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Case 1

Hormone Replacement Therapy

A 53-year-old woman comes to her physician for a routine gynecologic examination. Once in the
office, she starts to cry and asks how she knows when she is through menopause and how long it
will take. She explains that her life is not the same anymore and that it must be due to the
change. She has not been to the gynecologist for several years. Her friends and family encouraged
her to come today to get help.

What is the definition of menopause?
When does menopause normally occur?
Menopause is the point in time marked by the permanent cessation of menses. The diagnosis of
menopause is made retrospectively. Menopause is defined as the absence of a menstrual period for 6 to
12 months in a woman 45 years of age or older. The cessation of menses reflects a decline in ovarian
function. The average age of menopause is 51.4 years, with a normal age range of 48 to 55 years.
Perimenopause is defined as the time period between the onset of irregularities in the menstrual cycle and
the cessation of menses. The few years preceding menopause are characterized by a fluctuation of ovarian
function, with resulting menstrual irregularities as well as possible vasomotor symptoms and genital
atrophy. This time period is also referred to as the menopausal transition. The average length of transition
is 4 years. Each individual womans menopausal transition is variable, ranging from minimal symptoms
with cessation of menses noted in retrospect to very bothersome and life-limiting vasomotor symptoms
(hot flushes and night sweats) and menstrual irregularities.

The patient states that her last period was about 5 months ago but that she really has not been
herself for the last 2 years. During this time, she has been experiencing what she thinks are hot
flashes that have been getting progressively worse. They seem to occur most often at night, and she
does not remember when she last had a full nights sleep. Before this she usually adjusted quite
well to changes in her life. Now, she cannot seem to cope. She also notes that after years of a
rewarding sexual relationship, she has very little interest or enjoyment in sex.

What are the characteristic symptoms of menopause?
What are the endocrinology, physiology, and clinical course of hot flushes?
What vaginal changes are characteristic of menopause?
How does menopause affect sexual function?
The most common symptom of the menopausal period is the hot flush. While between 75% and 85% of
women experience hot flushes to some degree, only about 20% of women feel the need to treat this
symptom. During the menopausal transition, many women notice the onset of hot flushes before the
permanent cessation of menses. Hot flushes occur most typically during periods of amenorrhea or right
before a menstrual period when circulating estradiol levels are reduced. Hot flushes occur in response to
a relative reduction in estradiol levels that exist in the menopause compared to premenopause. Women
with hypogonadism secondary to gonadal dysgenesis who have always had low estrogen levels do not
experience hot flushes. It has been noted that there is a surge of luteinizing hormone (LH) just before the
onset of the hot flush. However, it is unlikely that the LH surge plays a causative role because women
with hypopituitarism and no LH surge still experience hot flushes. Hot flushes are caused by an
inappropriate stimulation of the heat-losing mechanism in the thermoregulatory center of the

hypothalamus. Core body temperature has been measured and noted to be normal when the body is
stimulated to lose heat to reduce core temperature. There is a corresponding decrease in core body
temperature after the hot flush occurs. A prodromal aura usually signals that the hot flush is going to
occur, followed by an increasing sense of warmth progressing from the waist and over the chest, neck,
and face. This sense of warmth is accompanied by peripheral vasodilation with a flushing of the skin,
perspiration, and, at times, heart palpitations and anxiety. Hot flushes last from seconds to minutes and
may be repetitive. They tend to occur more frequently at night and may be a source of significant sleep
disturbances. Chronic sleep deprivation can result in fatigue, depression, anxiety, and an overall decreased
sense of well-being. Hot flushes tend to decrease in frequency with time, although they may persist for
more than 3 to 5 years in up to 33% of women. The pattern of symptoms seen in this patient is typical of
the menopause experience. Insomnia and depression are symptoms of the menopausal period that may
occur as a result of, as well as independently of, hot flushes. However, the mood disturbances
experienced by this woman may be secondary to the disruption in her life from hot flushes.
Dyspareunia (painful intercourse) is another common symptom experienced after menopause. The
vagina is an estrogen-sensitive organ. When circulating estradiol levels decline after menopause, the
vaginal epithelium atrophies, the vagina loses elasticity and compliance, and lubrication decreases. As
discomfort with intercourse increases, enjoyment and interest decline. Women also report decreased
libido during perimenopause and beyond, unrelated to dyspareunia. The etiology of waning interest in
sexual activity is usually multifactorial, with a complex interplay of hormonal, psychological, and social
factors. Some women experience a new enjoyment of sexual activity after menopause with children
moving away and no risk of pregnancy or with a new partner.

The role of estrogen replacement therapy for relief of menopausal symptoms is discussed with the
patient. She is eager to experience relief of her symptoms but is concerned because she has read

that a risk of breast cancer and heart attack is associated with estrogen replacement therapy.
Further history shows the patient has no history of breast biopsy or abnormal mammogram and a
negative family history for breast, ovarian, and colon cancers. Her last mammogram was at age 50
and she does not do breast self-examination regularly. She has four children; she had her first
when she was 23 years of age. She breastfed each of her children for at least 6 months. She has no
known medical problems and is not taking any medications. She does not take vitamins or calcium
supplements. The patient works as a secretary, and she does not exercise regularly; she neither
smokes nor drinks alcohol. She gets one serving per day of dairy products, does not pay attention
to fat in her diet, and drinks four to five cups of coffee per day. The patients father died from a
heart attack at age 62; he had his first heart attack at age 47. Her mother is alive and well at age
78. The patient has never had her cholesterol measured.

What are the benefits of estrogen replacement therapy?
What are the risks of estrogen replacement therapy?
What are the contraindications of estrogen replacement therapy?
Estrogen is approved for use after menopause to treat menopausal symptoms and to prevent and treat
postmenopausal osteoporosis. Estrogen, compared with placebo, has consistently reduced the severity,
frequency, and intensity of hot flushes. With improvement in hot flush frequency, an improvement in sleep
and mood is also often noted. Estrogen therapy (ET) also effectively relieves symptoms of vaginal
dryness and discomfort with intercourse related to urogenital atrophy. ET alone is often sufficient to
improve decreased libido. If a lack of desire is related to vaginal discomfort, marked improvement is
often noted with replacement therapy. It is controversial whether the addition of testosterone, in a low

dose, to the hormone replacement therapy regimen may provide further improvement in the level of
sexual desire. Recognition of the multifactorial nature of female sexual response is crucial in treatment of
sexual issues around the menopausal transition.
Osteoporosis is a systemic skeletal disease characterized by a decrease in bone mass with
microarchitectural distortion associated with increased fragility of bone and susceptibility to fracture. The
sites most frequently involved with fracture include the vertebrae, hip, and wrist, although all bones are at
risk. Risk factors for osteoporosis include advanced age, female gender, slight build and lower body mass
index (BMI), white or Asian race, tobacco use, alcohol use, inadequate calcium intake, sedentary lifestyle,
high-protein diet, and excessive caffeine use. Medications associated with an increased risk of
osteoporosis include chronic corticosteroid use and excessive thyroid replacement. Peak bone mass is
reached for both trabecular and cortical bone by age 30. Thereafter, there is continuous age-related bone
loss. For the first 5 to 7 years after menopause, the rate of bone loss accelerates secondary to reduced
circulating estradiol levels. Estrogen replacement therapy prevents the accelerated bone loss associated
with menopause and effectively reduces the risk of fracture by up to 50%. Bone loss resumes at the
immediate postmenopausal accelerated rate after cessation of therapy. Other measures, such as adequate
calcium and vitamin D intake and exercise, are also important in the prevention and treatment of
Unopposed estrogen replacement therapy in a woman with an intact uterus is associated with an
increased risk of endometrial hyperplasia and carcinoma. Risk increases with increasing dose and duration
of use. Adding a progestin (combination hormone therapy [HT]) at currently recommended doses and
duration to the estrogen regimen effectively decreases the risk to that of women not taking any hormone
Prior to 2002, retrospective data suggested that HT was protective against heart disease.
Recently, the Womens Health Initiative (WHI), a large prospective, randomized, and controlled study,

showed an increase in the risk of coronary heart disease with the use of estrogen and progestin in healthy
postmenopausal women. Another study, the HERS trial, showed that hormone replacement therapy did
not reduce coronary events in women with established heart disease. Despite the improved lipid profiles
seen with estrogen, these recent studies do not support a role for estrogen-progestin in the primary or
secondary prevention of coronary disease in postmenopausal women. Both the WHI and HERS data have
been criticized since both included women initiating HT several years out from the menopause transition.
It is possible that HT benefits women starting treatment at the time of the menopause transition and loses
its benefit when initiated in the years after the menopause. Studies are ongoing to try to define which
women, if any, may derive cardiovascular benefit from postmenopausal HT.
The combination HT arm of the WHI also showed a small but significant increase in deep vein
thrombosis (DVT) and stroke risk in treated versus nontreated women. After 4 years, a small but
significant increase in breast cancer risk was also seen (Table 1).
In addition to confirming reduction in fracture risk, a reduction in colon cancer risk was seen in
the treated combination arm group. Of interest, the only significant differences in the estrogen-only
treatment arm (women who had a history of hysterectomy) was in fracture risk (less in the treated group)
and stroke risk (less in the untreated group) (Table 2).
The effect of HT/ET on the risk of developing Alzheimer disease is controversial. Retrospective
data suggest a decrease in risk in treated versus nontreated women. However, in the subset of women
over 65 in the WHI, more women developed dementia in the treated arm than in the untreated arm.
Sine the release of the WHI data, HT or ET is recommended for the treatment of symptoms and
utilized at the lowest dose for the shortest time possible. However, about 50% of women who initiate HT
or ET for relief of symptoms will have return of their symptoms when treatment is discontinued. More
study is needed to determine optimal regimens for tapering therapy in symptomatic women.

Women who are not candidates for hormone replacement therapy are those with conditions that
could be worsened by hormone use or conditions that would impair the metabolism of estrogen, leading
to unpredictable circulating estrogen levels. These risk factors are a history of one or more of the
following: breast cancer, endometrial cancer (except stage I disease), recent thromboembolic disease,
hormone-related thromboembolic disease, and acute or chronic hepatic disease. Other conditions, such as
migraine headaches and cholelithiasis, are relative contraindications in that they are not life threatening
but could be worsened with hormone use.
Hormone replacement therapy in postmenopausal women needs to be tailored to the risk and
benefit profile of each individual patient. The patient in this case will benefit from hormone replacement
therapy for symptom management. Her history does not contain any absolute or relative contraindications
to therapy. After thorough discussion of the current understanding of risks and benefits of HT with this
patient, treatment with HT to resolve her significant vasomotor and atrophy symptoms should be

Physical examination reveals the patient to be normotensive and of average weight. Breast
examination is normal, and breast self-examination was taught. Pelvic examination showed
atrophic vaginal changes, a normal-sized uterus, and adnexa that were not palpable. Rectal
examination was negative for masses. Additional age-appropriate preventive testing and initiation
of hormone therapy were discussed with the patient.

What are the components of routine health maintenance that are important to include in the
clinical encounter with this patient?

How should hormone replacement therapy be prescribed and how should the patient be
What follow-up should be recommended?
When would an endometrial biopsy be recommended?
Frequently, the only encounter the postmenopausal woman has with the health care system is for
gynecologic care. It is important to take full advantage of this opportunity to provide counseling on
healthy lifestyle recommendations and obtain appropriate screenings according to the patients age and
risk profile. The following describes screening recommendations for healthy, asymptomatic women.
EXAMINATION: Blood pressure, weight, and height should be obtained on an annual basis. Breast selfexamination should be reviewed and recommended to be done monthly. Clinical breast examination
should be done annually; mammography should be obtained annually after the age of 50. A pelvic
examination is recommended on an annual basis.
LABORATORY AND RADIOLOGIC TESTING: Before age 50, mammographic screening should be
obtained every 1 to 2 years beginning at age 40. A normal mammogram should be documented before
initiation of hormone replacement therapy. A Pap smear should be obtained annually; longer screening
intervals can be used in the low-risk patient with a history of annual normal Pap smears, especially after
normal Pap smears and concurrent negative human papilloma virus (HPV) testing.
After age 45, cholesterol screening with a lipid profile should be obtained every 5 years if normal,
and more frequently if abnormal. Fasting blood sugar is recommended to screen for diabetes starting at
age 45 and then every 3 years if normal. In women, thyroid-stimulating hormone (TSH) to screen for
thyroid disease should be obtained starting at age 50 and then every 5 years. Screening for colorectal
cancer should be initiated at 50. Methods include sigmoidoscopy, colonoscopy, barium enema, and fecal
occult blood testing. Testing interval and type are customized depending on individual patient preference

and risk factors. However, colonoscopy is the gold standard for detecting colon cancers early, and should
be repeated at 10-year intervals. The role of routine bone density measurements to detect osteoporosis
should be initiated in the early 60s; screening may be initiated earlier in postmenopausal women with risk
factors for osteoporosis such as family history of osteoporosis, personal history of early menopause,
chronic corticosteroid use, hyperthyroidism, or prior history of fracture.
LIFESTYLE AND NUTRITIONAL COUNSELING: Smoking cessation should be recommended if the
patient smokes. For postmenopausal women, 1200 to 1500 mg/day calcium and 400 IU vitamin D intake
should be recommended. This total is the sum of both dietary and supplemental intake. Counseling
regarding daily physical activity and an aerobic exercise program should be provided.
ET or HT should be prescribed for symptom relief and osteoporosis prevention. Estrogen alone is
indicated in a woman who does not have a uterus. In women with a uterus, estrogen alone increases the
risk of endometrial cancer and therefore progestin must be used in conjunction with estrogen. Optimal
endometrial protection has been reliably demonstrated with addition of progestin either in a cyclic
administration (12 to 14 days per month 5 mg medroxyprogesterone acetate [MPA] or equivalent) or
continuously (2.5 mg MPA or equivalent daily). Prescribing cyclic progestin has the disadvantage of
inducing menstrual-like bleeding on a monthly basis. Continuous progestin therapy avoids regular cyclic
bleeding but is often initially associated with a higher incidence of irregular bleeding that is unpredictable
in terms of amount, frequency, and duration. The safety of less frequent cyclic addition of progesterone is
currently being studied.
Estrogen can be administered by the oral route, transdermal patch, and topically applied solution
as well as transvaginal forms. Progestin can be given as an oral or transvaginal pill, as a transvaginal
cream or suppository, or by an intrauterine delivery system. Combinations of estrogen and progesterone
in oral and transdermal preparations are also available. The decision regarding which form of medication
to use is based primarily on patient preference, as all are effective.

The patient should be counseled that side effects include breast fullness, tenderness, or
enlargement that usually subsides with continued use. Initial water retention and weight gain may occur.
Substantial weight gain has not been demonstrated to be secondary to hormone therapy. When using a
cyclic regimen, normal menstrual bleeding may occur on completion of the progestin component.
Bleeding may be similar in amount to previous menses; however, the bleeding may be lighter or there may
be no bleeding. Bleeding that occurs at any other time is considered abnormal. If a woman is started on
continuous combined therapy, she should be warned about the likely occurrence of irregular bleeding.
There is no normal expected bleeding pattern with this regimen. The patient should be instructed to call
the physician if she experiences abnormal bleeding or experiences symptoms that are new, persistent, or
bothersome. After initiation of therapy, the patient should return in 3 months to review her response to
therapy and voice any questions or concerns. Once the patients response to therapy has stabilized,
continuation of therapy and risks and benefits of therapy should be re-evaluated on a regular basis.
Routine endometrial biopsies are not necessary before the initiation of hormone replacement
therapy in a woman who is amenorrheic or who is experiencing normal cyclic menstrual flow in
conjunction with severe menopausal symptoms. However, endometrial sampling is indicated in any
women who experiences intermenstrual or irregular bleeding, postmenopausal bleeding, or abnormal
bleeding while taking hormone replacement therapy.

Table CS-1
Rates per 10,000



Relative Risk (95%

Women per Year

Breast cancer
Heart attacks


Hormone Therapy

Confidence Interval)
1.26 (1.001.59)
1.29 (1.021.63)
1.41 (1.071.85)
2.11 (1.582.82)

Colon Cancer
Hip fractures



0.63 (0.430.92)
0.66 (0.440.99)

Rates per 10,000


Estrogen Therapy

Relative Risk

Women per Year

Breast cancer
Heart attack







Table CS-2

Colon cancer
Hip fracture
* Significant value.