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The “climacteric” comes from the Greek klimakterikos, which is literally defined as a rung in a ladder - a crucial time period or event. At this time in a woman’s life, her caregivers must be prepared to address the immediate symptoms and the long-term health consequences of menopause.Providers should be familiar with the risk and benefits of the medical and behavioral therapies available, particularly those of hormone replacement therapy.

The perimenopause is a period of approximately five years in which the ovaries gradually fail to produce estradiol.Ninety-five percent of women will experience spontaneous menopause between the ages of 45 to 55.In the early perimenopause, there are decreased numbers of ovarian follicles, FSH is slightly increased and women are asymptomatic.During the middle perimenopause, there is erratic maturation of ovarian follicles and women begin to experience altered menstrual cycle patterns.Late perimenopause is characterized by failure of ovulation and declining estradiol levels.The average woman will spend one third of her life in the post-menopausal period. An FSH level > 40 mIU/mL is consistent with menopause, although the diagnosis is usually made clinically and routine laboratory testing is not indicated. 

The perimenopausal period is frequently accompanied by climacteric symptoms, including hot flashes (flushing of the chest and face, often associated with sweating or palpitations), insomnia, vaginal dryness, dyspareunia, mood changes, and sleep disturbances. Symptoms last for a year or two in the majority of women, but up to 25 percent can have symptoms for more than five years. Many of these symptoms can be relieved by short-term hormone replacement therapy (HRT) given for three to five years. Therapies such as phytoestrogens (soy) and behavioral changes such as avoidance of caffeine and increased exercise are not well studied, but are felt to be safe (if not necessarily effective) alternatives for women who are intolerant of or reluctant to take HRT.[i] Topical estrogens and/or lubricants can effectively treat vaginal symptoms. Although the traditional psychoanalytic view of menopause is that it is “inevitably accompanied by reactive depression resulting from the loss of reproductive function,”[ii] there are, in fact, no data to support the assertion that menopause itself causes depression.[iii]^,[iv] Patients who complain of mood changes should be screened for signs and symptoms of depression that predated the onset of menopause and treated accordingly. Insomnia is occasionally reported, as is decreased libido; the latter is often treated with HRT but may also be treated with combined estrogen/testosterone (Estratest^TM).

Long-term Issues

It is clear that hormone replacement therapy effectively treats the symptoms of menopause and decreases the risk of osteoporotic fractures while it is being taken.[v]^,[vi] HRT probably decreases the risk of coronary heart disease as well, although this assertion has recently become controversial. Most of the data regarding use of HRT for the treatment of osteoporosis and coronary artery disease are based on observational studies (i.e. the Nurses Health Study) which suffer from selection bias and lack of racial diversity.Physicians discussing HRT with patients should, thus, also emphasize the importance of behavior modification (such as diet and exercise) in health promotion and disease prevention during this important period.

Osteoporosis:

Postmenopausal women develop osteoporosis at high rates.[vii] Lack of estrogen leads to increased osteoclast activity and rapid bone loss. Osteoporosis increases the risk of vertebral, hip, and other fractures, with high morbidity and cost, as well as high hip fracture-related mortality.[viii] Estrogen replacement clearly decreases postmenopausal bone loss and improves bone density; it has also been shown to decrease fractures by 30 to 60 percent.^5,6 Estrogen’s positive effect on calcium absorption and bone density appears to wane rapidly once it is stopped.[ix] As many fractures occur in very elderly women, the optimal duration of HRT for the purpose of osteoporotic fracture prevention is not certain. Additional therapies include weight-bearing exercise, calcium supplementation, vitamin D supplementation, bisphosphonates,[x] and raloxifene, a tissue-specific estrogen agonist/antagonist recently FDA-approved for this purpose.[xi] Treatment of osteoporosis is discussed at greater length in Chapter 15.

Cardioprotection:

Coronary artery disease is the leading cause of death in post-menopausal women. A 50 year old woman has a 46 percent lifetime probability of developing symptomatic coronary artery disease – far greater than her risk of breast or uterine cancer.[xii]There is evidence from observational studies that estrogen is cardioprotective. Cross-sectional and “ecological” studies show that premenopausal women are much less likely than men to have complications of coronary heart disease, and that this pattern changes in the postmenopausal period.In addition, there is a significant increase in LDL levels and decrease in HDL levels in post- menopausal women.

The role of HRT in the prevention of coronary heart disease, however, remains controversial. Case-control and cohort studies such as the Nurses’ Health Study and the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial indicated a strong cardioprotective effect.[xiii]^,[xiv] Women on estrogen replacement therapy in the Nurses’ Health Study had fewer cardiac events and lower mortality than those not on HRT.[xv] In the PEPI trial, women on HRT had decreases in low density lipoprotein (LDL), elevations in high-density lipoprotein (HDL), and increased fibrinogen levels.[xvi] HRT users had higher lipoprotein A1 levels (a measure of LDL level) than nonusers, and progesterone may actually enhance these effects.[xvii] However, in the HERS study, there was no reduction in the overall rate of CHD events in the treated group. The HERS study was a randomized controlled trial of estrogen plus medroxyprogesterone in women with established CHD.[xviii] Fibrinolytic activity may be increased in HRT users,[xix] and some markers of vascular inflammation are increased.[xx]^,[xxi] There has been some debate as to whether the addition of progestin decreases the cardioprotective effects of estrogen, but observational data suggest that it does not.[xxii] The Women’s Health Initiative Randomized Trial should provide a more definitive answer to the role of HRT in primary and secondary CHD prevention, but the results of this study will not be available until the year 2005. We believe that a patient-focused approach to CVD risk reduction in women should include attention to smoking, lipids, blood pressure, exercise, obesity and diet. Based on the available evidence, decisions about HRT should probably not be motivated by CVD risk reduction.

Possible benefits of HRT:

Results of various studies have been conflicting, but recent data show a possible protective effect against Alzheimer’s disease.[xxiii]^{,[xxiv],[xxv]} Large scale clinical trials are ongoing to assess this effect more rigorously. Some studies have shown that HRT leads to improvement in psychological symptoms in perimenopausal and depressed women. Vaginal estrogen cream has been shown to decrease urinary tract infections in older women.[xxvi]

Vaginal bleeding:

Many women taking hormone replacement therapy will experience vaginal bleeding of varying degrees. Cyclic methods of administration will produce cyclic bleeding; continuous estrogen/progesterone may have unpredictable spotting whichwanes over time. It is important to explain to patients that spotting is usually mild and that most women are again amenorrheic by 6 to 12 months. Women with abnormal vaginal bleeding should be thoroughly evaluated prior to receiving HRT. Similarly, women with unexpected bleeding on a cyclical regimen or with continued spotting after 12 months of continuous HRT should be evaluated for endometrial pathology. Endometrial cancer is a contraindication to hormone replacement therapy. 

Breast tenderness:

        Breast tenderness is an occasional side effect of hormone replacement therapy; it usually wanes after the first few months. Although breast cysts and fibroadenomas may become symptomatic when HRT is initiated, they are not themselves contraindications to therapy. A personal history of breast cancer, in contrast, is an absolute contraindication (see below).

Thrombosis:

Although the doses of estrogen and progestins in hormone replacement therapy are much lower than those found in oral contraceptives, HRT, like OCP use, is thought to increase the risk of deep venous thrombosis and pulmonary embolism. One prospective study did show an increased relative risk of pulmonary embolus in women who were current postmenopausal hormone users.[xxvii] A history of vascular thrombosis is felt to be an absolute contraindication to HRT use. 

Endometrial carcinoma:

Unopposed estrogen leads to endometrial hyperplasia and adenomas, as well as an increased incidence of endometrial carcinoma. The addition of progestin treatment appears to diminish this risk, but it is unclear whether in long-term users the risk of endometrial cancer will be avoided.[xxviii] As noted below, adding progestin decreases the risk of endometrial cancer, but may slightly increase the risk of breast cancer. 

Breast carcinoma:

There is still no consensus on whether HRT increases breast cancer risk, a question of great concern to many patients. The Nurses’ Health Study, a prospective cohort study of 121,700 female registered nurses showed that current users of postmenopausal HRT for greater than 5 and greater than 10 years had a relative risk (RR) of breast cancer of 1.36 and 1.47 respectively.[xxix] The relative risk of death due to breast cancer was 1.45 among women who had been on estrogen for more than 5 years. Past users at the time of the study and those with short-term estrogen use (less than 5 years), had no increased risk. A population-based case control study performed in King’s County, Washington compared 537 women diagnosed with breast cancer over a two year period with randomly selected controls with no history of breast cancer. This study showed no increased risk of breast cancer in those on HRT. More recently, a cohort study looked at 46,355 women enrolled in the Breast Cancer Detection Demonstration Project and concluded that estrogen-progestin regimens increased the risk of breast cancer compared to estrogen-only hormone replacement therapy.[xxx] The risk was only seen in women who had used HRT in the previous four years: for women on estrogen-only regimens the RR = 1.2 (95% CI 1.0-1.4) and for women on combined regimens the RR = 1.4 (95% CI 1.1-1.8). The same sorts of selection biases that make the observational studies of HRT and cardiovascular disease protection controversial apply to these observational studies of HRT and breast cancer risk.

A personal history of breast cancer is considered to be an absolute contraindication to HRT although some have called for a randomized controlled clinical trial to evaluate the risk of this therapy for breast cancer patients.[xxxi] A family history of breast or endometrial carcinoma is a relative contraindication; there are little data on increased risk in these women.

Adherence:

Women who are prescribed HRT have low rates of adherence to therapy, citing side effects and fears of negative outcomes as reasons for lack of adherence.Thorough discussion of possible side effects and close follow up may improve adherence.

Raloxifene

Raloxifene (Evista^TM) is a selective estrogen receptor modulator (SERM) recently approved by the FDA for the treatment of osteoporosis. SERMs are agents that bind to estrogen receptors, acting as estrogen agonists in some organs and antagonists in others. Raloxifene mimics the action of estrogens on bone and on lipids, but acts as a potent anti-estrogen in breast and uterine tissue. For this reason, it has been investigated as a potential “ideal agent” for the prevention and treatment of the long-term complications of menopause. Despite widespread interest in the use of raloxifene as an alternative to HRT, long-term data are lacking.

The risks of raloxifene may be less than those of hormone replacement therapy. In marked contrast to HRT, raloxifene decreased the risk of breast cancer by 76 percent during the three years of follow-up for the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, which randomized 7705 postmenopausal women with osteoporosis to placebo, raloxifene 60 mg qD and raloxifene 120 mg qD.[xxxii] The authors concluded that the number of women needed to treat with raloxifene to prevent one case of breast cancer (NNT) was 126. Raloxifene seems neither to increase nor decrease the risk of endometrial cancer, as evidenced by a 12-month randomized controlled trial comparing raloxifene, estrogen and placebo in 415 postmenopausal women.[xxxiii] The subjects were followed with endometrial biopsies and transvaginal ultrasound; there were no significant differences found between the raloxifene and placebo groups. A similar three-year study of the effects of raloxifene vs. placebo was conducted in 969 postmenopausal women who were followed with transvaginal ultrasound; there were no differences in symptoms (spotting, bleeding and discharge) or endometrial thickness between the placebo and raloxifene groups.[xxxiv] Raloxifene does increase the risk of venous thromboembolic disease (which tripled in the MORE trial)³² and was associated with peripheral edema, hot flashes and flu-like symptoms in a minority of women.

The benefits of raloxifene may also be less than those of HRT, although long-term data, as noted, are lacking. Raloxifene does not alleviate the short-term symptoms of menopause, such as hot flashes. Effects on coronary heart disease are unknown, although like HRT, raloxifene decreases serum homocysteine and LDL cholesterol levels. Raloxifene increases bone mineral density (BMD), although to a lesser extent than estrogen replacement – it is estimated to increase BMD by 1.6-2.7 percent[xxxv]^,32 in contrast to the 3.5-5 percent increase seen with estrogen replacement in the PEPI trial.¹⁶The MORE trial showed that raloxifene decreased the rate of vertebral fractures by 30-50 percent at three years. (10 percent of the placebo group had vertebral fractures compared to 6.6 percent and 5.4 percent of those on raloxifene 60 and 120-mg respectively).[xxxvi]There was no difference in the rate of non-vertebral fractures after three years of follow-up. Estrogen replacement therapy has been shown to decrease the rates of vertebral fractures by 60 percent and epidemiological studies indicate a 50 percent reduction in hip fractures in elderly women who have used HRT for a mean of 14 years.[xxxvii] We await longer-term data on the effect of raloxifene on fracture risk.

Much of the data on the effects of HRT comes from case-control and cohort studies, rather than randomized controlled trials. There are concerns about potential bias in such studies: for example, women on HRT may be better educated, more affluent, exercise more, ingest more alcohol, and have other differences that may confound cardiovascular outcomes. Most of the patients studied have been Caucasian. There are little data on minority women and HRT, but this population may have a different risk/benefit profile. African-American women, for example, have lower rates of osteoporosis, but higher rates of hypertension and of diabetes compared with Caucasians. Many studies have used surrogate markers rather than clinical endpoints, and many had short follow-up periods. The Women’s Health Initiative, a recently started multicenter randomized controlled clinical trial which plans a decade of follow-up, seeks to answer many of these questions. As mentioned, these data will be available in 2005. 

The US Preventive Health Task Force recommends that health care providers discuss possible risks and benefits of HRT with all postmenopausal women. Attention should be paid to climacteric symptoms, individual patient risks for osteoporosis and cardiovascular disease, family history of breast and endometrial cancer, whether the patient has had a hysterectomy, and individual patient preference. Careful follow-up with mammography, clinical breast exam, and gynecologic care is recommended. Women should also be advised about alternative therapies for climacteric symptoms, osteoporosis and cardiovascular risk reduction.[xxxviii]

Hormone Regimens

Options for hormone replacement therapy include oral, transdermal and vaginal preparations. Because transdermal delivery of HRT is uneven, and because it is not clear if the absence of first-pass metabolism by the liver changes the effect of HRT on the cardiovascular system, transdermal preparations are generally not used as first-line agents. Vaginal estrogen creams are most often used as short-term therapy of atrophic vaginitis. Oral regimens can be given as continuous or cyclic preparations; there are no compelling reasons to recommend one preparation over another, although combined preparations such as Prempro^TM and Premphase^TM have the advantage of being a single pill each day. Women who have undergone hysterectomy should receive unopposed estrogen, as they will receive no benefit from added progestins; all other women on HRT should receive both estrogen and progesterone to minimize the risk of endometrial cancer. Some standard HRT doses are listed in Table 1:

TABLE 1: Oral Hormone Replacement Therapy Regimens

We thank Drs. Daniel S. Donovan, Jr. and Eliza Lo Chin for their helpful comments and suggestions.
 

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