MENOPAUSE
I NTRODUCTION

Human follicles begin their development during the fourth
gestational month.

Approximately 1,000 to 2,000 germ cells migrate to the
gonadal ridge and multiply, reaching a total of 5 to 7
million around the fifth month of intrauterine life.

At this point, replication stops and follicle loss begins,
declining to approximately 1 million by birth.

. In the female, between 12 and 18 weeks gestation, the
germ cells enter meiosis and differentiate.

Over time, the population of oocytes will be depleted,
without regeneration, through recruitment and apoptosis
until fewer than a thousand oocytes exist and menopause
ensues.
INTRODUCTION

Menopause occurs at a median age of 51.4 years, with the
age range in normal women being 42 to 58 years.

Approximately 90% of women experience menopause
during the early 50s.

The other 10% of women experience menopause prior to
46 years of age (often termed early menopause),

with 1% of women experiencing menopause at an age
younger than 40 years (premature menopause or
premature ovarian failure )
I NTRODUCTION

The age of menopause appears to be determined largely
by genetics.

It does not appear to be related significantly to race,
parity, height, weight, socioeconomic status, or age at
menarche.

Evidence suggests that genetic and environmental factors
influence the age of menopaus.
R EPRODUCTIVE S TAGES

Reproductive aging is a continuum beginning in utero and
ending with menopause.

The staging system takes into account menstrual cyclicity,
endocrinology, and symptomatology, beginning with
menarche and ending with a woman's demise.(STRAW)

The foundation of the staging system is the final
menstrual period (FMP).

Five stages precede the FMP and two follow it, for a total
of seven stages. Stages -5 to -3 are called the reproductive
interval, stages -2 to -1 are termed the menopausal
transition, and stages +1 and +2 are known as the
postmenopause
R EPRODUCTIVE S TAGES

The menopausal transition begins with variation in the
menstrual cycle length (>7 days different from normal) in a
woman with an elevated follicle-stimulating hormone
(FSH) level. This stage ends with the FMP, which cannot be
determined conclusively until after 12 months of
amenorrhea.

Early postmenopause is defined as the first 5 years
following the FMP. Late postmenopause is variable in
length, beginning 5 years after the FMP and ending with
the woman's death.
E NDOCRINOLOGY

The entire endocrine system in women changes with
advancing age.

The somatotrophic axis begins to decline during the
fourth decade, prior to the loss of ovarian function.

This decline in growth hormone is accelerated during
ovarian failure and may, itself, accelerate the ovarian
failure.

Although the thyroid gland undergoes progressive fibrosis
with age and concentrations of T3 decline by 25% to 40%,
elderly women remain clinically euthyroid.
E NDOCRINOLOGY

during the late fourth decade, FSH levels begin to rise
even when cyclic menses continue(The most likely cause is
a decrease in functional granulosa cells from the oocyte
pool, with a decrease in inhibin B negative feedback )

gradual declines in estradiol concentrations.

Dehydroepiandrosterone (DHEA) and its sulfated
conjugate, DHEAS, have been shown to decrease with
aging(Evidence suggests that physiologic levels of DHEA
may protect against neoplasia, enhance insulin action,
protect against osteoporosis, increase immune
competency, and offer some cardioprotection. )
S YSTEMIC E FFECTS OF
D ECLINING O VARIAN F UNCTION

The endometrium becomes atrophic

the uterus decreases in size

The postmenopausal vagina, devoid of estrogen treatment,
becomes smaller in both length and caliber.

decreased elasticity of the vaginal wall.

The fallopian tubes contain both ciliated and secretory
components. After age 60, cilia begin to disappear in the isthmic
region, although they remain until a very old age in the ampulla
and infundibulum.

With cessation of the production of estrogen and progesterone,
glandular, ductal, and stromal involution occurs in mammary
glamds. Connective tissue of the lobule becomes indistinguishable
from other types of connective tissue. There is an accumulation of
adipose tissue in the breast.
M ENOPAUSAL S YNDROME

many symptoms associated with aging in women are due
to estrogen deficiency, but the decline in adrenal
androgens and growth hormone may contribute.

definitely a result of estrogen deprivation include
:vasomotor symptoms and urogenital atrophy

largely due to estrogen deficiency, but may be
exacerbated by the relative growth hormone decline:
Osteoporosis is likely, atherosclerotic CVD and
psychosocial symptoms including insomnia, fatigue, shortterm memory loss, and depression.

Both DHEAS and growth hormone may well have an
impact on these age-related symptoms.
VASOMOTOR S YMPTOMS
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VASOMOTOR S YMPTOMS

For most women, the hot flashes commence prior to the FMP,
although initially this may be perceived only as a sleep
disturbance.

In general, the episodes are noted more frequently at night,
and the dysfunctional sleep pattern that follows may result in
fatigue, irritability, loss of concentration, and depression

More than 80% of women who experience hot flashes will
experience them for longer than 1 year. Without treatment,
the symptoms usually subside slowly over 3 to 5 years.
VASOMOTOR S YMPTOMS
 Treatment
Estrogen therapy, in either oral or transdermal form, has a
greater than 95% efficacy for the treatment of hot flashes
For patients with contraindications to estrogen use,
vasomotor symptoms can be treated with progestins, α2adrenergic agonists (clonidine, methyldopa, lofexidine)
and antidepressants (selective serotonin reuptake
inhibitors [SSRIs], venlafaxine hydrochloride [Effexor]).
The SSRI/selective norepinephrine reuptake inhibitors
(SSNIs) and gabapentin appear to show modest reduction
in hot flashes when compared with placebo
G ENITOURINARY ATROPHY

decrease in circulating estrogen levels has deleterious
effects on urogenital epithelium. Up to 50% of
postmenopausal women experience symptoms of vaginal
atrophy.

The most common symptoms include dryness, irritation,
itching, burning, and dyspareunia.

Atrophic vaginitis is associated with a rise in vaginal pH,
which can lead to more frequent infections and worsening,
irritative symptoms.
G ENITOURINARY ATROPHY

Estrogen replacement therapy (ERT) is an effective
treatment for vaginal atrophy.

topical therapy by means of creams or vaginal rings may
be advisable to limit systemic absorption.

local estrogen therapy can be used effectively to treat
urogenital atrophy.

Vaginal estrogen cream or tablets can be used daily for
approximately 2 to 3 weeks and then twice weekly after
initial symptoms have improved and vaginal
vascularization (hence, hormone uptake) has increased.

Vaginal estrogen frequently will improve symptoms of
urinary frequency, dysuria, urgency, and postvoid
dribbling.
U RINARY T RACT I NFECTIONS

Recurrent UTIs in healthy postmenopausal women are
associated with urinary incontinence, cystocele, and
increased postvoid residual volumes. Other significant risk
factors include at least one episode of UTI prior to
menopause, urogenital surgery, and reduced urinary flow.

Changes in the vaginal environment after menopause also
may predispose a woman to UTI.

These alterations include the absence of lactobacilli,
elevated vaginal pH, and increased rate of vaginal
colonization with Enterobacteriaceae.

The intravaginal administration of estrogen has been
shown to reduce the rate of recurrent UTI by normalizing
the vaginal environment.
O STEOPOROSIS
 Primary osteoporosis usually affects women between the
ages of 55 and 70 years.

Approximately 30% of postmenopausal women have
osteoporosis.
 Secondary osteoporosis is caused by a specific disease
(such as hyperparathyroidism) or medication usage
(glucocorticoids, thyroid hormone excess,
anticonvulsants).
 The most common sites include the vertebrae and the
long bones of the arms and legs.
 Menopausal bone loss begins before the FMP during
stage -1.
O STEOPOROSIS

Bone loss following natural menopause is approximately 1%
to 2% per year, compared with 3.9% per year following
oophorectomy.

A woman's genetic background, lifestyle, dietary habits, and
coexisting disease will impact the development of
osteoporosis.

Cigarette smoking, caffeine use, and alcohol consumption are
associated with increased bone loss, while weight-bearing
activity appears to slow it.

The World Health Organization has defined osteoporosis as a
hip BMD value, as measured by dual x-ray absorptiometry
(DEXA), that is greater than 2.5 standard deviations below
the adult peak (mean level for young, white women: t-score).

Women with existing fractures, regardless of BMD, are also
classified as osteoporotic.
O STEOPOROSIS

Treatment
Hormone Replacement Therapy
(prevention of osteoporosis and is FDA approved )
decreased fracture risk has been an important topic of research
These studies have also reemphasized known risks of HRT, including
pulmonary embolus, stroke, deep vein thrombosis, and
gallbladder disease.
HRT benefits include reduction in hot flash frequency and severity,
improvement of atrophic vaginitis and UTIs, and prevention of
osteoporosis and fractures.
decreased risk of colorectal cancer.
O STEOPOROSIS
Calcitonin
Intranasal calcitonin has been shown to improve spinal bone density
and decrease the vertebral fracture rate in women with established
osteoporosis.
Bisphosphonates
pamidronate, alendronate, and risedronate
Raloxifene
selective estrogen receptor modulators (SERMs)
increases bone mass density in the spine and femoral neck and reduces
the risk of vertebral fracture by 30% to 50% over no treatment.
Calcium and Vitamin D 1,500 mg and 400 to 800 IU of vitamin D per day
is probably sufficient to reduce the risk of fragility fractures by
about 10%.
O STEOPOROSIS C ONCLUSIONS

An evidence-based approach is to recommend :
appropriate calcium and vitamin D intake,
smoking cessation,
weight-bearing exercise,
moderation in alcohol consumption,
and fall prevention.
If pharmacologic therapy is indicated, one of the above FDAapproved regimens should be instituted
An alternative (complementary) approach to prevention is to focus
on intervention beginning in childhood and adolescence, with
attention to achieving maximal peak bone mass and minimizing
premenopausal and postmenopausal bone loss.
C ARDIOVASCULAR D ISEASE

For women, CVD is largely a disease of postmenopause.

Women will now spend more than one third of their lives
beyond menopause.

A woman's risk of heart disease is far lower than a man's
risk until after menopause.

Randomized, controlled studies have failed to support a
protective role for HRT.

There is no evidence from well-designed prospective trials
supporting a role for either ERT or HRT for the primary
indication of cardiovascular protection.
A MERICAN H EART A SSOCIATION
R ECOMMENDATIONS

Secondary Prevention

HRT should not be initiated for the secondary prevention
of CVD.

Primary Prevention

There are insufficient data to suggest that HRT should be
initiated for the sole purpose of primary prevention of
CVD.
B REAST C ANCER

The most compelling reason to believe that long-term use
of postmenopausal estrogen increases the risk of breast
cancer is the inherent biologic plausibility.

Many of the risk factors associated with breast cancer are
thought to be linked to increased duration of exposure to
estrogen over a woman's lifetime.

These risk factors include early menarche, late
menopause, nulliparity, and older age at the birth of her
first child.

The association of estrogen therapy and breast cancer
remains controversial

This analysis reached the following conclusions:

Ever users of postmenopausal hormones had an overall
increased relative risk of breast cancer of 1.14.

Current users for 5 or more years had a relative risk of
1.35 (CI 1.21 to 1.49), and the risk increased with
increasing duration of use.