women who have undergone hysterectomy should not receive a progestin, as there are no other health benefits other than prevention of endometrial hyperplasia and carcinoma. (See "Menopausal hormone therapy: Benefits and risks", section on 'Endometrial hyperplasia and carcinoma'.)

The most extensively-studied formulation for endometrial protection is the synthetic progestin used in the WHI, medroxyprogesterone acetate (MPA) (2.5 mg daily). While MPA is endometrial protective, it was associated with an excess risk of CHD and breast cancer when administered with conjugated estrogen in the WHI. In addition, regimens using continuous versus cyclic MPA may be associated with a higher risk of breast cancer. (See "Menopausal hormone therapy and the risk of breast cancer", section on 'Effect of progestins'.)

Our first choice of progestin is natural micronized progesterone (200 mg/day for 12 days/month or 100 mg daily). There are reasons to believe that natural progesterone might be safer for the cardiovascular system (no adverse lipid effects) and possibly the breast. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Effects of progestins' and "Menopausal hormone therapy and the risk of breast cancer", section on 'Type of progestin'.)

For women who are perimenopausal or newly menopausal, we start with cyclic administration of oral micronized progesterone (200 mg/day for 12 days of each calendar month). Continuous administration in this population is associated with irregular, unscheduled bleeding due to the exogenous hormones and the continued endogenous ovarian function. For women who are ≥2 to 3 years postmenopause, we use a continuous regimen (micronized progesterone 100 mg/day); irregular and breakthrough bleeding is less of a problem once ovarian function has ceased. While there is often early breakthrough bleeding even after menopause, most women do eventually develop amenorrhea, a desired goal of continuous administration. (See "Preparations for menopausal hormone therapy", section on 'Bleeding patterns'.)

Side effects and bleeding — Some women are unable to tolerate cyclic progestin administration (with any type of oral progestin) because of mood side effects and bloating. In addition, cyclic progestins almost always result in monthly withdrawal bleeding, which can be a lifestyle concern for many women. For any of these concerns, we suggest switching to a continuous regimen. This often resolves the issue of mood symptoms and bloating. However, for women who are newly menopausal, breakthrough bleeding can be anticipated. (See "Preparations for menopausal hormone therapy", section on 'Bleeding patterns'.)

Women who cannot tolerate oral progestins — Some women are unable to tolerate any oral progestin, whether given in a cyclic or continuous regimen. In this case, we sometimes suggest off-label use of the lower dose levonorgestrel-releasing intrauterine device (IUD) (table 3). (See "Preparations for menopausal hormone therapy", section on 'Levonorgestrel-releasing intrauterine device'.)

Other progestins that have been used include quarterly regimens (progestin administered only every third month). However, quarterly progestin administration is not considered to be standard therapy and cannot be recommended. Vaginal progesterone regimens have also been tried, but endometrial safety data are limited [24]. (See "Menopausal hormone therapy: Benefits and risks", section on 'Protective effect of progestins' and "Preparations for menopausal hormone therapy", section on 'Progestin preparations'.)

Conjugated estrogen/bazedoxifene — Another option is the combination of bazedoxifene, a selective estrogen receptor modulator (SERM), with conjugated estrogen. This product is available in the United States for the treatment of menopausal vasomotor symptoms and osteoporosis prevention. In this combination, the SERM bazedoxifene prevents estrogen-induced endometrial hyperplasia so that administering a progestin is not necessary. Potential candidates include women with moderate-to-severe hot flashes who have breast tenderness with standard estrogen-progestin therapy (EPT) or women who cannot tolerate any type of progestin therapy because of side effects. Like other SERMs, the risk of VTE is increased with bazedoxifene. To date, no additive effect on VTE has been observed with the combination conjugated estrogen/bazedoxifene, but longer studies are needed to fully address this risk. (See "Menopausal hot flashes", section on 'Bazedoxifene/conjugated estrogen'.)

Duration of therapy — For women who choose estrogen or combined EPT, short-term use is suggested (generally not more than five years or not beyond age 60 years [25]). However, hot flashes persist for an average of 7.4 years, and many women continue to have symptoms for more than 10 years. Some women with persistent symptoms choose longer-term therapy. (See 'Extended use of MHT' below and "Menopausal hot flashes", section on 'Duration'.)

For women who experience recurrent, bothersome hot flashes after stopping estrogen, we initially suggest nonhormonal options before considering resuming estrogen. For those who do not get adequate relief with nonhormonal therapies, we consider extended use of hormone therapy. (See 'Extended use of MHT' below.)

Data on the attributable risks and benefits of MHT for a period of five years in women ages 50 to 59 years are available and can be used for evidence-based decision making (figure 1) [5]. (See "Menopausal hormone therapy: Benefits and risks", section on 'Estimates of risk in women 50 to 59 years'.)

Monitoring with mammography — Routine mammograms and breast exams are recommended in women taking MHT, even when used short-term. In the WHI, the risk of breast cancer with combined EPT did not increase until the fourth year. However, abnormal mammograms were more common with both ET and EPT (although more common with EPT). The majority of abnormal mammograms in the WHI represented requests for additional views. Of note, stopping therapy for one to two months before a mammogram does not reduce recall rates. (See "Menopausal hormone therapy and the risk of breast cancer", section on 'Abnormal mammography'.)

Use of oral contraceptives during the menopausal transition — A low-estrogen oral contraceptive (OC) is an option for perimenopausal women who seek relief of menopausal symptoms, who also desire contraception, and who in some instances need control of bleeding when it is heavy [26]. Most of these women are between the ages of 40 and 50 years and are still candidates for OCs. For them, an OC containing 20 mcg of ethinyl estradiol provides symptomatic relief while providing better bleeding control than conventional MHT, because the OC contains higher doses of both estrogen and progestin (which suppresses the hypothalamic-pituitary-ovarian axis). OCs should be avoided in obese perimenopausal women because they are at greater risk for thromboembolism.

Contraindications to OC use in this population include smoking, hypertension, and migraine headaches. (See "Overview of the use of estrogen-progestin contraceptives", section on 'Perimenopausal women'.)

Contraception remains important during perimenopause, as women cannot be certain of infertility until they reach menopause (ie, 12 months without menses). The possibility of pregnancy in women ages 45 to 49 years not using contraception is estimated to be 2 to 3 percent, falling to less than 1 percent after age 50 years. (See "Effect of advanced age on fertility and pregnancy in women", section on 'Fertility'.)

In our practice, when women taking a low-dose OC during perimenopause reach age 50 or 51 years, we discuss stopping the pill altogether or changing to a postmenopausal estrogen regimen if necessary for symptoms. If estrogen is then given, the same recommendations for use would apply. (See "Overview of the use of estrogen-progestin contraceptives", section on 'Perimenopausal women'.)

Because women at this age are apt to have hot flushes when estrogen is stopped abruptly, we suggest tapering the OC by one pill per week as described for ET in the following section.

Stopping hormone therapy — Many women have no trouble stopping estrogen. Observational studies report that 40 to 50 percent of women who start MHT stop within one year [27], and 65 to 75 percent stop within two years [28], often with no assistance from their healthcare provider.

However, abrupt withdrawal of exogenous estrogen at any age may result in the return of hot flashes and other menopausal symptoms. This was illustrated in a cross-sectional survey of 8405 women who had participated in the WHI combined estrogen-progestin trial, all of whom were instructed to abruptly discontinue their MHT when the trial was stopped [29]. Compared with patients in the placebo group, the women who abruptly discontinued hormone were significantly more likely to develop moderate to severe symptoms whether they had hot flashes at baseline (56 versus 22 percent) or did not have hot flashes at baseline (21 versus 5 percent).

Tapering — Although tapering MHT has not been proven to be more effective than stopping treatment abruptly, we suggest a gradual taper, particularly in women with a history of severe vasomotor symptoms.

Many women have no difficulty with recurrent symptoms when they stop MHT, while others have symptoms severe enough to require resumption of therapy. Based upon the WHI results, one can anticipate that roughly 55 percent will have some recurrent vasomotor symptoms if MHT is stopped abruptly [29].

Data regarding the strategy of abrupt cessation of MHT versus tapering are conflicting. Survey data suggest that women who taper MHT have lower menopausal scores after stopping than women who stopped abruptly [30,31]. However, in a randomized trial, 91 postmenopausal women who were on MHT for at least three years (primarily for hot flashes) were randomly assigned to either an abrupt or gradual discontinuation (over six months) of their MHT [32]. Vasomotor symptoms were worse in the abrupt group during the first three months, but worse in the taper group at six months, with no differences between groups by 9 to 12 months. After stopping therapy, a similar percentage resumed therapy in the two groups (42 and 36 percent in the abrupt and taper groups, respectively). In a second trial, a rapid taper over two weeks did not seem to be better than stopping abruptly, but the duration of follow-up (four weeks) was too short to adequately assess recurrent symptoms [33].

When tapering, one approach is to decrease the estrogen by one pill per week every few weeks (ie, six pills per week for two to four weeks, then five pills per week for two to four weeks, etc) until the taper is completed. The progestin is tapered on the same schedule. In our experience, some women with severe, recurrent symptoms during or after a three to six-month taper go back on their estrogen. We then try a much slower taper, sometimes over one year (six pills per week for two months, five pills per week for one month, etc).

For women taking a transdermal preparation, we do a gradual dose reduction (the transdermal preparations come in a variety of doses: 0.1, 0.075, 0.05, 0.0375, 0.025, 0.0114 mg patches), usually over three to six months, and if unsuccessful, we repeat the taper over one year.

Implications of stopping — The implications of stopping EPT include:

Return of estrogen deficiency symptoms is common. In women who have recurrent vasomotor symptoms after stopping therapy, there is currently no way to determine whether the symptoms will resolve quickly or persist for a prolonged time. For women who experience recurrent, bothersome hot flashes after stopping estrogen, we initially suggest nonhormonal options before considering resuming estrogen. (See "Menopausal hot flashes", section on 'Nonhormonal pharmacotherapy' and 'Extended use of MHT' below.)

Resumption of bone loss [34-36]. (See "Postmenopausal hormone therapy in the prevention and treatment of osteoporosis".)

Decrease in breast cancer risk [37,38]. (See "Menopausal hormone therapy and the risk of breast cancer", section on 'Post-WHI rates'.)

The effect of estrogen cessation on coronary disease, particularly in young postmenopausal women, is unclear [38,39].

Extended use of MHT — Both the North American Menopause Society and the American College of Obstetrics and Gynecology agree that use of MHT should be individualized and not discontinued solely based upon patient age. They suggest that extended use of MHT (beyond age 60 or even 65 years) may be reasonable when the clinician and patient agree that the benefits of symptom relief outweigh the risks [40,41]. As noted, over 40 percent of women ages 60 to 65 years have persistent hot flashes that can impair sleep and quality of life.

For women who choose extended use of MHT (more than five years or beyond age 60 years), we restart estrogen at the lowest dose possible and make plans for a future attempt to stop the estrogen.

SPECIAL ISSUES

Bioidentical hormone therapy — We suggest against the use of custom-compounded bioidentical hormone therapy as there is no evidence for their safety or efficacy when compared with approved and commercially available products for menopausal hormone therapy (MHT) [42-45]. The term “bioidentical hormone” technically refers to a hormone with the same molecular structure as a hormone that is endogenously produced (eg, 17-beta estradiol). However, in popular culture, the term refers to the use of custom-compounded, multi-hormone regimens (pills, gels, sublingual tablets, or suppositories) with dose adjustments based upon serial hormone monitoring. The hormones most commonly compounded are estradiol, estrone, estriol, progesterone, testosterone, and dehydroepiandrosterone (DHEA) [42-45].

Many postmenopausal women are turning to this approach because of safety concerns about conventional hormone preparations. However, there are no large clinical trials that have determined the efficacy, safety, or adverse effects of these preparations [43]. “Bioidentical hormones” are derived from soy and plant extracts and are modified to be structurally identical to endogenous hormones, the same approach used for most approved and commercially available menopausal hormone preparations (with the exception of conjugated equine estrogens [CEEs]). The quality of the compounded products may be substandard in some cases [46]. In one study, potencies ranged from 67.5 to 268 percent of the amount specified on the labeling [47]. One pharmacokinetic study reported highly variable patterns of absorption with a commonly used bioidentical combination estrogen preparation; serum estradiol and estrone concentrations were lower than expected when compared with a comparable dose of a commercially available transdermal estradiol preparation [48].

A number of expert groups, including the North American Menopause Society [1], American College of Obstetricians and Gynecologists [49], and the Endocrine Society [45], have issued scientific statements advising against the use of custom-compounded hormones. Key points of the 2016 Endocrine Society statement include:

There are numerous approved estrogen and progestin formulations in all countries for MHT; therefore, there is no rationale for use of non-approved products.

There are no randomized trials demonstrating either efficacy or safety of compounded bioidentical hormone therapy for treating menopausal symptoms.

The contents, dose, quality, and sterility of these products are not subject to regulatory oversight. When tested, potencies and patterns of absorption of compounded estrogens have been highly variable [47,48].

These products are not required to include package inserts or the standard warnings that all approved estrogens provide.

In spite of warnings against the use of bioidentical hormones, there has been continued growth of the industry. In a survey of compounding and community pharmacies in the United States, it was estimated that prescription rates for custom-compounded bioidentical hormones now approach those of US Food and Drug Administration (FDA)-approved MHT prescriptions [44]. Similar results were reported in a second study [50]. This highlights the importance of physician and patient education about the differences between approved products and less-regulated hormone formulations.

Role of androgen therapy — The known decrease in ovarian androgen production rates and serum androgen concentrations has caused concern that menopause might be associated with a decline in libido. An age-associated decline in sexual desire has been observed in both men and women. However, it is unclear whether the decline in libido in women is age or menopause related, since studies in women have not shown a significant correlation between libido and the serum estradiol or testosterone concentration [51].

Clinical trials of exogenous testosterone replacement suggest modest benefits of testosterone therapy in some postmenopausal women. However, there are potential risks associated with androgen replacement, and the use of testosterone is limited by the lack of approved and commercially available products for women. Until the beneficial effects of androgen replacement are better established, it cannot be routinely recommended to postmenopausal women. (See "Overview of androgen deficiency and therapy in women" and "Sexual dysfunction in women: Management", section on 'Androgens'.)

Migraines — Migraine headaches (with or without aura) are not considered to be a contraindication to MHT. For women with hot flashes and estrogen-associated migraines (which typically worsen during perimenopause), estrogen therapy (ET) often improves both symptoms. In this setting, we suggest continuous transdermal hormone regimens (as opposed to cyclic regimens) to avoid triggering estrogen-withdrawal headaches. The effect of MHT on stroke risk in postmenopausal women with migraines is not well studied. However, low doses of transdermal estradiol (≤50 mcg, the dose range we routinely recommend) have not been associated with an excess risk of stroke in normal women (see 'Dose' above). The topics of menopause, hormone therapy, and migraine are reviewed in more detail separately. (See "Estrogen-associated migraine", section on 'Migraines and menopause'.)

Depression in perimenopausal women — Mood disorders are common during the menopausal transition, often coexisting with vasomotor symptoms. Our approach is to choose initial therapy based upon the woman’s predominant symptom. If her main concern is depression and hot flashes are not severe, we start with an SSRI. On the other hand, if vasomotor symptoms are the major symptom and depression or mood symptoms are mild, we start with MHT (see 'Starting estrogen' above). For women in whom depression and vasomotor symptoms are both severe, we start both estrogen and an SSRI and refer to a psychopharmacologist for further consultation and monitoring. In our experience, many women require both MHT and estrogen for optimal symptom relief. The efficacy of estrogen for depression occurring after menopause is unclear [52].

The risk of depression during perimenopause is higher than during the pre- or postmenopausal years. Perimenopausal depression includes both new-onset (first episode) depression as well as a relapse in women with a history of depression. (See "Clinical manifestations and diagnosis of menopause", section on 'Depression'.)

In one trial of ET for perimenopausal depression, 50 perimenopausal women with major depression, dysthymia, or minor depressive disorders received transdermal estradiol (0.1 mg) or placebo for 12 weeks. Remission of depression occurred in 68 percent of patients compared with only 20 percent receiving placebo [53].The Kronos Early Estrogen Prevention Study (KEEPS), a trial of MHT in younger menopausal women ages 45 to 54 years who underwent extensive mood evaluations, reported that four years of oral estrogen appeared to improve mood, as women receiving oral conjugated estrogen combined with micronized progesterone had lower depression and anxiety scores than those receiving either transdermal estradiol with micronized progesterone or placebo [54].

SSRIs are effective for perimenopausal depression, and some provide modest benefit for hot flashes as well [55,56] (see "Menopausal hot flashes", section on 'Nonhormonal pharmacotherapy'). Data also suggest that adding estrogen to antidepressant therapy may result in additional benefit for perimenopausal women with depression [57].

Primary ovarian insufficiency — Data from the Women’s Health Initiative (WHI), a set of MHT trials in older postmenopausal women, should not be extrapolated to women with premature ovarian failure (now termed primary ovarian insufficiency [POI], defined as menopause before age 40 years). Hormone therapy is started at a younger age in these women, and current guidelines suggest that therapy should be continued until the average age of menopause (age 50 to 51 years) to prevent premature bone loss, coronary heart disease (CHD), and stroke. At that point, if hormone therapy is stopped and menopausal symptoms are moderate to severe, the same discussion of potential risks and benefits of MHT should take place. (See "Management of spontaneous primary ovarian insufficiency (premature ovarian failure)", section on 'Duration of treatment'.)

Breast cancer patients — Although women with breast cancer often experience early menopause due to adjuvant chemotherapy and may have vasomotor symptoms due to tamoxifen therapy, ET should not be prescribed. The epidemiologic data and clinical trial data have been inconsistent, but the increased risk of breast cancer recurrence with ET in one trial (Hormonal Replacement After Breast Cancer – Is It Safe? [HABITS]) is of great concern. We therefore do not recommend estrogen for women with a personal history of breast cancer. We suggest that other established means of controlling symptoms or preventing osteoporosis should be utilized before considering ET in these women. (See "Menopausal hormone therapy and the risk of breast cancer", section on 'Personal history of breast cancer'.)

Women with endometrial cancer — Women with low-risk disease and menopausal symptoms are candidates for hormone therapy; for younger women, this is also important to decrease the long-term health consequences of estrogen deficiency. Nonhormonal options are preferred for women with intermediate-risk or high-risk disease. (See "Overview of approach to endometrial cancer survivors", section on 'Menopausal symptoms'.)

Known thrombophilia — MHT increases the risk of venous thrombosis by approximately twofold. This appears to be true for oral preparations, but perhaps not for transdermal preparations. However, available data come from observational studies, not clinical trials. Data suggest that women who have factor V Leiden and use oral hormone therapy have a 15-fold increased risk of venous thromboembolism (VTE). Therefore, oral MHT should be avoided in postmenopausal women with prothrombotic mutations. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Venous thromboembolism'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient education: Menopause (The Basics)")

Beyond the Basics topics (see "Patient education: Menopause (Beyond the Basics)" and "Patient education: Menopausal hormone therapy (Beyond the Basics)" and "Patient education: Nonhormonal treatments for menopausal symptoms (Beyond the Basics)" and "Patient education: Vaginal dryness (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

The goal of menopausal hormone therapy (MHT) is to relieve menopausal symptoms, most importantly hot flashes (vasomotor symptoms). Other symptoms associated with perimenopause and menopause that respond to estrogen therapy (ET) include mood lability/depression, genitourinary syndrome of menopause (GSM; vaginal atrophy), and sleep disturbances (when related to hot flashes). (See 'Goals of therapy' above.)

Healthy symptomatic women in their 50s should be reassured that the absolute risk of complications for healthy, postmenopausal women taking MHT for five years is very low (figure 1). (See 'Importance of patient age' above.)

For healthy, peri/postmenopausal women within 10 years of menopause (or < age 60 years) with moderate-to-severe vasomotor symptoms, we suggest MHT as the treatment of choice (Grade 2B). Exceptions include women with a history of breast cancer, coronary heart disease (CHD), a previous venous thromboembolic event or stroke, active liver disease, or those at high risk for these complications. (See 'Choosing candidates' above.)

We suggest transdermal 17-beta estradiol for many women starting MHT (Grade 2C). The transdermal route is particularly important in women with hypertriglyceridemia or risk factors for thromboembolism. However, the baseline risk of both venous thromboembolism (VTE) and stroke is very low in otherwise healthy, young postmenopausal women. Therefore, if a patient prefers an oral preparation over a transdermal one (cost or personal preference), we consider oral estrogen to be safe. All types and routes of estrogen are equally effective for hot flashes. (See 'Starting estrogen' above.)

For women who experience recurrent, bothersome hot flashes after stopping estrogen, we initially suggest nonhormonal options. However, if this approach is unsuccessful and symptoms persist, we resume MHT at the lowest dose possible in carefully selected women. (See 'Extended use of MHT' above.)

For women with an intact uterus who choose ET, progestin therapy must be added to prevent endometrial hyperplasia and carcinoma. (See 'Adding a progestin' above.)

We suggest micronized progesterone as our first-line progestin because it is effective for endometrial hyperplasia, is metabolically neutral, and does not appear to increase the risk of either breast cancer or CHD, although data are limited (Grade 2C). (See 'Adding a progestin' above.)

Recommendations for women who choose not to take systemic estrogen, have contraindications to estrogen, or have stopped their MHT and are having recurrent symptoms are found elsewhere. (See 'Extended use of MHT' above and "Menopausal hot flashes", section on 'Nonhormonal pharmacotherapy'.)

The use of vaginal estrogen is reviewed in detail elsewhere. (See "Clinical manifestations and diagnosis of genitourinary syndrome of menopause (vulvovaginal atrophy)" and "Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)", section on 'Vaginal estrogen therapy'.)

We currently suggest not using MHT for the prevention of chronic disease (osteoporosis, CHD, or dementia) (Grade 2B). However, women who cannot tolerate other options for osteoporosis may be reasonable candidates. (See 'Choosing candidates' above.)

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