3043 Menopause and Postmenopausal Hormone Therapy CHAPTER 395

Brown DL et al: Ovarian stromal hyperthecosis: Sonographic features

and histologic associations. J Ultrasound Med 28:587, 2009.

Haak CS et al: Hair removal in hirsute women with normal testosterone levels: A randomized controlled trial of long-pulsed diode laser

vs. intense pulsed light. Br J Dermatol 163:1007, 2010.

Martin KA et al: Evaluation and treatment of hirsutism in premenopausal women: An Endocrine Society clinical practice

guideline. J Clin Endocrinol Metab 103:1233, 2018.

Mc Cartney CR, Marshall JC: Polycystic ovary syndrome. N Engl

J Med 375:1398, 2016.

Rosenfield RL, Ehrmann DA: The pathogenesis of polycystic ovary

syndrome (PCOS): The hypothesis of PCOS as functional ovarian

hyperandrogenism revisited. Endocr Rev 37:467, 2016.

Van Zuuren EJ, Fedorowicz Z : Interventions for hirsutism excluding laser and photoepilation therapy alone: Abridged Cochrane

systematic review including GRADE assessments. Br J Dermatol

175:45, 2016.

Menopause is the permanent cessation of menstruation due to loss

of ovarian follicular function. It is diagnosed retrospectively after

12 months of amenorrhea. The average age at menopause is 51 years

among U.S. women. Perimenopause refers to the time period preceding menopause, when fertility wanes and menstrual cycle irregularity

increases, until the first year after cessation of menses. The onset of perimenopause precedes the final menses by 2–8 years, with a mean duration

of 4 years. Smoking accelerates the menopausal transition by 2 years.

Although the peri- and postmenopausal transitions share many

symptoms, the physiology and clinical management of the two differ.

Low-dose oral contraceptives have become a therapeutic mainstay in perimenopause, whereas postmenopausal hormone therapy (HT) has been

a common method of symptom alleviation after menstruation ceases.

PERIMENOPAUSE

■ PHYSIOLOGY

Ovarian mass and fertility decline sharply after age 35 and even more

precipitously during perimenopause; depletion of primary follicles,

a process that begins before birth, occurs steadily until menopause

(Chap. 392). In perimenopause, intermenstrual intervals shorten

significantly (typically by 3 days) as a result of an accelerated follicular phase. Follicle-stimulating hormone (FSH) levels rise because of

altered folliculogenesis and reduced inhibin secretion. In contrast to

the consistently high FSH and low estradiol levels seen in menopause,

perimenopause is characterized by “irregularly irregular” hormone

levels. The propensity for anovulatory cycles can produce a hyperestrogenic, hypoprogestagenic environment that may account for the

increased incidence of endometrial hyperplasia or carcinoma, uterine

polyps, and leiomyoma observed among women of perimenopausal

age. Mean serum levels of selected ovarian and pituitary hormones

during the menopausal transition are shown in Fig. 395-1. With transition into menopause, estradiol levels fall markedly, whereas estrone

levels are relatively preserved, a pattern reflecting peripheral aromatization of adrenal and ovarian androgens. Levels of FSH increase more

than those of luteinizing hormone, presumably because of the loss of

inhibin as well as estrogen feedback.

395 Menopause and

Postmenopausal Hormone

Therapy

JoAnn E. Manson, Shari S. Bassuk

LH or FSH, IU/L

80

70

0–2–4–6 2 4 6

FSH (IU/L)

LH (IU/L)

Estradiol or estrone, pg/mL

Estrone (pg/mL)

Estradiol (pg/mL)

8

Menopause, years

60

50

40

30

20

10

0

200

180

160

140

120

100

80

60

40

20

0

FIGURE 395-1 Mean serum levels of ovarian and pituitary hormones during the

menopausal transition. FSH, follicle-stimuating hormone; LH, luteinizing hormone.

(Data from G Rannevik et al: A longitudinal study of the perimenopausal transition:

altered profiles of steroid and pituitary hormones, SHBG and bone mineral density.

Maturitas 21:103, 1995.)

■ DIAGNOSTIC TESTS

The Stages of Reproductive Aging Workshop +10 (STRAW+10) classification provides a comprehensive framework for the clinical assessment

of ovarian aging. As shown in Fig. 395-2, menstrual cycle characteristics are the principal criteria for characterizing the menopausal

transition, with biomarker measures as supportive criteria. Because

of their extreme intraindividual variability, FSH and estradiol levels

are imperfect diagnostic indicators of perimenopause in menstruating

women. However, a consistently low FSH level in the early follicular

phase (days 2–5) of the menstrual cycle does not support a diagnosis

of perimenopause, while levels >25 IU/L in a random blood sample

are characteristic of the late menopause transition. FSH measurement

can also aid in assessing fertility; levels of <20 IU/L, 20 to <30 IU/L,

and ≥30 IU/L measured on day 3 of the cycle indicate a good, fair, and

poor likelihood of achieving pregnancy, respectively. Anti-müllerian

hormone and inhibin B may also be useful for assessing reproductive

aging.

■ SYMPTOMS

Determining whether symptoms that develop in midlife are due to

ovarian senescence or to other age-related changes is difficult. There is

strong evidence that the menopausal transition can cause hot flashes,

night sweats, irregular bleeding, and vaginal dryness, and there is

moderate evidence that it can cause sleep disturbances in some women.

There is inconclusive or insufficient evidence that ovarian aging is a

major cause of mood swings, depression, impaired memory or concentration, somatic symptoms, urinary incontinence, or sexual dysfunction. In one U.S. study, nearly 60% of women reported hot flashes

in the 2 years before their final menses. Symptom intensity, duration,

frequency, and effects on quality of life are highly variable.

TREATMENT

Perimenopause

PERIMENOPAUSAL THERAPY

For women with irregular or heavy menses or hormone-related

symptoms that impair quality of life, low-dose combined oral

contraceptives are a staple of therapy. Static doses of estrogen and

progestin (e.g., 20 μg of ethinyl estradiol and 1 mg of norethindrone acetate daily for 21 days each month) can eliminate vasomotor symptoms and restore regular cyclicity. Oral contraceptives

provide other benefits, including protection against ovarian and

endometrial cancers and increased bone density, although it is

not clear whether use during perimenopause decreases fracture

risk later in life. Moreover, the contraceptive benefit is important,

given that the unintentional pregnancy rate among women in

their forties rivals that of adolescents. Contraindications to oral

contraceptive use include cigarette smoking, liver disease, a history

3044 PART 12 Endocrinology and Metabolism

of thromboembolism or cardiovascular disease, breast cancer, or

unexplained vaginal bleeding. Progestin-only formulations (e.g.,

0.35 mg of norethindrone daily) or medroxyprogesterone (DepoProvera) injections (e.g., 150 mg IM every 3 months) may provide

an alternative for the treatment of perimenopausal menorrhagia in

women who smoke or have cardiovascular risk factors. Although

progestins neither regularize cycles nor reduce the number of

bleeding days, they reduce the volume of menstrual flow.

Nonhormonal strategies to reduce menstrual flow include the

use of nonsteroidal anti-inflammatory agents such as mefenamic

acid (an initial dose of 500 mg at the start of menses, then 250 mg

qid for 2–3 days) or, when medical approaches fail, endometrial

ablation. It should be noted that menorrhagia requires an evaluation to rule out uterine disorders. Transvaginal ultrasound with

saline enhancement is useful for detecting leiomyomata or polyps,

and endometrial aspiration can identify hyperplastic changes.

TRANSITION TO MENOPAUSE

For sexually active women using contraceptive hormones to alleviate

perimenopausal symptoms, the question of when and if to switch

to HT must be individualized. Doses of estrogen and progestogen

(either synthetic progestins or natural forms of progesterone) in

HT are lower than those in oral contraceptives and have not been

documented to prevent pregnancy. Although a 1-year absence of

spontaneous menses reliably indicates ovulation cessation, it is not

possible to assess the natural menstrual pattern while a woman is

taking an oral contraceptive. Women willing to switch to a barrier

method of contraception should do so; if menses occur spontaneously, oral contraceptive use can be resumed. The average age of final

menses among relatives can serve as a guide for when to initiate this

process, which can be repeated yearly until menopause has occurred.

Stage –5 –4 –3b

Reproductive

Principal criteria

Supportive criteria

Descriptive characteristics

Menopausal transition Postmenopause

Perimenopause

Variable

Variable* Variable* Variable Stabilizes

Variable

Length

Persistent

≥7-day

difference in

length of

consecutive

cycles

Endocrine

 FSH

 AMH

 Inhibin B

Antral follicle

count

Interval of

amenorrhea

of ≥60

days

Variable Remaining

lifespan

1–3 years 2 years 3–6 years

(1+1)

–3a –2 –1 +1a +1b +1c +2

Terminology

Early Peak Late Early Late Early Late

Duration

Menstrual

cycle

Variable

to regular

Regular Regular

Low

Low

Low

Low

Low

Low

Low

Low

Low Low

Low

Low

Very low

Very low

Very low

Very low

Subtle

changes in

flow/

length

Menarche FMP (0)

>25 IU/L**

Low

Low

Symptoms

*Blood draw on cycle days 2–5 = elevated.

**Approximate expected level based on assays using current international pituitary standard.

Vasomotor

symptoms

Likely

Vasomotor

symptoms

Most likely

Increasing

symptoms of

urogenital atrophy

FIGURE 395-2 The Stages of Reproductive Aging Workshop +10 (STRAW +10) staging system for reproductive aging in women. AMH, anti-müllerian hormone; FSH,

follicle-stimulating hormone. (Reproduced with permission from SD Harlow et al: Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the

unfinished agenda of staging reproductive aging. Menopause 19:387, 2012.)

MENOPAUSE AND POSTMENOPAUSAL HT

One of the most complex health care decisions facing women is whether

to use postmenopausal HT. Once prescribed primarily to relieve vasomotor symptoms, HT has been promoted as a strategy to forestall various disorders that accelerate after menopause, including osteoporosis

and cardiovascular disease. In 2000, nearly 40% of postmenopausal

women aged 50–74 in the United States had used HT. This widespread

use occurred despite the paucity of conclusive data, until recently, on

the health consequences of such therapy. Although many women rely

on their health care providers for a definitive answer to the question of

whether to use postmenopausal hormones, balancing the benefits and

risks for an individual patient is challenging.

Although observational studies suggest that HT prevents cardiovascular and other chronic diseases, the apparent benefits may result

at least in part from differences between women who opt to take

postmenopausal hormones and women who do not. Those choosing HT tend to be healthier, have greater access to medical care, are

more compliant with prescribed treatments, and maintain a more

health-promoting lifestyle. Randomized trials, which eliminate these

confounding factors, have not consistently confirmed the benefits

found in observational studies. Indeed, the largest HT trial to date, the

Women’s Health Initiative (WHI), which examined >27,000 postmenopausal women aged 50–79 (mean age, 63) for an average of 5–7 years,

was stopped early because of an overall unfavorable benefit-risk ratio

in the estrogen-progestin arm and an excess risk of stroke that was

not offset by a reduced risk of coronary heart disease (CHD) in the

estrogen-only arm.

The following summary offers a decision-making guide based on a

synthesis of currently available evidence. Prevention of cardiovascular

disease is eliminated from the equation due to lack of evidence for such

benefits in randomized clinical trials.

3045 Menopause and Postmenopausal Hormone Therapy CHAPTER 395

■ BENEFITS AND RISKS OF POSTMENOPAUSAL HT

See Table 395-1.

Definite Benefits • SYMPTOMS OF MENOPAUSE Compelling evidence, including data from randomized clinical trials, indicates that

estrogen therapy is highly effective for controlling vasomotor and

genitourinary symptoms. Alternative approaches, including the use

of antidepressants (such as paroxetine, 10–25 mg/d; paroxetine salt,

7.5 mg/d; or venlafaxine, 37.5–75 mg/d), γ-aminobutyric acid analogues (such as gabapentin, 300 mg nightly, up to 900 mg in divided

doses; or pregabalin, 75–150 mg/d twice per day), or clonidine

patch (0.1–0.3 mg weekly), may also alleviate vasomotor symptoms,

although they are less effective than HT. Paroxetine is the only nonhormonal drug approved by the U.S. Food and Drug Administration

for treatment of vasomotor symptoms. Bazedoxifene, an estrogen

agonist/antagonist, in combination with conjugated estrogens has

also received approval for this use. Cognitive behavioral therapy and

clinical hypnosis have been shown in randomized trials to help with

vasomotor symptom management. Weight loss, mindfulness-based

stress reduction, stellate ganglion block, and the consumption of

S-equol soy derivatives are also promising strategies, although more

trials are needed. For genitourinary syndrome of menopause, the

efficacy of low-dose vaginal estrogen is similar to that of oral or transdermal estrogen; oral ospemifene or vaginal prasterone are additional

options.

OSTEOPOROSIS (See also Chap. 411)

Bone density By reducing bone turnover and resorption rates, estrogen

slows the aging-related bone loss experienced by most postmenopausal

women. More than 50 randomized trials have demonstrated that postmenopausal estrogen therapy, with or without a progestogen, rapidly

increases bone mineral density at the spine by 4–6% and at the hip by

2–3% and that those increases are maintained during treatment.

Fractures Data from observational studies indicate a 50–80% lower

risk of vertebral fracture and a 25–30% lower risk of hip, wrist, and

other peripheral fractures among current estrogen users; addition of

a progestogen does not appear to modify this benefit. In the WHI,

5–7 years of either combined estrogen-progestin or estrogen-only

therapy was associated with a 33% reduction in hip fractures and

25–30% fewer total fractures among a population unselected for

osteoporosis. Bisphosphonates (such as alendronate, 10 mg/d or

70 mg once per week; risedronate, 5 mg/d or 35 mg once per week;

ibandronate, 2.5 mg/d or 150 mg once per month or 3 mg every

3 months IV; or zoledronic acid, 5 mg once per year IV) and denosumab (60 mg twice per year SC) increase bone mass density by

reducing bone resorption and have been shown in randomized trials to

decrease fracture rates. Other treatment options include bazedoxifene

in combination with conjugated estrogens; the selective estrogen receptor modulator (SERM) raloxifene (60 mg/d); and parathyroid hormone

(teriparatide, 20 μg/d SC). Unlike estrogen, these alternative therapies

do not appear to have adverse effects on the endometrium or breast.

Increased weight-bearing and resistance exercise; adequate calcium

intake (1000–1200 mg/d through diet or supplements in two or three

divided doses); and adequate vitamin D intake (600–1000 IU/d) may

also reduce the risk of osteoporosis-related fractures. According to a

2011 report by the Institute of Medicine (now the National Academy

of Medicine), 25-hydroxyvitamin D blood levels of ≥50 nmol/L are

sufficient for bone-density maintenance and fracture prevention. The

Fracture Risk Assessment (FRAX®

) score, an algorithm that combines

an individual’s bone-density score with age and other risk factors to

predict her 10-year risk of hip and major osteoporotic fracture, may be

of use in guiding decisions about pharmacologic treatment (see https://

www.sheffield.ac.uk/FRAX/).

Definite Risks • ENDOMETRIAL CANCER (WITH ESTROGEN

ALONE) A combined analysis of 30 observational studies found a

tripling of endometrial cancer risk among short-term users (1–5 years)

of unopposed estrogen and a nearly tenfold increased risk among longterm users (≥10 years). These findings are supported by results from

the randomized Postmenopausal Estrogen/Progestin Interventions

(PEPI) trial, in which 24% of women assigned to unopposed estrogen

for 3 years developed atypical endometrial hyperplasia—a premalignant lesion—as opposed to only 1% of women assigned to placebo.

Use of a progestogen, which opposes the effects of estrogen on the

endometrium, eliminates these risks and may even reduce risk (see

later).

VENOUS THROMBOEMBOLISM A meta-analysis of observational studies found that current oral estrogen use was associated with a 2.5-fold

increase in risk of venous thromboembolism in postmenopausal

women. A meta-analysis of randomized trials, including the WHI,

found a 2.1-fold increase in risk. Results from the WHI indicate a nearly

twofold increase in risk of pulmonary embolism and deep-vein thrombosis with estrogen-progestin and a 35–50% increase in these risks with

estrogen-only therapy. Transdermal estrogen, taken alone or with certain progestogens (micronized progesterone or pregnane derivatives),

appears to be a safer alternative with respect to thrombotic risk.

BREAST CANCER (WITH ESTROGEN-PROGESTIN) An increased risk of

breast cancer has been found among current or recent estrogen users

in observational studies; this risk is directly related to duration of use.

In a meta-analysis of 51 case-control and cohort studies, short-term

use (<5 years) of postmenopausal HT did not appreciably elevate breast

cancer incidence, whereas long-term use (≥5 years) was associated with

a 35% increase in risk. In contrast to findings for endometrial cancer,

combined estrogen-progestin regimens appear to increase breast cancer risk more than estrogen alone. Data from randomized trials also

indicate that estrogen-progestin raises breast cancer risk. In the WHI,

women assigned to receive combination hormones for an average of

5.6 years were 24% more likely to develop breast cancer than women

assigned to placebo, but 7.1 years of estrogen-only therapy did not

increase risk. Indeed, the WHI showed a trend toward a reduction in

breast cancer risk with estrogen alone, although it is unclear whether

this finding would pertain to formulations of estrogen other than

conjugated equine estrogens or to treatment durations of >7 years. In

the Heart and Estrogen/Progestin Replacement Study (HERS), combination therapy for 4 years was associated with a 27% increase in breast

cancer risk. Although the latter finding was not statistically significant,

the totality of evidence strongly implicates estrogen-progestin therapy

in breast carcinogenesis.

Some observational data suggest that the length of the interval

between menopause onset and HT initiation may influence the association between such therapy and breast cancer risk, with a “gap time”

of <3–5 years conferring a higher HT-associated breast cancer risk.

(This pattern of findings contrasts with that for CHD, as discussed

later in this chapter.) However, this association remains inconclusive

and may be a spurious finding attributable to higher rates of screening

mammography and thus earlier cancer detection in HT users than in

nonusers, especially in early menopause. Indeed, in the WHI trial, hazard ratios for HT and breast cancer risk did not differ among women

50–59, those 60–69, and those 70–79 years of age at trial entry. (There

was insufficient power to examine finer age categories.) Additional

research is needed to clarify the issue.

GALLBLADDER DISEASE Large observational studies report a twoto threefold increased risk of gallstones or cholecystectomy among

postmenopausal women taking oral estrogen. In the WHI, women

randomized to estrogen-progestin or estrogen alone were ~55% more

likely to develop gallbladder disease than those assigned to placebo.

Risks were also increased in HERS. Transdermal HT might be a safer

alternative, but further research is needed.

Probable or Uncertain Risks and Benefits • CORONARY HEART

DISEASE/STROKE Until recently, HT had been enthusiastically recommended as a possible cardioprotective agent. In the past three

decades, multiple observational studies suggested, in the aggregate, that

estrogen use leads to a 35–50% reduction in CHD incidence among

postmenopausal women. The biologic plausibility of such an association is supported by data from randomized trials demonstrating

that exogenous estrogen lowers plasma low-density lipoprotein (LDL)

cholesterol levels and raises high-density lipoprotein (HDL) cholesterol

3046 PART 12 Endocrinology and Metabolism

TABLE 395-1 Benefits and Risks of Postmenopausal Hormone Therapy in the Overall Study Population of Women aged 50–79 Years in the

Intervention Phase of the Women’s Health Initiative (WHI) Estrogen-Progestin and Estrogen-Alone Trialsa

ESTROGEN-PROGESTIN ESTROGEN ALONE

OUTCOME EFFECT

RELATIVE BENEFIT

OR RISK

ABSOLUTE BENEFIT

OR RISKb

RELATIVE BENEFIT OR

RISK

ABSOLUTE BENEFIT OR

RISKb

Definite Benefits

Symptoms of

menopause

Definite improvement ↓65–90% decreased

riskc

↓65–90% decreased riskc

Osteoporosis Definite increase in bone mineral density and

decrease in fracture risk

↓33% decreased risk

for hip fracture

6 fewer cases

(11 vs 17) of hip

fracture

↓33% decreased risk for

hip fracture

6 fewer cases (13 vs 19)

of hip fracture

Definite Risksh

Endometrial

cancer

Definite increase in risk with estrogen alone

(see below for estrogen-progestin)

See below See below 4.6 excess cases

(observational studies)

Pulmonary

embolism

Definite increase in risk ↑98% increased risk 9 excess cases

(18 vs 9)

↑35% increased risk (n.s.) 4 excess cases

(14 vs 10)

Deep-vein

thrombosis

Definite increase in risk ↑87% increased risk 11.5 excess cases

(25 vs 14)

↑48% increased risk 7.5 excess cases

(23 vs 15)

Breast cancer Definite increase in risk with long-term use

(≥5 years) of estrogen-progestin

↑24% increased risk 8.5 excess cases

(43 vs 35)

↓21% decreased risk

(n.s.)

7 fewer cases (28 vs 35)

Gallbladder

disease

Definite increase in risk ↑57% increased risk 47 excess cases

(131 vs 84)

↑55% increased risk 58 excess cases

(164 vs 106)

Probable or Uncertain Risks and Benefitsh

Coronary heart

diseased

Probable increase in risk among older women

and women many years past menopause;

possible decrease in risk or no effect in

younger or recently menopausal womene

↑18% increased risk

(n.s.)

6 excess cases

(41 vs 35)

No increase in risk No difference in risk

Myocardial

infarction

Significant interaction by age group for

estrogen alone, with reduced risk in

younger—but not older—women (p for trend

by age = .02)

↑24% increased risk

(n.s.)

6 excess cases

(35 vs 29)

No increase in riske No difference in riske

Stroke Probable increase in risk ↑37% increased risk 9 excess cases

(33 vs 24)

↑35% increased risk 11 excess cases

(45 vs 34)

Ovarian cancer Probable increase in risk with long-term use

(≥5 years)

↑41% increased risk

(n.s.)

1 excess case

(5 vs 4)

Not available Not available

Endometrial

cancer

Probable decrease in risk with estrogenprogestin during long-term follow-up (see

above for estrogen alone)

↓33% decreased riskf 3 fewer cases

(7 vs 10)

See above See above

Urinary

incontinence

Probable increase in risk ↑49% increased risk 549 excess cases

(1661 vs 1112)

↑61% increased risk 852 excess cases

(2255 vs 1403)

Colorectal

cancer

Probable decrease in risk with estrogenprogestin; possible increase in risk in older

women with estrogen alone (p for trend by

age = .02 for estrogen alone)

↓38% decreased risk 6.5 fewer cases

(10 vs 17)

No increase or decrease

in riske

No difference in riske

Type 2 diabetes Probable decrease in risk ↓19% decreased risk 16 fewer cases

(72 vs 88)

↓14% decreased risk 21 fewer cases

(134 vs 155)

Dementia

(age ≥65)

Increase in risk in older women (but

inconsistent data from observational studies

and randomized trials)

↑101% increased risk 23 excess cases

(46 vs 23)

↑47% increased risk (n.s.) 15 excess cases

(44 vs 29)

Total mortality Possible increase in risk among older women

and women many years past menopause;

possible decrease in risk or no effect in

younger or recently menopausal women (p for

trend by age <.05 for both trials combined)

No increase in risk No difference in risk No increase in riske No difference in riske

Global indexg Probable increase in risk or no effect among

older women and women many years past

menopause; possible decrease in risk or no

effect in younger or recently menopausal

women (p for trend by age = .02 for estrogen

alone)

↑12% increased risk 20.5 excess cases

(189 vs 168)

No increase in riske No difference in riske

a

The estrogen-progestin arm of the WHI assessed 5.6 years of conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) versus placebo. The

estrogen-alone arm of the WHI assessed 7.1 years of conjugated equine estrogens (0.625 mg/d) versus placebo. b

Number of cases per 10,000 women per year. c

The WHI

was not designed to assess the effect of hormone therapy (HT) on menopausal symptoms. Data from other randomized trials suggest that HT reduces risk for menopausal

symptoms by 65–90%. d

Coronary heart disease is defined as nonfatal myocardial infarction or coronary death. e

There was a significant interaction by age; that is, the

association between HT and the specified outcome was different in younger women and older women. f

This is the risk reduction that was observed during a cumulative

13-year follow-up period (5.6 years of treatment plus 8.2 years of postintervention observation). g

The global index is a composite outcome representing the first event for

each participant from among the following: coronary heart disease, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer (estrogen-progestin

arm only), hip fracture, and death. Because participants can experience more than one type of event, the global index cannot be derived by a simple summing of the

component events. h

Includes some outcomes where results were divergent between the estrogen-progestin arm and the estrogen-alone arm.

Abbreviation: n.s., not statistically significant.

Source: Data from JE Manson et al: Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health

Initiative randomized trials. JAMA 310:1353, 2013.

3047 Menopause and Postmenopausal Hormone Therapy CHAPTER 395

levels by 10–15%. Administration of estrogen also favorably affects

lipoprotein(a) levels, LDL oxidation, endothelial vascular function,

fibrinogen, and plasminogen activator inhibitor 1. However, estrogen

therapy has unfavorable effects on other biomarkers of cardiovascular

risk: it boosts triglyceride levels; promotes coagulation via factor VII,

prothrombin fragments 1 and 2, and fibrinopeptide A elevations; and

raises levels of the inflammatory marker C-reactive protein.

Randomized trials of estrogen or combined estrogen-progestin

in women with preexisting cardiovascular disease have not confirmed the benefits reported in observational studies. In HERS (a

secondary-prevention trial designed to test the efficacy and safety

of estrogen-progestin therapy with regard to clinical cardiovascular outcomes), the 4-year incidence of coronary death and nonfatal

myocardial infarction was similar in the active-treatment and placebo

groups, and a 50% increase in risk of coronary events was noted during the first year among participants assigned to the active-treatment

group. Although it is possible that progestin may mitigate estrogen’s

benefits, the Estrogen Replacement and Atherosclerosis (ERA) trial

indicated that angiographically determined progression of coronary

atherosclerosis was unaffected by either opposed or unopposed estrogen treatment. Moreover, no cardiovascular benefit was found in the

Papworth Hormone Replacement Therapy Atherosclerosis Study, a

trial of transdermal estradiol with and without norethindrone; the

Women’s Estrogen for Stroke Trial (WEST), a trial of oral 17β-estradiol;

or the Estrogen in the Prevention of Reinfarction Trial (ESPRIT), a trial

of oral estradiol valerate. Thus, in clinical trials, HT has not proved

effective for the secondary prevention of cardiovascular disease in

postmenopausal women.

Primary-prevention trials also suggest an early increase in cardiovascular risk and an absence of cardioprotection with postmenopausal

HT. In the WHI, women assigned to 5.6 years of estrogen-progestin

therapy were 18% more likely to develop CHD (defined in primary

analyses as nonfatal myocardial infarction or coronary death) than

those assigned to placebo, although this risk elevation was not statistically significant. However, during the trial’s first year, there was a

significant 80% increase in risk, which diminished in subsequent years

(p for trend by time = .03). In the estrogen-only arm of the WHI, no

overall effect on CHD was observed during the 7.1 years of the trial or

in any specific year of follow-up. This pattern of results was similar to

that for the outcome of total myocardial infarction.

However, a closer look at available data suggests that timing of

initiation of HT may critically influence the association between such

therapy and CHD. Estrogen may slow early stages of atherosclerosis but

have adverse effects on advanced atherosclerotic lesions. It has been

hypothesized that the prothrombotic and proinflammatory effects

of estrogen manifest themselves predominantly among women with

subclinical lesions who initiate HT well after the menopausal transition, whereas women with less arterial damage who start HT early in

menopause may derive cardiovascular benefit because they have not

yet developed advanced lesions. Data from experiments in nonhuman

primates and from some recent randomized trials in humans support

this concept. Conjugated estrogens had no effect on the extent of

coronary artery plaque in cynomolgus monkeys assigned to receive

estrogen alone or combined with progestin starting 2 years (~6 years

in human terms) after oophorectomy and well after the establishment

of atherosclerosis. However, administration of exogenous hormones

immediately after oophorectomy, during the early stages of atherosclerosis, reduced the extent of plaque by 70%. In the Early versus

Late Intervention Trial with Estradiol (ELITE), a 6-year trial among

643 healthy postmenopausal women that was designed to test whether

effects of estrogen on the development and progression of atherosclerosis depend on age at initiation of therapy, oral 17β-estradiol

administered with or without vaginal micronized progesterone significantly slowed carotid atherosclerotic progression in women within

6 years of menopause onset (mean age, 55.4 years) but not in women

>10 years past menopause onset (mean age, 65.4 years) (p for interaction = .007). On the other hand, in the Kronos Early Estrogen Prevention

Study (KEEPS), a 4-year trial among 729 healthy postmenopausal

women within 3 years of menopause onset at trial entry (mean age,

53 years), neither oral conjugated estrogens nor transdermal estradiol,

administered with oral micronized progesterone, affected carotid atherosclerotic progression. However, the low prevalence of this endpoint

in the overall study population may have curtailed power to detect a

treatment difference.

Lending further credence to the timing hypothesis are results of

subgroup analyses of data from observational studies and large clinical

trials. For example, among women who entered the WHI trial with a

relatively favorable cholesterol profile, estrogen with or without progestin led to a 40% lower risk of incident CHD. Among women who

entered with a worse cholesterol profile, therapy resulted in a 73%

higher risk (p for interaction = .02). The presence or absence of the

metabolic syndrome (Chap. 408) also strongly influenced the relation

between HT and incident CHD. Among women with the metabolic

syndrome, HT more than doubled CHD risk, whereas no association was observed among women without the syndrome. Moreover,

although there was no association between estrogen-only therapy and

CHD in the WHI trial cohort as a whole, such therapy was associated

with a CHD risk reduction of 40% among participants aged 50–59; in

contrast, a risk reduction of only 5% was observed among those aged

60–69, and a risk increase of 9% was found among those aged 70–79 (p

for trend by age = .08). For the outcome of total myocardial infarction,

estrogen alone was associated with a borderline-significant 45% reduction and a nonsignificant 24% increase in risk among the youngest and

oldest women, respectively (p for trend by age = .02). Estrogen was

also associated with lower levels of coronary artery calcified plaque

in the younger age group. Although age did not have a similar effect

in the estrogen-progestin arm of the WHI, CHD risks increased with

years since menopause (p for trend = .08), with a significantly elevated

risk among women who were ≥20 years past menopause. For the outcome of total myocardial infarction, estrogen-progestin was associated

with a 9% risk reduction among women <10 years past menopause

as opposed to a 16% increase in risk among women 10–19 years past

menopause and a twofold increase in risk among women >20 years

past menopause (p for trend = .01). In the large observational Nurses’

Health Study, women who chose to start HT within 4 years of menopause experienced a lower risk of CHD than did nonusers, whereas

those who began therapy ≥10 years after menopause appeared to

receive little coronary benefit. Observational studies include a high

proportion of women who begin HT within 3–4 years of menopause,

whereas clinical trials include a high proportion of women ≥12 years

past menopause; this difference helps to reconcile some of the apparent

discrepancies between the two types of studies.

For the outcome of stroke, WHI participants assigned to estrogenprogestin or estrogen alone were ~35% more likely to suffer a stroke

than those assigned to placebo. Whether or not age at initiation of

HT influences stroke risk is not well understood. In the WHI and the

Nurses’ Health Study, HT was associated with an excess risk of stroke in

all age groups. Further research is needed on age, time since menopause,

and other individual characteristics (including biomarkers) that predict

increases or decreases in cardiovascular risk associated with exogenous HT. Furthermore, it remains uncertain whether different doses,

formulations, or routes of administration of HT will produce different

cardiovascular effects.

COLORECTAL CANCER Observational studies have suggested that

HT reduces risks of colon and rectal cancer, although the estimated

magnitudes of the relative benefits have ranged from 8 to 34% in various meta-analyses. In the WHI (the sole trial to examine the issue),

estrogen-progestin was associated with a significant 38% reduction in

colorectal cancer over a 5.6-year period, although no benefit was seen

with 7 years of estrogen-only therapy. However, a modifying effect of

age was observed, with a doubling of risk with HT in women aged

70–79 but no risk elevation in younger women (p for trend by age = .02).

COGNITIVE DECLINE AND DEMENTIA A meta-analysis of 10 casecontrol and two cohort studies suggested that postmenopausal HT is

associated with a 34% decreased risk of dementia. Subsequent randomized trials (including the WHI), however, have failed to demonstrate any

benefit of estrogen or estrogen-progestin therapy on the progression of

3048 PART 12 Endocrinology and Metabolism

Stroke Deep-vein

thrombosis

Breast

cancer

Colorectal

cancer

All

cancers

All

fractures

Death from

any cause

Coronary Diabetes

heart

disease

Intergroup difference in no. of events

per 1000 women over 5 yr

–20

–15

–10

–5

0

2.5

Benefits

A CEE+MPA Trial Risks

2.5

5.0 5

10

15

20

3.0

–0.5 –0.5

–12.0

–5.0 –5.5

Stroke Deep-vein

thrombosis

Breast

cancer

Colorectal

cancer

All

cancers

All

fractures

Death from

any cause

Coronary Diabetes

heart

disease

Intergroup difference in no. of events

per 1000 women over 5 yr

–20

–15

–10

–5

0

Benefits

B CEE+Alone Trial Risks

–0.5

2.5 5

10

15

20

–2.5 –1.5

–4.0

–8.0

–5.5

–13.0

–5.5

FIGURE 395-3 Benefits and risks of the two hormone therapy (HT) formulations evaluated in the Women’s Health Initiative, in women aged 50–59 years. Results are

shown for the two formulations, conjugated equine estrogens (CEE) alone or in combination with medroxyprogesterone acetate (MPA). Risks and benefits are expressed

as the difference in number of events (number in the HT group minus the number in the placebo group) per 1000 women over 5 years. (Reproduced with permission from JE

Manson, AM Kaunitz. Menopause Management--Getting Clinical Care Back on Track. N Engl J Med 374:803, 2016.)

mild to moderate Alzheimer’s disease and/or have indicated a potential

adverse effect of HT on the incidence of dementia, at least in women

≥65 years of age. Among women randomized to HT (as opposed to

placebo) at age 50–55 in the WHI, no effect on cognition was observed

during the postintervention phase. Determining whether timing of initiation of HT influences cognitive outcomes will require further study.

OVARIAN CANCER AND OTHER DISORDERS On the basis of limited

observational and randomized data, it has been hypothesized that

HT increases the risk of ovarian cancer and reduces the risk of type 2

diabetes mellitus. Results from the WHI support these hypotheses. The

WHI also found that HT use was associated with an increased risk of

urinary incontinence and that estrogen-progestin was associated with

increased rates of lung cancer mortality.

ENDOMETRIAL CANCER (WITH ESTROGEN-PROGESTIN) In the WHI,

use of estrogen-progestin was associated with a nonsignificant 17%

reduction in risk of endometrial cancer. A significant reduction in risk

emerged during the postintervention period (see later).

ALL-CAUSE MORTALITY In the overall WHI cohort, estrogen with or

without progestin was not associated with all-cause mortality. However, there was a trend toward reduced mortality in younger women,

particularly with estrogen alone. For women aged 50–59, 60–69, and

70–79 years, relative risks (RRs) associated with estrogen-only therapy

were 0.70, 1.01, and 1.21, respectively (p for trend = .04).

OVERALL BENEFIT-RISK PROFILE Estrogen-progestin was associated with an unfavorable benefit-risk profile (excluding relief from

menopausal symptoms) as measured by a “global index”—a composite outcome including CHD, stroke, pulmonary embolism, breast

cancer, colorectal cancer, endometrial cancer, hip fracture, and death

(Table 395-1)—in the WHI cohort as a whole, and this association did

not vary by 10-year age group. Estrogen-only therapy was associated

with a neutral benefit-risk profile in the WHI cohort as a whole. However, there was a significant trend toward a more favorable benefit-risk

profile among younger women and a less favorable profile among older

women, with RRs of 0.84, 0.99, and 1.17 for women aged 50–59, 60–69,

and 70–79 years, respectively (p for trend by age = .02). The balance

of benefits and risks of estrogen with and without progestin among

women aged 50–59 is shown in Fig. 395-3.

CHANGES IN HEALTH STATUS AFTER DISCONTINUATION OF HT In the

WHI, many but not all risks and benefits associated with active use of

HT dissipated within 5–7 years after discontinuation of therapy. For

estrogen-progestin, an elevated risk of breast cancer persisted (RR =

1.28; 95% confidence interval [CI], 1.11–1.48) during a median cumulative 13-year follow-up period (5.6 years of treatment plus 8.2 years of

postintervention observation), but most cardiovascular disease risks

became neutral. A reduction in hip fracture risk persisted (RR = 0.81;

95% CI, 0.68–0.97), and a significant reduction in endometrial cancer

risk emerged (RR = 0.67; 95% CI, 0.49–0.91). For estrogen alone,

3049 Menopause and Postmenopausal Hormone Therapy CHAPTER 395

the reduction in breast cancer risk became statistically significant

(RR = 0.79; 95% CI, 0.65–0.97) during a median cumulative 13-year

follow-up period (6.8 years of treatment plus 6.6 years of postintervention observation), and significant differences by age group persisted

for total myocardial infarction and the global index, with more favorable results for younger women. During a median cumulative 18-year

follow-up, estrogen alone was associated with a significant reduction

in all-cause mortality in women aged 50–59 years (RR = 0.79; 95% CI,

0.64–0.96); the protective effect was seen primarily in those with bilateral

oophorectomy (RR = 0.68; 95% CI, 0.48–0.96).

APPROACH TO THE PATIENT

Postmenopausal HT

The rational use of postmenopausal HT requires balancing the

potential benefits and risks. Table 395-2 provides one approach

to decision-making. This approach applies to women with menopausal symptoms who are age 45 years and older or to women who

have had removal of both ovaries, regardless of age. Women below

age 45 years or those with uncertain menopausal status may need

additional clinical evaluation before determining a management

plan. The clinician should first assess whether the patient has moderate to severe hot flashes and/or night sweats—the primary indication for initiation of systemic HT—that do not subside in response

to behavioral/lifestyle modifications. (A patient handout with suggested lifestyle modifications can be found at http://www.menopause.org/docs/for-women/mnflashes.pdf.) Systemic HT may also be

used to prevent osteoporosis in women at high risk of fracture who

TABLE 395-2 Approach to Initiating Menopausal Hormone Therapy for

Vasomotor Symptom Management

1. Vasomotor symptom assessment

Confirm that hot flashes and/or night sweats are adversely affecting sleep,

daytime functioning, or quality of life

2. Risk factor assessment

 Confirm that there are no absolute contraindications to menopausal hormone

therapy

 Breast, endometrial, or other estrogen-dependent cancer

 Cardiovascular disease (heart disease, stroke, transient ischemic attack)

 Active liver disease

 Undiagnosed vaginal bleeding

3. Menopausal hormone therapy initiation

RECOMMEND

CONSIDER WITH

CAUTION AVOID

Age <60 years

and

Menopause onset within

10 years

and

Low risk of breast

cancera

 and

cardiovascular diseaseb

Age ≥60 years

OR

Menopause onset

>10 years prior

OR

Moderate risk of

breast cancera

 or

cardiovascular diseasea

High risk of

breast cancera

 or

cardiovascular diseaseb

OR

Age ≥60 years or

menopause onset

>10 years prior

and

Moderate risk of

breast cancera

 or

cardiovascular diseaseb

a

For online tools to assess breast cancer risk, see AH McClintock et al: Breast

cancer risk assessment: A step-wise approach for primary care providers on

the front lines of shared decision making. Mayo Clin Proc 95:1268, 2020. b

For

online tools to assess cardiovascular disease risk, see D Lloyd-Jones et al: Use

of risk assessment tools to guide decision-making in the primary prevention of

atherosclerotic cardiovascular disease: A special report from the American Heart

Association and American College of Cardiology. Circulation 139:e1162, 2019.

Source: Data from AM Kaunitz, JE Manson: Management of menopausal symptoms.

Obstet Gynecol 126:859, 2015 and Manson JE et al: Algorithm and mobile app for

menopausal symptom management and hormonal/non-hormonal therapy decision

making: A clinical decision-support tool from The North American Menopause

Society. Menopause 22:247, 2015.

cannot tolerate alternative osteoporosis therapies. (Vaginal estrogen

or other medications may be used to treat genitourinary syndrome

of menopause in the absence of vasomotor symptoms [see below].)

The benefits and risks of such therapy should be reviewed with the

patient, giving more emphasis to absolute than to relative measures

of effect and pointing out uncertainties in clinical knowledge where

relevant. Because chronic disease rates generally increase with age,

absolute risks tend to be greater in older women, even when RRs

remain similar. Potential side effects—especially vaginal bleeding

that may result from use of the combined estrogen-progestogen formulations recommended for women with an intact uterus—should

be noted. The patient’s own preference regarding therapy should be

elicited and factored into the decision. Contraindications should be

assessed routinely and include unexplained vaginal bleeding; liver

dysfunction or disease; venous thromboembolism; known blood

clotting disorder or thrombophilia (transdermal estrogen may be

an option); untreated hypertension; history of endometrial cancer

(except stage 1 without deep invasion), breast cancer, or other estrogendependent cancer; and history of CHD, stroke, or transient ischemic attack. Relative contraindications to systemic HT include an

elevated risk of breast cancer (e.g., women who have one or more

first-degree relatives with breast cancer, susceptibility genes such as

BRCA1 or BRCA2, a personal history of cellular atypia detected by

breast biopsy); hypertriglyceridemia (>400 mg/dL); an elevated risk

of cardiovascular disease; and active gallbladder disease (transdermal estrogen may be an option in the latter three cases because it

has a less adverse effect on triglyceride levels, clotting factors, and

inflammation factors than oral HT). Primary prevention of heart

disease should not be viewed as an expected benefit of HT, and an

increase in the risk of stroke as well as a small early increase in the

risk of coronary artery disease should be considered. Nevertheless,

such therapy may be appropriate if the noncoronary benefits of

treatment clearly outweigh the risks. Reassess benefits and risks

at least once every 6–12 months, assuming the patient’s continued

preference for HT, or if the patient’s health status changes. A woman

who suffers an acute coronary event or stroke while taking HT

should discontinue therapy immediately.

Many options for systemic HT are available. Estrogen alone is

recommended for women with hysterectomy, whereas estrogen

plus progestogen is recommended for women with a uterus. In

the United States, the most commonly prescribed oral estrogens

for systemic treatment of vasomotor symptoms are 17β-estradiol

(1.0 or 0.5 mg/d or other doses) and conjugated equine estrogens

(CEE; 0.625, 0.45, or 0.3 mg/d or other doses). The most commonly

prescribed transdermal estrogen products are 17β-estradiol skin

patches (0.035 or 0.05 mg/d or other doses). The most commonly

prescribed progestogens are medroxyprogesterone acetate (MPA;

2.5, 5, or 10 mg/d) and micronized progesterone (100 or 200 mg/d).

Also available are oral estrogen-progestin combinations, such as

oral CEE and MPA, oral 17β-estradiol or ethinyl estradiol with

norethindrone acetate, oral estradiol with progesterone, and other

options. CEE/bazedoxifene may be an option for women with a

uterus, especially those with concerns about breast tenderness,

breast density, or uterine bleeding. Contraindications to CEE/bazedoxifene are similar to those for systemic HT.

Short-term use (<5 years for estrogen-progestogen and <7 years

for estrogen alone) is appropriate for relief of menopausal symptoms among women without contraindications to such use. However, such therapy should be avoided by women with an elevated

baseline risk of future cardiovascular events. Women who have contraindications for or are opposed to HT may derive benefit from the

use of certain antidepressants (including venlafaxine, fluoxetine, or

paroxetine), gabapentin or pregabalin, or clonidine.

Long-term use (≥5 years for estrogen-progestogen and ≥7 years for

estrogen alone) is more problematic because a heightened risk of breast

cancer must be factored into the decision, especially for estrogenprogestogen. Reasonable candidates for such use include postmenopausal women who have persistent severe vasomotor symptoms