Clinical Manifestations of Menopause

Major risk factors for fracture are advanced age, Caucasian or Asian race, and female gender as well as a personal history of fracture after age 50 or a family history of osteoporosis or related fractures in a first-degree relative. Other risk factors include, but are not limited to, current low bone mass, low body mass index, inadequate calcium and vitamin D intake, sedentary lifestyle, cigarette smoking, hypothalamic amenorrhea, premature menopause, use of certain medications such as glucocorticoids or gonadotropin-releasing hormone agonists, medical conditions such hyperthyroidism and hyperparathyroidism, and excessive use of alcohol.

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 manifestations:

  • 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 symptoms. These symptoms often improve with the use of topical or systemic estrogen.
    • There is a reduction in the thickness of vaginal epithelium and vaginal vascular flow and increased vaginal pH. The vaginal epithelium shows a loss of rugation and elasticity. Maturation of the vaginal epithelium is estrogen dependent. After menopause, there is a shift in the maturation index, with a preponderance of immature cell types (basal and parabasal) over mature cell types (intermediate and superficial).
    • The vaginal walls lose elasticity and compliance; the vagina becomes smaller, and the size of the upper vagina diminishes. This results in increased likelihood of trauma, infection, dyspareunia (painful intercourse), and painful pelvic examination.
    • The labia minora have a pale, dry, thin appearance, and there is a reduction of the fat content of the labia majora.
    • The pelvic tissues and ligaments that support the uterus and the vagina may lose their tone, predisposing to disorders of pelvic relaxation.
    • The epithelium of the urethra and bladder mucosa becomes atrophic; there is a loss of urethral and bladder wall elasticity and compliance.
    • Urinary tract symptoms resulting from changes in the mucosal lining of the urethra and bladder may lead to increased symptoms of dysuria, nocturia, urinary frequency, urgency, and urge incontinence.
    • Urinary conditions such as urinary stress incontinence may progressively worsen after menopause because of urethral changes and a loss of pelvic support. There is an increased incidence of asymptomatic bacteriuria and urinary tract infection in the postmenopausal woman.
  • Uterine changes
    • The endometrial tissue becomes thin, with atrophic histologic changes.
    • The myometrium atrophies, and the uterine corpus decreases in size. There is a reversal of the corpus: cervical length ratio compared with the reproductive years.
    • The squamocolumnar junction of the cervix migrates higher in the endocervical canal; the cervical os frequently becomes stenotic.
    • Fibroids, if present, may reduce in size but do not disappear.
  • Breast changes
    • Progressive fatty replacement of breast tissue with atrophy of active glandular units occurs, with regression of fibrocystic changes.
    • After menopause, the mammographic appearance of the breast becomes progressively more radiolucent in response to decreasing sex hormone levels.
    • HT increases breast density and reduces the sensitivity of mammograms.
  • Skin changes
    • Skin collagen content and skin thickness decrease proportionately with time after menopause.
    • Sunlight and cigarette smoke exposure accelerate skin aging.
  • Hair changes. As estrogen decreases, circulating androgens increase and the chance of developing increased facial hair and androgenic alopecia increases.
  • Central nervous system (CNS) changes
    • Estrogen receptors are located throughout the brain. Cognitive function, as measured by some parameters, may decline with advancing age.
    • 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.
  • Cardiovascular disease
    • The incidence of cardiovascular disease increases after the age of 50 years in women, coincident with the age of menopause.
    • Cardiovascular disease is the cause of the largest number of deaths of menopausal women. The mortality rate from cardiovascular disease among American women is greater than the next 14 causes of death combined.
    • 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.
  • Vasomotor symptoms (VMSs) or hot flashes
    • Hot flashes are the second most common perimenopausal/menopausal symptom after abnormal bleeding. There are differences in incidence depending on the ethnic background of the woman. African-American women report hot flashes the most frequently, followed by Hispanic, Caucasian, Chinese, and Japanese Americans. Differences in body mass index may be a more important predictor of hot flashes than ethnic background.
      • These symptoms have a circadian rhythm and are more frequent in the early evening. No clinical trials have confirmed that hot flashes are precipitated by caffeine, alcohol, or stress. They do appear to be exacerbated by cigarette smoking, sedentary lifestyle, and induced menopause.
      • Hot flashes last for 1 to 2 years in most women but may last for as long as 10 years.
    • Symptoms are the result of inappropriate stimulation of the body’s heat-releasing mechanisms by the thermoregulatory centers in the hypothalamus. Although the core body temperature is normal, the body is stimulated to lose heat. The role of estrogen in causing VMSs is unclear. Estrogen administration diminishes the frequency and severity of symptoms in a dose-dependent manner.
    • 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. Palpitations 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 function.
    • Treatment
      • Lifestyle changes, such a regular exercise, avoiding smoking, wearing cool clothes, and lowering room air temperature, may help to minimize symptoms.
      • 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.
      • 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.
      • 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.
  • 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.
  • 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 may be a primary disease state, resulting from estrogen deficiency or aging, or may be secondary to other diseases, conditions, or medications that affect calcium and bone metabolism. It is a silent disease, becoming symptomatic only when fractures have occurred.
    • Epidemiology and etiology
      • Peak trabecular bone mass is reached in the late 20s and peak cortical bone mass in the early 30s. Thereafter, there is a gradual loss of bone with aging. Bone loss is accelerated for the first 5 to 10 years after menopause as a direct result of declining estrogen levels. Osteoporosis is more common in women than in men because of lower peak bone mass and higher rates of bone loss. Trabecular bone loss is more rapid in early postmenopause, resulting in an increase in distal forearm fractures after age 45 and vertebral fractures beginning at age 55. Cortical bone loss is more gradual, resulting in an increased incidence of hip fractures in women after age 65.
      • Major risk factors for fracture are advanced age, Caucasian or Asian race, and female gender as well as a personal history of fracture after age 50 or a family history of osteoporosis or related fractures in a first-degree relative. Other risk factors include, but are not limited to, current low bone mass, low body mass index, inadequate calcium and vitamin D intake, sedentary lifestyle, cigarette smoking, hypothalamic amenorrhea, premature menopause, use of certain medications such as glucocorticoids or gonadotropin-releasing hormone agonists, medical conditions such hyperthyroidism and hyperparathyroidism, and excessive use of alcohol.
      • Osteoporosis has reached epidemic proportions in the United States, causing an estimated 1.5 million fractures annually. Four out of five Americans with osteoporosis are women. In 2002, an estimated $18 billion was spent in direct care expenditures for osteoporotic fractures.
        • Approximately 25% of white American women older than 60 years of age who are not treated have vertebral compression fractures. These are the most common fractures. There are about 700,000 osteoporosis-related vertebral fractures a year.
        • Approximately 32% of untreated white American women older than 75 years of age suffer hip fractures; 24% over the age of 50 will die in the first year after fracture. Of those who survive, 20% no longer live independently. There are over 300,000 hip fractures a year. Fractures also can occur at the distal forearm and other sites.
      • 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.
    • Diagnosis. Osteoporosis is a silent disease, becoming symptomatic only when a fracture occurs. Most common fractures are vertebral compression fractures (which can be symptomatic or asymptomatic), a Colles fracture of the forearm, or a hip fracture, although all bones are at risk.
    • Imaging modalities can be used to detect bone loss and bones at risk for fracture at an earlier stage. However, not all osteoporotic fractures are associated with measured low bone mass.
      • Peripheral densitometry devices such as quantitative ultrasound (QUS) can be used on the wrist, finger, or heel. Precision is poorer than with x-ray-based studies. QUS should not be used for monitoring therapy.
      • Dual-energy x-ray absorptiometry (DEXA) is the most popular technique used today to measure bone mass. It is the gold standard to which all other methods are compared, having excellent precision and low radiation dose. Independent measurements can be made at the hip, spine, and, if indicated, distal forearm.
      • Quantitative computed tomography gives the most precise measurement of bone mass at specific sites. However, its use has been limited by expense and higher radiation dose.
    • The definition of osteoporosis is based on DEXA T scores. A T score is based on the mean peak bone mass of a normal young adult population and is expressed in standard deviations from the mean in this reference group. A T score equal to 0 is average, greater than 0 is above average, and less than 0 is below average. The lower the T score, the higher the risk of having a fracture is. Osteopenia (decreased bone density) is defined as a T score between -1 and -2.5. Osteoporosis is defined as a T score less than -2.5.
    • 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. Although no one can alter her genetic predisposition, many lifestyle factors can affect fracture risk.
      • Adequate calcium intake can be obtained through diet or supplementation; 1500 mg of elemental calcium daily is recommended after the age of 50. This can be obtained through diet or supplements.
      • 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.
      • Weight-bearing exercise has a positive effect on the skeleton and may reduce fracture risk and decrease the risk of falling.
      • Reducing the risk of falling is essential for the prevention of fractures. This includes safety factors such as optimizing medications that may affect balance, removing dangerous obstacles, providing aids for ambulation and lighting, and using hip protectors.
      • Cigarette smoking and excessive alcohol consumption increase the risk of fractures and are associated with lower bone mass.
    • There are many medications used to prevent bone loss and/or treat low bone density. With the exception of Teriparatide, these work by slowing bone breakdown during bone remodeling. They are called antireabsorptive agents.
      • Bisphosphonates are very effective at preventing bone loss and decreasing the risk of fractures in people with low bone mass. Some are also approved for treating glucocorticoid-induced osteoporosis. Dosing is variable, ranging from once a week to once a year, depending on the type of bisphosphonate. They can be administered orally or intravenously.
      • Selective estrogen receptor modulators (SERMs) such as Raloxifene are taken orally daily and are related to tamoxifen. Raloxifene is approved for prevention of osteoporosis and is effective in reducing the vertebral fracture rate.
      • Calcitonin nasal spray in limited studies has been shown to increase vertebral bone mass and decrease vertebral fracture risk.
      • HT and ET are effective in preventing osteoporosis and reducing hip and vertebral fractures. However, due to other medication-associated risk factors, it is not recommended that they be used primarily for this indication unless other medications are not appropriate.
      • Teriparatide (rhPTH 1-34) is given as a daily injection for up to 18 to 24 months. It has an anabolic bone effect and decreases vertebral and nonvertebral fractures. Effect on hip is not proven.
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  1. Excellent presentation and very valuable information you have share here for aging women who have this concern. Very good.

  2. Well written and good info

  3. Informative.
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    Best Regards,

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