Freeman EW et al. Venlafaxine in the treatment of premenstrual dysphoric disorder. Obstet Gynecol.

2001;98:737.

Kroll R, Rapkin AJ. Treatment of premenstrual disorders. J Reprod Med. 2006;51:359.

Landen M et al. Compounds with affinity for serotonergic receptors in the treatment of premenstrual dysphoria:

a comparison of buspirone, nefazodone and placebo. Psychopharmacology (Berl.). 2001;155:292.

Brown C et al. A new monophonic oral contraceptive containing drospirenone: effect on premenstrual

symptoms. J Reprod Med. 2002;47:14.

Beyaz [product information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022532s004lbl.pdf Accessed June 20, 2015.

Yonkers KA et al. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric

disorder. Obstet Gynecol. 2005; 106:492.

Lopez LM et al. Oral contraceptives containing drospirenone for premenstrual syndrome. Cochrane Database

Syst Rev. 2012;(2):CD006586. doi:10.1002/14651858.CD006586.pub4.

Sundstrom I et al. Treatment of premenstrual syndrome with gonadotropin-releasinghormone agonist in a low

dose regimen. Acta Obstet Gynaecol Scand. 1999;78:891.

O’Brien PM, Abukhalil IE. Randomized controlled trial of the management of premenstrual syndrome and

premenstrual mastalgia using luteal phase-only danazol. Am J Obstet Gynecol. 1999;180(1, Pt 1):18.

p. 1027

Menopause is the natural progression of reproductive aging in women. It

is characterized by declining ovarian function and decreased synthesis

of sex hormones.

Case 51-1 (Question 1),

Figure 51-1

Management of women who experience distressing symptoms

associated with menopause, including hot flushes and genitourinary

atrophy, is targeted at relieving symptoms while minimizing risks.

Case 51-1 (Questions 1–6),

Case 51-2 (Questions 1–2),

Figure 51-2

Estrogen therapy (ET), the most effective treatment for menopausal

symptoms, is associated with significant risks, including thromboembolic

disease and breast and endometrial cancer. Progestogens are added to

systemic estrogen therapy (EPT) to provide protection against

endometrial hyperplasia and cancer in women with an intact uterus.

Women must be adequately counseled so that they can make educated

decisions about treatment.

Case 51-1 (Questions 3, 5),

Table 51-1

Hormone therapy (HT), including ET and EPT, can be achieved through

a wide variety of dosage formulations and dosing regimens. Based on

the current understanding of the risks and benefits of systemic HT, use

should be limited to the management of menopausalsymptoms at the

lowest effective dose for the shortest time possible.

Case 51-1 (Questions 4, 5),

Table 51-2 and 51-3

The optimal time for the use of HT is controversial; some studies

suggest decreased cardiovascular risk when HT is initiated soon after

menopause, whereas other studies show an increased risk of breast

cancer when HT is started shortly after menopause.

Case 51-1 (Question 3)

Nonhormonal drugs, including serotonergic antidepressants and

antiepileptic drugs, are useful alternatives in women who are unable or

unwilling to take HT. Although use of herbal medicines for menopausal

symptoms is common, efficacy and safety data on these products are

limited.

Case 51-1 (Questions 2, 6),

Case 51-2 (Question 2),

Table 51-4

As vaginal atrophy does not wane with time after menopause, long-term

use of low-dose vaginal estrogen can be recommended.

Case 51-2 (Questions 1, 2)

INCIDENCE, PREVALENCE, AND

EPIDEMIOLOGY

The perimenopausal or climacteric phase in the female aging process (i.e., the time

between the reproductive and nonreproductive years) is distinguished by waning

ovarian function and irregular menstrual cycles. Menopause, the last spontaneous

episode of physiologic uterine bleeding, is usually identified retrospectively after 12

months of amenorrhea and typically occurs 4 to 5 years after the onset of the

perimenopause. If needed, menopause can be confirmed by a follicle-stimulating

hormone (FSH) level greater than 40 international units/mL. Postmenopause is

characterized by significantly decreased hormone levels that may contribute to an

increased risk of disease, including osteoporosis and cardiovascular disease

(CVD).

1,2

The average age of women at menopause has remained relatively constant at 51

years despite a significant increase in life expectancy.

3 Women today may spend onethird of their lives in the postmenopausal state. There are an estimated 40 million

postmenopausal women in the United States who are at risk for menopause-related

health issues.

3,4 Age at menopause appears to be determined primarily by genetics but

may be decreased by low body weight and poor health status. Cigarette smoking

decreases age at menopause by 1 to 2 years.

5 Higher socioeconomic status and prior

oral contraceptive use may increase age at menopause.

5 Cytotoxic drugs and

radiotherapy may induce ovarian failure, and bilateral oophorectomy results in

surgically induced menopause. Onset of menopause before age 40 is termed

premature ovarian failure.

p. 1028

p. 1029

PATHOPHYSIOLOGY

Perimenopause results from an age-related acceleration in oocyte (immature female

egg) degeneration and resistance to gonadotropins. The aging follicles produce less

inhibin, which triggers increased production of FSH (Fig. 51-1).

6 Despite this

increase in FSH levels, the declining ovary is unable to consistently produce mature

follicles, resulting in frequent anovulatory cycles during the years approaching

menopause. However, spontaneous ovulation can still occur, and contraception

should be used if pregnancy is not desired. When all ovarian follicles have been

depleted, menopause occurs. This corresponds with a 10- to 20-fold increase in FSH

levels and a threefold increase in luteinizing hormone levels, which peak 1 to 3 years

after menopause.

7

Postmenopausal estrogen production is approximately 10% of premenopausal

levels.

7,8 After menopause, circulating estrogen is largely estrone, whereas the more

potent estradiol is the primary estrogen during the reproductive years.

7 Unlike the

reproductive years, estrogen levels postmenopausally do not vary in a cyclic pattern.

The source of postmenopausal estrogen is androstenedione, an androgen converted to

estrogen by an aromatase enzyme found predominantly in fat, liver, and skin. Enzyme

levels increase with age and body weight, resulting in higher estrogen levels in

women with greater body fat.

7,9 The source of progesterone after menopause is the

adrenal gland, because the failed ovary no longer produces progesterone. Androgen

production declines by approximately 50% with normal aging; however, after

menopause, the androgen-to-estrogen ratio increases markedly owing to the greater

drop in estrogen levels, often resulting in mild symptoms of androgenism, such as

hirsutism.

10

CLINICAL PRESENTATION

The decrease in estrogen production associated with menopause can result in clinical

symptoms, such as hot flushes and genitourinary atrophy. The risk for CVD, the

leading cause of death in postmenopausal women, appears to be amplified by

estrogen deficiency.

1,2,5,11 Postmenopausal osteoporosis may result from estrogen

deficiency (see Chapter 110, Osteoporosis). Loss of estrogen has also been

associated with adverse effects on cognition, neurologic functioning, well-being, and

sexual health.

2 Other consequences of menopause may not yet be elucidated.

Signs and Symptoms

HOT FLUSHES

CASE 51-1

QUESTION 1: L.K., a 50-year-old woman, is having sudden feelings of warmth over her chest accompanied

by flushing of her skin and increased sweating for the past month, especially after drinking coffee or wine or if

she is upset. These symptoms often wake her at night. She had a menstrual period 3 weeks ago, but recently

her menses have been irregular (five menses in the past 12 months.) Her physical examination is normal for a

50-year-old woman. Her last mammogram 6 months ago was normal. She does not smoke, and her body mass

index is 24 kg/m

2

. She has hypertension that is controlled with hydrochlorothiazide 12.5 mg daily and migraine

headaches without aura that she treats with sumatriptan 50 mg orally (PO) as needed. Her family history is

positive for osteoporosis, but negative for CVD and breast cancer. Which of L.K.’s current symptoms are

consistent with menopause?

Figure 51-1 Perimenopausal changes in hypothalamus–pituitary–ovary axis. Dashed line indicates inhibitory

effect, Solid line indicates stimulatory effect and Wider line indicates more pronounced effect. FSH, folliclestimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.

p. 1029

p. 1030

It appears that L.K. is having hot flushes, a vasomotor symptom (VMS)

experienced by 60% to 80% of women during the menopause transition.

12 The onset

of VMS may precede the last menstrual period, but the prevalence peaks 1 year after

menopause and declines with time since menopause.

13 Symptoms persist an average

of 7 years; up to 30% of women may experience symptoms for longer than 10 years.

14

Obesity and surgically induced menopause are risk factors for more severe hot

flushes.

15 Symptoms include a feeling of warmth in the chest, neck, and facial areas

that may be accompanied by visible flushing and increased sweating. Nocturnal hot

flushes (night sweats) cause nighttime awakening and may lead to insomnia and sleep

deprivation. Hot flushes average approximately 4 minutes in duration and are

characteristically episodic rather than continuous, but may occur hourly in women

with severe symptoms.

10

Increased environmental temperature, ingestion of hot

liquids or alcohol, and mental stress may provoke hot flushes.

The specific trigger for hot flushes is unknown, but they are clearly associated

with the declining estrogen concentrations that occur during menopause. It is

postulated that the drop in estrogen leads to a decrease in serotonin levels and an

increase in the levels of norepinephrine and its metabolite, 3-methoxy-4-

hydroxyphenylglycol. These hormones are involved in temperature regulation, and

their fluctuations trigger an inappropriate activation of the body’s heat-release

mechanisms, leading to the cutaneous vasodilation and sweating seen with hot

flushes.

10,16

Cognitive and mood changes, including depression, are not uniformly associated

with menopause, but are reported more frequently in women during the

perimenopausal period.

17 Vaginal atrophy and urinary symptoms are also associated

with menopause (see Case 51-2 Question 1).

10,18

Overview of Therapy

Menopausal symptoms, while distressing, are not associated with increased

mortality. Therefore, the goal of drug therapy in a symptomatic woman is to relieve

symptoms and improve quality of life without increasing the risk of serious adverse

outcomes related to the agents used.

TREATMENT

CASE 51-1, QUESTION 2: L.K. is seeking relief for her hot flushes but is not sure that she wants to use

medications for this problem. What nonmedication therapies are appropriate for the management of L.K.’s hot

flushes?

Lifestyle Modifications

First-line treatment for hot flushes is lifestyle modification, including avoidance of

known triggers (e.g., hot beverages, alcohol, warm environments), wearing layered

clothing, and use of personal cooling devices. Data on the efficacy of regular

exercise, acupuncture, and relaxation techniques for VMS are limited.

19–21

If the

patient continues to experience bothersome symptoms, drug therapy should be

considered. It is noteworthy that placebo responses greater than 50% have been seen

in clinical trials evaluating interventions for hot flushes.

22

Black Cohosh

Black cohosh (Cimicifuga racemosa), an herbal product derived from a plant in the

buttercup family, has a long tradition of use for the management of menopausal

symptoms. It does not appear to have estrogenic effects, but may exert a serotonergic

effect.

23 The efficacy of black cohosh for hot flushes is controversial; however, good

results are reported in trials using a standardized extract containing 1 mg triterpene

glycosides/20 mg tablet taken twice daily.

24 Black cohosh is generally well tolerated,

but use beyond 12 months has not been evaluated. The most common adverse effects

are gastrointestinal upset and rash. There have been case reports of hepatotoxicity

which cannot be directly attributed to black cohosh.

23,24

Phytoestrogens

Phytoestrogens, including isoflavones and lignans, are plant-based substances that

exert mild estrogenic effects. Although epidemiologic studies show an association

between higher dietary soy intake and fewer menopausal symptoms, meta-analyses of

clinical trials of phytoestrogens concluded that they have minimal benefits on VMS.

22

However, several trials of the soy-derived isoflavone, genistein, reported significant

improvement in VMS, which warrants further investigation.

22

In general, isoflavones

are well tolerated; the most commonly reported side effect is gastrointestinal

intolerance. Endometrial stimulation is rare but has been reported in a small number

of patients after long-term use.

25,26 Because of their estrogenic effects, phytoestrogens

should be avoided or used cautiously in women with a history of estrogen-dependent

disease.

L.K. does not have any estrogen-dependent diseases and therefore could try either

black cohosh or phytoestrogens for her hot flushes if lifestyle modifications do not

provide adequate benefit. She should be counseled that these products have mixed

data supporting their benefits and phytoestrogens could potentially have side effects

similar to hormone therapy.

Hormone Therapy

CASE 51-1, QUESTION 3: L.K. returns to clinic after 2 months. She initiated lifestyle modifications and

tried black cohosh but has noted worsening of her flushes, awakening multiple times nightly from night sweats,

which is causing daytime fatigue and irritability. She asks about hormone therapy to control her hot flushes. Is

L.K. a candidate for hormone therapy?

Hormone therapy (HT) has received a great deal of scientific and media attention

during the past decade. The Women’s Health Initiative (WHI), the only large,

prospective study of estrogen therapy (ET) and estrogen/progestogen (EPT) therapy

in postmenopausal women, and several large cohort studies have provided a great

deal of data, some of it conflicting, on the risks and benefits of hormone use after

menopause.

27–29 Before selecting a treatment option, women should be evaluated for

contraindications to HT and counseled about its possible risks and benefits (Table

51-1).

Established Benefits of Hormone Therapy

Vasomotor Symptoms

Estrogen, with or without a progestogen, is well documented to reduce the frequency

and severity of hot flushes. In women with hot flushes, HT has been shown to

improve quality of life and depressive symptom.

27 During perimenopause,

combination hormonal contraceptives are effective in reducing VMS as well as

preventing pregnancy.

Osteoporosis

Estrogen, with or without a progestogen (ET/EPT), is proven to prevent bone loss

associated with menopause, reducing the risk of osteoporotic hip and vertebral

fractures by approximately 25%.

29 Many estrogen products are US Food and Drug

Administration (FDA)-approved for the prevention (but not treatment) of

osteoporosis (Table 51-2), and ET or EPT may be used for the prevention of

osteoporosis in recently menopausal women, even in the absence of menopausal

symptoms, if alternate osteoporosis therapies cannot be used.

27 Systemic ET

maintains bone density, but bone loss resumes with estrogen discontinuation.

Alternative therapies should be considered in women at risk for osteoporosis who

stop ET or avoid its use altogether (see Chapter 110, Osteoporosis).

27,30

p. 1030

p. 1031

Table 51-1

Risks and Benefits of Postmenopausal Hormone Therapy

Evidence

Absolute or Relative

Contraindications and

Patient Considerations References

Established Benefits

a

VMS Systemic ET (in women

without a uterus) or EPT (in

women with a uterus) is most

effective therapy for hot

flushes. There may be a

dose–response relationship.

Oral and TD estrogens are

equally effective.

This is the primary indication

for the use of systemic

hormone therapy.

45,79

Osteoporosis Numerous clinical trials

support reduced risk of

vertebral and hip fractures

with the use of estrogen.

Provides bone protection

during use of ET/EPT for

menopausalsymptoms. May

be used in recently

menopausal women at risk for

osteoporosis if other therapies

are not feasible.

30,33,80

Vaginal atrophy Numerous studies show both

local and systemic estrogens

reverse the atrophy induced

by menopause.

Localized therapy should be

used for patients with

symptoms related solely to

vaginal atrophy.

74,78

Established Risks

a

Thromboembolic

disease

Increased risk of DVT and

PE, greatest within the first

year of use, risk with EPT

possibly greater than with ET.

TD estrogen has lower risk

than oral estrogen.

Absolute contraindication:

current tobacco use, history of

thrombosis.

Relative contraindication:

obesity, women 65 years and

older.

Therapy should be

discontinued before surgery or

anticipated period of

immobilization.

40–43,46

Breast cancer Risk increased ˜25% after 5

years of use, increases with

continued use. Greater risk

with EPT and shorter

exposure gap.

Absolute contraindication:

personal history of breast

cancer.

Relative contraindication:

strong family history of breast

cancer.

27,36,37

Cardiovascular

disease

Increased risk of MI, when

started >10 years after

menopause or in women ≥60

years old (see also

unconfirmed benefit).

Relative contraindication:

age 60 years or older, >10

years postmenopause.

27

Endometrial cancer Risk related to dose and

duration of use.

Addition of adequate

progestogen reduces or

eliminates risk.

Rationale for the use of

concomitant progestogen in

women with uterus.

Absolute contraindication:

undiagnosed postmenopausal

vaginal bleeding, prior history

of endometrial cancer.

34

Ischemic stroke 30%–50% increased risk for

ischemic stroke seen. Doserelated risk seen with both ET

and EPT, may be less with

nonoral route. Risk greater

with increasing age (because

of underlying age-related risk

of stroke). HT does not

affect risk of hemorrhagic

stroke.

Absolute contraindication:

history of stroke or transient

ischemic attacks, current

tobacco use.

Relative contraindication:

obesity, uncontrolled

hypertension, uncontrolled

diabetes.

33,81

Gallbladder disease ˜60% increased risk of

cholecystitis, cholelithiasis

seen with ET and EPT, less

risk with nonoral route

Relative contraindication:

history of gallbladder disease.

29,47

Hypertriglyceridemia Oral estrogen increases

triglycerides. Nonoral route

has less effect. EPT may

have less effect than ET

alone owing to attenuating

effect of progestogen.

Relative contraindication:

hypertriglyceridemia.

If estrogen is to be used in

woman with elevated TG,

select transdermal route and

monitor TG levels.

27,82

Unconfirmed Benefits

b

Cardiovascular

disease

No increased risk or possible

decreased risk when initiated

prior to age 60 and within 10

Prevention of CVD is not a

primary indication for use; this

information can reassure

31,32

years of menopause (see also

established risk).

patient needing HT for

menopause symptoms or

replacement for women with

premature ovarian failure.

Colorectal cancer Decreased risk is seen with

EPT but not with ET.

May be secondary benefit in

women using for hot flushes.

83

p. 1031

p. 1032

Recurrent

UTIs

Low-dose localized estrogen

treatment can decrease risk for

recurrent UTIs.

May be secondary benefit in

women using localized therapy

for vaginal atrophy.

84

Diabetes

mellitus

Decreased incidence of newonset diabetes in women taking

EPT or ET.

This suggests that DM is not a

contraindication for women who

wish to use EPT/ET.

27

Unconfirmed Risks

b

Ovarian

cancer

Increased risk seen with

ET/EPT, longer durations of

treatment

Relative contraindication:

strong family history of ovarian

cancer.

85

Lung cancer Reports of protective effect but

in WHI increased mortality from

lung cancer seen in older

current/past smokers.

Absolute contraindication:

current tobacco use (owing to

increased risk of TED).

27,28

Urinary

incontinence

Systemic estrogen caused or

worsened urinary incontinence,

not seen with ultralow dose

Avoid systemic estrogen in

women with urinary

incontinence, monitor for new

onset in women taking HT.

48,86

Cognitive

effects

Studies report worsening of

dementia in women with

preexisting dementia; no

improvement or protection in

older women taking HT.

Absolute contraindication:

patients with evidence of

dementia.

Avoid use in women ≥65 years.

87

Migraine

headaches

HT may cause worsening of

migraine headaches.

Absolute contraindication:

migraine with aura (increased

risk of stroke).

Relative contraindication:

migraine without aura—monitor

for changes in HA frequency.

88