Menopause Jianhong Zhou I DIFINITION A Menopause 1

Jianhong Zhou
A Menopause
1. Menopause is a natural biologic process, and is not defined as a disease of estrogen
deficiency. It is the permanent cessation of menses occurring as a result of loss of
ovarian activity. Menopause is retrospectively defined as the absence of menses after the
final menstrual period (FMP). The FMP can only be determined when it is followed by
amenorrhea for 1 year. The cessation of menses reflects the reduction of ovarian estrogen
production to levels insufficient to produce proliferation of the endometrial lining.
2. Menses usually cease spontaneously between 40 and 58 years of age; the median age of
menopause is 51.4 years, with 90% becoming menopausal between the ages of 45 to 55
years of age. The average age of menopause has been stable worldwide for centuries, in
spite of increasing longevity. However, age of menopause can be affected by current
cigarette smoking and genetic predisposition.
3. Premature menopause is defined as the permanent cessation of menses occurring before
40 years of age.
4. Menopause can be spontaneous or induced by surgery, chemotherapy, radiation, or other
exogenous influences.
B Preimenopause
1. The perimenopause or menopause transition refers to the period just before menopause. It
ends with the FMP.
2. This period is marked by variation in menstrual cycle length and flow, reflecting a rise in
levels of follicle-stimulating hormone (FSH).
3. The median age of onset of menstrual irregularity is 47.5 years; the transition lasts an
average of 4 years. Nevertheless, 10% of women abruptly stop menstruating without
having cycle irregularity.
C Postmenopause begins with the FMP and continues for the duration of the women’s life.
A Ovarian function. A period of waxing and waning ovarian function occurs before
menopause. It is a time of fluctuation in hormone production and reduced fecundability. It
may be difficult to differentiate changes due to menopause from those related to aging.
1. The number of remaining ovarian follicles is reduced and those remaining are less
sensitive to gonadotropin stimulation. Aging of the female reproductive system begins at
birth, and consists of the steady loss of oocytes from atresia or ovulation. Follicular
function varies not only from one individual to another, but also from cycle within the
same individual. As follicular maturation declines, ovulation becomes less frequent in
2. Although fertility rates are markedly reduced, conception can occur during this time of
fluctuating ovarian activity.
B Endocrinology
1. Inhibin production by the ovary depends on the number of existing ovarian oocytes and
therefore is reduced. Inhibin B exerts a negative feedback on the secretion of FSH by the
2. An increase in FSH levels results from the decreased circulating levels of inhibin and the
loss of negative feedback. This is the earliest evidence of a change in ovarian function.
Elevated FSH level can be seen with both normal and abnormal cycles. The hallmark of
reproductive aging is the elevation of FSH to greater than 10 mIU/ml in the early
follicular phase (between day 2 and 5 of the menstrual cycle).
3. Luteinizing hormone (LH) secretion escapes the negative feedback of inhibin, and LH
levels are not affected by the loss of inhibin production. LH levels rise much later in the
transition than FSH levels; sustained elevations may not be seen until after menopause.
4. Estradiol levels fluctuate but remain within the wide range of normal until follicular
development ceases altogether. Estradiol levels may actually rise in perimenopause due to
an increase in the number of recruited remaining follicles from the increase in FSH levels.
Estradiol also has a negative feedback effect on FSH levels.
5. Progesterone levels fluctuate depending on the presence and adequacy of ovulation and
are frequently low during perimenopause.
6. Androgen levels are unchanged or slightly decreased in perimenopause. Levels are more
affected by aging than by failing ovarian function.
C Menstrual cycles. Changes in the menstrual cycle reflect changes in ovarian function
and circulating levels of ovarian steroids and pituitary gonadotropins.
1. Changes in menstrual cycle regularity occur as a woman progress through her 40s.
Cycle length is determined by the length of the follicular phase. The secretory phase
should be a constant 12 to 14 days. The length of time between menses, or cycle length,
is variable and may be normal length, shortened, or prolonged. Bleeding may be heavier
or lighter than previous menses and last for longer or shorter duration of time than was
previously usual.
2. Shortening of cycle length often occurs early in perimenopause and is associated with
ovulatory cycles, a shortened follicular phase, and elevated FSH levels.
3. Anovulatory cycles and prolonged cycles become more frequent as menopause
approaches, resulting in dysfunctional uterine bleeding (DUB) and oligomenorrhea.
DUB is defined as abnormal bleeding not caused by pelvic pathology, medications,
systemic disease, or pregnancy. It is a diagnosis of exclusion.
A Ovarian function. Follicular reserve is depleted and is finally manifested by a
permanent cessation in menses.
1. Few follicular units remain in the postmenopausal ovary, and those present are no
longer capable of a normal response despite stimulation by markedly elevated
a. FSH receptors are absent on a cellular level.
b. Estradiol production by the ovary depends on FSH stimulation of follicles, and is
negligible in the postmenopausal ovary. The greatest decline in estradiol levels are in the
first year after the FMP and decrease more gradually in subsequent years.
c. Estrone, a less potent estrogen than estradiol, is produced in negligible amounts by the
postmenopausal ovary. It is derived from metabolism of estradiol and from peripheral
aromatization of androstenedione in adipose and muscle tissue. Estrone becomes the
predominant estrogen in menopause.
2. Ovarian stromal tissue continues to produce androgenic steroid hormones for several
years after menopause.
a. Although there is a lack of FSH receptors, ovarian stromal cells possess LH receptors
and respond with the production of ovarian androgens (e.g., androstenedione,
testosterone, and dehydroepiandrosterone [DHEA].
b. Androstenedine and DHEA production continues but at a decreased rate. Testosterone
production remains stable or may be slightly increased.
B Endocrinology
1. FSH levels are elevated 10 to 20 times above premenopausal levels, reaching a plateau 1
to 3 years after menopause, after which there is a gradual decline. This reflects loss of the
negative feedback effects of both inhibin and estradiol. FSH levels never return to the
premenopausal range, even with estrogen replacement therapy, reflecting the influence of
2. LH levels rise two- to threefold after menopause, reaching a plateau in 1 to 3 years, after
which there is a gradual decline. This reflects the loss of the negative feedback effect of
estradiol. LH levels never reach those of FSH because of the shorter circulating half-life
of LH (30 minutes as opposed to 4 hours).
3. Although ovarian estrogen production is negligible after menopause, there is individual
variation in circulating estrogen levels because of peripheral conversion of androgenic
precursors to estrone.
a. Androgens, which serve as precursors for estrone, continue to be produced by the
postmenopausal ovary and the adrenal gland.
b. Aromatase enzymes that convert androgens to estrone primarily (and estradiol to a
lesser degree) are present in peripheral tissues but are predominantly present in adipose
c. Estrogen levels vary with the degree of adiposity. Obesity can lead to a state of relative
estrogen excess.
4. Peripheral testosterone levels are decreased despite sustained or increased production
rates by the ovary. Circulating testosterone levels are the net result of androstenedione
and testosterone production by the adrenal gland and the ovary.
a. Testosterone and androstenedione production by the adrenal gland continue to fall with
progressive age.
b. Testosterone production by the ovaries does not decrease for several years after
c. Androstenedione production by the ovary is markedly reduced after menopause and
accounts for the fall in circulating testosterone levels.
5. DHEA levels are reduced after menopause. However, DHEA sulfate levels, which reflect
adrenal gland activity, are unchanged.
6. Sex hormone-binding globulin (SHBG) is decreased by 40% in association with the
decrease of estradiol. As a result of the decrease in SHBG, the ratio of free androgen to
SHBG is increased, allowing more circulating unbound testosterone.
C Premature menopause or premature ovarian failure is the cessation of menses in a
woman younger than 40 years of age. Premature ovarian failure can be transient. When
it is permanent, it is equivalent to premature menopause.
1. The frequency of premature ovarian failure is 0.3%. This is the diagnosis in 5% to 10% of
women with secondary amenorrhea.
2. Most women with premature menopause undergo premature oocyte atresia and follicular
depletion. This results from one of three mechanisms:
a. Decreased initial germ cell number at birth
b. Accelerated oocyte atesia after birth
c. Postnatal germ cell destruction
3. A small number of affected women have abundant remaining follicles and elevated
gonadotropins, suggesting a resistance to gonadotropin stimulation or the presence of
biologically inactive gonadotropins.
A Manifestation of estrogen excess. During perimenopause, some women present with
evidence of estrogen excess rather than deficiency, due to a transient increase from
increased FSH levels.
1. Abnormal uterine bleeding (AUB) is bleeding that is excessive in amount, duration, and
frequency. It can occur due to prolonged exposure of the uterine lining to estrogen
stimulation unopposed by progesterone. It may also be due to structural or systemic
abnormalities. AUB without known structural or endocrine causes is called dysfunctional
uterine bleeding (DUB).
a. Anovulatory cycles, common to the perimenopausal transition, lead to unopposed
estrogen stimulation of the endometrial lining. This in turn can cause AUB, due to
dyssynchronous shedding of the endometrium, which occurs with increased frequency in
perimenopausal women. The type of AUB seen most commonly in the perimenopause
transition is due to anovulatory cycles.
b. Increased endogenous estrogen can also be caused by increased peripheral conversion
of androgen precursors to estrone and estradiol. This is most frequently seen in obese
perimenopausal women.
c. Less commonly, pathologic conditions are associated with increased estrogen production
(ovarian tumors) or decreased metabolic clearance of estrogen (hepatic or renal disease),
leading to elevated circulating estrogen levels.
d. There are many other causes of AUB not related to sex hormone fluctuation. Examples
are endometrial polyps, fibroids, pregnancy, infection, coagulopathy, disorders of thyroid
or prolactin regulation, chronic illness, and exogenous medications.
e. Uterine leiomyoma, previously present, may grow during menopause transition due to
estrogen excess. This may result in AUB and pelvic symptoms such as pain or pressure.
2. Endometrial neoplasia
a. Prolonged unopposed estrogen stimulation of the endometrial lining may lead to
excessive endometrial proliferation and subsequent endometrial pathology.
b. Abnormal uterine bleeding that occurs either in woman older than 40 years of age or in a
younger woman with risk factors (history of chronic anovulation or unopposed estrogen,
prolonged bleeding, obesity) must be evaluated with pelvic examination, pregnancy test,
lab work as indicated by history, and endometrial sampling to rule out disease. Office
endometrial biopsy, with or without pelvic ultrasonography, is usually sufficient.
Dilation and curettage (D&C) with hysteroscopy and sonohysterography are
alternatives for diagnostic testing.
c. Simple endometrial hyperplasia has low risk of progression to endometrial carcinoma
and can be treated medically.
d. Complex endometrial hyperplasia without atypia is a more advanced type of
hyperplasia, with a 3% risk of progressing to endometrial carcinoma. Complex
hyperplasia may also be treated medically, followed up with posttreatment tissue
e. Complex endometrial hyperplasia with atypia is associated with an increased risk of an
associated endometrial carcinoma. Because of an approximately 25% risk of progression
to endometrial carcinoma, hysterectomy is the treatment of choice for this condition.
However, if medical management is elected, hysteroscopy with D&C is necessary first to
rule out the coexistence of endometrial cancer.
f. Endometrial cancer should be suspected in all perimenopausal women who present with
abnormal bleeding. As much as 10% of postmenopausal bleeding is secondary to a
carcinoma. Treatment is surgical.
B Manifestations of hormonal fluctuation
1. Menstrual cycle changes. Some change in the character of established menstrual cycles
is the most common manifestation of perimenopause. Ninety percent of women may
experience menstrual changes in perimenopause.
a. Menorrhagia is defined as increased blood flow (more than 80 mL) during menses,
or bleeding that lasts longer than 7 days. Cycles are regular and ovulatory. Increased
flow may result from a relative reduction in progesterone levels. Increased bleeding at
regular intervals is also called hypermenorrhea.
b. Metrorrhagia is bleeding at irregular intervals or between menses. Shortening of
cycle length is a common change reported early in the menopausal transition. Cycle
length remains longer than 21 days but is typically shorter than cycles experienced
during the reproductive years. Cycles are ovulatory with a shortened follicular phase.
c. Oligomenorrhea is the decreased frequency of menstruation. As menopause
approaches, missed periods are common, and cycle length increases until a permanent
cessation of menses occurs.
d. Amenorrhea is the absence of menses.
2. Other symptoms. Many women who are still menstruating experience a variety of
symptoms traditionally attributed to menopause.
a. Hot flashes are symptoms of vasomotor instability. This is the second most common
perimenopausal symptom, reported by 75% of perimenopausal women. Hot flashes
can come and go over time and are not consistent from cycle to cycle. They typically
are present for up to 2 years after the FMP, but may persist for up to 10 years. When
they occur with sleep and are associated with perspiration, they are called night sweats.
Peripheral vasodilation is associated with a rise in skin temperature, resulting in a hot
flash. There may also be a modest increase in heart rate at the same time. Although
there is no objective link between alcohol, caffeine, and hot flashes, there are
anecdotal reports supporting an association.
b. Headaches may worsen during perimenopause, and then improve again after
menopause. There may be a hormonal link, but this has not been well studied.
c. Sleep disturbance. Interrupted sleep, with or without hot flashes, is reported by
one-third to one-half of U.S. women in this age group.
d. Mood disturbance is reported by 10% of perimenopausal women. This includes
symptoms of irritability, depression, insomnia, fatigue, and difficulty with memory or
concentrating. Sleep deprivation and midlife stresses may be strong contributing
factors. There is no evidence that cognitive function actually deteriorates with
perimenopause or menopause.
e. Sexual function such as libido, arousal, and vaginal lubrication and elasticity can be
affected by the onset of perimenopause. These changes can be due to many causes,
including hormonal fluctuation, medications, sleep disturbance, loss of partner, and
life stresses.
f. Weight gain occurs for many women during the menopause transition, possibly due to
aging and lifestyle. Obesity increases a woman’s risk for other health problems, such
as cardiovascular disease and diabetes. A theory that weight gain during this time may
also be due to a decrease in metabolically active tissue and less overall time spent in
the secretory phase of the cycle as menses become farther apart needs further study.
C Treatment
1. Progestogen (natural progesterone or synthetic progestin) supplementation.
Periodic administration of a progestogen is used to treat conditions associated with
estrogen excess.
a. DUB can be treated with intermittent progestogen in 12- to 14-day monthly cycles,
which provides estrogen antagonism and allows for the orderly sloughing of the
endometrium. Therapy may also be administered continuously, preventing withdrawal
bleeding. These therapies decrease the incidence of anovulatory uterine bleeding and
the development of endometrial neoplasia.
b. Simple and complex hyperplasia may be treated effectively with progestogen
supplementation. Treatment with progestin or progesterone as described for DUB is
prescribed. Follow-up biopsy is performed after 3 months of treatment to verify
resolution of the hyperplasia.
c. Complex hyperplasia with atypia may be treated with high-dose progestogen if
surgical therapy is not an option, once the presence of carcinoma has been excluded
by such methods as ultrasonography, hysteroscopy, and D&C. Follow-up biopsy after
3 months of treatment is mandatory to verify resolution.
(1) Progestogen is given daily for 3-6 months.
(2) Megestrol (a strong progestin) is given daily for 3 -6 months.
2. Combination (estrogen-progestin) hormonal contraceptives are useful for both
contraception and treating symptoms in perimenopausal women who are normotensive
nonsmokers without other risk factors. Choices include oral contraceptive pills, vaginal
ring, and contraceptive patch.
a. Low-dose combination hormonal contraceptives (35μg ethinyl estradiol or less) can
be an effective treatment for abnormal bleeding and hot flashes associated with
b. These medications are obviously also an effective method of contraception for
women in whom this is still a concern. There is no increased risk using combination
hormonal contraceptives in perimenopausal-aged women without risk factors
compared to younger women.
c. Because combination hormonal contraceptives contain five to seven times the
estrogen equivalent of postmenopausal hormone therapy, it is desirable to change
therapy with the onset of menopause. FSH levels fluctuate rapidly and are not
consistent in perimenopause. Therefore, FSH is not a reliable test for evaluating or
predicting menopause status and the need for contraception. One suggested option is
to continue combination hormonal contraception in women who tolerate it and have
no risk factors until the age of 50 to 55.
d. Other methods of contraception may be considered as well, as long as pregnancy is
an issue.
3. Hormone therapy (HT) refers to the combined use of estrogen and progestogen in
subcontraceptive doses. Estrogen therapy (ET) refers to the use of estrogen without a
progestogen, usually only given in women who have underdone hysterectomy.
a. HT and ET may be used to treat perimenopausal symptoms in women with
oligomenorrhea before permanent cessation of menses. There are many variations in
dose, drug types, and delivery systems for HT and ET.
b. Progestogen is added to estrogen in women who have their uterus. Otherwise,
unopposed estrogen increases the risk of endometrial neoplasia in these women. The
risk is related to duration of use and dose. The absolute risk of endometrial cancer is 1
per 1000 in postmenopausal women. In general, the risk increases to 1 per 100 in
women on unopposed estrogen.
4. Scheduled nonsteroidal anti-inflammatory drugs (NSAIDs) effectively reduce
menstrual blood flow in 40% to 60% in women with ovulatory cycles. NSAIDs block
prostaglandin synthetase activity and should be initiated at the onset of menses and
given on a regular schedule until past the risk of heavy flow.
5. Alternative therapies such as herbal remedies, acupuncture, and non-Food and Drug
Administration (FDA)-approved hormones require further study.
A Target organ response to decreased estrogen. Estrogen-responsive tissues are present
throughout the body. Chronic reduction of estrogen may result in any of the following
1. Urogenital atrophy. The vagina, urethra, bladder, and pelvic floor are
estrogen-responsive tissues. Decreased estrogen levels after menopause result in a
generalized atrophy of these structures. About 25% of women seek medical help for
associated systemic estrogen.
2. Uterine changes
a. The endometrial tissue becomes thin, with atrophic histologic changes.
b. The myometrium atrophies, and the uterine corpus decreases in size. There is
areversal of the corpus: cervical length ratio compared with the reproductive years.
c. The squamocolumnar junction of the cervix migrates higher in the endocervical
canal; the cervical os frequently becomes stenotic.
d. Fibroids, if present, may reduce in size but do not disappear.
3. Breast changes
a. Progressive fatty replacement of breast tissue with atrophy of active glandular units
occurs, with regression of fibrocystic changes.
b. After menopause, the mammographic appearance of the breast becomes progressively
more radiolucent in response to decreasing sex hormone levels.
c. HT increases breast density and reduces the sensitivity of mammograms.
4. Skin changes
a. Skin collagen content and skin thickness decrease proportionately with time after
b. Sunlight and cigarette smoke exposure accelerate skin aging.
5. Hair changes. As estrogen decreases, circulating androgens increase and the chance of
developing increased facial hair and androgenic alopecia increases.
6. Central nervous system (CNS) changes
a. Estrogen receptors are located throughout the brain. Cognitive function, as measured
by some parameters, may decline with advancing age.
b. Reduced estrogen levels may affect cognitive function and moods after menopause,
although the precise contribution has not been fully defined. It is unclear to what
extent giving hormone therapy affects cognitive function. Giving HT in menopause
does not appear to have a beneficial effect on the prevention of Alzheimer disease.
7. Cardiovascular disease
a. The incidence of cardiovascular disease increases after the age of 50 years in women,
coincident with the age of menopause.
b. Cardiovascular disease is the cause of the largest number of death of menopausal
women. The mortality rate from cardiovascular disease among American women is
greater than the next 14 causes of death combined.
c. Endogenous estrogen appears to protect against cardiovascular disease in
premenopausal women. Nevertheless, taking HT in menopause may not protect
against and may increase the risk of some vascular disease. This is especially true in
women with a prior history of cardiovascular disease.
8. Vasomotor symptoms (VMSs) or hot flashes
a. Hot flashes are the second most common perimenopausal/menopausal symptom after
abnormal bleeding.
b. Symptoms are the result of inappropriate stimulation of the body’s heat-releasing
mechanisms by the thermoregulatory centers in the hypothalamus.
c. VMSs are characterized by progressive vasodilation of the skin over the head, neck,
and chest, causing a skin temperature rise. They are accompanied by reddening of the
skin, a feeling of intense body heat, and perspiration. Palpitation or tachycardia may
accompany the flush. The flush may last 1 to 5 minutes and recur with variable
frequency. Flashes may vary from being annoying to totally disruptive to normal life
d. Treatment
(1) Lifestyle changes, such a regular exercise, avoiding smoking, wearing cool
clothes, and lowering room air temperature, may help to minimize symptoms.
(2) HT and ET consistently reduce or eliminate hot flashes, as do combined
hormonal contraceptives such as birth control pill. Results are dose related, and
optimal results may be achieved over several weeks.
(3) Progestogen, clonidine, gabapentin, and herbal remedies are used to treat hot
flashes in women in whom estrogen is contraindicated. Relief is not as complete
as that seen with estrogen therapy.
(4) Venlafaxine and selective serotonin reuptake inhibitors(SSRIs), given in low
doses, have been effective in reducing or eliminating vasomotor instability in up
to 60% of symptomatic women.
9. Altered menstrual function. Oligomenorrhea is followed by amenorrhea. If irregular
vaginal bleeding or bleeding after 6 months of amenorrhea occurs, endometrial disease
(e.g., polyps, hyperplasia, or neoplasia) must be ruled out.
10. Osteoporosis is a disorder characterized by compromised bone strength predisposing
to an increased risk of fracture. Bone strength reflects the integration of two main
features: bone density and bone quality. Osteoporosis is a “silent” disease, becoming
symptomatic only when fractures have occurred.
a. Epidemiology and etiology
(1) Peak trabecular bone mass is reached in the late 20s and peak cortical bone mass
in the early 30s. Bone loss is accelerated for the first 5 to 10 years after
menopause as a direct result of declining estrogen levels.
(2) Osteoporosis has reached epidemic proportions in the US, causing an estimated
1.5 million fractures annually.
(3) Osteoporosis results when bone resorption outweighs bone formation.
Trabecular bone is at greater risk than cortical bone because it is more
metabolically active and structurally more porous.
b. Diagnosis. Osteoporosis is a silent disease, becoming symptomatic only when a
fracture occurs. Most common fractures are vertebral compression fractures, a Colles
fracture of the forearm, or a hip fracture, although all bones are at risk.
c. Prevention and treatment of osteoporosis is important. The higher a woman’s bone
mass at the onset of menopause, the more bone she will have to lose to be at risk for
osteoporotic fractures. Many lifestyle factors can affect fracture risk.
(1) Adequate calcium intake can be obtained through diet or supplementation;
1500mg of elemental calcium daily is recommended after the age of 50. This can
be obtained through diet or supplements.
(2) Vitamin D is essential for the absorption of calcium and reduces fracture risk as
well as the risk of falling: 600 to 800 IU/day is recommended, although up to
2000 IU/day is safe. Vitamin D can be obtained through diet, supplementation,
and sun exposure to the unprotected skin.
(3) Weight-bearing exercise has a positive effect on the skeleton and may reduce
fracture risk and decrease the risk of falling.
(4) Reducing the risk of falling is essential for the prevention of fractures.
(5) Cigarette smoking and excessive alcohol consumption increase the risk of
fractures and are associated with lower bone mass.
A Benefits and indications. The goals of HT are to (1) reduce symptoms resulting
from estrogen depletion such as hot flushes, sleeplessness, and mood disorders; (2)
treat vaginal dryness and atrophy; and (3) minimize the risk of disorders that may be
more frequent during hormone therapy. Randomized controlled trials and observational
studies published since 1998 highlighted the benefits of hormone therapy. However,
studies published after 2002 suggested a small but significant increase in the rate of
cardiovascular disease, stroke, venous thrombotic embolism, and breast cancer
associated with use of HT. Hormone or estrogen replacement therapy is the most
effective treatment for the relief of menopause-related symptoms and menopausal
osteoporosis. However, each woman has a unique risk profile that may lead to more or
less overall benefit from HT. It is important to consider the relative risks and benefits
of HT for each patient before recommending these medications. If the decision is made
to use HT, it should be given in the lowest doses for the duration of time needed to
achieve the desired effect.
B Recent studies. Data from recent studies show that:
1. Is the most effective treatment for hot flushes. Some, but not all, studies showed a
benefit in sense of well-being.
2. Significantly improves vaginal atrophy and dyspareunia.
3. Has been shown to prevent and treat osteopenia and osteoporosis and decrease
incidence of bone fractures.
4. Does not seem to prevent cognitive impairment or dementia in menopausal women.
5. Does not protect against cardiovascular disease in menopause, though lipid profiles
are improved.
6. Increases the risk of stroke in users. The absolute risk is approximately from 20 to
25 cases per year among 10,000 otherwise healthy postmenopausal women.
7. Increases the risk of venous thromboembolism (VTE). The incidence of VTE in
healthy postmenopausal women is 16 to 22 cases per 10,000 women per year. HT
increases this risk twofold.
8. With combined estrogen and progestogen does not increase the risk of endometrial
cancer. Estrogen alone is associated with an increased risk of developing endometrial
cancer and should therefore not be used in women with a uterus.
9. Increases the incidence of breast cancer in users, but the risk returns to normal
within 5 years after discontinuation. The effect of hormones on breast cancer risk is
similar to that of alcohol consumption, obesity, and parity. The risk is slightly higher
in those women using both estrogen and progestogen compared to estrogen alone.
The risk of breast cancer in healthy postmenopausal women is approximately 30
cases per 10,000 women per year. The use of HT adds approximately 8 to 17 cases
per 10,000 women per year to this baseline risk.
C Current studies to watch
1. Kronos Early Estrogen Prevention Study (KEEPS) is an ongoing study evaluating
estrogen given either orally or transdermally to recently postmenopausal women to
see if starting HT earlier modifies the effect on atherosclerotic disease. Progesterone
is given to women who have their uterus.
2. The Early versus Late Intervention Trial with Estradiol (ELITE) study is
currently evaluating women less than 6 years postmenopausal versus women greater
than 10 years postmenopausal and the effect of estradiol on the development of
atherosclerotic changes. Progesterone is given to women with their uterus.
3. The Study of Women Across the Nation (SWAN) is observing midlife transition and
normal aging in women of five different American ethnic groups.
D Risks and contraindications
1. Absolute contraindications include:
a. Undiagnosed abnormal genital bleeding
b. Known or suspected breast cancer or estrogen-dependent neoplasia
c. Active or history of thrombosis
d. History of stroke or myocardial infarction in the previous year
e. Active liver dysfunction or disease
f. Known hypersensitivity to HT/ET
2. Endometrial cancer. Estrogen therapy increases the risk of endometrial hyperplasia
and carcinoma when used without progestogen in a woman with her uterus.
a. Addition of a progestogen for at least 12 days per month reduced that risk of
endometrial cancer to less than 1% to 2%.
b. In some cases hormone therapy may be considered in women who have been
successfully treated for stage I endometrial carcinoma and are asymptomatic.
3. Commonly used schedules of HT
a. The mainstay of HT is estrogen, which is usually given in a daily or continuous
fashion. Progestogen is added to estrogen therapy to prevent endometrial
hyperplasia and carcinoma in women who have their uterus.
b. Abnormal bleeding that occurs with HT must be evaluated with endometrial
sampling and possibly ultrasound to rule out endometrial disease. Bleeding that
continues after sampling and appropriate management should be evaluated with
hysteroscopy or sonohysterography.
c. Side effects of progestogens may be associated with their mineralocorticoid
antagonist activity. Premenstrual tension syndrome-like symptoms such as fluid
retention and swelling, mood disturbance and depression, mastalgia, and headache
are reported. Adjustment in dose, schedule, and route of administration may help
relieve symptoms. Concerns about the possible effect of progestogen with
estrogen and increases risk of breast cancer have been raised by results of the
WHI study.
4. Route of administration of systemic hormones affects first pass through the liver,
metabolism, and resulting serum levels of hormones. HT and ET may be
administered through the following routes with FDA-approved products.
a. Transdermal patches contain either estrogen alone or estrogen plus progestogen
and are changed once or twice a week, depending on the product.
b. Percutaneous gel or emulsion dispenses estrogen in metered doses and is used
c. The vaginal ring contains estrogen only and is changed every 3 months.
d. Oral estrogen or oral estrogen plus progestogen is the most common route of
administration. When administering HT, a single pill containing both estrogen and
progentin may be given or they may be given in separate pills, on a daily basis.
5. Local applications
a. Topical estrogen is used intravaginally to treat symptoms of urogenital atrophy
and dyspareunia. Estrogen-containing creams, tablets, and synthetic rings are
available for this use. Peak systemic absorption is in the first few days of initial
use. Once the vaginal mucosa becomes cornified, there is minimal systemic
absorption of estrogen.
b. A progestin-containing intrauterine device may provide endometrial protection
and avoid the side effects of systemic progestogen.
A Health risk assessment and physical examination
1. Identification of risk factors in medical, surgical, social, family, and lifestyle
2. Assessment for problems including abnormal bleeding, sexual function issues,
sleep disturbance, urinary dysfunction, and hot flashes
3. Annual determination of height, weight, and blood pressure
4. Annual physical examination, including breast and pelvic examination
B Age-risk-appropriate screenings. Evidenced-based testing is performed to detect
early disease in low-risk, asymptomatic patients.
1. Lipid profile assessment every 5 years beginning at age 45
2. Fasting blood sugar screening every 3 years beginning at age 45
3. Thyroid-stimulating hormone testing every 5 years beginning at age 50
4. Mammography every 1 to 2 years from 40 to 50 years of age, annually after 50
years of age
5. Cervical cytology every 1 to 3 years depending on age, risk, high-risk human
papilloma virus DNA testing, and previous Pap history
6. Osteoporosis screening beginning at age 65 years, and earlier in women with risk
factors for fractures or in women whose decision to begin treatment would be
influenced by screening results
7. Routine screening for colon cancer beginning in low-risk women at age 50 years.
Options include yearly fecal occult blood testing and/or flexible sigmoidoscopy
every 5 years, colonscopy every 10 years, or double-contrast barium enema every
5 years
C Promotion of a healthy lifestyle
1. Discuss smoking cessation and alcohol limitation as needed.
2. Make nutritional assessment and recommendations about weight control, dietary fat,
cholesterol, calcium, vitamin D, and caloric intake.
3. Assess contraceptive needs and risk for STDs.
4. Make exercise assessment and recommendations.
5. Identify physical, emotional, and substance abuse risk and history, as well as high
risk behaviors.
6. Screen for symptoms of depression.
7. Counsel about prevention of falls in appropriate women.
8. Encourage home and occupational patient education.
9. Provide individually appropriate patient education.
10. Assess vaccination update status.
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