MP Trt Guide 2015

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Treatment of Symptoms of the Menopause: An

Endocrine Society Clinical Practice Guideline

Cynthia A. Stuenkel, Susan R. Davis, Anne Gompel, Mary Ann Lumsden,

M. Hassan Murad, JoAnn V. Pinkerton, and Richard J. Santen

University of California, San Diego, Endocrine/Metabolism (C.A.S.), La Jolla, California 92093; Monash

University, School of Public Health and Preventive Medicine (S.R.D.), Melbourne 03004, Australia;

Universite´ Paris Descartes, Hoˆ pitaux Universitaires Port Royal-Cochin Unit de Gyne´ cologie Endocrnienne

(A.G.), Paris 75014, France; University of Glasgow School of Medicine (M.A.L.), Glasgow G31 2ER,

Scotland; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; University

of Virginia, Obstetrics and Gynecology (J.V.P.), Charlottesville, Virginia 22908; and University of Virginia

Health System (R.J.S.), Charlottesville, Virginia 22903

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 Recom-

mendations, 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 meet-

ing 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 Meno-

pause 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 symp-

tomatic postmenopausal women who are under age 60 or under 10 years since the onset of meno-

pause. 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. (J Clin Endocrinol Metab 100: 3975–4011, 2015)

ISSN Print 0021-972X ISSN Online 1945-7197

Printed in USA

Received May 7, 2015. Accepted August 28, 2015.

First Published Online October 7, 2015

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 ther-

apy; 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 re-

uptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; VMS, vasomotor symp-

toms; VTE, venous thromboembolism; VVA, vulvovaginal atrophy.

SPECIAL FEATURE

Clinical Practice Guideline

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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. (2ⱍQQEE)

1.2 If establishing a diagnosis of menopause is neces-

sary for patient management in women having undergone

a hysterectomy without bilateral oophorectomy or pre-

senting with a menstrual history that is inadequate to as-

certain menopausal status, we suggest making a presump-

tive diagnosis of menopause based on the presence of

vasomotor symptoms (VMS) and, when indicated, labo-

ratory testing that includes replicate measures of FSH and

serum estradiol. (2ⱍQQEE)

2.0 Health considerations for all menopausal

women

2.1 When women present during the menopausal tran-

sition, 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 prog-

estogen therapy (EPT) for those with a uterus. (2ⱍQQEE)

Cardiovascular risk

3.1b For women ⬍age 60 or ⬍10 years past meno-

pause onset considering MHT for menopausal symptom

relief, we suggest evaluating the baseline risk of cardio-

vascular disease (CVD) and taking this risk into consid-

eration when advising for or against MHT and when se-

lecting type, dose, and route of administration. (2ⱍQQEE)

3.1c For women at high risk of CVD, we suggest initi-

ating nonhormonal therapies to alleviate bothersome

VMS (with or without climacteric symptoms) over MHT.

(2ⱍQQEE)

3.1d For women with moderate risk of CVD, we sug-

gest transdermal estradiol as first-line treatment, alone for

women without a uterus or combined with micronized

progesterone (or another progestogen that does not ad-

versely modify metabolic parameters) for women with a

uterus, because these preparations have less untoward ef-

fect on blood pressure, triglycerides, and carbohydrate

metabolism. (2ⱍQQEE)

Venous thromboembolic events

3.1e For women at increased risk of venous thrombo-

embolism (VTE) who request MHT, we recommend a

nonoral route of ET at the lowest effective dose, if not

contraindicated (1ⱍQQEE); for women with a uterus, we

recommend a progestogen (for example, progesterone and

dydrogestone) that is neutral on coagulation parameters.

(1ⱍQQQE)

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. (2ⱍQQEE)

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. (2ⱍQQEE)

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 ap-

proved by the US Food and Drug Administration (FDA)

and comparable regulating bodies outside the United

States and recommend against the use of custom-com-

pounded 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 com-

bination of conjugated equine estrogens (CEE)/bazedox-

ifene (BZA) (where available) as an option for relief of

VMS and prevention of bone loss. (2ⱍQQQE)

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. (2ⱍQQEE)

3.3b We recommend against adding tibolone to other

forms of MHT. (1ⱍQQEE)

3.3c We recommend against using tibolone in women

with a history of breast cancer. (1ⱍQQEE)

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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 hyper-

plasia and cancer. (1ⱍQQQE)

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.

(1ⱍQQQE)

3.4c We suggest that the decision to continue MHT be

revisited at least annually, targeting the shortest total du-

ration of MHT consistent with the treatment goals and

evolving risk assessment of the individual woman. (Un-

graded best practice statement)

3.4d For young women with primary ovarian insuffi-

ciency (POI), premature or early menopause, without con-

traindications, we suggest taking MHT until the time of

anticipated natural menopause, when the advisability of

continuing MHT can be reassessed. (2ⱍQQEE)

Stopping considerations

3.4e For women preparing to discontinue MHT, we

suggest a shared decision-making approach to elicit indi-

vidual preference about adopting a gradual taper vs

abrupt discontinuation. (2ⱍQQEE)

4.0 Nonhormonal therapies for VMS

4.0 For postmenopausal women with mild or less both-

ersome 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. (2ⱍQQEE)

4.1 Nonhormonal prescription therapies for VMS

4.1a For women seeking pharmacological management

for moderate to severe VMS for whom MHT is contrain-

dicated, or who choose not to take MHT, we recommend

selective serotonin reuptake inhibitors (SSRIs)/serotonin-

norepinephrine reuptake inhibitors (SNRIs) or gabapen-

tin or pregabalin (if there are no contraindications).

(1ⱍQQQE)

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 ga-

bapentin or pregabalin, we suggest a trial of clonidine (if

there are no contraindications). (2ⱍQQEE)

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, acupunc-

ture, paced breathing, and hypnosis. (2ⱍQQEE)

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. (2ⱍQQEE)

5.1b For women who do not produce sufficient vaginal

secretions for comfortable sexual activity, we suggest vag-

inal lubricants. (2ⱍQQEE)

5.2 Vaginal estrogen therapies

5.2a For women without a history of hormone- (estro-

gen) dependent cancers who are seeking relief from symp-

toms of genitourinary syndrome of menopause (GSM) (in-

cluding VVA) that persist despite using vaginal lubricants

and moisturizers, we recommend low-dose vaginal ET.

(1ⱍQQQE)

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 in-

cludes 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. (2ⱍQQEE)

5.2d For women using low-dose vaginal ET, we suggest

against adding a progestogen (ie, no need for adding pro-

gestogen to prevent endometrial hyperplasia). (2ⱍQEEE)

5.2e For women using vaginal ET who report post-

menopausal bleeding or spotting, we recommend prompt

evaluation for endometrial pathology. (1ⱍQQEE)

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. (2ⱍQQQE)

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5.3b For women with a history of breast cancer pre-

senting with dyspareunia, we recommend against os-

pemifene. (1ⱍQEEE)

Method of Development of Evidence-

based Clinical Practice Guidelines

The Clinical Guidelines Subcommittee (CGS) of The En-

docrine Society deemed management of menopause a pri-

ority area in need of a practice guideline and appointed a

Task Force to formulate evidence-based recommenda-

tions. The Task Force followed the approach recom-

mended by the Grading of Recommendations, Assess-

ment, Development, and Evaluation (GRADE) group, an

international group with expertise in development and

implementation of evidence-based guidelines (1). A de-

tailed description of the grading scheme has been pub-

lished elsewhere (2). The Task Force used the best avail-

able 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 de-

scriptions 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 recom-

mendation, strong recommendations use the phrase “we

recommend” or “we recommend against” and the number

1, and weak recommendations use the phrase “we sug-

gest” or “we suggest against” and the number 2. Cross-

filled circles indicate the quality of the evidence, such that

QEEE denotes very low quality evidence; QQEE, low

quality; QQQE, moderate quality; and QQQQ, high qual-

ity. The Task Force has confidence that persons who re-

ceive care according to the strong recommendations will

derive, on average, more good than harm. Weak recom-

mendations require more careful consideration of the per-

son’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 prefer-

ences; therefore, these remarks should be considered sug-

gestions. In this guideline, the Task Force made several

statements to emphasize the importance of shared decision

making, general preventive care measures, and basic prin-

ciples 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 inten-

tion of these statements is to draw attention and remind pro-

viders 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 guide-

line. Item 14 states that a procedure for updating the

guideline is provided. This process has not been formal-

ized. Item 20 suggests that the potential resource implica-

tions of applying the recommendations have been consid-

ered. 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. Par-

ticipants in the guideline development must include a ma-

jority of individuals without conflict of interest in the mat-

ter 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; owner-

ship interest (eg, stocks, stock options, or ownership in-

terest excluding diversified mutual funds); honoraria or

other payments for participation in speakers’ bureaus, ad-

visory boards, or boards of directors; or other financial

benefits. Completed forms are available through the En-

docrine 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 system-

atic reviews to provide evidence supporting this guideline.

The first compared the effect of oral vs transdermal es-

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trogens on the risk of venous and arterial thrombotic

events. Low-quality evidence derived from 15 observa-

tional 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 ques-

tion evaluated the effect of MHT on mortality. Data from

43 randomized controlled trials (RCTs) demonstrated no

association between all-cause mortality, regardless of hor-

mone 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 meno-

pause 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 obser-

vational studies suggested that natural progesterone may

be associated with a reduced risk for breast cancer com-

pared 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 dis-

turbance (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 dura-

tion, from a few years to more than 13 years (13–16).

ET has long been recognized as the most effective treat-

ment for the relief of bothersome vasomotor and vaginal

symptoms associated with menopause. However, pre-

scriptions 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 selec-

tive estrogen receptor modulators (SERMs) as solo or

combination therapies; and expanded choices of nonhor-

monal prescription medications. In this guideline, we em-

phasize 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 ben-

efits of MHT. An accepted philosophy is that a fully in-

formed patient should be empowered to make a decision

that best balances individual QOL benefits against poten-

tial health risks (21).

1.0 Diagnosis and symptoms of menopause

1.1 We suggest diagnosing menopause based on the

clinical criteria of the menstrual cycle. (2ⱍQQEE)

1.2 If establishing a diagnosis of menopause is neces-

sary for patient management in women having undergone

a hysterectomy without bilateral oophorectomy or pre-

senting with a menstrual history that is inadequate to as-

certain menopausal status, we suggest making a presump-

tive diagnosis of menopause based on the presence of VMS

and, when indicated, laboratory testing that includes rep-

licate measures of FSH and serum estradiol. (2ⱍQQEE)

Technical remark

Table 1 summarizes other etiologies of secondary

amenorrhea to be considered in the differential diagnosis.

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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 oo-

phorectomy, elevated FSH levels and estradiol concentra-

tions ⬍20 pg/mL on several occasions support but do not

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).

Figure 1. Approach to menopause guideline. Numbers correspond to section of text addressing selected clinical issue.

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confirm the diagnosis. A distinction between the late peri-

menopause 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 chemo-

therapy-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, persis-

tent 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 back-

grounds, the percentage of women reporting hot flashes

varies (25–27). In a cross-sectional study of premeno-

pausal women (mean age, 48 y), one-third reported “ever”

experiencing hot flashes (28). A comparison between

VMS experienced during the premenopause vs the post-

menopause may be informative when counseling a post-

menopausal woman regarding symptom relief, although

to our knowledge, the presence and frequency of premeno-

pausal hot flashes have not been studied as being predic-

tive of response to therapy in the postmenopause. Persis-

tence 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 be-

comes generalized, lasts from 2 to 4 minutes, and can be

associated with profuse perspiration, palpitations, or anx-

iety. Triggers include spicy food or alcohol. At night, va-

somotor instability manifests as hot flashes or night

sweats, which may represent different physiological mech-

anisms. The differential diagnosis includes several entities

distinguishable by clinical features (Table 2). New-onset

VMS in older (age, ⱖ65 y) postmenopausal women may

be associated with, but not necessarily causally related to,

increased risk of major CHD and all-cause mortality (29).

Association with sleep. In polysomnography studies, noc-

turnal 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 di-

rectly 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 continu-

ously high gonadotropins. An important contributing fac-

tor is aging, which likely is also involved in sleep distur-

bances 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 neuroregula-

tors kisspeptin, neurokinin B, and dynorphin (35). Alter-

ations of thermoregulatory systems are mechanistically

involved because women with hot flashes exhibit a nar-

rowing of the thermoregulatory-neutral zone (32).

Whereas premenopausal women initiate mechanisms to

dissipate heat when the core body temperature increases

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

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by 0.4°C, this happens with much lower increases in tem-

perature in menopausal women (36). Core body temper-

ature 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 per-

spiration 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 meno-

pause” (GSM) combines the conditions of VVA and uri-

nary 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 symp-

toms—dysuria, urinary frequency, and recurrent urinary

tract infections—increase in severity with time since

menopause.

Other signs and symptoms

The menopausal decline of estradiol increases bone re-

sorption and contributes to fractures (38).

Possible related signs and symptoms

Research has suggested (but not proven) a direct rela-

tionship between menopause and mood changes, mild de-

pressive 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 tran-

sition, 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 mor-

tality from CVD and cancer and maintain QOL, optimiz-

ing diet and exercise to maintain healthy weight are

important measures, as are counseling regarding alco-

hol use and smoking cessation and identifying and treat-

ing hypertension, glucose intolerance, and dyslipi-

demias (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 postmeno-

pausal women ⬍65 years of age and at high risk of os-

teoporosis, 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 ini-

tiating ET for those without a uterus and EPT for those

with a uterus. (2ⱍQQEE)

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)

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.

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Evidence

In postmenopausal women, ET improves menopause-

associated (climacteric) symptoms (eg, VMS, genitouri-

nary 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 in-

cidence of self-reported diabetes. In addition, combined

EPT reduced the risk of colorectal cancer and, in cumu-

lative follow-up of the WHI, endometrial cancer (38, 44).

MHT is not appropriate for all symptomatic meno-

pausal women (Figure 2). There are no commonly recog-

nized 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 con-

ditions 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).

Risks and benefit overview

Healthcare providers and patients should choose MHT

based on individual risks and benefits utilizing a shared

Figure 2. Approach to the patient with VMS contemplating MHT.

TIA, transient ischemic attack.

Table 4. Specific Cautions to Use of Systemic MHT or

SERMs

a,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 medication

Known liver impairment or disease

Known protein C, protein S, or antithrombin deficiency,

or other known thrombophilic disorders

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 conditions

Also apply to conjugated estrogens/BZA, ospemifene, and tibolone

therapies.

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.

Specific to CEE ⫾combination with BZA.

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.

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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 esti-

mate 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 specif-

ically in women 50 to 59 years of age or ⬍10 years since

menopause onset. Because of the number of women par-

ticipants 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 evi-

dence regarding younger postmeno-

pausal women.

Estimations of risks and benefits

previously published in The Endo-

crine Society’s 2010 Scientific State-

ment utilized both observational

and RCT data. However, updated

outcomes from the WHI are now

available. Accordingly, the up-

dated reanalysis of the WHI (44) is

considered by many to provide the

best available data on risks and ben-

efits in women ages 50 to 59, but not

in those younger than age 50. The

2010 Statement expresses attribut-

able (excess) benefits and risks as the

number of affected women/1000 us-

ers/5 years of therapy, assuming that

most women initiating MHT will

consider therapy for 5 years. Main-

taining 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, represent-

ing the effects of CEE with or with-

out MPA, cannot be extrapolated to

other MHT regimens. However, in

the absence of RCTs with other spe-

cific 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.

Benefits of MHT

Vasomotor symptoms

ET is the most effective treatment for VMS and im-

proving QOL in symptomatic women (38). In a dose-de-

pendent manner, MHT reduces hot flash frequency by

approximately 75% and severity by 87%, compared with

50% with placebo (38, 45, 46).

Figure 3. 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].

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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 addi-

tional 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 ther-

apy remains appropriate treatment for major depres-

sion (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 hor-

mone 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 signif-

icant reduction in vertebral fractures and a borderline sig-

nificant 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 preva-

lence 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 per-

sist after discontinuation (44).

Endometrial cancer. During 13 years of cumulative fol-

low-up of the WHI, combined CEE and MPA was asso-

ciated 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 hyper-

plasia and cancer (38, 65, 66), whereas concurrent prog-

estogen 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 dydro-

gesterone, in combination with estrogen, have been asso-

ciated with an approximate 2-fold increase in endometrial

cancer when continued beyond 5 years in a large obser-

vational study (68). In contrast, one RCT comparing mi-

cronized 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 for-

mulation 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).

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 hyper-

plasia 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 trans-

dermal estradiol when initiated in recently menopausal

women (77–79). This increase occurs as a function of du-

ration of ET (38, 80–82) with a linear trend in the largest

study (83). Insufficient numbers of patients may confound

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Table 5. Commonly Prescribed Hormone Therapies

Preparation Doses Comments

Systemic estrogen therapies

Oral estrogen tablets

Micronized E2 0.5, 1.0, 2.0 mg/d

Estradiol valerate

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

Dydrogesterone

10 mg/d

Chlormadinone acetate

5, 10 mg/d

Medrogestone

5 mg/d

Nomegestrol acetate

3.75, 5 mg/d

Promegestone

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 progestin

LNorg 20

␮

g released/d IUD for 5-y use

␮

g/d IUD for 3-y use

Vaginal gel progesterone

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 Cycle3dEalone,3dE⫹progesterone

E2 ⫹dydrogesterone

1–2 mg/5–10 mg/d Cyclic and continuous

E2 ⫹cyproterone acetate

2 mg/1 mg/d Continuous

E2 ⫹MPA

1–2 mg/2–10 mg/d Continuous

CEE ⫹BZA

0.45 mg/20 mg/d Continuous

Transdermal

E2 ⫹Neta 50

␮

g/0.14–0.25 mg/patch Twice weekly

E2 ⫹LNorg 45

␮

g/0.015 mg/patch Once weekly

Abbreviations: IUD, intrauterine device; E, estrogen; E2, 17-

␤

estradiol; LNorg, levonorgestrel; Neta, norethindrone acetate or norethisterone

acetate; qd, once daily.

Not all preparations and doses are available in all countries.

Only available outside the United States.

Not approved in the United States for endometrial protection when administered with postmenopausal estrogen.

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.

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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 estro-

gen-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 in-

terpretation of existing data. The aromatase enzyme,

which increases with obesity, results in enhanced endog-

enous estrogen production, which may minimize the ad-

ditional 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 pri-

mate (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 com-

bined 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 inva-

sive 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). How-

ever, observational data suggest that progesterone or dy-

drogesterone (5, 89) may be associated with a lower risk,

but further studies are required to confirm this. Observa-

tional 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 per-

sisted 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 compa-

rable 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 postmeno-

pausal 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 revascu-

larization (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 start-

ing 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 con-

troversial. 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 com-

posite 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 pre-

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vention 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) af-

ter 4 years of therapy (104) but may have been underpow-

ered 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 in-

creased 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 es-

trogen type, dose, or route of administration. Some ob-

servational studies suggest that transdermal estradiol in

doses ⱕ50

␮

g 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 in-

creases 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). Observa-

tional studies (108–112) and meta-analyses (4, 113) sug-

gest 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 be-

tween 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 for-

mulations containing MPA and normethytestosterone de-

rivatives appear to be associated with greater risk than

other progestogens (108, 109, 111). A recent meta-anal-

ysis 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 over-

all 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 in-

creased 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 meno-

pause (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). Observa-

tional studies (128–130) reported a reduction in mortality

with MHT, as did one small RCT with composite end-

points (103). This is consistent with meta-analyses that

reported a 30–40% mortality reduction (131, 132). In

summary, further data are required for definitive conclu-

sions 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 improve-

ment (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 de-

cisions regarding MHT for symptom relief (Figure 2).

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However, no clinical trial evidence is available to support

the practice of incorporating risk assessment instru-

ments for quantifying cardiovascular (CHD, stroke,

and VTE) and breast cancer risks among women con-

sidering MHT. Nevertheless, we feel that risk assess-

ment instruments are useful to facilitate decision-mak-

ing regarding MHT.

Cardiovascular risk

3.1b For women ⬍age 60 or ⬍10 years past meno-

pause 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. (2ⱍQQEE)

3.1c For women at high risk of CVD, we suggest initi-

ating nonhormonal therapies to alleviate bothersome

VMS (with or without climacteric symptoms) over MHT.

(2ⱍQQEE)

Technical remarks

High risk includes known MI, cerebrovascular disease,

and peripheral arterial disease, abdominal aortic aneu-

rysm, diabetes mellitus, chronic kidney disease, and 10-

year CVD risk ⬎10% (40).

3.1d For women with moderate risk of CVD, we sug-

gest transdermal estradiol as first-line treatment, alone for

women without a uterus or combined with micronized

progesterone (or another progestogen that does not ad-

versely modify metabolic parameters) for women with a

uterus because these preparations have less untoward ef-

fect on blood pressure, triglycerides, and carbohydrate

metabolism. (2ⱍQQEE)

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 founda-

tion 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 di-

abetes 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 con-

veys the highest risk of subsequent MI and stroke (142).

We feel that methods to integrate these factors to catego-

rize 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 guide-

lines (143). However, specific cutoffs for the safe use of

MHT have not been formally validated, and practice dif-

fers from country to country.

The Menopause Decision-Support Algorithm (63)

starts with calculating the American College of Cardiol-

ogy (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 ar-

tery calcium score, C-reactive protein, and ankle-brachial

index can further stratify risk (144); inflammatory mark-

ers and lipid ratios predict treatment-related CHD events

(145).

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 es-

tradiol with micronized progesterone might have less del-

eterious metabolic effects than oral therapies, but there are

no RCTs that have evaluated the safety of these prepara-

tions 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/Pro-

gestin Replacement Study [19%]; WHI [4.4–7.7%]), but

these trials were not powered to assess differences in CVD

Table 6. Evaluating CVD Risk in Women

Contemplating MHT

10-y CVD Risk

Years Since Menopause Onset

<5y 6to10y

Low (⬍5%) MHT ok MHT ok

Moderate (5–10%) MHT ok (choose

transdermal)

MHT ok (choose

transdermal)

High (⬎10%)

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.

High risk includes known MI, stroke, peripheral artery disease, etc.

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outcomes. A few short-term RCTs have evaluated glucose

control in diabetic women taking a variety of MHT prep-

arations 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, partic-

ularly 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 met-

abolically 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 (1ⱍQQEE); for

women with a uterus, we recommend a progestogen (for

example, progesterone and dydrogestone) that is neutral

on coagulation parameters. (1ⱍQQQE)

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 be-

cause research has shown a high risk of VTE recurrence

(114). A history of VTE due to pregnancy, oral contra-

ceptives, 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 con-

traindication to oral but not necessarily transdermal MHT

(151). In some countries, a history of any VTE is a con-

traindication 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. (2ⱍQQEE)

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. (2ⱍQQEE)

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 recommend-

ing (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 ⱖ1.75. On this basis, the

excess or attributable risk should increase in women at

higher categories of risk (90, 152). As another consider-

ation, 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 ⱖ3% should be considered

for preventive therapy with tamoxifen or raloxifene (126),

whereas the American Society of Clinical Oncology guide-

lines suggest discussing such therapy in women with a risk

of ⱖ1.67% (153), consistent with enrollment criteria of

breast cancer prevention trials. Prevention recommenda-

tions differ outside the United States. Another consider-

ation is to take into account the data suggesting that breast

cancer risk is associated with combined estrogen/proges-

togen use, but less so, if at all, with CEE alone.

We suggest one potential algorithm for MHT counsel-

ing, extrapolated from breast cancer prevention trial en-

rollment 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 accom-

plished by qualitative methods or preferably with readily

available quantitative risk assessment tools. The National

Cancer Institute Breast Cancer Risk Assessment Tool pro-

Table 7. Breast Cancer Risk Cutoffs for Counseling

Before Recommending MHT

Risk

Category

5-y NCI or IBIS Breast Cancer

Risk Assessment, %

Suggested

Approach

Low ⬍1.67 MHT ok

Intermediate 1.67–5 Caution

High ⬎5 Avoid

Abbreviations: IBIS, International Breast Intervention Study; NCI,

National Cancer Institute.

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.

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.

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vides a standardized online risk calculator for 5-year risk

of invasive breast cancer (154). The International Breast

Intervention Study calculator predicts 10-year and life-

time risk (155, 156). For women with strong family his-

tories of breast cancer, several other methods are available

(155). Although these provide useful predictive informa-

tion, all are limited by only moderate discriminatory ac-

curacy (155). Mammographic breast density, when added

to these methods, may emerge as an important objective

risk for women contemplating MHT (157–159).

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 experi-

enced by breast cancer survivors, and limitations of non-

hormonal therapies for relief of VMS present a persistent

clinical challenge. As recently summarized, it is not pos-

sible from currently available studies to draw firm con-

clusions regarding the risks of MHT in this population

(38), but adding estrogen seems counterintuitive when

current breast cancer therapies interrupt or decrease es-

trogen levels. Future studies taking into account estrogen

receptor status, time since diagnosis and therapy, mastec-

tomy 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 estra-

diol levels to monitor therapy except when symptoms do

not improve with escalating doses, particularly after

changing the mode of administration from oral to trans-

dermal. 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

␮

g), 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 ex-

tensively, and alleviate climacteric symptoms in a dose-

dependent fashion. CEE, derived from pregnant mares’

urine and used for decades, contain more than 200 com-

pounds with varying estrogenic potency (160). Oral mi-

cronized estradiol and other oral estrogen preparations

may result in up to 5-fold higher levels of circulating es-

trone and 10- to 20-fold higher estrone sulfate than trans-

dermally 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 pri-

mary advantage of transdermal ET is to alleviate the first-

pass hepatic metabolic effect (166) of oral estrogens re-

sulting 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, hy-

pertriglyceridemia, 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 out-

comes that compare transdermal with oral therapies.

Vaginal delivery of systemic estrogens. Estradiol acetate

vaginal rings, delivering 50 or 100

␮

g of estradiol daily

(Table 5), provide consistent systemic estradiol levels for

3 months per ring insertion. They are indicated for treat-

ment of moderate to severe VMS and VVA due to meno-

pause (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 dis-

cuss 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 var-

ious formulations (Table 5) are administered in two reg-

imens. The combined sequential regimen includes estro-

gen for 20 to 25 days and a progestogen for 12 to 15 days

each month. This approach is preferred for recently meno-

pausal woman who are prone to breakthrough bleeding

during the first year or two of therapy. The combined

continuous regimen utilizes both an estrogen and pro-

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gestogen 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 oc-

cur, and one observational study reported higher breast

cancer incidence (173).

Progestogen alone. For those who do not tolerate ET, pro-

gestogens can relieve VMS. In RCTs, oral synthetic pro-

gestogens (Table 5) (174, 175) and micronized progester-

one (176) were effective. Clinical outcome trials are

lacking in women with breast cancer; thus, progestogen

therapy is best avoided, except under limited circum-

stances in these patients, because the effect on recurrence

is unclear (80).

Custom-compounded hormones

3.1i We recommend using MHT preparations ap-

proved by the FDA and comparable regulating bodies out-

side 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 lack-

ing to justify salivary measurements due to inter- and in-

tra-assay variability, variable salivary flow rates depen-

dent 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 com-

bination of CEE/BZA (where available) as an option for

relief of VMS and prevention of bone loss. (2ⱍQQQE)

Evidence

The combination of CEE with the SERM/BZA (avail-

able 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) com-

pared with MHT (CEE 0.45 mg/MPA 1.5 mg) (178–180).

Benefits

Vasomotor symptoms. The number and severity of mod-

erate-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 pre-

vented in postmenopausal women at risk for osteoporosis

(182), as reflected by reduction of serum bone turnover

markers and enhancement of bone mineral density vs pla-

cebo (180, 181). At 12 months, CEE/BZA was less effec-

tive 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 mat-

uration at 12 weeks (181). Women reported a lower in-

cidence of dyspareunia.

Quality of life. Secondary endpoints included improve-

ments in sleep, health-related QOL, and improved treat-

ment 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 en-

dometrial hyperplasia nor endometrial cancer was in-

creased (180, 189).

Potential risks

Adverse events. Although an osteoporosis trial found a

2-fold risk of VTE with BZA 20-mg therapy alone (190),

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there was no additive effect on VTE when BZA was com-

bined 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, en-

dometrial, ovarian), and mortality were similar to placebo

(191), but studies were underpowered to draw firm con-

clusions regarding these endpoints.

3.3 Tibolone

3.3a For women with bothersome VMS and climacteric

symptoms and without contraindications, we suggest ti-

bolone (in countries where available) as an alternative to

MHT. (2ⱍQQEE)

3.3b We recommend against adding tibolone to other

forms of MHT. (1ⱍQQEE)

3.3c We recommend against using tibolone in women

with a history of breast cancer. (1ⱍQQEE)

Evidence

Tibolone belongs to the group of normethyltestoster-

one progestogen derivatives and has metabolites that ex-

hibit estrogenic, progestogenic, and androgenic effects

(192). This agent (193) is available in many countries out-

side 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. Ti-

bolone also improves sleep, mood, and urogenital atrophy

and may improve libido (194–197).

Bone loss and fracture. Tibolone prevents postmeno-

pausal 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 ⱖ60

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 tender-

ness is low (around 3%), (201, 202), and neither mam-

mographic density nor invasive breast cancer was in-

creased; 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 hyper-

plasia and cancer. (1ⱍQQQE)

3.4b We recommend informing women about the pos-

sible increased risk of breast cancer during and after dis-

continuing EPT and emphasizing the importance of ad-

hering to age-appropriate breast cancer screening.

(1ⱍQQQE)

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).

Duration of therapy

3.4c We suggest that the decision to continue MHT be

revisited at least annually, targeting the shortest total du-

ration of MHT consistent with the treatment goals and

evolving risk assessment of the individual woman. (Un-

graded 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 pro-

posed 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 sug-

gest 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 contin-

uation yearly and discuss the risks (and individual bene-

fits) beyond 5 years (55, 56). Patients likely to consider

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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 reas-

sessed. (2ⱍQQEE)

Stopping considerations

3.4e For women preparing to discontinue MHT, we

suggest a shared decision-making approach to elicit indi-

vidual preference about adopting a gradual taper vs

abrupt discontinuation. (2ⱍQQEE)

Evidence

A number of studies have compared methods (ie, taper

protocols vs abrupt cessation) to facilitate the discontinua-

tion 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 discontinu-

ation of MHT, whereas in contrast, bone density is stable

for some years after discontinuing bisphosphonate ther-

apy. Bisphosphonates, however, remain in bone indefi-

nitely, and most expert groups do not recommend initi-

ating bisphosphonate therapy for osteoporosis prevention

in women aged 50 to 59. Adverse effects such as osteone-

crosis 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 per-

sistent risk of ovarian cancer up to a decade after discon-

tinuing 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 both-

ersome 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. (2ⱍQQEE)

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; T

dose may need to be

increased (209).

Abbreviation: TG, triglycerides.

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Evidence

As hot flashes result from alterations of the thermoreg-

ulatory 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 contrain-

dicated, or who choose not to take MHT, we recommend

SSRIs/SNRIs or gabapentin or pregabalin (if there are no

contraindications). (1ⱍQQQE)

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, des-

venlafaxine, citalopram, and escitalopram demonstrate

statistically significant efficacy with a reduction of fre-

quency 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).

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 meno-

pausal women, although studies are small (213, 217, 228–

234). Caution is advised in the use of paroxetine in pa-

tients taking tamoxifen because paroxetine markedly

interferes with the metabolism of tamoxifen to its metab-

olite, 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 deter-

mine the relative efficacy of one over another. We describe

suggested daily doses, efficacy, side effects, and contrain-

dications 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 require-

ments vary widely, as determined by empiric dose escala-

tion, 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 reason-

ably well tolerated.

Choice of SSRI/SNRI vs gabapentin/pregabalin

A randomized, crossover, multicenter trial that com-

pared 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 pa-

tients preferred venlafaxine over gabapentin. The quality

of this comparative evidence is low due to imprecision.

Relative efficacy of nonhormonal prescription ther-

apies vs estrogens

A limited number of head-to-head RCTs have com-

pared varying estrogen doses, preparations, and routes of

administration with nonhormonal agents (213, 240, 244).

None of the RCTs established statistically significant su-

periority of one treatment regimen over another. How-

ever, when these and other published data are taken into

account (213, 217, 236, 245), the limited evidence avail-

able 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 ga-

bapentin or pregabalin, we suggest a trial of clonidine (if

there are no contraindications). (2ⱍQQEE)

Evidence

Clonidine

Several RCTs demonstrated that this

␣

-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 com-

plementary medicine therapies, we suggest counseling re-

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garding the lack of consistent evidence for benefit for botan-

icals, black cohosh, omega-3 fatty acids, red clover, vitamin

E, and mind/body alternatives including anxiety control,

acupuncture, paced breathing, and hypnosis. (2ⱍQQEE)

Evidence

Clinical trials with these agents have reported incon-

sistent 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 meno-

pausal 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 non-

steroidal compounds that have both estrogenic and anti-

Figure 4. 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).

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estrogenic properties. Caution is advised because some of

these agents, when consumed as supplements, can exert

estrogenic effects, a concern in breast cancer survivors al-

though dietary soy appears to have no adverse effects on

breast cancer prognosis (248).

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. (2ⱍQQEE)

Evidence

Vaginal moisturizers (eg, polycarbophil-based mois-

turizer, 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 ap-

proaches 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 lu-

bricant during intercourse.

5.1b For women who do not produce sufficient vaginal

secretions for comfortable sexual activity, we suggest vag-

inal lubricants. (2ⱍQQEE)

Evidence

Vaginal lubricants are used to enhance the sexual ex-

perience in women with symptoms of VVA by alleviating

vaginal dryness and preventing dyspareunia (258). Lubri-

cants do not treat the underlying problem and only briefly

alleviate symptoms. Several OTC options are available. Be-

cause data do not demonstrate the superiority of one to an-

other, 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- (estro-

gen) dependent cancers who are seeking relief from symp-

toms of GSM (including VVA) that persist despite using

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

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vaginal lubricants and moisturizers, we recommend low-

dose vaginal ET. (1ⱍQQQE)

Evidence

A 2006 Cochrane meta-analysis of vaginal estrogens

(261) compared 19 efficacy trials and found that all prod-

ucts 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 (vag-

inal dryness or dyspareunia) and urinary symptoms (dys-

uria 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). Ad-

verse effects include potential transfer to partner via

penile or oral absorption and, with vaginal creams, res-

idue 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, al-

though not all studies demonstrate this effect (267, 275).

When vaginal epithelium is restored (after several weeks of

ET), systemic absorption may decrease (276, 277).

Low-dose therapies

Low-dose vaginal ring. Low-dose vaginal rings result in

estradiol levels that remain within the normal postmeno-

pausal range; however, bone resorption and lipid levels

decrease, suggesting possible systemic effects (278, 279).

Insertion and removal at 3-month intervals may be diffi-

cult, 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-

␮

g tablet provides stan-

dard 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 place-

ment of the tablet may provide less introital benefit than

creams.

Promestriene (estradiol diether). This is a low-dose estro-

gen used outside the United States. Evidence is limited to

studies of poor quality and very few RCTs (282).

Intermediate-dose vaginal estrogen

The 25-

␮

g 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 ⱖ0.3 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 in-

troitus to the vaginal apex, and provide the emollient effect

of vehicle. Some systemic absorption exists (284, 285).

Table 10. Classification of Government-Approved Vaginal Estrogens

Type Dose Serum Estradiol Level

Low dose ⬍20 pg/mL

Silastic estradiol vaginal ring 7.5

␮

Estradiol vaginal tablet 10

␮

Promestriene (estradiol diether) ovule

10 mg

Estriol ovule

0.5 mg

Estriol ⫹progesterone ⫹Lactobacillus Doderleini ovule

0.2 mg ⫹2mg⫹341 mg

Promestriene cream

3mg

Estriol cream

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

␮

Some ⬎20 pg/mL

High dose (systemic) 35–200 pg/mL

Estradiol vaginal ring 50 and 100

␮

Vaginal estradiol ⬎0.5 mg

Vaginal CEE ⬎0.5 mg

Not approved or recommended in United States.

No longer available in United States.

Predominantly estrone sulfate; LH suppression reflects systemic absorption.

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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 re-

garding the FDA-approved dosing of estradiol 2- to 4-g

vaginal cream, administered daily for 1 to 2 weeks, fol-

lowed 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 con-

centration 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 pro-

file 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 dura-

tion of RCTs of vaginal ET (261). Side effects include

vulvovaginal candidiasis (289, 290) and, with higher dos-

ing and systemic absorption, vaginal bleeding and breast

pain (289). Increased CVD or VTE risk has not been re-

ported (261). This may reflect an actual neutral effect due

to the absence of a first-pass hepatic effect by vaginal es-

trogens, 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 in-

cludes 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 aro-

matase 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 ab-

sorbed 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-

␮

g vaginal tablet, breast can-

cer recurrence did not increase (relative risk, 0.78; 95%

CI, 0.48–1.25) (294). These data are insufficient, how-

ever, to conclude safety and to recommend this approach.

Endometrial cancer

The effect of low-dose vaginal ET on endometrial can-

cer 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 endome-

trial cancer was closed prematurely without complete en-

rollment (295). In the absence of RCT findings to guide

practice recommendations, the decision to use ET remains

controversial and involves assessing the severity of post-

menopausal 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. (2ⱍQQEE)

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 pro-

gestogen to prevent endometrial hyperplasia). (2ⱍQEEE)

5.2e For women using vaginal ET who report post-

menopausal bleeding or spotting, we recommend prompt

evaluation for endometrial pathology. (1ⱍQQEE)

Evidence

Bleeding or spotting in a woman using only vaginal

estrogens is uncommon in the absence of endometrial pa-

thology. 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 endo-

metrial hyperplasia or cancer as determined by endome-

trial biopsy (263, 266, 304). Vaginal administration of

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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 un-

known whether endometrial proliferation, hyperplasia, or

cancer can occur after long-duration treatment (⬎1y)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 ultra-

sound, followed by endometrial biopsy if endometrial

thickening is present, may be prudent. Intermittent (pos-

sibly 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. (2ⱍQQQE)

5.3b For women with a history of breast cancer pre-

senting with dyspareunia, we recommend against os-

pemifene. (1ⱍQEEE)

Evidence

Benefits

Not all women are comfortable using vaginal ET, and

women may prefer an oral medication specifically indi-

cated 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 (in-

cluding 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 ⱖ5 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 en-

dometrium (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 lack-

ing. 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, ques-

tions 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 de-

velop 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 epide-

miological, physiological, and descriptive data character-

izing reproductive changes that occur during the transi-

tion to menopause. However, clinical management

decisions are often based on the extrapolation of obser-

vational data collected from studies conducted in younger,

reproductive age women. RCTs of frequently prescribed

therapies, such as oral contraceptives, MHT, and mea-

sures 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 premeno-

pausal women due to surgery, the range of disorders man-

ifesting 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 re-

productive technology, but we fall short on adequately

managing estrogen deficiency. Pressing questions remain

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regarding optimal treatment preparation, dosing and reg-

imens, 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 postmeno-

pausal 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 con-

clusive evidence remains elusive, and questions persist re-

garding 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 ade-

quately 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 inter-

ests: North American Menopause Society (Chair, Exam

Committee), National Women’s Law Center-Well Wom-

en’s Project; Significant financial interest or leadership

position: none declared. Susan R. Davis, MBBS, PhD—

Financial or Business/Organizational Interests: Interna-

tional Menopause Society, North American Menopause

Society, Menopause, Maturitas, Climacteric, Trimel Phar-

maceuticals Canada, Lawley Pharmaceuticals Australia,

Abbott Pharmaceuticals; Significant Financial Interest or

Leadership Position: International Menopause Society,

National Health and Medical Research Council, Austra-

lia, Bupa Health Foundation. Anne Gompel, MD, PhD—

Financial or Business/Organizational Interests: European

Society for Contraception, European Society of Endocri-

nology, Groupe d’Etude sur la Ménopause et le Vieillisse-

ment Hormonal, Société Française de Sénologie et Pa-

thologie Mammaire; Significant financial interest or

leadership position: none declared. Mary Ann Lumsden,

MD, PhD—Financial or Business/Organizational Inter-

ests: —Financial or Business/Organizational Interests: In-

ternational Menopause Society, British Menopause Soci-

ety; 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 Preven-

tive Medicine; Significant financial interest or leadership

position: none declared. JoAnn V. Pinkerton, MD—Fi-

nancial or business/organizational interests: North Amer-

ican Menopause Society, Menopause Journal, OBG Man-

agement, 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 Posi-

tion: North American Menopause Society, Academy of

Women’s Health, South Atlantic Association of ObGyn.

Richard J. Santen, MD—Financial or business/organiza-

tional 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. Dis-

closures prior to this time period are archived.

** Evidence-based reviews for this guideline were pre-

pared 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.

Address all correspondence and requests for reprints to: The

Endocrine Society, 2055 L Street NW, Suite 600, Washington,

DC 20036. E-mail: govt-prof@endocrine.org; Phone: 202–971-

3636. Send commercial reprint requests for orders over 100 to:

https://www.endocrine.org/corporate-

relations/commercial-reprints. Send commercial reprint requests

for orders under 100 to: Society Services, E-mail: society

services@endocrine.org; Phone: 202–971-3636; Fax:

202–736-9705.

Cosponsoring Associations: The Australasian Menopause

Society, the British Menopause Society, European Menopause

and Andropause Society, the European Society of Endocrinol-

ogy, and the International Menopause Society.

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