Menopause
Menopause
is a normal stage of life. Its health consequences have only become apparent as
life expectancy has increased well beyond the 6th decade of life for women. It is estimated that women living in
developed countries will live at least one-third of their lives after
menopause. Functionally, menopause may be considered an “estrogen withdrawal
syndrome.” It is recognizable by the loss of menses and, for most women, by
the appearance of signs and symptoms such as hot flashes, insomnia, vaginal
atrophy, decreased breast size and reduced skin elasticity. Osteoporosis and
cardiovascular disease rep- resent longer term consequences of estrogen
deficiency (Fig. 24.1). Both are more indolent and less predictable than the
early signs and symptoms of menopause.
Physiology of menopause
The postmenopausal ovary is small
and essentially devoid of follicles. The appearance of the postmenopausal
ovary, coupled with the observation that oophorectomy is associated with
menopausal symptoms, led to the original theory that follicular depletion was
responsible for menopause. More recent evidence suggests that menopause has
origins in both the central nervous system and the ovary. In addition, men
appear to experience a similar, albeit later and more subtle change, called
andropause. Both changes can be referred to as “gonadopause” and associated
mechanisms in the central nervous system and gonads seem to be quite extensive
and to reflect the general aging process.
Fertility decreases dramatically
in women beginning at about age 35 but accelerating after the age of 40. The
accelerated fall after 40 may be the first sign of impending ovarian failure.
Although ovarian follicles remain visible on ultrasound, attempts at artificial
induction of ovulation with injected gonadotropins are largely unsuccessful
after about age 45 years. This suggests that a
physiologic defect develops within the oocytes or follicles prior to their
depletion. About 3–4 years before menopause is apparent, serum
follicle-stimulating hormone (FSH) levels begin to rise subtly and ovarian
estrogen, anti-Müllerian hormone, inhibin and progesterone production falls.
Menstrual cycle length tends to decrease as the follicular phase progressively
shortens. Ultimately, ovulation and menstruation cease entirely. The age of
onset of menopause has changed very little over time – even the Ancient Greeks
mention the age of 50 as typical. Age of menopause is affected by multiple
factors. Maternal menopausal age is predictive of a daughter’s menopausal age.
Age of menarche does not affect age of menopause. Most agree that race and
parity have no effect. Smokers enter menopause at an earlier age than
nonsmokers.
Although ovarian failure is a major component of menopause, functional
alterations also occur at the level of the pituitary. Changes
arise in the
intrinsic rhythms that
control sleep and
the neuroendocrine axes. Such changes in the circadian oscillator lead
to diminished nocturnal melatonin secretion and altered sleep, decreased
responsiveness of the gonadotropin axis to steroid feedback and decreased
adrenal steroid production. Aging is also associated with a more general
decline in central dopaminergic and noradrenergic neuronal function. Estrogen
deficiency further exacerbates the dopamine deficiency by increasing the ratio
of norepinephrine to dopamine.
During menopause, the decrease in
ovarian estrogen and inhibin production reduces negative feedback signals to
the pituitary and hypothalamus and results in a progressive rise in gonadotropin
levels. Because inhibin acts exclusively to regulate FSH (Chapter 1), FSH
levels rise disproportionately to luteinizing hormone (LH) levels. When in
doubt, persistent elevation of serum FSH levels confirms the
diagnosis of menopause. Although
ovarian estrogen production essentially ceases, the ovary continues to make the
androgens testosterone and androstenedione. Most of this steroid biosynthesis
occurs in the hilar cells of the medulla of the gland and very little occurs in
the stroma. Hilar cells share a common embryologic origin with testicular
Leydig cells, the main androgen-secreting cells in the male (Chapter 5).
Although ovarian estrogen production ceases at menopause, post- menopausal
women are not completely estrogen deficient. Peripheral tissues such as fat,
liver and kidney express the enzyme aromatase and can convert circulating
androgens to estrogens. The major difference between direct ovarian estrogen
secretion and peripheral conversion is that most of the estrogen produced by
the latter process is estrone. Estrone is the estrogen produced from
aromatization of androstenedione, the major androgen secreted by the
postmenopausal ovary and adrenal gland (Chapter 2). Estrone is a very weak
estrogen compared with estradiol. In the typical concentrations found in
postmenopausal women, estrone does not provide protection against the long-term
consequences of estrogen deficiency. Obese postmenopausal women are somewhat
protected from this. Fat is a particularly rich source of aromatase activity
and obese postmenopausal women can produce substantial amounts of estrone.
These high quantities of endogenous estrone provide some protection against the
risk of menopausal vasomotor symptoms and osteoporosis but at a cost. Prolonged
exposure of the endometrium to estrogen stimulation that is unopposed by postovulatory
progesterone will increase the risk for the development of endometrial
hyperplasia and carcinoma (Chapter 42). The endometrium is never converted from
proliferative physiology to secretory morphology and this unregulated growth
favors neoplastic change. A similar risk of endometrial stimulation is present
in women receiving estrogen alone for postmenopausal hormone replacement. For
this reason, women who still have their uterus but require or choose
postmenopausal estrogen replacement should also be given progesterone in a continuous
or cyclic fashion.
Signs and symptoms
Hot flashes
Hot flashes or flushes occur
in about 75% of menopausal women. Nocturnal hot flashes often wake a woman from
sleep and may produce significant sleep deprivation or insomnia. During a hot
flash most women note a sensation of pressure in their head followed by a flush
of heat or burning. This sensation begins on the head or neck area and passes
over the entire body. Sweating invariably accompanies the flush. While there
are profound physiologic changes associated with hot flashes, the mechanism by
which estrogen deficiency produces this symptom is not known. The physiologic
changes include an initial increase in skin conductance and then temperature, a
reflection of peripheral vasodilatation. Core body temperature subsequently
drops by an average of 0.2°C. Circulating estrogen levels do not change before
or after the flash but LH, cortisol, dehydroepiandrosterone (DHEA),
androstenedione and the proopiomelanocortin (POM-C) derived peptides all do. It
is believed that the hot flash represents an initial change in central
thermoregulation that elicits a number of compensatory mechanisms. These
mechanisms transiently raise, but ultimately reduce the core body temperature
to the new set point. Central nervous system catecholamines are involved in
hypothalamic temperature regulation and the impact of estrogen deficiency on
noradrenergic neuronal function likely has a role in hot flashes. Some
hypothesize that estrogen deficiency predisposes to vasodilatation within the
hypothalamus. This results in an increase in hypothalamic temperature and a response favoring a
reduction in the core body temperature.
In addition to hot flashes, most
menopausal women experience vaginal atrophy and changes in their breasts and
skin. Vaginal atrophy can lead to decreased vaginal lubrication. This may
be physically uncomfortable, may predispose to urinary tract infections and may
result in dyspareunia during intercourse. These changes are directly related to
the loss of estrogen stimulation in target tissues and can largely be reversed
by estrogen replacement.
Bone changes
Bone loss in women actually
begins at about age 30. It accelerates at menopause. The most rapid bone loss
occurs in the first 3–4 years after menopause. Bone loss occurs more quickly in
women who smoke and in very thin women. African-American race and fluoride
treatment of the water supply are associated with a lower incidence of
osteoporosis. The most common site of osteoporosis-related fractures is the
vertebral body, an effect that may be noted clinically as back pain and the
development of a “dowager’s hump.” The upper femur, humerus, ribs and distal
forearm are also frequently affected by postmenopausal bone loss. Upper femoral
fractures that involve the hip joint may be life-threatening because of an accompanying risk of venous thromboembolic disease.
Osteoporosis resulting
from prolonged estrogen deficiency involves a reduction in the quantity of bone
without alterations in its chemical composition. Bone formation by osteoblasts
is normal in estrogen- deficient women but the rate of bone resorption by
osteoclasts is increased. Trabecular bone is affected first, followed by
cortical bone. Estrogen appears to antagonize the effects of parathyroid
hormone (PTH) on calcium mobilization. This may occur as a direct effect of
estrogen on bone because estrogen receptors have been found on bone cells in
culture.
Cardiovascular changes
Estrogen receptors are present on
blood vessels and estrogen appears to clinically decrease vascular resistance
and increase blood flow. One potential mechanism by which estrogen may improve
blood flow is through its demonstrated ability to decrease the production of
endothelin, a potent vasoconstrictor, by vascular endothelium. Estrogen therapy
is also associated with an increase in high-density lipoproteins and decrease
in low-density lipoproteins. Despite these mechanistic findings, the results of
several recent large population studies have suggested that postmenopausal
hormone replacement therapy (HRT) may have untoward cardiovascular effects.
These results need to be taken in context with risks and benefits weighed for a
particular patient. For instance, one arm of the Women’s Health Initiative,
which is the largest randomized trial of HRT, showed that use of combinations
of estrogen and progestin in the treatment of postmenopausal women resulted in
seven additional cases of heart disease, eight pulmonary emboli, eight strokes
and eight additional cases of breast cancer among 10 000 women treated for 1
year. At the same time, there were six fewer cases of colon cancer and five
fewer hip fractures. This resulted in 20 women who were harmed by therapy out
of 10000 undergoing treatment. Although recent data have relaxed prohibitions
somewhat, postmenopausal estrogen replacement regimens in the years after
release of the results of the Women’s Health Initiative have been severely
retstricted, with most practitioners limiting therapy to the treatment of hot
flashes and vaginal atrophy. When given, estrogen has typically been provided
in the lowest dose and for the shortest duration possible. Alternative
medications and delivery systems for postmenopausal
hormone replacement are under investigation.
