Menopause 2

CARDIOVASCULAR
Coronary artery disease (CAD) is known to be increasingly prevalent with older age in both men and women. Menopause increases the risk for women still further, independent of age. Prior to menopause, the risk of CAD for women lags behind the risk for men by approximately 10 years. After menopause, women come to have similar risks of CAD as men of the same age. As a result, the rate of death in women from CAD is increasing. The Framingham study was pivotal in showing the relationship between menopause and increased cardiovascular mortality rate (Kannel, 1976).
The benefit of estrogen on cardiovascular mortality rates is due to many factors. One mechanism appears to be estrogen’s effects on lipid metabolism, which includes reducing low-density lipoprotein (LDL) and increasing high-density lipoprotein (HDL). Studies have suggested that the best predictors of CAD in men and women are different (Assman, 1998) and that triglycerides, HDL, and lipoprotein(a) may be more significant in women (Erikkson, 1999). Women with elevated lipoprotein(a) levels should be treated more aggressively, and the treatment considered should include ERT as well as a statin. A positive relationship between ERT and reduction of primary cardiovascular risk has been demonstrated in several studies, and the reduction in risk in women who are taking ERT may be similar to the risk reduction of those receiving specific lipid-lowering therapy (Darling, 1997).
The Heart and Estrogen/Progestin Replacement (HERS) Study (Hulley, 1998; Wells, 1999; Grady, 1998), a study of 2763 postmenopausal women with known CAD, compared the effect of continuous combined HRT versus that of placebo over an average of 4.2 years. No beneficial reduction of CAD event rates was initially observed in the HRT groups. In fact, the initial adverse event rate was higher in the treatment arm than in the placebo arm, which offset a later reduction in risk in the HRT group. An 11% reduction in LDL level and a 10% increase in HDL level were apparent in the treatment group. These observations together suggest that the protective effects of estrogen on cardiovascular morbidity result from many mechanisms and not solely from lowering of lipids, and that estrogen alone is not adequate therapy for secondary prevention of CAD.
The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, which included 875 healthy postmenopausal women, compared various CAD risk factors as predictors of outcomes in women who received various HRT regimens by randomizing the participants to receive placebo or 1 of 5 regimes of estrogen/progestin therapy (Writing Group for the PEPI Trial, 1995). All treatment groups showed an overall improvement in HDL and LDL levels compared to the placebo group. The improvement in HDL level was better in the group that received unopposed estrogen than in the other treatment groups; however, individuals using unopposed estrogen also had the highest rate of endometrial hyperplasia.
The Nurses’ Health Study demonstrated an approximately 11% risk reduction for primary cardiovascular disease in postmenopausal women using HRT compared with women who had never used HRT, irrespective of duration of use (Grodstein, 2000). The risk reduction did not appear to be dose dependent. ERT has a role in primary prevention of CAD.
The greatest beneficial effect of estrogen appears to be on endothelial function. Women undergoing angioplasty appear to be protected against restenosis by ERT (Abu-Halawa, 1998). Progression of early atherosclerosis in postmenopausal women who smoked, as measured by carotid intimal thickness, was greater over time than in women who smoked and were on ERT (Teeds, 1999).
BREAST CANCER ISSUES
ERT is known to benefit postmenopausal women in a multitude of ways, although some data indicate that ERT increases the risk of breast cancer. Estrogen's possible link to cancer is also suggested by the fact that the risk of breast cancer is increased in women with an earlier age at menarche and later age at menopause. With early age at pregnancy, however, and the interruption of menstrual hormonal changes, a reduction in risk is observed.
Data suggest a slightly increased RR with estrogen use at approximately 1.1-1.3 (Schairer, 2000; Collaborative Group on Hormonal Factors in Breast Cancer, 1997), but not all the evidence supports this finding (Gapstur, 1999). The risk appears to be related to duration of use, with longer-term users being more affected (Lando, 1999).
Data suggest that the addition of sequential progestin to the regime increases the RR of subsequently developing breast cancer beyond the risk of estrogen alone, although the suggestion has been made that continuous combined HRT using much smaller doses of progestin attenuates this risk (Ross, 2000). Most earlier studies evaluating breast cancer risk and ERT were conducted at a time when the progestin in HRT was administered on a cyclical basis.
Notably, women with a history of using HRT have more localized tumors as well as better survival rates. That is, women receiving HRT who are diagnosed with breast cancer are found to have more favorable staging at the time of diagnosis (Collaborative Group on Hormonal Factors in Breast Cancer, 1997), including smaller tumor size, negative lymph node involvement, and more well-differentiated tumor histology (Colditz, 1990; Holli, 1990; Strickland, 1992; Squiteri, 1994; Bonnier, 1995; Salmon, 1995; Harding, 1996; Magnusson, 1996; Fowble, 1999).
A beneficial effect on breast cancer mortality rates has been shown in postmenopausal women who have received HRT compared with controls who have no prior history of HRT use (Schairer, 2000). Study findings do not agree on whether this is due to earlier detection or to effects of the therapy itself on breast tissue. The general belief is that any increase in risk is small and that each patient should be evaluated as a candidate for ERT on an individual basis, with consideration of the overall balance of risks and benefits. An essential precept in the management of menopause is that each individual is unique and that therapy should be tailored accordingly.
CENTRAL NERVOUS SYSTEM EFFECTS
The association of estrogen and memory function is an intriguing area of research. Normal aging itself induces a decline in certain cognitive capabilities, and a lack of estrogen may contribute to this process. If this is the case, postmenopausal ERT may be able to preserve this function and slow or even prevent decline in certain cognitive functions. An inherent difficulty in this area of study is the limitations of objective cognitive testing for functions such as memory. In general, ERT is associated with better performance on memory testing in postmenopausal women than in postmenopausal controls who are not receiving ERT (Sherwin, 1997; Resnick, 1997). The estrogen effect is one of slowing the decline of preserved memory function. Further clinical research must be conducted in this area to differentiate the benefits of estrogen in cognitive function in women who develop clinical dementia and those who do not.
Currently, data suggest that women have a higher incidence of Alzheimer disease than men, even after allowing for the longer life span of women, because Alzheimer disease is primarily an age-related condition (Anderson, 1999). ERT appears to reduce the RR of developing this condition and/or to delay its onset (Tang, 1996; Kawas, 1997). Estrogen has not been demonstrated to show an improvement in cognitive function in patients with Alzheimer disease, that is, it cannot reverse previous cognitive decline and therefore has no role as a sole treatment modality in Alzheimer disease. However, estrogen may be beneficial as adjuvant therapy in conjunction with cholinesterase inhibitors.
Perimenopause is frequently a time of depressive symptoms associated with direct hormonal effects through variation in levels and changes in life circumstances and secondary to effects such as estrogen-related sleep disturbance and vasomotor symptoms. However, major depression is associated with the female sex at all ages, and objective demonstration of a cluster of cases around menopause has been difficult, although this appears to be anecdotally true.
Regardless of whether the criteria for a definitive diagnosis of major depression are met, depressive symptoms should always be considered in the context of level of functioning; any impairment warrants consideration of intervention.
In all but a very few cases, distinguishing the etiology of the symptoms as menopausal versus primary depression is usually not possible. Treatment of depressive symptoms with estrogen in perimenopause, the postpartum period (Gregoire, 1996), and premenstrual syndrome is common, with observed resultant improvement in functioning and mood, both subjective and objective, in many clinical instances. Clinical depression, however, warrants treatment with antidepressants, with estrogen showing benefit as adjuvant therapy in this scenario.
The microcellular effects of estrogen in the CNS have yet to be clearly outlined but may reveal intricate processes by which estrogen has a direct effect in CNS functioning. One of these processes may turn out to be a reduction in free radical damage by ERT.
MENOPAUSE MARKERS
Gonadotropin secretion increases dramatically after menopause. FSH levels are higher than LH levels, and both rise to even higher levels than in the surge during the menstrual cycle. The FSH rise precedes that of LH. The large cyclical variation of estradiol and estrone observed during the menstrual years ceases, and fluctuation in levels is small and inconsequential, with the mean being very much lower. The levels of circulating estradiol have very different ranges before and after menopause, and these levels are obviously much lower in menopause. Smears of the vaginal epithelium provide a composite picture of endogenous and exogenous estrogen stimulation over time; the more estrogen, the greater the number of superficial cells. No specific changes related to menopause have been found in thyroid function.
Endometrial biopsy can show a range of endometrial appearances, from mildly proliferate to atrophic. No secretory changes are observed after menopause because no ovulation occurs, and therefore no corpus luteum forms to produce progesterone. Endometrial hyperplasia is a sign of hyperstimulation by estrogen from either endogenous sources or replacement therapy and may be a precursor of endometrial cancer. Endometrial hyperplasia can also be suggested by ultrasonography (an endometrial thickness of >5 mm), which is useful in trying to exclude hyperplasia and cancer of the endometrium in postmenopausal women.
REPLACEMENT THERAPY
Among the many reasons to treat symptoms of estrogen level fluctuation prior to actual menopause are to provide relief of vasomotor symptoms, reduce the risk of unwanted pregnancy, avoid the irregularity of menstrual cycles, and mitigate the long-term effects of menopause (eg, osteoporosis, cardiovascular disease, decline in cognitive function).
The time to begin therapy depends on the patient’s current illness(es), if any, and medical history. Whether a woman is perimenopausal or postmenopausal helps in choosing the most suitable type of therapy. Each patient should make a choice after receiving counseling on all the facts and an explanation of the options. For example, the perimenopausal woman may be started on HRT if either she or her spouse has undergone a sterilization procedure, whereas the same woman may need an OCP if she still needs birth control. Many factors, including personal history, family history, smoking, peer and commercial influences, culture, ethnicity, and economics, also play roles in the final decision, and all must be carefully weighed by the doctor and patient together.
Adverse effects of replacement therapy may include bloating, mastodynia, vaginal bleeding, and headaches. Unexplained adverse effects are often the reason for discontinuation of therapy, and reassuring counseling as well as options and dose combinations should be tried before therapy is stopped.
HRT can be administered systemically through the oral, transdermal, or topical routes or locally via the vaginal route using cream, ring, or tablet. Topical preparations are used solely to treat vaginal symptoms.
Contraindications to estrogen therapy are undiagnosed vaginal bleeding, severe liver disease, pregnancy, and venous thrombosis. Well-differentiated and early endometrial cancer, once treatment for the malignancy is completed, is no longer an absolute contraindication. Estrogen receptor–positive breast carcinoma has traditionally been a contraindication, but this has also been challenged recently. Progestins alone may relieve symptoms if the patient is unable to tolerate estrogens, but the other concomitant protective effects of estrogen are lost. Alternative products—ranging from herbal preparations to dietary supplements containing various phytoestrogens—are reputed to ease the transition from perimenopause to postmenopause and are widely available. However, these agents require rigorous and objective evaluation, which has yet to be conducted.