Preparations for menopausal hormone therapy

INTRODUCTION — Menopausal hormone therapy (MHT) is commonly used to treat vasomotor symptoms and genitourinary syndrome of menopause (GSM). The benefits of MHT outweigh the risk 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).

This topic will review the available estrogen and progestin preparations, as well as other types of hormone preparations. An overview of the risks and benefits of MHT, treatment of menopausal symptoms with MHT (including choice of therapy), complementary and nonhormonal treatment options, and the use of estrogen in women with early menopause (primary ovarian insufficiency [POI]) are reviewed separately. (See "Menopausal hormone therapy: Benefits and risks" and "Treatment of menopausal symptoms with hormone therapy" and "Menopausal hot flashes" and "Management of primary ovarian insufficiency (premature ovarian failure)", section on 'Importance of estrogen therapy'.)

ESTROGEN PREPARATIONS — Estrogen is available in many forms: oral, transdermal, topical gels, emulsions and lotions, intravaginal creams and tablets, and vaginal rings. In some countries, estrogen can also be given as a subcutaneous implant (table 1) [1]. Once a decision has been made to treat a woman with menopausal hormone therapy (MHT), 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 (see 'Progestin preparations' below). Estrogen doses used for women who have menopausal symptoms are typically lower than doses used to treat women with primary ovarian insufficiency (POI). (See "Management of primary ovarian insufficiency (premature ovarian failure)", section on 'Importance of estrogen therapy'.)

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 menopausal symptoms with hormone therapy" and "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment".)

Systemic estrogens — Systemic estrogen is most often administered orally or transdermally (table 1). One vaginal ring containing an estrogen dose high enough to treat hot flashes is also available [2]. Other vaginal estrogens are low-dose preparations used for genitourinary syndrome of menopause (see 'High dose (systemic estrogen)' below and 'Low dose' below). There are several important differences between transdermal and oral preparations:

●Estrogens administered orally, but not transdermally, undergo hepatic metabolism, the "first-pass effect." The high portal vein estrogen concentrations seen with oral administration increases the hepatic production of most proteins produced by the liver, including thyroxine-binding globulin (TBG), corticosteroid-binding globulin (CBG), sex hormone-binding globulin (SHBG), triglycerides, high-density lipoprotein (HDL) cholesterol, and clotting factors, whereas their production is only minimally increased by transdermal estrogen administration [3,4]. Furthermore, the saturation of bile with cholesterol is adversely affected by oral, but not transdermal, estrogen [5].

●All estrogens are effective for managing menopausal symptoms such as hot flashes. Transdermal estrogen is as effective as oral estrogen for preserving bone density (figure 1) [6]. Transdermal estrogen administration is associated with a lower risk of venous thrombosis and stroke, and it has less of an effect on serum lipid concentrations when compared with a comparable dose of oral estrogen [3,4,7]. (See 'Transdermal estrogen' below and "Menopausal hormone therapy and cardiovascular risk", section on 'Lipids' and "Menopausal hormone therapy and cardiovascular risk", section on 'Venous thromboembolism'.)

Oral estrogen — A number of oral estrogen preparations are available (table 1):

●Oral micronized 17-beta estradiol is structurally identical (bioidentical) to the main product of the premenopausal ovary. Oral 17-beta estradiol is poorly absorbed unless it is micronized, in which case it is absorbed through the lymphatic system. Therefore, all commercially available oral 17-beta estradiol products are micronized.

●Conjugated equine estrogens (CEEs) are comprised mostly of estrone sulfate with small amounts of equilin sulfate, dihydroequilin sulfate, and many other estrogens [1] and are derived from pregnant mares' urine. In order for estrogens to appear in the urine, they must undergo conjugation to become more polar and soluble in water.

●Esterified estrogens, which result in serum estradiol and estrone levels that are comparable with those seen with conjugated estrogen [8].

●Estropipate, a salt of estrone sulfate and piperazine.

●Ethinyl estradiol, the estrogen used in almost all oral contraceptive preparations. Ethinyl estradiol is much more potent than the other estrogens used for MHT and, therefore, is used in very low doses (5 mcg). Ethinyl estradiol is used in at least one combined estrogen-progestin product that contains 2.5 to 5 mcg of ethinyl estradiol with 0.5 or 1 mg norethindrone acetate, respectively (table 1).

Source — Most oral estrogen preparations, with the exception of CEEs, are derived from plant sources. There is no evidence that plant-derived estrogens have any safety and efficacy advantages over those derived from pregnant mare urine (eg, CEE). However, in our experience, many women prefer the plant-derived estrogens.

Efficacy/potency — The different oral estrogens have similar efficacy. Conjugated estrogen and estrone sulfate are absorbed from the gastrointestinal tract primarily as estrone sulfate, which is biologically inactive [9]. Oral estradiol is converted to estrone and then estrone sulfate in liver and other tissues. In women taking oral estradiol, circulating estrone sulfate accumulates as a large precursor pool. The estrone sulfate is then continuously desulfated and converted to estradiol. Therefore, even though oral estrogen is administered in a single daily dose, the resulting serum estradiol concentrations vary little between doses [10].

The potency, and therefore the doses, of these estrogen preparations differ, but they differ little in efficacy [10]. In general, 0.625 mg of conjugated estrogens or esterified estrogen is considered equivalent to 1 mg of micronized 17-beta estradiol, 0.05 mg of transdermal estradiol, or 5 mcg of ethinyl estradiol (table 1). (See 'Dose equivalents' below.)

These doses protect bone and relieve vasomotor symptoms in most women. Lower doses are effective for vasomotor symptoms in many women; most experts recommend starting with low-dose estrogen unless the patient has severe symptoms. The dose can be titrated up if symptoms are not completely relieved by the low dose of estrogen. (See 'Dosing' below.)

Transdermal estrogen — There are many transdermal estrogen preparations available that contain 17-beta estradiol with a wide range of dosing options, from 0.014 to 0.1 mg/day (ie, 14 to 100 mcg/day). A transdermal dose of 0.05 mg/day [6] is approximately equivalent to 1 mg of oral 17-beta estradiol and a 0.625 mg daily oral dose of conjugated estrogens [1]. The package labeling for transdermal estrogens expresses doses in "mg" rather than "mcg" (eg, 0.014, 0.05, 0.1 mg).

The lowest-dose patch containing 0.014 mg of 17-beta estradiol is approved for prevention of osteoporosis. In some women, that dose is also adequate for relief of hot flashes in some women [11,12]. For women with a uterus, addition of a progestin is recommended, although the optimal interval for its administration is not known. For this low-dose patch (0.014 mg), many clinicians administer a 14-day cycle of oral progestin every 6 to 12 months as suggested by the US Food and Drug Administration (FDA), although this has not been well studied.

Topical estradiol — A wide range of topical estradiol preparations are commercially available, all of which are effective for the treatment of vasomotor symptoms. The preparations available in the United States include the following (table 1):

●A lotion-like emulsion that is applied to the thighs or calves of each leg (foil packets, one packet per leg, total dose of 3.48 g/day, which delivers 0.05 mg estradiol/day) [13].

●There are several gels available:

•One gel is packaged in a non-aerosol, metered-dose pump and is applied once daily on one arm (from wrist to shoulder). The recommended daily dose is 1.25 g, which delivers 0.75 mg estradiol/day [14]. In one trial of 221 postmenopausal women with vasomotor flushes, a significant decrease in the frequency of flushes was seen with this dose when compared with placebo [15].

•A second gel is supplied in foil packets and is available in three doses: 0.25, 0.50, and 1.0 mg of estradiol [16].

•A third gel is administered via a pump in two doses (0.87 g, which contains 0.52 mg of estradiol, and 1.7 g, which contains approximately 1 mg of estradiol) [17].

●Lastly, a topical skin spray is available that delivers 1.53 mg of estradiol with each spray [18,19].

The topical estrogen spray preparation has been associated with adverse effects in children and pets who were exposed to the drug via skin contact [20]. The drug is sprayed on the skin between the elbow and wrist, on the inside of the forearm. Eight cases of unintended exposure have been reported in children ages 3 to 5 years. Adverse events have included nipple swelling and breast development in girls and breast enlargement in boys, occurring weeks to months after the drug was initiated in the adult. In some cases, the effects were reversible after the estrogen spray was discontinued.

Adverse events in pets exposed to the topical spray (mammary/nipple enlargement and vulvar swelling) have also been reported.

Dosing — Low-dose estrogen is effective for hot flashes in many women and is associated with fewer side effects. (See "Menopausal hormone therapy: Benefits and risks" and "Treatment of menopausal symptoms with hormone therapy", section on 'Dose'.)

"Ultra-low doses" of estrogen (transdermal estradiol 0.014 mg/day and oral micronized 17-beta estradiol 0.25 mg/day) also appear to prevent bone loss [11,21] and are effective for hot flashes in some women. (See 'Transdermal estrogen' above and "Menopausal hormone therapy in the prevention and treatment of osteoporosis".)

Dose equivalents — Many studies of the safety and efficacy of postmenopausal estrogen have used conjugated estrogen 0.625 mg. This is considered to be standard-dose estrogen; low-dose preparations, in general, contain one-half the standard dose. The doses of other estrogens that are similarly effective for the treatment of hot flashes as 0.625 mg of CEE include (table 1):

●1 mg micronized 17-beta estradiol

●0.05 mg/day transdermal 17-beta estradiol

●1.25 mg piperazine estrone sulfate

●Estradiol gels and sprays are available in different strengths and delivery systems (pump, foil packets). Dosing equivalents depend upon the individual preparation. Measurement of estradiol levels may be warranted when trying to adjust dosing.

Vaginal estrogen

High dose (systemic estrogen) — Higher doses of vaginal estrogen can be used to treat vasomotor symptoms, much like any of the preparations for systemic use [22]. As an example, a vaginal ring is available in two doses, releasing 0.05 mg/day or 0.1 mg/day over three months. A progestin needs to be added for women with a uterus. We do not recommend these higher vaginal estrogen doses (ie, systemic estrogen doses) in women who need therapy for genitourinary symptoms only (table 1).

Low dose — Vaginal estrogen is most commonly used in very low doses for the management of vaginal atrophy (now known as GSM). These low-dose vaginal preparations are not associated with cardiovascular or oncologic complications. The absorption of estrogen from the vagina and its efficacy for GSM is reviewed separately. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Vaginal estrogen therapy'.)

Not recommended

Depot estrogen — Estrogen is also available in some, but not all, countries as long-acting (three to four weeks) injections of either estradiol cypionate or estradiol valerate. Given the other effective estrogen options, we do not use this approach (table 1).

Compounded bioidentical hormone therapy — 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, multihormone regimens with dose adjustments based upon serial hormone monitoring.

Many postmenopausal women are turning to this approach because of safety concerns about conventional hormone preparations. However, we agree with a number of expert groups, including the North American Menopause Society, American College of Obstetricians and Gynecologists, and Endocrine Society, all of whom advise against the use of custom-compounded hormones, most importantly because of the lack of stringent quality controls regarding purity and dosing [23-25]. This issue is discussed in detail separately. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Compounded bioidentical hormone therapy'.)

Misleading terminology — Some of the terms used by this industry to describe hormone preparations can be confusing and misleading. Examples include:

●Bioidentical hormones – 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, a hormone produced by the ovary). However, in popular culture, the term now typically refers to the use of custom-compounded, multihormone regimens with dose adjustments based upon serial hormone monitoring. Most expert groups advise against this approach. (See 'Compounded bioidentical hormone therapy' above and "Treatment of menopausal symptoms with hormone therapy", section on 'Compounded bioidentical hormone therapy'.)

●Natural versus synthetic – This term "natural" is often used to refer to estrogens that are derived from plant sources. With the exception of CEEs that are derived from urine of pregnant mares, virtually all estrogens used for MHT are derived from plant sources. However, these same estrogens can also be considered "synthetic" because the plant precursors must be extracted and converted to the desired estrogen through a multistep process. For example, 17-beta estradiol is synthesized from diosgenin, a compound naturally occurring in plants (Mexican Dioscorea species). Diosgenin is then converted to estrone and hydrogenated to 17-beta estradiol [26].

The custom-compounded bioidentical industry claims that their products are "natural" and "plant-derived," and that commercially available estrogens that are regulated and approved in most countries are synthetic and not "plant-based." In fact, all of the hormones used for their products are synthesized using the same process as described above for regulated and approved hormones, ie, precursors are extracted from plant sources, and the plant precursor is then converted to estrogen in the lab. However, quality controls for these processes vary widely in terms of their quality controls.

PROGESTIN PREPARATIONS — Endometrial hyperplasia and cancer can occur after as little as six months of unopposed estrogen therapy; as a result, a progestin should be added in women who have not had a hysterectomy. Women who have undergone hysterectomy should not receive a progestin. All of the progestin regimens described below are effective for the prevention of endometrial cancer, whether oral or transdermal estrogen is used [27]. Available progestin preparations are reviewed here. (See "Menopausal hormone therapy: Benefits and risks", section on 'Endometrial hyperplasia and carcinoma'.)

Micronized progesterone — Natural oral micronized progesterone is structurally identical (bioidentical) to the progesterone secreted by the human ovary. Most experts now prefer micronized progesterone (MP) over medroxyprogesterone acetate (MPA), the synthetic progestin most commonly used in the past, as it has a number of advantages. Both progestins are effective for endometrial protection, but unlike MPA, which has been associated with an excess risk of cardiovascular events and breast cancer, MP is metabolically neutral (ie, does not negate the beneficial effects of estrogens on lipids) and does not appear to increase the risk of either breast cancer or cardiovascular disease, although data are limited [28-32]. (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' and "Treatment of menopausal symptoms with hormone therapy", section on 'Compounded bioidentical hormone therapy'.)

The usual dose is 200 mg/day cyclically or 100 mg/day continuously; 200 mg/day for 12 days is the most carefully studied dose [29,32-34].

Although small studies of intravaginal progesterone suggest that it might be a useful alternative for menopausal women taking estrogen who cannot tolerate oral progestins [35,36], additional data are needed before recommending this approach.

Medroxyprogesterone acetate — The most commonly prescribed synthetic progestin historically has been MPA, given in a cyclic (5 to 10 mg/day) or continuous (1.25 to 2.5 mg/day) regimen. Most studies of the efficacy of progestins, including the Women's Health Initiative (WHI), have used this compound. Although MPA has proven efficacy for preventing endometrial hyperplasia, it appears to be associated with an excess risk of breast cancer and possibly coronary heart disease (CHD). In addition, it has unfavorable effects on lipids. (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' and "Menopausal hormone therapy and cardiovascular risk", section on 'Lipids'.)

Intolerance to progestins — Many women have difficulty tolerating progestins, most commonly because of adverse effects on mood. There are some alternative options, but all need require further study before recommending them for routine use. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Side effects'.)

Levonorgestrel-releasing intrauterine device — Levonorgestrel-releasing intrauterine systems (LNG-IUS) are contraceptive agents that are also effective and approved in some countries for endometrial protection for menopausal women taking estrogen [37]. They are not approved for this indication in the United States, but many clinicians have used them off-label for women who cannot tolerate oral progestins.

We will consider switching to an LNG-IUS if they are unable to tolerate oral progestins and we anticipate that they will be on estrogen for at least another three years (the lower-dose LNG-IUS is approved for up to three years of use) [38]. LNG-IUS provide very high intrauterine but low systemic concentrations of levonorgestrel; almost all women develop a nonproliferative, atrophic endometrium. LNG-IUS are also an attractive option for perimenopausal women who either need contraception, are having heavy bleeding, or both.

Two meta-analyses of trials in women using LNG-20 combined with estrogen therapy reported that the intrauterine device (IUD) was as good [39] or better [40] than estrogen combined with systemic progestins for preventing endometrial hyperplasia. Data for LNG-14 are more limited, but in a study of 150 peri- and postmenopausal women using the LNG-14 in addition to transdermal estradiol, no cases of endometrial hyperplasia were seen [41]. However, only 101 (67 percent) of the 150 women underwent endometrial biopsy. In a second study, among 102 women who used two consecutive systems (LNG-14 for the first three years, after which LNG-20 was inserted), endometrial biopsies showed atrophy in all but two women; theirs showed weak proliferation [42]. There were no cases of hyperplasia.

An observational study in Finland reported that when LNG-IUS was used for protection against endometrial hyperplasia in menopausal women, there was an increased risk of breast cancer whether or not the women were taking estradiol. The study may not have controlled for risk factors for postmenopausal breast cancer such as obesity [43].

Quarterly progestin regimens — Quarterly progestin regimens are probably not adequate for endometrial protection, and we suggest against this approach. Administration of MPA for 14 days every 3 months has been investigated as a strategy for women who have difficulty tolerating progestin therapy [44,45]. However, these regimens may be associated with higher than normal rates of endometrial hyperplasia [46]. With increasing concerns about the role of progestin exposure on the risk of breast cancer, there is renewed interest in these types of regimens, particularly with the increasing use of lower doses of estrogens. However, data are not yet available on quarterly progestin regimens for low-dose estrogen.

Tissue selective estrogen complexes (TSECs) — TSECs refers to the combination of a selective estrogen receptor modulator (SERM) and an estrogen. The combination of bazedoxifene, a SERM, and conjugated estrogen is available in the United States for the treatment of menopausal vasomotor symptoms and osteoporosis prevention. Its role in the management of women who cannot tolerate progestin therapy remains unclear, and we do not suggest its routine use.

The SERM bazedoxifene prevents estrogen-induced endometrial hyperplasia so that administering a progestin is not necessary in women with a uterus. It may be useful for women with moderate to severe hot flashes who have breast tenderness with standard estrogen-progestin therapy or for women who cannot tolerate any type of progestin therapy because of side effects. Like other SERMs, bazedoxifene is associated with increased risk of venous thromboembolic events. The role of combination conjugated estrogen-bazedoxifene for menopausal symptoms and bone loss is reviewed in more detail separately. (See "Menopausal hot flashes", section on 'Bazedoxifene/conjugated estrogen' and "Selective estrogen receptor modulators for prevention and treatment of osteoporosis", section on 'Bazedoxifene-conjugated estrogen'.)

COMBINATION ESTROGEN-PROGESTIN PRODUCTS

Oral — Although many postmenopausal women in the United States receive oral medroxyprogesterone acetate (MPA) or micronized progesterone (MP), there are combination preparations that contain other progestins derived from testosterone (19-nortestestosterone), such as norethindrone acetate and norgestimate, and the 17-alpha spironolactone derivative drospirenone (table 1).

In a trial of 1142 postmenopausal women randomly assigned to receive oral estradiol alone (1 mg/day) or in combination with drospirenone 0.5, 1, 2, or 3 mg/day for 13 months, all of the combination drospirenone-estradiol regimens decreased the risk of endometrial hyperplasia when compared with unopposed estrogen [47]. Hyperkalemia was not observed in any patient, and favorable changes in lipids were noted in all of the drospirenone-estradiol groups (decreases in serum total cholesterol, triglycerides, and low-density lipoprotein [LDL] cholesterol concentrations and increases in serum high-density lipoprotein [HDL] when compared with baseline).

Menopausal women with severe symptoms who plan to take hormone therapy typically prefer regimens that (1) contain "bioidentical" hormones, (2) are easy to use, and (3) will not result in weight gain or other adverse effects. An oral capsule containing 1 mg 17-beta-estradiol (E2) combined with 100 mg MP (both bioidentical) is effective and approved for the treatment of hot flashes; it is also endometrial protective [48,49]. In a one-year trial of the oral E2/MP capsule versus placebo, the combined hormone therapy had no clinically meaningful effect on either weight or blood pressure when compared with placebo [50].

This preparation should provide an attractive alternative to women who are currently using compounded bioidentical hormone therapies. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Compounded bioidentical hormone therapy'.)

Transdermal — Combination patches are also available. One contains 17-beta estradiol (0.05 mg/day) with norethindrone acetate (0.14 or 0.25 mg/day) applied twice weekly. This preparation appears to be comparable with other combined regimens for relief of vasomotor flushes and prevention of endometrial hyperplasia [51]. A second combination patch contains 17-beta estradiol (0.045 mg/day) with levonorgestrel (0.15 mg/day) and is applied once a week (table 1).

OTHER HORMONE PREPARATIONS

Androgens — Exogenous testosterone therapy has been shown to improve some aspects of female sexual function in carefully selected populations of postmenopausal women (eg, those who develop female sexual interest/arousal disorder after undergoing bilateral oophorectomy). Testosterone, at the doses usually used to treat hypoactive sexual desire disorder (HSDD), does not appear to have any beneficial effects on bone density, mood, cognition, or vasomotor symptoms. Testosterone preparations in doses appropriate for women have not been approved in most countries. (See "Overview of androgen deficiency and therapy in females" and "Overview of sexual dysfunction in females: Management", section on 'Androgens'.)

Androgen production, sexual function, and the role of androgen therapy after menopause are reviewed in detail separately. (See "Overview of androgen deficiency and therapy in females" and "Overview of sexual dysfunction in females: Epidemiology, risk factors, and evaluation", section on 'Age and menopause'.)

Tibolone — Tibolone, a drug that has been widely used in Europe and other countries for many years for hot flashes, is a synthetic steroid whose metabolites have estrogenic, androgenic, and progestogenic properties. It is not available in the United States. Tibolone reduces vasomotor symptoms when compared with placebo, but it is less effective than estrogen therapy [52]. It also has a beneficial effect on bone mineral density (BMD), and it may have a modest effect for symptoms of sexual dysfunction. However, tibolone increases the risk of recurrence in women with a history of breast cancer, and it may increase the risk of stroke in women over age 60 [52]. The effects of tibolone on bone and sexual function are reviewed separately. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Overview of sexual dysfunction in females: Management", section on 'Tibolone'.)

The vascular, breast, and endometrial effects of tibolone include the following:

●Stroke – The Long-term Intervention on Fracture with Tibolone (LIFT) trial, which was designed to determine the effect of tibolone on the risk of vertebral fracture in postmenopausal women (n = 4538, average 68 years), was stopped early because of an excess risk of stroke in women receiving tibolone when compared with placebo (relative risk [RR] 2.2) [53]. However, there were no significant differences in the risk of coronary heart disease (CHD) or venous thromboembolism between the two groups.

●Mammographic density – Tibolone does not appear to increase mammographic density or the frequency of abnormal mammograms requiring follow-up [54].

●Risk of breast cancer – Data on the risk of breast cancer with tibolone have been conflicting. However, in a meta-analysis of four trials including 5500 women without breast cancer taking tibolone or placebo, there was no evidence of differences in breast cancer risk between the two groups (odds ratio [OR] 0.52, 95% CI 0.21-1.25) [52]. However, other data suggest there may be an increased risk [55].

●Breast cancer recurrence – In women with a personal history of breast cancer, tibolone may increase the risk of recurrence [52,56]. This was illustrated in the Livial Intervention following Breast Cancer; Efficacy, Recurrence, and Tolerability Endpoints (LIBERATE) trial, which was designed to compare the efficacy and safety of tibolone versus placebo for vasomotor symptoms in 3148 breast cancer survivors who were randomly assigned to receive tibolone 2.5 mg or placebo [56]. After a mean follow-up of three years, 237 of 1556 women on tibolone (15 percent) had a breast cancer recurrence, compared with 138 of 1213 (11.4 percent) in the placebo group (hazard ratio [HR] 1.40, 95% CI 1.16-1.79).

●Vaginal bleeding and endometrial hyperplasia – While some women have vaginal bleeding with tibolone [57,58], the rate of unscheduled bleeding is lower than that for menopausal hormone therapy (MHT) [52,59], and many develop amenorrhea. In the LIFT trial, vaginal bleeding occurred in nearly 10 percent of women taking tibolone, significantly more than the 3 percent taking placebo [53]. However, tibolone had a better bleeding profile than combined continuous estrogen-progestin therapy in the Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES); amenorrhea was reported more often in the tibolone group (71 to 78 percent) than in the hormone therapy group (45 percent) [59].

The risk of endometrial hyperplasia does not appear to be increased with tibolone, although data are conflicting. The Million Women Study, an observational study, reported an increased risk of endometrial hyperplasia with tibolone [60]. However, results from the THEBES trial described above (a randomized clinical trial of 3240 women) did not confirm this [59]. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Menopause".)

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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: Non-estrogen treatments for menopausal symptoms (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Estrogen preparations – Estrogen is available in many forms: transdermal, oral, topical gels and lotions, intravaginal creams and tablets, and vaginal rings (table 1). In some countries, estrogen can also be given as a subcutaneous implant All types and routes of estrogen are equally effective for hot flashes, but transdermal preparations are associated with a lower risk of venous thromboembolism and stroke. (See 'Estrogen preparations' above and "Treatment of menopausal symptoms with hormone therapy", section on 'Route'.)

●Progestin preparations – Endometrial hyperplasia and cancer can occur after as little as six months of unopposed estrogen therapy; as a result, a progestin should be added in women who have not had a hysterectomy. Women who have undergone hysterectomy should not receive a progestin. (See 'Progestin preparations' above and "Treatment of menopausal symptoms with hormone therapy", section on 'Progestins'.)

●Intolerance to standard oral progestins – For women unable to tolerate standard oral progestins, alternative approaches include a levonorgestrel-releasing intrauterine system (LNG-IUS; its use is off-label in the United States) or the combination conjugated estrogen-bazedoxifene regimen. The approach to women with progestin intolerance is reviewed separately. (See 'Tissue selective estrogen complexes (TSECs)' above and 'Levonorgestrel-releasing intrauterine device' above and "Treatment of menopausal symptoms with hormone therapy", section on 'Side effects'.)

●Other hormone preparations – Tibolone, a drug that has been widely used in Europe and other countries for many years for hot flashes, is a synthetic steroid whose metabolites have estrogenic, androgenic, and progestogenic properties. It is not available in the United States. Tibolone reduces vasomotor symptoms (although less so than estrogen), improves bone density, and may have a modest effect on symptoms of sexual dysfunction. On the other hand, tibolone increases the risk of recurrence in women with a history of breast cancer, and it may increase the risk of stroke in women over age 60. (See 'Other hormone preparations' above.)

●Dosing and administration – The practical aspects and recommendations for managing menopausal symptoms with hormone therapy are reviewed separately. (See "Treatment of menopausal symptoms with hormone therapy".)