CHAPTER 18
Menopause
KEY POINTS
1 A woman in the developed world will spend approximately a third of her life beyond
menopause, so addressing the health and quality of life concerns of menopausal
women is critically important.
2 Health and quality of life concerns of menopausal and aging women include
vasomotor symptoms, symptomatic vulvovaginal atrophy, sexual dysfunction,
1022osteoporosis, cardiovascular disease, cancer, and cognitive decline.
3 Hot flashes and night sweats (vasomotor symptoms) affect up to 75% of
perimenopausal women and may last 10 years or longer.
4 Hormone therapy is the most effective treatment for vasomotor symptoms. Low-dose
paroxetine is another approved option. Lifestyle changes, relaxation response
techniques, acupuncture, soy and herbal products are popular interventions with
limited efficacy beyond placebo.
5 Contraindications to systemic hormone therapy use include known or suspected
breast or endometrial cancer, abnormal vaginal bleeding, cardiovascular disease
(including coronary heart disease, cerebrovascular disease, and thromboembolic
disorders), and active liver or gallbladder disease. Relative contraindications include
high-risk states for the above disorders.
6 The genitourinary syndrome of menopause, which includes symptomatic
vulvovaginal atrophy, affects at least 50% of menopausal women with an adverse
impact on sexual function and quality of life.
7 Vaginal application of low doses of estrogen is an effective and safe treatment of
vaginal dryness, dyspareunia, and certain urinary symptoms. Other options include
systemic hormone therapy, vaginal lubricants and moisturizers, oral ospemifene,
vaginal dehydroepiandrosterone, and pelvic physical therapy.
8 Sexual concerns are common after menopause, etiology is generally multifactorial,
and effective treatment options are available.
9 Osteoporosis and fractures increase with menopause and aging. Modifying risk
factors and pharmacologic interventions effectively prevent and treat osteoporosis
and reduce fracture risk.
10 Cardiovascular disease is an important health concern for menopausal women. A
healthy lifestyle and treatment of associated diseases including hyperlipidemia,
hypertension, and diabetes reduce risk, morbidity, and mortality.
11 Breast cancer is a major health concern for menopausal women and regular
screening is indicated.
12 Cognitive decline and dementia are highly prevalent in older women and risk
reduction should be optimized beyond menopause.
Menopause, the permanent cessation of menstruation caused by ovarian
failure, occurs at an average age of 52 years, with a range of 40 to 58 years.
Despite a great increase in the life expectancy of women, the age at menopause
has remained remarkably constant. [1] A woman in the developed world will
live approximately 30 years, or greater than a third of her life, beyond
menopause. Therefore, it is important to ensure these years are as healthy
and productive as possible. The age at menopause appears to be genetically
determined and is unaffected by race/ethnicity or age at menarche. Early
menopause describes menopause occurring between the ages of 40 and 45 years
1023and occurs in approximately 5% of women. Premature menopause describes
permanent loss of ovarian function before the age of 40, such as following
bilateral oophorectomy. Primary ovarian insufficiency (POI) describes loss
of ovarian function before the age of 40 years, which may not be permanent.
POI occurs in approximately 1% of women. Factors associated with early
menopause or POI include toxic exposures, genetic abnormalities, autoimmune
disorders, and pelvic surgery. Women who smoke experience an earlier
menopause (1), as do many women exposed to chemotherapy or pelvic radiation.
Fragile X premutations, Turner mosaic karyotypes, and ovarian surgery or
hysterectomy, despite retention of ovaries, may result in early menopause or POI
(2).
Although menopause is associated with changes in the hypothalamic and
pituitary hormones that regulate the menstrual cycle, menopause is not a
central event, but rather an indication of primary ovarian failure. At the level
of the ovary, there is a depletion of ovarian follicles, most likely secondary to
apoptosis or programmed cell death. The ovary is no longer able to respond to the
pituitary’s follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and
ovarian estrogen and progesterone production ceases. The ovarian–
hypothalamic–pituitary axis remains intact during the menopausal
transition; thus, FSH levels rise in response to ovarian failure and the
absence of negative feedback from the ovary. Atresia of the follicular
apparatus, in particular granulosa cells, leads to decreased production of estrogen
and inhibin, resulting in elevated FSH levels, a cardinal sign of menopause.
Antimüllerian hormone (AMH) is produced by small ovarian follicles, so
levels decrease with declining ovarian reserve (3).
Androgen production from the ovary continues beyond the menopausal
transition caused by sparing of ovarian stroma and theca cells. Androgen
concentrations are lower in menopausal women than in women of reproductive
age. This finding appears to be associated with aging and decreased functioning
of the ovary and adrenal glands over time rather than with menopause per se.
Menopausal women continue to have low levels of circulating estrogens,
principally from peripheral aromatization of ovarian and adrenal androgens.
Adipose tissue is a major site of aromatization, so obesity affects many of the
sequelae of menopause. Obesity is a risk factor for breast cancer and a protective
factor for osteoporosis, likely as a result of the impact of higher levels of
endogenous free estrogens, though still within the menopausal range.
Menopause is defined retrospectively as the time of the final menstrual
period followed by 12 months of amenorrhea. Postmenopause describes the
period following the final menses.
The STRAW (Staging of Reproductive Aging Workshop) criteria describe
1024the changes that encompass the transition from reproductive life to
postmenopause (4). The late reproductive stage is marked by decreased fertility
and onset of menstrual cycle changes. The early menopausal transition is
characterized by increased variability in menstrual cycle lengths (≥7 days), and
the late menopausal transition by amenorrhea of ≥60 days. Early postmenopause
describes approximately 5 to 8 years after the final menstrual period and is
followed by late postmenopause. Rising FSH levels, a reduced ovarian antral
follicle count, and declining levels of inhibin-B and AMH accompany
menstrual cycle changes.
The pathophysiologic consequences of menopause may be best understood by
considering that the ovary is a woman’s only source of oocytes, her primary
source of estrogen and progesterone, and a major source of androgens.
Menopause results in infertility secondary to oocyte depletion. Ovarian cessation
of progesterone production appears to have no clinical consequences, except for
the increased risk of endometrial proliferation, hyperplasia, and cancer associated
with continued endogenous estrogen production or administration of unopposed
estrogen therapy (ET) after menopause. The effects of declining androgen
concentrations that occur with aging have yet to be determined.
The clinical consequences of menopause are related primarily to estrogen
deficiency. It is difficult to distinguish the impact of estrogen deficiency from that
of aging, as aging and menopause are inextricably linked. Studying the effects of
estrogen deficiency and replacement in young women with ovarian failure or of
drugs that suppress estrogen synthesis (such as gonadotropin-releasing hormone
antagonists) helps to distinguish between the effects of aging and estrogen
deficiency. These models are imperfect, though, and differ from natural
menopause in many ways.
[2] Principal health and quality of life concerns of menopausal women
include vasomotor symptoms, the genitourinary syndrome of menopause
(GSM), sexual dysfunction, osteoporosis, cardiovascular disease (CVD),
cancer, and cognitive decline. Options for caring for menopausal women have
increased greatly since hormone therapy (HT) was first introduced in the 1960s.
There are many choices of hormone type, dose, and method of administration. In
addition to HT, other pharmacologic options include estrogen agonist/antagonists,
centrally acting agents, and bisphosphonates. Women are requesting more
information on complementary and alternative (CAM) therapies, which are being
studied more carefully. The many options available make caring for the
postmenopausal woman more challenging and more rewarding.
HEALTH CONCERNS AFTER MENOPAUSE
1025Vasomotor Symptoms
[3] Vasomotor symptoms affect up to 75% of perimenopausal women.
Symptoms last for 1 to 2 years after menopause in most women, but may
continue for up to 10 years or longer in others (5,6). Hot flashes are the
primary reason women seek care at menopause. Hot flashes interrupt daily
activities, disrupt sleep, and disturb women at work (7,8). Many women report
difficulty concentrating and emotional lability during the menopausal transition.
Treatment of vasomotor symptoms often will improve cognitive and mood
symptoms if they are secondary to sleep disruption and resulting daytime
fatigue. The incidence of thyroid disease increases as women age; therefore,
thyroid function tests should be performed, if vasomotor symptoms are
atypical or resistant to therapy.
The physiologic mechanisms underlying hot flashes are incompletely
understood. A central event, likely in the hypothalamus, drives an increased core
body temperature, metabolic rate, and skin temperature; this reaction results in
peripheral vasodilation and sweating. The central event may be triggered by
noradrenergic, serotoninergic, and/or dopaminergic activation. Hypothalamic
neurons containing kisseptin, neurokinin B (NKB), and dynorphin receptors
(KNDy neurons) appear to play an important role in hot flashes. Peripheral
infusion of NKB intravenously induces a typical hot flash, while blocking NKB
activity reduces hot flashes (9). Although an LH surge often occurs at the time of
a hot flash, it is not causative, as vasomotor symptoms occur in women without
pituitary glands. In symptomatic postmenopausal women, hot flashes likely are
triggered by small elevations in core body temperature acting within a narrow
thermoneutral zone (10). Exactly how estrogen and alternative therapies play a
role in modulating these events is unknown. Vasomotor symptoms are a
consequence of estrogen withdrawal, not simply estrogen deficiency. For
example, a young woman with premature menopause caused by Turner syndrome
will have very high FSH levels and low estrogen levels, but will not experience
hot flashes until she is treated with estrogens and that therapy is withdrawn.
Lifestyle interventions may safely decrease vasomotor symptoms. Being in
a cool environment is associated with fewer subjective and objective hot
flashes (11), so women experiencing symptoms should be advised to keep the
room temperature low and wear light, layered clothing (see Table 18-1).
Overweight women and those who smoke often have more severe vasomotor
symptoms than women of normal weight and nonsmokers. These findings
provide additional reasons to encourage women to lose weight and stop smoking
(12). Many menopausal women are interested in trying CAM therapies for relief
of hot flashes. These are diverse medical and health care products and practices
generally not considered part of conventional medicine. Vasomotor symptoms are
1026particularly sensitive to placebo effects. Numerous nutritional supplements and
products claim to relieve hot flashes but these assertions are rarely
supported by controlled trials (13). Phytoestrogens are plant-derived substances
that may act as estrogen agonist/antagonists, with their effects modulated through
interactions with the estrogen receptor. Although they decrease hot flash severity
and frequency, symptom improvement is comparable to that seen with placebo
treatment (14). Black cohosh is another popular alternative treatment, with
efficacy similar to placebo (15).
Table 18-1 Options for the Treatment of Vasomotor Symptoms
Hormone Therapy
Estrogen therapy
Progestin therapya
Combination estrogen/progestin therapy
Combination conjugated estrogen/bazedoxifene
Nonhormonal Prescription Medications
Centrally acting alpha agonist
Clonidinea
Selective serotonin and norepinephrine reuptake inhibitors
Paroxetine
Venlafaxinea
Escitaloprama
γ-aminobutyric acid analogs
Gabapentina
Pregabalina
Nonprescription Medicationsa
Isoflavone supplements
Soy products
Black cohosh
Lifestyle Changes
Reducing body temperature
Maintaining a healthy weight
Smoking cessation
Relaxation response techniques
Yoga
1027Acupuncture
aNot U.S. Food and Drug Administration–approved for treatment of vasomotor symptoms.
Acupuncture reduces vasomotor symptoms in several studies, although a
traditional Chinese medicine approach may be no more effective than shallow or
“sham” needling techniques (16,17). Exercise, yoga, and paced respiration
demonstrated an improvement in hot flashes in several uncontrolled studies, with
additional health benefits, including stress reduction. Women may choose to use
alternative and complementary therapies for relief of symptoms, but they should
be aware that the safety and efficacy of these approaches often are unproven.
[4] Systemic ET is the most effective treatment for vasomotor symptoms (see
Table 18-2). Although low-dose formulations are often effective, younger
women and those with recent oophorectomy may require higher doses.
Progestin therapy must be given concurrently if a woman has a uterus,
although with low-dose ET, intermittent progestin treatment may be an
option. Oral contraceptives (OCPs) are an excellent option for healthy,
nonsmoking, perimenopausal women with bothersome hot flashes. The
supraphysiologic doses of estrogens and progestins in OCPs treat vasomotor
symptoms while controlling irregular bleeding. A tissue-selective estrogen
complex that combines conjugated estrogen (CE) (0.45 mg) and the
agonist/antagonist, bazedoxifene (BZA) (20 mg) (1 tablet orally daily) is
approved for the treatment of vasomotor symptoms (VMS) in menopausal
women with a uterus. BZA provides endometrial protection, so a progestin is not
needed (18).
HT should be used at the lowest effective dose for the duration necessary
to meet treatment goals. For the majority of healthy women with bothersome
hot flashes at the menopausal transition, the benefits of HT will outweigh
risks.
Because vasomotor symptoms appear to be the result of estrogen
withdrawal, rather than simply low estrogen levels, if cessation of ET is
desired, the dose should be reduced slowly over time. This recommendation is
based on clinical experience, as few controlled trials have been performed to
examine the optimal way to discontinue HT. Abruptly stopping treatment may
result in a return of disruptive vasomotor symptoms in approximately 50% of HT
users (19). The dose and dosing interval may be reduced slowly over months or
even years, depending on the patient’s symptoms. For women unable to
discontinue HT without return of bothersome symptoms, long-term use may
be an option, depending on health status, a careful review of risks and
benefits, and shared decision making (20).
1028For women who choose not to take estrogen or when it is contraindicated, other
options are available (see Table 18-1) (13). Progestin therapy alone, including
medroxyprogesterone acetate and micronized progesterone, reduces hot flash
frequency and severity (21,22). Various agents that alter central neurotransmitter
pathways reduce VMS. Agents that decrease central noradrenergic tone, such as
clonidine, decrease hot flashes, although the effect size is limited. Potential side
effects include orthostatic hypotension and drowsiness.
Table 18-2 Approved Estrogen/Progestogen Prescription Products for Menopausal
Symptoms in the United States
10291030Selective serotonin and serotonin norepinephrine reuptake inhibitors
(SSRIs/SNRIs) reduce hot flash frequency and severity and are the mainstay
of nonhormonal VMS treatment. Although paroxetine, venlafaxine, and
escitalopram have been shown in randomized controlled trials (RCTs) to be
more effective than placebo and may be used off-label (23,24), only a very
low dose of paroxetine (7.5 mg) is FDA approved for this indication (25). Side
effects of SSRIs/SNRIs include nausea, drowsiness, dry mouth, insomnia, and
sexual dysfunction. Paroxetine inhibits the enzyme system that converts
tamoxifen to its active form, so should not be used by women taking
tamoxifen for breast cancer prevention or treatment.
Gabapentin and pregabalin are γ-aminobutyric acid analogs approved for
the treatment of seizures and neuropathic pain. These agents reduce hot
flash frequency and severity significantly more than placebo in several
RCTs, so are an off-label option for VMS treatment (26,27). As side effects
include disorientation, dizziness, and drowsiness, use of gabapentin and
pregabalin is best limited to bedtime for the treatment of night sweats and
associated sleep disruption. Women principally bothered by night sweats and
disrupted sleep may benefit from sleeping medication. In an RCT, the prescription
insomnia treatment, eszopiclone, significantly improved sleep with a positive
impact on next-day functioning, mood, and quality of life (28). Antihistamines,
including diphenhydramine hydrochloride, are inexpensive, over-the-counter
agents that may improve sleep in women with bothersome night sweats.
A potential therapy for VMS is an agent that blocks hypothalamic NKB
activity. Although not yet commercially available, RCTs confirm that an oral
antagonist to the NKB receptor (NK3R) significantly reduces hot flashes
compared with placebo, independent of any hormonal effects (9).
1031Genitourinary Syndrome of Menopause
[6] GSM describes anatomic changes and symptoms secondary to estrogen
deficiency affecting the labia, vagina, urethra, and bladder (29). Symptoms
include bothersome genital irritation, dryness, and burning; urinary
urgency, dysuria, and recurrent urinary tract infections (UTIs); and dryness
and pain with sexual activity. Vulvovaginal atrophy (VVA) is a component of
GSM (30). Bothersome VVA symptoms are highly prevalent, affecting at
least 50% of menopausal women, with a significant adverse impact on
quality of life (31,32). Although vasomotor symptoms generally improve with
time, GSM typically worsens in the absence of treatment. Many effective
therapies are available for GSM/symptomatic VVA (33).
Nonhormonal vaginal products available over-the-counter are often an initial
treatment intervention. Vaginal lubricants (water, silicone, or oil based) reduce
friction and increase comfort with penetrative sexual activity, including
intercourse. Long-acting vaginal moisturizers used two to three times weekly
line the vagina, retaining moisture and reducing symptoms (34).
Activity that stretches, stimulates, and strengthens the genital area promotes
vulvovaginal health. If indicated, genital activity, with or without a partner,
should be encouraged after menopause. Pelvic physical therapy (PT) and use of
vaginal dilators effectively treat severe dyspareunia (35). The use of laser therapy
for the treatment of GSM remains controversial with few controlled trials (36,37).
[7] If nonhormonal therapies are ineffective, ET is approved for the
treatment of vaginal dryness, dyspareunia, and related symptoms. Low doses
of estrogen applied vaginally are preferred to systemic ET in the absence of
vasomotor symptoms because of minimal absorption and a high degree of
safety (33). Several formulations are available, including vaginal estradiol tablets
and creams, and a ring (see Table 18-2) (38). Low doses of vaginal estrogen
cream (0.5 g) are effective when used only two or three times weekly. An
estradiol vaginal tablet (10 μg, 4 μg) inserted twice weekly may be less messy
than estrogen cream. An estradiol-containing vaginal ring (7.5 μg per day) is
another convenient formulation, which is placed in the vagina every 3 months and
slowly releases a low dose of estradiol (39).
Endometrial safety has been confirmed with the use of low-dose vaginal
ET for up to 1 year, but long-term clinical trials have not been performed.
An analysis of data from more than 45,000 women in the Women’s Health
Initiative (WHI) Observational Study was very reassuring, with no increased risk
of endometrial cancer seen in users of vaginal ET compared with nonusers (40).
There also was no increased risk of breast cancer or CVD in vaginal ET users.
Women using vaginal ET should be reminded to report any vaginal bleeding,
and a thorough evaluation should be performed. Typically, concurrent
1032progestin therapy is not prescribed with low-dose vaginal estrogen
preparations.
Vaginal ET reduces certain urinary problems in menopausal women,
including frequency, urgency, and recurrent UTIs (41). Incontinence does
not appear to improve with vaginal ET, and is likely worsened by systemic
HT (42,43).
Studies of the low-dose estradiol vaginal ring and tablet confirm that serum
estrogen levels generally remain within the normal range for postmenopausal
women (44). Given minimal systemic absorption, low doses of vaginal ET
may be an option even for women with a history of estrogen-responsive
cancers or CVD (33,45).
Vaginal use of the hormone dehydroepiandrosterone (DHEA) (0.5% daily)
effectively treats moderate to severe dyspareunia secondary to VVA and is
approved for this indication (46). Circulating levels of estradiol, estrone,
testosterone, and DHEA remain within the normal postmenopausal range.
Endometrial biopsies showed inactive or atrophic uterine lining after one year of
treatment (47).
The estrogen agonist/antagonist, ospemifene (60 mg/day) is an oral agent
approved for the treatment of moderate to severe dyspareunia associated
with VVA (48). Sexual function improves, including reduced sexual pain and
increased arousal and desire (49). Endometrial safety was confirmed at 1 year
(50). As with other estrogen agonist/antagonists, ospemifene may increase the
risk of VTE and vasomotor symptoms, reduces breast density, and has favorable
effects on bone.
Sexual Dysfunction
[8] Sexual problems are highly prevalent, reported in approximately 40% of
US women, with 12% reporting a sexual problem associated with personal
distress (51). Although sexual problems generally increase with aging,
distressing sexual problems peak in midlife women (aged 45 to 64) and are lowest
in women 65 years or older. The etiology of female sexual dysfunction is often
multifactorial, including depression or anxiety, relationship conflict, stress,
fatigue, prior abuse, medications, or physical problems that make sexual
activity uncomfortable, such as endometriosis or GSM. The impact of
menopause per se on sexual function is uncertain (52). Bothersome VMS
causing sleep disruption and fatigue and dyspareunia secondary to GSM are
aspects of the menopause transition that may directly affect sexual desire and
pleasure. Aging, concurrent illness, psychological changes, and relationship and
social factors impact sexual functioning in older women, irrespective of the direct
physiologic and hormonal changes of menopause.
1033ET effectively treats vaginal dryness, dyspareunia, and vasomotor
symptoms, but does not appear to have a direct effect on sexual interest,
arousal, or orgasmic response, independent from its role in treating
menopausal symptoms. In contrast to ET, androgen therapy may improve
sexual function in selected populations of menopausal women (53). The
impact of declining androgen levels with aging and the efficacy of testosterone in
treating female sexual dysfunction remain controversial. Potential risks of
androgen therapy include hirsutism, acne, irreversible deepening of the
voice, and adverse changes in liver function and lipids. As most androgens
are aromatized to estrogens, there is potential for an increased risk of
cardiovascular events and breast cancer. No androgen products are approved
for use in women.
Although VVA and dyspareunia respond well to systemic or local ET, oral
ospemifene, and vaginal DHEA, most other sexual problems may be
effectively treated without hormones. Relationship quality and conflict, stress,
and fatigue predict sexual satisfaction, so couples often benefit from counseling,
lifestyle changes, and sex therapy. Underlying depression and anxiety should be
treated, and antidepressant medication may need adjustment. Bupropion may be
an alternative to an SSRI, or added to SSRI treatment in the setting of FSD.
In women with and without depression, increased sexual arousal and orgasm are
observed with bupropion in small RCTs (54). Sildenafil citrate may benefit
women who develop problems with arousal and orgasmic response on SSRIs,
but generally it is no more effective than placebo for most female sexual
problems (55,56). Even though sexual problems are common, the majority of
women with distressing sexual problems do not seek formal care, but when they
do, it is typically the woman, rather than the physician, who initiates the
conversation (57). Clinicians should routinely ask their menopausal patients
about sexual concerns, as many effective interventions are available (58).
Osteoporosis
[9] Low bone mass and osteoporosis affect an estimated 35 million US
women, or approximately 66% of women older than age 50 years (59).
Because therapy is most likely to benefit those at highest risk, it is important to
review a woman’s risk factors for osteoporosis when making decisions regarding
bone density screening and treatment (Table 18-3). Low bone mass and
osteoporosis are principal risk factors for fractures, which are associated
with an enormous economic cost, pain, disability, and even increased
mortality. Nonmodifiable risk factors include age, race (Asian, Caucasian),
small body frame, early menopause, prior adult fracture, and family history
of osteoporosis. Modifiable risk factors include inadequate intake of calcium
1034and vitamin D, smoking, low body weight, excess alcohol use, and a
sedentary lifestyle. Medical conditions associated with an increased risk of
osteoporosis include anovulation during the reproductive years (e.g.,
secondary to excess exercise or an eating disorder), hyperthyroidism,
hyperparathyroidism, chronic renal disease, rheumatoid arthritis, and
diseases requiring systemic corticosteroid use.
Table 18-3 Risk Factors for Osteoporosis
Nonmodifiable
Age
Race (White, Asian)
Small body frame
Early menopause
Prior adult fracture
Family history of osteoporosis
Modifiable
Inadequate intake of calcium and vitamin D
Smoking
Low body weight
Excess alcohol use
Sedentary lifestyle
Associated Medical Conditions
Anovulation during reproductive years (e.g., due to excessive exercise or disordered
eating)
Hyperthyroidism
Hyperparathyroidism
Chronic renal disease
Rheumatoid arthritis
Conditions requiring systemic corticosteroid use
Bone mineral density (BMD) measurements may be used to determine
fracture risk, diagnose osteoporosis, and identify women who would benefit
from therapeutic interventions. Dual x-ray absorptiometry (DXA) of the hip
and spine is the primary technique for BMD assessment. BMD is reported as
absolute density (grams mineral/cm2) and in relation to two norms. T score is the
standard deviation (SD) above or below the mean for a healthy 30-year-old
woman. Z score is the SD above or below the mean for a woman of similar age.
1035Normal BMD is defined by a T score ê-1, low BMD or osteopenia by a T
score between -1 and -2.5, and osteoporosis by a T score Ä-2.5. Although there
is a strong association between BMD and fracture risk, a woman’s age, risk for
falls, and overall health status significantly influence fracture risk. Evaluation of
BMD by DXA is recommended for all women aged 65 and older, regardless
of risk factors, and for younger postmenopausal women with one or more
risk factors, other than being White and menopausal (60).
Women should be counseled to alter modifiable risk factors as an
important step in the prevention of osteoporosis and fractures (Table 18-4).
Women with diets deficient in calcium and vitamin D will benefit from
dietary modification and supplementation. Daily intake of calcium 1,200 mg
and vitamin D 800 to 1,000 IU is recommended (60). Calcium intake should
be achieved principally through diet. Treatment with calcium and vitamin D
does not appear to directly reduce fracture risk (61). Reducing the risk of
osteoporosis and fractures is another of the many health benefits of regular
weight-bearing and muscle-strengthening exercise, smoking cessation, and
limiting alcohol intake. Other interventions to reduce fracture risk include a home
safety assessment (installing a shower grab bar, carpeting stairs), vision
correction, and avoiding central nervous system depressant medications.
Table 18-4 Recommendations to Reduce Risk of Falls and Fracture
Dietary calcium (1,200 mg/day) with supplementation only if dietary intake insufficient
Vitamin D (800–1,000 IU/day) through diet and/or supplements
Regular weight-bearing and muscle-strengthening exercises
Improve balance
Increase strength
Reduce risk of falls and fractures
Stop smoking
Limit alcohol use
Limit central nervous system depressants
Visual correction, when needed
Home safety assessment
Carpet stairs
Install grab bars in tubs and showers
Night lights
1036Cosman F, de Beur SJ, LeBoff MS, et al; National Osteoporosis Foundation. Clinician’s
guide to prevention and treatment of osteoporosis. Osteoporos Int 2014;25(10): 2359–
2381.
Table 18-5 Options for Osteoporosis Prevention and Treatment
Bisphosphonates
Alendronate (Fosamax) (35 or 70 mg/week orally)
Risedronate (Actonel) (35 mg/week or 150 mg/month orally)
Ibandronate (Boniva) (150 mg/month orally or 3 mg/every 3 months intravenous)
Zoledronic Acid (4 mg every 1 to 2 years intravenous)
Additional potential benefits: none
Potential risks: esophageal ulcers, osteonecrosis of jaw (rare), atypical femoral
fractures (rare) Zoledronic acid: hypocalcemia, atrial fibrillation, renal impairment
Side effects: gastrointestinal distress, arthralgias/myalgias
Hormone Therapy
Estrogen or estrogen/progestin therapy
Additional potential benefits: treatment of vasomotor symptoms and urogenital atrophy
Potential risks: breast cancer, gallbladder disease, venous thromboembolic events,
coronary heart disease, stroke
Side effects: vaginal bleeding, breast tenderness
Tissue-Selective Estrogen Complex
Bazedoxifene (20 mg)/Conjugated estrogens (0.45 mg) (Duavee) (1/day orally)
Additional potential benefits: treatment of vasomotor symptoms and urogenital atrophy
Potential risks: breast cancer, endometrial cancer, gallbladder disease, venous
thromboembolic events, coronary heart disease, stroke
Estrogen Agonist/Antagonist
Raloxifene (Evista) (60 mg/day orally)
1037Additional potential benefits: reduced risk of breast cancer
Potential risks: venous thromboembolic events, stroke
Side effects: vasomotor symptoms, leg cramps
Other
Forteo (Teriparatide) (20 μg/day subcutaneously)
Tymlos (Abzioparatide) (80 μg/day subcutaneously)
Additional potential benefits: none
Potential risks: osteosarcoma (after long-term use in rodents), hypercalcemia
Side effects: musculoskeletal pain
Prolia (Denosumab) (60 mg subcutaneously every 6 months)
Additional potential benefits: none
Potential risks: rash, serious infection, hypocalcemia
Side effects: musculoskeletal pain
Pharmacologic treatment is indicated for all women with osteoporosis (T
score <–2.5), women with a prior hip or vertebral fracture, and women with
low BMD at high fracture risk. FRAX, an online fracture risk assessment
tool, provides the 10-year probability of a major osteoporotic fracture for an
individual woman. FRAX helps to identify women with low BMD (T score
between –1 and –2.5) who will benefit from pharmacologic therapy (62). Prior
to initiating treatment, excluding secondary causes of osteoporosis is advised.
Evaluation may include a comprehensive metabolic panel, complete blood count,
thyroid stimulating hormone level, parathyroid hormone level, 25-OH vitamin D
level, and 24-hour urine collection for calcium.
Drugs used in the prevention and treatment of osteoporosis are principally
antiresorptive agents that reduce bone loss and anabolic drugs that stimulate new
bone formation (Table 18-5). HT effectively prevents and treats osteoporosis
and is FDA approved for osteoporosis prevention. In observational studies,
current ET use, especially if started soon after menopause and continued long
term, reduces osteoporosis-related fractures (63). The WHI trial confirmed a
significant (34%) reduction in hip fractures in healthy women randomized to
HT (CE 0.625 mg per day) after a mean follow-up of 5.6 years (64). Combined
1038with calcium and vitamin D, even very low-dose ET (CE 0.3 mg per day;
transdermal estradiol 0.014 mg per day) produces significant increases in
BMD compared with placebo (65).
The tissue-selective estrogen complex (BZA/CE) is approved for
osteoporosis prevention in postmenopausal women with a uterus (18). The
estrogen agonist/antagonist raloxifene (60 mg orally daily) prevents vertebral
fractures in women with low bone mass and osteoporosis, though does not
appear to reduce the risk of nonvertebral fractures (66). Raloxifene exercises
estrogen-like actions on bone and lipids without stimulating the breast or
endometrium. Raloxifene is approved to reduce the risk of invasive breast cancer
in women at high risk. In an RCT of approximately 10,000 older postmenopausal
women with heart disease or multiple risk factors, raloxifene had no significant
effect on death from any cause, coronary events, or total stroke, though risk of
fatal stroke and venous thromboembolic disease was increased. The risks of
clinical vertebral fractures and invasive breast cancer were significantly reduced
(67).
Bisphosphonates specifically inhibit bone resorption and are very effective
for the prevention and treatment of osteoporosis. Many convenient
formulations are available, including alendronate (35 mg and 70 mg orally
weekly), risedronate (35 mg orally weekly, 150 mg orally monthly),
ibandronate (150 mg orally monthly, 3 mg intravenous every 3 months), and
zoledronic acid (5 mg intravenous every 1 to 2 years) (60). Women should
take oral bisphosphonates on an empty stomach with a large glass of water
and remain upright with nothing else to eat or drink for at least 30 minutes.
Creatinine clearance must be normal. The major side effect is gastrointestinal
distress. Very rare adverse events include esophageal ulceration, osteonecrosis of
the jaw, and atypical femoral fractures. These rare complications are more likely
with high-dose intravenous and long-term bisphosphonate use. As residual
antifracture effects persist for several years after stopping bisphosphonates, it is
reasonable for women to take a “drug holiday” and discontinue treatment after 3
to 5 years, if fracture risk is reduced after initial treatment.
Denosumab (60 mg subcutaneously every 6 months) is a monoclonal
antibody to the receptor activator of nuclear factor-κB ligand. It is approved
for the treatment of postmenopausal osteoporosis and decreases both
vertebral and hip fractures (68). Rare adverse events are similar to those with
bisphosphonates. Unlike most treatments for osteoporosis that inhibit bone
resorption, parathyroid hormone (PTHrP 1–34) (teriparatide 20 lg and
abaloparatide 80 lg subcutaneously daily) stimulates new bone formation,
resulting in significant reductions in vertebral and nonvertebral fractures
(69). Treatment duration typically is 18 to 24 months. Women treated with
1039denosumab, teriparatide, or abaloparatide should initiate an alternative treatment
upon stopping, as rapid bone loss follows discontinuation. Calcitonin nasal spray
(Miacalcin, 200 IU per day intranasal) is an approved, but rarely prescribed
treatment for established osteoporosis.
Cardiovascular Disease
CVD is the leading cause of death for women and 90% of women have one or
more risk factors. Nonmodifiable risk factors include family history and age.
Modifiable risk factors include a sedentary lifestyle, obesity, and smoking.
Medical conditions associated with an increased risk of heart disease include
diabetes, hypertension, and hyperlipidemia. [10] Advising women to alter
modifiable risk factors for CVD and adequately treating diabetes,
hypertension, and hyperlipidemia are important components of the
comprehensive care of midlife women.
Although epidemiologic studies identify an approximately 50% decrease in
coronary heart disease (CHD) in woman who use HT (70), data from RCTs do
not support the use of HT for CHD prevention. Observational studies are prone to
bias, and women who used HT in the past were generally healthier and at lower
risk for CHD than nonusers (71). The WHI randomized, placebo-controlled
trial of combination estrogen–progestin therapy (EPT) showed that rather
than prevent CHD, EPT increased the risk of cardiovascular events in older
women (72). The WHI was a 15-year study sponsored by the National Institutes
of Health to examine ways to prevent heart disease, osteoporosis, and breast and
colorectal cancer in women. There were several different studies in WHI,
involving more than 160,000 healthy postmenopausal women. The WHI clinical
trial enrolled approximately 27,000 women nationwide between the ages of 50
and 79 years. The average age of women in the study was 63 years. The objective
of the WHI RCT was to assess the major health benefits and risks of the most
commonly used HT preparation at the time. Women with a uterus were
randomized to EPT (CE 0.625 mg/MPA 2.5 mg) versus placebo while
hysterectomized women were randomized to ET (CE 0.625 mg) versus placebo.
In the EPT trial, after an average of 5 years of follow-up, risks (hazard ratio
[HR]) were increased for CHD (1.3), breast cancer (1.3), stroke (1.4), and
pulmonary embolism (PE) (2.1), and decreased for hip fracture (0.7) and
colorectal cancer (0.6) (72). The absolute excess risk attributable to EPT was
small, with seven to eight additional CHD events, breast cancers, strokes,
and pulmonary embolisms per 10,000 woman-years. In the ET trial, after an
average follow-up of 7 years, there was no increased risk of heart disease or
breast cancer in estrogen users. Outcomes were similar to those seen in the
EPT WHI trial with respect to venous thromboembolism, stroke, and
1040osteoporotic fractures; there was no effect on colorectal cancer (73).
Further analyses of WHI confirmed that the increased risk of CHD
occurred principally in older women and those who were a number of years
beyond menopause (Table 18-6). No increased risk of CHD was seen in
women between the ages 50 and 59 or within 10 years of menopause (74).
Although stroke was increased with HT regardless of age or years since
menopause, the absolute excess risk of stroke in the younger women was
minimal. These data do not support a role for HT in the prevention of heart
disease, but they do provide reassurance regarding the safety of HT use for
bothersome hot flashes and night sweats in otherwise healthy women under
age 60 or within 10 years of menopause.
Table 18-6 Absolute Excess Risk of Coronary Heart Disease and Mortality with
Hormone Therapy Use in WHI
1041FIGURE 18-1 Women’s Health Initiative hormone therapy trials: absolute risks (cases per
10,000 person-years) for outcomes in the intervention phases of the estrogen–progestin and
estrogen-alone trials by age group. CEE, conjugated equine estrogens; MPA,
medroxyprogesterone acetate. (Redrawn from Kaunitz AM, Manson JE. Management of
menopausal symptoms. Obstet Gynecol 2015;126:859–876. In: Manson JE, Chlebowski
RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the
intervention and extended poststopping phases of the Women’s Health Initiative
randomized trials. JAMA 2013;310(13):1353–1368).
An overview of WHI findings, including both the EPT and ET trials and
postintervention (median 13 years of cumulative follow-up), confirmed that
the absolute risk of adverse events associated with HT use was considerably
lower in younger women (ages 50 to 59 years) than in older women (75). In
this reanalysis, in the intervention phase, a statistically significant increase in
CHD events was no longer seen with EPT use. In both trials, women receiving
HT had a lower risk of vasomotor symptoms, diabetes, and hip fractures and a
higher risk of venous thromboembolism, gallbladder disease, and stroke. Breast
cancer risk was increased in the EPT trial with a reduced risk in the ET trial
observed during the poststopping phase (see Fig. 18-1) (75,76). In an analysis of
mortality with HT use, neither EPT (median 5.6 years) or ET (median use
7.2 years) was associated with risk of all-cause, cancer, or cardiovascular
1042mortality with 18 years of cumulative follow-up (77).
The WHI trials examined treatment only with CEs and medroxyprogesterone
acetate. The effects of other oral estrogen agents, transdermal estradiol, other
progestins, or cyclic HT may be different. In observational studies,
transdermal ET is not associated with an increased risk of venous
thromboembolic disease (78). The average age of women participating in these
trials was more than 15 years beyond the age at which women typically initiate
HT for the treatment of vasomotor symptoms. The “timing hypothesis”
proposes that early initiation of HT, presumably when there is less
atherosclerosis in blood vessels, may result in a more favorable risk–benefit
profile. The findings of the Early Versus Late Intervention Trial With
Estradiol (ELITE) support this hypothesis. HT for 5 years (oral estradiol 1
mg/day with cyclic progesterone vaginal gel in women with a uterus) was
associated with less progression of subclinical atherosclerosis (carotid artery
intima-media thickness [CIMT]) than placebo when initiated within 6 years after
menopause. In contrast, HT had no effect on CIMT when initiated in women
more than 10 years after menopause (79).
Breast Cancer
Breast cancer is a major health concern for menopausal women, as it is the
most common cancer in women and the second leading cause of cancer death
(80). The lifetime risk of invasive breast cancer for US women is 12%; therefore,
any therapies that increase or reduce this risk will have a major impact on
women’s health. [11] Regular screening mammography reduces the risk of
death from breast cancer. The optimal screening interval remains
controversial. It is generally recommended that women at average risk be
offered initiation of screening mammography at age 40, beginning no later
than age 50 years (81). Screening every 1 or 2 years is advised until at least the
age of 75 years. Whether annual or biennial screening is elected should be based
on informed, shared decision making that includes a discussion of benefits and
harms.
Risk factors for breast cancer include age, family history, early menarche, late
menopause, certain genetic carrier states, and prior breast disease, including
epithelial atypia and cancer. Risk is reduced in women who had bilateral
oophorectomy or a term pregnancy before the age of 30. Many of these risk
factors are consistent with the hypothesis that prolonged estrogen exposure
increases breast cancer risk.
Current, long-term use of HT, generally defined as greater than 5 years, is
associated with an increased risk of breast cancer (relative risk [RR] = 1.3) in
observational studies (82). Use of estrogen alone appears to confer a lower risk
1043than combined therapy with estrogen and progestin (83). The WHI randomized
controlled trial demonstrated an increased risk of breast cancer in women
randomized to EPT after approximately 5 years of use (HR = 1.2) (72). The
attributable risk of breast cancer in women randomized to EPT is less than 1
additional case per 1,000 women per year. In contrast, there was no increased
risk of breast cancer with the use of estrogen alone in women with a prior
hysterectomy after an average of 7 years of use (73). HT should not be
prescribed to women with a history of breast cancer and should be used by
women at high risk only after a careful assessment of potential benefits and
risks. A randomized trial of HT use in women with a history of breast cancer and
bothersome hot flashes was stopped after only 2 years, as more new breast
cancers were diagnosed in women randomized to HT (84).
The estrogen agonist/antagonist tamoxifen (20 mg per day orally) is used
in the treatment of estrogen-receptor positive breast cancer. Tamoxifen and
raloxifene reduce the risk of breast cancer in high-risk women by
approximately 50% and are approved for this indication (85). The risk of
venous thromboembolism is increased approximately threefold with the use
of tamoxifen and raloxifene, similar to the increase seen with HT. Tamoxifen
acts as an estrogen agonist in the endometrium, increasing the risk of endometrial
polyps, hyperplasia, and cancer, whereas no endometrial stimulation is seen with
raloxifene. Aromatase inhibitors (AIs) have become the preferred adjuvant
therapy for postmenopausal women with early-stage, hormone receptor–
positive breast cancer (86). Circulating estrogen levels are very low with
associated bone loss, vasomotor symptoms, and GSM.
Dementia
[12] Cognitive decline and dementia are common concerns of menopausal
and aging women. Alzheimer disease is the most common form of dementia
and women are at greater risk for developing the disease than men. The
number of affected individuals in the United States is estimated at over 5
million of which two-thirds are women. Although observational studies suggest
that HT may decrease the risk of Alzheimer disease, this finding has not been
supported by RCTs in older women. The WHI Memory Study (WHIMS) was a
randomized placebo-controlled study of women aged 65 years or older enrolled in
WHI to assess the effect of HT on cognitive function. Women in WHIMS
randomized to EPT experienced a significant twofold increased risk of
probable dementia. The increased risk of dementia seen in women
randomized to estrogen alone was not statistically significant (75). HT should
not be used to prevent or treat dementia. Women should be encouraged to engage
in behaviors that are associated with a lower risk of dementia, including
1044exercising regularly, not smoking, treating underlying hypertension and diabetes,
avoiding head injury, improving hearing, active learning, and staying socially
engaged (87).
HORMONE THERAPY USE
The use of unopposed estrogen is associated with an increased risk of
endometrial hyperplasia and cancer. Therefore, combination EPT is
necessary for all women with a uterus. Treatment may be provided in a
sequential manner, with estrogen daily and progestin for 12 to 14 days of
each month, or in a continuous-combined fashion with estrogen and a lower
dose of progestin daily. Sequential regimens result in regular, predictable vaginal
bleeding. The majority of women using continuous-combined regimens will
experience amenorrhea by the end of 1 year of therapy, but the bleeding that does
occur is irregular and unpredictable. Low-dose combination HT products (e.g.,
CE/MPA 0.45/1.5 and 0.3/1.5 mg per day) generally result in a lower incidence of
breakthrough bleeding and breast tenderness (88).
To reduce overall progestin exposure, women using low doses of oral or
transdermal estrogens may elect off-label intermittent progestin use (e.g., 14 days
every 3 months) (89). A progestin-releasing intrauterine system approved for
contraception in premenopausal women provides endometrial protection in
estrogen-treated menopausal women, although it is not approved for this
indication (90). Increased endometrial surveillance is advised with these
alternative regimens.
There may be additional benefits and reduced risk with nonoral
administration of ET. Systemic delivery of estradiol by skin patch, spray, gel,
or vaginal ring avoids the “first pass hepatic effect” of oral estrogens on
lipids, binding globulins, and clotting factors. Women with thyroid disease do
not require adjustment of thyroid replacement when initiating nonoral ET, as
thyroid globulin levels do not increase. Free testosterone levels do not decline
with nonoral ET, as sex hormone–binding globulin levels are unchanged, which
may be a benefit for women with low libido (91). In a trial of oral versus
transdermal E2 in early menopausal women, transdermal, but not oral ET was
associated with a significant yet moderate improvement in sexual function
compared with placebo (92).
In contrast to oral administration, observational studies do not show an
increased risk of venous thromboembolic events with transdermal estradiol
(78) and possibly a lower risk of stroke (93). Gallbladder disease may not
increase with use of transdermal ET, as with oral (94). Although transdermal
ET does not appear to increase the risk of venous thromboembolic events or
1045gallbladder disease in observational studies, HT remains contraindicated in
women at high risk for venous thromboembolic disease and in those with
active liver or gallbladder disease.
Popularized by the media, many women are interested in using “bioidentical
hormones” for treatment of menopausal symptoms. Bioidentical generally refers
to hormones structurally identical to “natural” hormones made by the ovary,
including estradiol and progesterone. FDA-approved oral and transdermal
estradiol products are available in a wide range of doses, as is an oral form of
micronized progesterone. Progesterone should be taken at bedtime, as it may
cause drowsiness. There is potentially significant increased risk and no known
benefit to the use of custom-compounded “bioidentical” HT formulations,
preparations that are “custom” mixed and packaged by a compounding
pharmacist for an individual patient (95). Women who request natural HT
formulations should be prescribed FDA-approved formulations containing
estradiol and micronized progesterone. All nonoral ET formulations
(transdermal patches, topical spray and gels, and intravaginal ring) contain natural
estradiol (see Table 18-2 for FDA-approved HT formulations).
[5] Contraindications to HT use include known or suspected breast or
endometrial cancer, undiagnosed abnormal genital bleeding, CVD (including
CHD, cerebrovascular disease, and thromboembolic disorders), and active
liver or gallbladder disease. Relative contraindications include high-risk
states for the above disorders. If alternative treatments for bothersome VMS are
ineffective, HT may be appropriate for a woman with a relative contraindication,
following a thorough assessment of potential risks and benefits.
HT is an appropriate option for most healthy woman with bothersome hot
flashes. If she is under age 60 years or within 10 years of menopause, it is
highly likely that benefits will outweigh risks. As with any therapy, HT
should be used at the lowest effective dose for the duration necessary to meet
treatment goals (20,76). The need for continued HT use should be assessed at
least annually. Although HT risks increase with advancing age and duration
of use, long-term use may be appropriate for women with persistent hot
flashes after thorough assessment of benefits and risks and shared decision
making. As HT risks differ depending on formulation, dose, route of
administration, and whether a progestin is needed, treatment should be
individualized based on a woman’s needs and preferences.
SUMMARY
There are many options available to address the health and quality of life concerns
of menopausal women. The primary indication for HT is the alleviation of hot
1046flashes and associated symptoms. Women should be informed of the
potential risks and benefits of all therapeutic options. Care should be
individualized based on a woman’s medical history, needs, and preferences
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