Menopause: A Close-Up Look
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
As the life expectancy has increased markedly, more and more women are living longer after menopause. In western society, women can anticipate living for approximately 80 years, spending more than one third of their lives in the postmenopausal period. Menopause refers to the complete or permanent cessation of menstruation; an interval of 6 to 12 months of amenorrhea is usually necessary to establish the diagnosis of menopause. The median age of menopause in the United States is 51.4 years, with a range of 48 to 55 years. Although it has been suggested that the age of menopause may be increasing. When menopause occurs at 35 years of age or younger, it is classified as premature menopause.
The biologic event of menopause marks a meaningful life passage for every woman. It is a transition made from the reproductive stage of life to the non-reproductive stage. This transition is the period of declining ovarian function, which usually becomes apparent clinically over the 2 to 5 years around menopause. The population of postmenopausal women continues to rise; currently approximately 470 million women in the world are of age 50 and older- a figure that is projected to increase to 1.2 billion by 2030. It is estimated that 25 million women each year pass into menopause. Several studies have shown that both the number of cigarettes smoked and the duration of smoking affects the onset of menopause and it induces earlier menopause.
Menopause should be looked on as a hormonal deficient state. The primary alteration in the reproductive endocrine system is probably in the ovary, which demonstrates decreasing responsitivity to stimulation by pituitary gonadotrophins, leading to a further drop in estrogen levels. Several years before menopause and during the perimenopausal phase, which is the time just before menopause, there is a gradual increase in circulating FSH toward the upper limit for normal during the menstrual cycle, a concomitant decrease in serum estradiol level, no significant change in LH level, and only a slight decrease in serum progesterone. These changes are still associated with follicular maturation and corpus luteum development. After age 40, it is more common for the follicular phase to be shorter. However, serum LH levels later become elevated but still to a lesser extent than FSH levels. Anovulatory cycles may be interspersed with ovulatory cycles, and consequent anovulatory bleeding may occur. The progressive decline in ovarian follicles and the increased resistance to gonadotropins give rise to decreased estrogen production and also inhibin levels. The combination of decreased inhibin and estradiol levels is probably responsible for the early elevation of FSH.
During the perimenopausal years, estradiol is the principal circulating estrogen, is made almost entirely by the maturing ovarian follicles during each cycle, and is therefore primarily derived from the ovary. After the menopause, ovarian estrogen production decreases markedly secondary to the failure of adequate follicular recruitment, growth, and maturation. Estradiol levels decline to 20 to 25 pg/ ml or less after the menopause, and therefore estrone now becomes the principal circulating estrogen. Serum levels of testosterone are slightly lower than in the perimenopausal state.
A variety of problems or symptoms arise at or after the menopause, which have an impact on the quality of life. In addition,the increases in morbidity related to several serious conditions, such as osteoporosis and cardiovascular disease are seen in postmenopausal years.
- Cardiovascular Disease: It is the leading cause of death in American women, with 500,000 deaths occurring annually, most of which are atherosclerosis - mediated disorders, mainly myocardial infarction and strokes. Twice as many women die of cardiovascular disease than of cancer. After menopause there is a considerable increase in serum cholesterol. Most studies also found an increase in triglycerides, a significant increase in LDL, and a significant decrease in HDL, notably after acute estrogen withdrawal as in the case of surgical castration.
- Psycho-neuro-endocrine Effects: Headaches, tiredness, lethargy, irritability, anxiety, nervousness, depression, sleep difficulties, inability to concentrate, and hot flushes are symptoms for which perimenopausal and post menopausal women frequently seek medical assistance. As many as 85% of post menopausal woman have hot flushes, and up to 45% of them continue to experience hot flushes for 5 to 10 years after the menopause. Characteristically, a hot flush begins in the head and facial areas with a sensation of warmth followed by facial flushing that may radiate down the neck and to other parts of the body. Each hot flush averages 2.7 minutes and is associated with an increase in temperature, increased pulse rate, increased blood flow in the hand and increased skin conductance, followed by a decline in temperature and profuse perspiration over the area of flush distribution. Episode of hot flush during sleep are referred to as night sweats.
A rapid estrogen withdrawal rather than a low estrogen level by itself is likely to induce hot flushes. Synchronous with the onset of each hot flush is the release of a pulse of LH. Sleep deprivation and interrupted sleep may develop in postmenopausal women. Although estrogen does not alter the duration of sleep significantly, the sleep latency interval is significantly reduced and the percentage of time spent in REM sleep is significantly increased.
Hypoestrogenic levels after the menopause provide a biochemical framework for possible development of depression. Although other nonspecific menopausal complaints, such as headache, tiredness, lethargy, irritability, anxiety, and nervousness, may also be due to family, social, and personal environmental factors.
- Skin and Uro-genital Effects: Loss of ovarian function and decreased estrogen levels after the menopause reduce skin thickness secondary to a significant decrease in epidermal thickness and collagen content. As a result of postmenopausal skin thinning, skin is clinically lax, is more transparent, has more readily visible capillaries and blood vessels, and is also more easily bruised. Additionally, the vaginal epithelial cells contain less glycogen and the acidity of the vagina changes after the menopause. Coital difficulties need not arise from thinning of the vaginal epithelium as long as regular coital activity is maintained. With severe atrophy or atrophic vaginitis, however dysparunia may occur. Sexual response remains intact, but because of age related neuro-endocrine and circulatory alterations in postmenopausal women, the timing and extent of the phases of sexual stimulation and pattern of response change occurs.
Urodynamic evaluations indicate a 30% drop in urethral closure pressure at rest and during stress in urethral closure pressure at rest and during stress in postmenopausal women because of atrophy of the urethral mucosa, which is emryologically derived from uro-genital sinus and is estrogen sensitive. Senile urethritis or atrophic urethritis secondary to hypoestrogenism may occur in postmenopausal women. The condition is clinically characterized by urgency, frequency, dysuria, and suprapubic pain in the absence of urinary tract infection.
- Bone Effect: osteoporosis is one of the most significant long-term sequelae of menopause but can be readily prevented of reduced through appropriate preventive management. Osteoporosis is responsible for 1.5 million fractures annually and $6 billion in healthcare costs. 25% of women or 5 million women will have radiologic evidence of osteoporosis by 60 years of age. Of women living to 80 years, one in four can expect to have fracture of hip. The incidence of hip fractures in women doubles each decade after 50 years. Hip fractures are six times more common in women than in men, with 85% of such fractures occurring in women. In the initial period of up to 4 to 5 years after the menopause, there is accelerated loss of bone mineral mass, after which the rate of further loss is a little lower and more age-related. This bone loss produces osteopenia, which is defined as decreased calcification of density of bone. Thus, the three most common fractures seen in postmenopausal women are of the vertebrae, ultra distal radius, and the neck of femur, all of which are sites of high trabecular bone composition.
RISK FACTORS ASSOCIATED WITH POSTMENOPAUSAL OSTEOPOROSIS:
Reduce weight for height ratio, white or asian ethnicity, nulliparity, alcohol abuse, positive family history, low calcium intake, high sodium intake, cigarette smoking, early menopause, sedentary life-style, high caffeine intake, high protein intake, secondary loss (glycocorticoid therapy, hyperthyrodism, hypoparathyroidism)
Evaluation and Workup:
For women who undergo natural menopause at the normal expected age and for those who undergo hysterectomy and bilateral salpingo-oopherectomy, evaluation usually includes a complete history (including dietary practice) and physical examination. Pap smear, mammogram and lipid profile. Because osteopenia and osteoporosis are important long-term sequelae of the menopause, determination of bone mass is frequently recommended. Dual energy x-ray absorptiometry (DEXA) for measuring bone density appears to be reliable and promising and is preferred.
FSH and LH levels are sometimes evaluated to confirm the diagnosis of menopause. Other appropriate workups should be performed when there are relevant symptoms, such as workup related to urinary continence problems, psycho emotional states (depression and anxiety).
Adequate calcium intake appears to play an important role in preventing osteoporosis and fracture. The daily intake of calcium for postmenopausal women should be at least 1200 mg. The contribution of calcium supplementation or increased calcium intake by itself without estrogen replacement therapy is probably small but remains to be clearly defined. If calcium supplementation is needed, calcium can be given as calcium carbonate, calcium chloride, calcium lactate, calcium gluconate, bone meal, and dolomite or calcium citrate. A simple way of administering calcium supplement is to use an antacid (Tums), which contains calcium.
Foods which promote calcium absorption, are: protein, lactose, carbohydrate, and acids- lactic, citric.
Foods which inhibit calcium absorption, are: oxalates- leafy vegetables, phytic acid- grains, high phosphorus- meat, carbonated beverages, fat, and fiber.
Finally, calcium supplements should be given with a meal rather than during fasting or on an empty stomach because the fraction of calcium absorbed is markedly less in the later situations.
Besides its positive effects on cardiovascular fitness, exercise should be advocated to retard bone loss because prolonged immobilization results in accelerated bone demineralization. Postmenopausal women should perform low impact, weight bearing exercises, such as walking, jogging, tennis, racquetball, or dancing, in moderation.
- Hormone Replacement Therapy:
Whether or not to take HRT (hormone replacement therapy) is an issue that may have important short and long term implications for health and vitality during the transition of menopause and into the ensuing years. Fortunately, our growing medical knowledge is revealing new insights into the role of HRT, not only regarding short-term symptom relief, but also as protection against conditions and diseases once believed to be the inevitable consequences of aging. The decision for or against HRT requires balancing the known and potential benefits and risks with each woman's distinct preferences and needs. The benefits of HRT are, reducing the likelihood of developing coronary heart disease, preventing osteoporosis, and possible preventing Alzheimer's disease, colon cancer, macular degeneration, urinary incontinence, and skin aging.
However, even when the decision to initiate HRT is made, there are still many choices: which estrogen and progestin to use, and in which doses, when to begin treatment and how long to continue, and which type of treatment regimen and route of administration to use. Above all, it is important to avoid the pitfalls of a "one size fits all" approach. Because response to therapy both in terms of efficacy and side effects may be highly variable, it is important that the health care providers monitor the response. Such an approach, in which therapy is chosen and adjusted according to the patient's needs, helps to ensure that more women gain the important long-term benefit of HRT.
Potential Risks and problems of HRT: breast cancer, endometrial cancer, venous thromboembolic disease
The Women's Health Initiative (WHI) is a randomized, multicenter, double-blind, placebo-controlled set of three trials and one observational study sponsored by the National Institutes of Health is to examine the effects of various interventions on the common causes of morbidity and mortality in postmenopausal women. The WHI provides health care providers and patients with much-needed prospective data regarding the effects of Hormone Replacement Therapy (HRT) on postmenopausal health. One arm of the WHI followed 16,608 healthy patients aged 50 to 79 years at baseline, with intact uterus, taking either hormone replacement therapy (HRT; conjugated equine estrogen plus medroxyprogestrone acetate) or placebo. On July 9, 2002, 5.2 years after study initiation, the HRT portion of the trial was halted due to the observation that the risks of treatment outweighed its benefit, namely, that the increases conferred in the risk for cardiovascular disease, thromboembolism, and breast cancer were greater than the decreases demonstrated in osteoporosis and colorectal cancers.
For details please visit: www.fda.gov/womens/menopause
- Alternative and Complementary Therapy for menopause:
- Selective Estrogen Receptor Modulator (SERM):
Selective estrogen receptor modulators (SERMs) are synthetic compounds that bind estrogen receptors and produce agonistic activity in some tissues while acting as estrogen antagonists in other tissues. A number of compounds that exhibit the properties of SERMs are either in clinical use or are in development. Four SERMs are approved for use in the United States: 1) clomiphene, 2) tamoxifen 3) toremifene, and 4) raloxifene. Clomiphene is among the most widely prescribed drugs for the management of infertility in women. Tamoxifen, originally developed as a medical therapy for the treatment of breast cancer, was found to have estrogenic activity on bone remodeling and in cholesterol metabolism. It also was found to have estrogenic activity in the endometrium, resulting in an increase in relative risk of benign and malignant neoplasms. Tamoxifen has been approved by FDA for the treatment of breast cancer and to reduce the incidence of breast cancer in healthy women at high risk of breast cancer. More studies comparing tamoxifen and raloxifene for breast cancer prevention currently are underway. Toremifene also is indicated for the treatment of estrogen-receptor-positive breast cancer in postmenopausal women. Raloxifene is approved for the prevention and treatment of osteoporosis in postmenopausal women. Tibolone has not yet received FDA approval. However, it has been used in Europe for approximately 20 years for the treatment of menopausal symptoms and prevention of osteoporosis. Other SERMs (idoxifene, droloxifene, and levormeloxifene) have shown adverse gynecologic, gastrointestinal, and genito-urinary effects that resulted in the suspension of phase three trials.
Neither raloxifene nor tamoxifen should be used in women with a history of venous thromoembolic events, including pulmonary emboli, deep vein thrombosis, or renal vein thrombosis. Any abnormal uterine bleeding should be investigated in women taking tamoxifen or raloxifene. Consideration should be given to tamoxifen therapy for women at high risk for developing breast cancer. Raloxifene is appropriate therapy for women who are candidates for chemoprevention of osteoporosis and established osteoporosis to prevent osteoporotic fractures. The use of tamoxifen for chemoprevention should be limited to 5 years. Co-administration of local vaginal estrogen therapy may be used for the relief of vaginal dryness in patients receiving raloxifene or tamoxifen therapy. Individualized risk assessment should be performed to determine whether a patient is a candidate for breast cancer risk reduction by chemoprevention, unless she has ductal carcinoma in situ or lobular carcinoma in situ in which case, the benefit of chemoprevention already has been documented.
Bisphosphonates act as specific inhibitors of osteoclast mediated bone resorption. These agents reduce bone turnover by reducing the number of sights at which bones are modeled. Thus, bone formation exceeds bone absorption at these remodeling sights leading to progressive gains in bone mass. The increase bone mineral density at both the spine and hip is seen and reduce fractures in women with established osteoporosis at all assessed locations by approximately 30-50%. Bisphosphonates may cause upper gastrointestinal side effects and are contraindicated in individuals with reflux, gastro-esophageal reflux disease, and other esophageal abnormalities. This class of agents has very poor absorption, typically less than 1% of the administered dose. It is, therefore, very important that they be taken on an empty stomach only with plain water, that the patient remain upright for at least 30 minutes, and that no additional food or drink be ingested during this period. Alendronate and risedronate also can be used to treat osteoporosis in individuals with established disease. Fracture reduction in this treatment population has been demonstrated for both of these agents.
In conclusion, menopause has attracted attention as a topic of growing scientific interest with respect to both research and public health perspectives. Hormonal treatment and non-hormonal treatments have been studied and used for more than 30 years. Few health care decisions, however, are as complex and have needed to be so individualized. Lifestyle changes remain the best way to maintain quality of life and prevent the diseases of aging. Weight control, exercise, diet, and not smoking are still the safest approaches to a healthy life.
- World Health Organization
Research on the Menopause
- Center for Disease Control and Prevention (CDC)
Hormone Replacement Therapy: Knowledge and Use in the United States (pdf)
- National Institutes of Health (NIH)
- The North American Menopause Society (NAMS)
Promoting women's health and quality of life through an understanding of menopause
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