Climacteric

Menopause rarely occurs as a sudden loss of ovarian function. For some years before menopause, the ovary begins to show signs of impending failure. Anovulation becomes common, with resulting unopposed estrogen production and irregular menstrual cycles (see Chapter 33). On occasion, heavy menses, endometrial hyperplasia, and increasing mood and emotional changes may occur. In some women, hot flashes (or flushes) and night sweats begin well before menopause is reached. These perimenopausal symptoms may last 3 to 5 years before there is complete loss of menses and postmenopausal levels of hormones are reached.

Some women may suffer a more abrupt loss of estrogen. This usually occurs following a surgical intervention that removes or damages the ovaries or their blood supply or, on occasion, following chemotherapy or radiotherapy for cancer. Women who reach menopause before the age of 40 years are said to have premature menopause or premature ovarian failure. Other causes of premature ovarian failure include abnormal karyotypes involving the X chromosome, the carrier state of the fragile X syndrome, galactosemia, and autoimmune disorders that may cause failure of a number of other endocrine organs.

Some women continue to produce estrogen indirectly in substantial amounts for many years after menopause. Androstenedione from the ovary and the adrenal gland is converted in peripheral fat tissues to estrone, which is then capable of maintaining the vagina, skin, and bone in reasonable cellular tone and reducing the incidence of flashes. Although this unopposed estrogen may be beneficial to women, it may also be responsible for the increased incidence of endometrial or breast cancer, particularly among obese women. For this reason, it is important that postmenopausal women have regular breast examinations and, if abnormal vaginal bleeding occurs, endometrial sampling.

The ovary produces a sequence of hormones during a normal menstrual cycle. Under the influence of luteinizing hormone (LH), cholesterol from the liver is used to produce the androgens androstenedione and testosterone in the theca cells of the ovarian follicle. They, in turn, are converted in the granulosa cells immediately surrounding the oocytes into estrogen. Following ovulation, the luteal cells (luteinized granulosa cells) manufacture and secrete progesterone as well as estrogen. The synthesis of these sex hormones depends on the presence of viable follicles and ovarian stroma and the production of follicle-stimulating hormone (FSH) and LH in adequate amounts to induce their biosynthetic activity. The ovarian and adrenal (for comparison) steroid biosynthetic pathways are depicted in Figure 35-1.

FIGURE 35-1 Diagrammatic representation of the steroid biosynthetic pathways. Ovarian sex steroid pathways are in red and adrenal in blue. Cmpd B, corticosterone; Cmpd S, II-deoxycortisol; DH, hydroxylase; DHEA, dehydroepiandrosterone; DOC, desoxycorticosterone; LH, luteinizing hormone; P450c, cytochrome P450.

Loss of estrogen is associated with urogenital atrophy and osteoporosis (Table 35-1). Although postmenopausal women have a higher incidence of heart disease and of cancer, the relationship between these adverse events and reduced endogenous estrogen production, as well as the effects of hormonal therapy on them, remains unclear and controversial.

TABLE 35-1 CONSEQUENCE OF ESTROGEN LOSS

Remodeling of bone continues throughout life, but with estrogen deprivation, osteoclastic activity far exceeds the osteoblasts’ ability to lay down bone. Under these conditions, osteopenia and finally osteoporosis occur. An early clinical sign of osteoporosis is a loss of height greater than 1.5 inches because of vertebral compression fracture, which may be accompanied by acute and chronic back pain. Other important osteoporotic events include wrist and hip fractures. Ten to 15 years after menopause has occurred, women begin to fracture their bones at a rate exceeding that of men by a factor of threefold to fivefold. About 200,000 women break a hip each year in the United States, and the annual cost of osteoporotic fractures and their complications has been estimated to be in excess of $14 billion. The earlier women are deprived of estrogen in their lives, the earlier osteoporotic bone loss begins. Most calcium is lost from trabecular bone, and as a consequence, the spinal column and femoral neck are the bones most commonly fractured.

Risk factors for osteoporosis include a family history of osteoporosis, slender body composition, white or Asian ethnic origin, sedentary lifestyle, alcohol consumption, cigarette smoking, thyroid excess, or use of corticosteroid or anticonvulsant medications. The North American Menopause Society recommends bone mineral density screening for osteoporosis in women with risk factors who are 50 years of age or older and in women without risk factors who are 65 years or older. The preferred screening modality is dual-energy x-ray absorptiometry measurements of the total hip and spine. The results of these studies are expressed in T scores, which are standard deviations (SDs) from the peak bone mineral density of normal young adults. Osteoporosis is defined as a T score of less than −2.5 SD. Drug therapy is recommended in postmenopausal women with a T score of less than −2.5 SD or a T score of −2.0 to −2.5 SD plus an additional risk factor for fracture. If bone mineral density measurements are used to monitor the effects of drug therapy, they should be repeated after at least 6 months of treatment.

Reducing the risk for osteoporotic fracture entails several changes of diet and lifestyle. Postmenopausal women should consume 1200 to 1500 mg of calcium and 400 to 600 U of vitamin D daily, which are contained in two to three portions of dairy products. Those who cannot or will not include dairy products in their meals should be encouraged to use calcium and vitamin D supplements. Excessive supplementation should be discouraged to avoid renal complications. Walking and weight-bearing exercises both help to increase bone mineral mass and reduce the risk for fracture-causing falls. The risk for falling can be reduced further by elimination of throw rugs in the home, placement of handrails in the bathroom, and minimizing the use of alcoholic beverages. Smoking should be discouraged for many other health reasons in addition to osteoporosis prevention. Patients receiving replacement therapy for hypothyroidism should be tested to ensure that they are not receiving an excessive (and potentially bone density–depleting) dose.

Pharmacologic treatments for osteoporosis include estrogen (with or without a progestin), selective estrogen receptor modulators (SERMs), bisphosphonates, calcitonin, and parathyroid hormone. Data from the Women’s Health Initiative (WHI) study, sponsored by the National Institutes of Health, demonstrated that combined estrogen and progestin therapy reduced postmenopausal total fractures by 24% compared with controls, with a 34% reduction of hip fractures. This translates to a reduction of the hip fracture rate from 15 to 10 cases per 10,000 postmenopausal women per year. SERMs, such as raloxifene, have been found to be beneficial for the prevention of vertebral fractures, but data are lacking regarding the prevention of hip fracture. Bisphosphonates, such as alendronate, are effective in both preventing and, at higher doses, treating osteoporosis without requiring long-term, continued use. In general, bisphosphonates have few adverse side effects. However, they must be taken properly (empty stomach, upright position, and with a large glass of water) to minimize the risk for esophagitis and esophageal ulcers. Both calcitonin and parathyroid hormone are second-line adjunctive treatments for osteoporosis.

For four decades, ovarian hormone therapy has been advocated for an expanding set of prophylactic indications. Initially, hormone therapy was provided for the treatment of hot flashes and the symptoms of genitourinary atrophy. Later, increasing evidence revealed that prevention of osteoporosis was a specific benefit of ovarian hormone therapy.

A number of large observational cohort and case-control studies suggested ovarian hormone therapy might prevent or delay the onset of arteriosclerotic heart disease and Alzheimer’s disease through a number of diverse mechanisms. On the other hand, observational studies have raised concerns about ovarian hormone therapy and the risks for venous thrombosis, pulmonary embolism, and breast cancer. Although observational studies provide useful information, they are subject to several sources of bias. Table 35-2 lists some of the biases that may occur during observational studies.

TABLE 35-2 SOME OF THE INHERENT BIASES IN OBSERVATIONAL STUDIES

Randomized controlled trials tend to minimize the biases of observational studies. However, they are difficult and time-consuming to do when the conditions being observed are relatively uncommon. The Women’s Health Initiative (WHI) study attempted to sort out the risks and benefits of ovarian hormone therapy. More than 16,000 women were entered into one arm of the study comparing a combined preparation of conjugated estrogens and medroxyprogesterone acetate with placebo. After 5 years of follow-up, this combined ovarian hormone arm was halted in July 2002. The previously reported protection from osteoporotic fracture was confirmed by the WHI study. In addition, a 37% reduction in the rate of colorectal cancer was found. This would result in six fewer cases of colorectal cancer (10 vs 16) per 10,000 women per year. Combined ovarian hormone use, however, was found to increase the risks for coronary artery disease events (by 29%), stroke (by 41%), thromboses (by 100%), and breast cancer (by 26%). Although most of the risks increased after 1 to 2 years of use, increased risk for breast cancer became apparent only after 4 years of use. There was no significant increase in death rates between treatment and placebo groups (Figure 35-2). Contrary to several previous studies, the WHI found an overall harmful rather than protective effect on cognitive decline and dementia.

FIGURE 35-2 Disease rates for women taking estrogen plus progestin or placebo.

(Data from the Women’s Health Initiative Study Group, 2002.)

In February 2004, the estrogen-only arm of the WHI was halted owing to a significantly increased risk for stroke. It confirmed a protective effect against hip fracture, whereas none of the other significant findings in the combined arm were found to be present. The risk for breast cancer was not increased in the estrogen-only arm of the WHI.

The WHI study has been widely criticized for studying women who, for the most part, were well past the age of menopause when they were entered into the study (average age was 63 years). Laboratory and animal studies have shown an arteriosclerotic protective effect of estrogen after gonadectomy, when begun immediately. Additional analysis of WHI data has failed to confirm increased coronary artery events in subjects who began therapy less than 10 years after the menopause.

Although definite limitations of the WHI study have been identified, the findings have had a significant effect on clinical practice, and the routine use of hormone therapy after menopause is now viewed with caution. The general consensus is that combined ovarian hormone therapy is indicated primarily for the relief of significant menopausal symptoms such as frequent hot flashes, genitourinary discomfort, and other quality-of-life issues. The length of treatment should be minimized depending on the individual patient’s clinical course and preference, after informed consent. On the other hand, most experts recommend that younger hypoestrogenic women, such as those who undergo premature menopause or bilateral oophorectomy, should take hormonal therapy.

A large observational cohort study, the Million Women Study (MWS), is addressing the risks and benefits of hormone therapy after menopause. More than 1 million women have been enrolled in the United Kingdom, and thus far no long-term results have been fully analyzed or reported. After a little more than 4 years of follow-up, however, the MWS reported an increased breast cancer risk with hormone therapy. Table 35-3 lists these results.

TABLE 35-3 RELATIVE RISKS (CONFIDENCE INTERVALS) OF BREAST CANCER WITH DURATION OF CURRENT USE OF HORMONES

Data from Speroff L: The Million Women Study and breast cancer. Maturitas 46:1-6, 2003.

The need for prevention and treatment of osteoporosis may be determined by bone densitometry studies rather than ovarian status, with bisphosphonates or raloxifene as the first line of treatment in the absence of concomitant significant menopausal symptoms.

Women who still have a uterus should not be given unopposed estrogen for the treatment of menopausal symptoms because of the high risk for developing endometrial hyperplasia and endometrial adenocarcinoma. Concurrent progestin is protective for endometrial disease and may be given for 12 days per month or for 14 days per quarter with predictable uterine bleeding on withdrawal. Patients who seek complete amenorrhea may use continuous combined estrogen and progestin (e.g., conjugated estrogens, 0.625 mg, and medroxyprogesterone acetate, 2.5 mg daily). This latter regimen is characterized by unpredictable breakthrough bleeding, with most patients achieving amenorrhea within a year. It should be kept in mind, however, that the estrogen-only arm of the WHI study suggests that progestins may be the more important element of risk for breast cancer in patients receiving hormonal therapy. In view of this finding, thought should be given to minimizing exposure to progestins.

Severe continuous bleeding or intermittent bleeding after more than 4 months of hormonal therapy should prompt a search for uterine pathology. Optimization of menopausal symptom control, while reducing adverse side effects of therapy, may be accomplished by using the lowest effective dose and by substituting continuous transdermal estrogen for oral estrogen preparations when symptoms are not adequately controlled. When the patient’s main concerns are with genitourinary symptoms, vaginal estrogen cream, tablets, or rings may be used on an as-needed basis without necessarily adding a progestin.

The biologic effect of estrogenic substances is mediated by the translocation of a ligand-estrogen receptor complex into the nucleus where various estrogen-responsive genes are activated or repressed. At least two estrogen receptors, α and β, are presently known to exist. They exert different biologic effects and exist in different proportions in different tissues. In addition, different ligands bound in complex with the same receptor manifest different biologic activity. The use of SERMs attempts to take advantage of these facts to produce some of the biologic effects of native estradiol. SERMs in use today include clomiphene, tamoxifen, and raloxifene. Unlike estradiol and other SERMs in current use, raloxifene does not stimulate endometrial or breast duct epithelial proliferation. However, raloxifene does appear to reduce osteoclast activity and prevent osteoporosis (at least in the spine). Hence, raloxifene has some of the bone-sparing effect of estradiol without the risk for endometrial hyperplasia or carcinoma, and in fact, it may prove to be protective of breast cancer in the same way as tamoxifen. However, raloxifene appears to worsen rather than ameliorate vasomotor symptoms. Perhaps new SERMs discovered in the future will provide symptom relief as well as skeletal protection.

Increasingly, an emphasis is placed on the importance of lifestyle changes as a strategy for decreasing the inevitable effects of the aging process. The most important change that anyone can make overall to increase longevity, reduce heart disease, and reduce calcium loss from bone is to stop smoking. Controlling weight, engaging in regular exercise, and eating a healthier, low-fat, and balanced diet should be strongly recommended, especially in women with diabetes, hypertension, or significantly elevated blood lipids. All counseling about the effects of menopause should include a discussion of these issues and recommendations along with any possible medical therapies. In particular, the statin drugs are especially important for postmenopausal women with unfavorable lipid profiles because they significantly reduce the risk for cardiovascular disease and serendipitously protect against osteoporosis.

Phytoestrogens (plant products that are functionally or structurally similar to estrogen) and herbal substances have been marketed to consumers as the “natural” alternative to traditional hormone therapy for the symptoms of perimenopause and menopause. Women should be made aware that even placebos may decrease some of the symptoms, such as hot flashes, and that some herbal preparations have been shown to be ineffective or even harmful. Also, patients should be made aware of the less rigorous evaluation and regulation that these products undergo.

With proper counseling, appropriate screening, and professional care, the signs, symptoms, and sequelae of the climacteric can be managed successfully. Short-term use of hormonal therapy for symptom control, healthy lifestyle changes, appropriate monitoring, and medical or surgical intervention when necessary should provide a safe and effective level of care.