Individualizing HRT is the best strategy for ensuring adherence and providing long-term benefits. At a symposium held on October 23, 2000, a panel of experts focused on how to help women decide whether to begin HRT and consider its risks and benefits.
This program was supported by an unrestricted educational grant from Pfizer Inc.
Successfully Individualizing HRT: Delivering Benefits and Minimizing Risks
"The perimenopausal transition is a time of erratic ovarian function that can be frustrating for both the patient and her healthcare provider," said Alan Altman, MD, Assistant Clinical Professor of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Brookline, MA. "The erratic levels of estrogen produced by the ovaries have important diagnostic and therapeutic consequences."
Most physicians have been taught that the initiating change for menopause was the diminished production of estradiol by the senescent ovary, which then stimulated an increase in follicle-stimulating hormone (FSH). However, the earliest physiological changes detectable now appear to be a decrease in the production of Inhibin B after the follicular volume dips beneath a threshold of approximately 20,000 follicles. The result of this "pushing" of the ovary is a shorter follicular phase, which then leads to a shorter cycle. The production of estradiol also may increase during this time to levels that surpass the estradiol production in a woman in her 20s. This presents a clinical situation where hyperestrogenism may occur, leading to bloating, breast tenderness, and an increase in bleeding or intermenstrual bleeding. Hyperestrogenism also may induce more progesterone receptors in the luteal phase, sometimes leading to the new development of premenstrual syndrome. With further follicular decline, the more classic symptoms of hypoestrogenism appear that are expected in the perimenopausal transitions.
"Unfortunately, Mother Nature has not divided these into 'early' and 'late' phases," Altman added. "In fact, these phases can interchange from cycle to cycle and illustrate why perimenopausal symptoms derive directly from these phases of hyper- and hypoestrogenism." This fluctuation in phases is why the measurement of FSH for any sort of diagnostic or therapeutic information can be extremely misleading. Diagnosis is best made by using the bioassay and listening to patients' symptomatology. In fact, the first and often only treatment that is necessary for the perimenopausal transition is validation of each patient's symptoms, that she is experiencing a natural and often gradual transition. It also offers a time to discuss important lifestyle changes such as smoking cessation, diet, and aerobic and strength-training exercises.
There is a wide range of therapeutic options available. Many patients are using over-the-counter herbal remedies, part of a multimillion dollar industry that is totally unregulated. However, the use of lignans and isoflavones, especially soy isoflavones, can be partially successful in relieving moliminal symptomatology.
The use of traditional hormone replacement therapy (HRT) for the perimenopausal patient is not optimal because of the lack of ovarian suppression. In fact, HRT can cause more problems than no therapy at all, observed Altman. When hormone therapy is necessary, one good approach is the use of the 20-µg birth control pill, which offers ovarian suppression and many other noncontraceptive benefits. If a low-dose oral contraceptive cannot be used, then estrogen or progesterone augmentation alone is possible. "Yet single-hormone augmentation," cautioned Altman, "can often backfire when phases of perimenopause interchange and the patient using estrogen suddenly becomes hyperestrogenic and, thus, more symptomatic." When using estrogen augmentation, it may not be necessary to use a progestogen if the patient is still cycling normally.
One approach is to make the transition to the use of HRT should be gradual, for example, shifting from an oral contraceptive containing 20 µg of ethinyl estradiol (EE) to a preparation containing 5 µg EE or its equivalent (plus a progestin in women with an intact uterus). Several combination products are available: conjugated equine estrogen plus medroxyprogesterone acetate (MPA); 17b-estradiol plus norgestimate; and ethinyl estradiol plus norethindrone acetate.
A goal of continuous combined therapy is to achieve amenorrhea. Two products, combining conjugated equine estrogen plus MPA and estradiol plus norgestimate, currently provide cumulative amenorrhea in about 30% of patients at 3 months. In separate studies, ethinyl estradiol and norethindrone acetate resulted in amenorrhea in 87% at 3 months.
"We've got so many more options when individualizing hormone replacement therapy," concluded Altman. "There is no 'one-size-fits-all' approach. By being attentive to patients' histories and needs when prescribing appropriate and beneficial HRT, if one choice is not perfect, we can find one that is more acceptable."
Cardiovascular Effects of Estrogens and Progestins
"More than half of all deaths in women after age 50 are due to vascular diseases, with the most common related to ischemia secondary to atherosclerosis," said Philip Sarrel, MD, Professor of Obstetrics, Gynecology, and Psychiatry, Yale University School of Medicine, New Haven, CT. "A relationship between the development of atherosclerosis and loss of ovarian hormone production has been recognized for more than 50 years."
A variety of estrogens, including 17b-estradiol, ethinyl estradiol, and conjugated estrogens, have been reported to have beneficial effects on lipid metabolism. In studies in which estrogen use has been associated with decreased cardiovascular mortality, it has been estimated that at least 25% of protection reflects positive actions on lipid metabolism.
Estrogens also act directly on the arterial wall because endothelial cells contain estrogen receptors and many of the beneficial actions of estrogen on these cells appear to be modulated by estrogen receptors. In fact, when Rosenfeld summarized the estrogen actions demonstrated in basic research, he found that there are at least 25 intraendothelial cell actions of estrogen, and all of them help prevent atherosclerosis. "Estrogens stimulate nitric oxide production, arguably their most important effect, and one that is largely estrogen-receptor dependent," observed Sarrel. For example, administration of ethinyl estradiol, 17b- estradiol, and conjugated estrogens to postmenopausal women has demonstrated enhanced endothelial vasodilator response in different arteries, including brachial and coronary vessels. Withdrawal of estrogen can lead to acute nitric oxide depletion resulting in vasomotor instability and vasoconstrictive events.
Progestins downregulate the estrogen receptor and can oppose the cardioprotective effects of estrogens. Natural progesterone appears to have minimal effects on the arterial actions of estrogens. In contrast, medroxyprogesterone acetate (MPA) has been reported to inhibit the antiatheromatous actions and to induce vasospasm and ischemia. These actions of MPA, initially reported in monkeys, also can occur and be clinically significant in postmenopausal women. Laboratory studies of norethindrone acetate (NA) suggest that this particular progestin lacks the estrogen-negating effects of MPA. The combination of estradiol and NA was found to have a significant additional preventive anti- atherogenic effect compared with estradiol alone in ovariectomized rabbits, suggesting that NA may have an estrogen-enhancing effect on the cardiovascular system. However, additional data on NA and other progestins in humans are needed to determine further their cardiovascular effects. Moreover, MPA and NA have not been compared directly in the same study.
"Optimal hormone replacement therapy, from a cardioprotective point of view, should provide protective levels of estrogen," Sarrel concluded. "This therapy should also include a progestin that, while protecting the endometrium, has a minimal effect on downregulation of the estrogen receptor."
The Role of Progestins in Bone Health Maintenance
"With baby-boomers entering menopause, and the elderly becoming a larger segment of the community, osteoporosis contributes to ever-increasing morbidity, mortality, and public health expense," said David J. Portman, MD, Assistant Clinical Professor, Ohio State University College of Medicine; and Director, Columbus Center for Women's Health Research, Columbus, OH. "In fact, more than 300,000 hip fractures occur annually, and 25% of these patients die within the first year."
The hypoestrogenic state is clearly associated with a precipitous fall in bone mineral density (BMD), so primary goals are to maintain peak bone mass and prevent first fracture, before clinical and visibly identifiable osteoporosis occurs. Because women who have higher circulating estradiol levels are at much lower risk for fracture than those who have lower, near undetectable levels, it is important to identify women's lifelong fracture risk based on their lifelong exposure to estrogen. In this regard, there currently are a proliferation of devices to measure bone density, and many studies have confirmed that measuring any site is helpful.
When evaluating methods to prevent bone loss, the Early Postmenopausal Intervention Cohort (EPIC) study has shown that women in early menopause, who are supplemented with elemental calcium alone - the most natural first-line intervention - are, on average, losing bone mass. So, if a patient wants to adhere to this natural regimen, she must be monitored closely.
Progestins also play a role in bone health, and conventional wisdom is that the main objective for adding progestin to hormone replacement therapy is to protect the endometrium. But can progestins impact bone metabolism? Studies have shown that 20-30 milligrams of MPA have elicited a bone effect by suppressing bone resorption markers, although other studies have required 100 milligrams of MPA to achieve the same effect. However, in the 3-year long Post-menopausal Estrogen/Progestin Intervention (PEPI) trial, a large randomized, calcium-controlled group did not demonstrate any progestin bone effect whether MPA or micronized progesterone were used continuously or cyclicly with conjugated estrogens.
When bone remodeling becomes very active in the menopause with estrogen withdrawal, there is a greater increase in resorption than forma- tion, resulting in a net loss of bone. Because bone has both estrogen and androgen receptors, the progestins derived from androgens, such as norethindrone, may improve bone mineral density. In fact, norethindrone has been shown in some studies to uncouple bone formation from absorption, and actually increase formation of new bone. However, definitive data are lacking.
Norethindrone, alone, has been shown to prevent bone loss in leuprolide acetate and other GnRH-agonist-induced menopause and appears to act synergistically with estrogen replacement as well. In the 2-year long Continuous Hormones As Replacement Therapy (CHART study), one milligram of norethindrone added to either 5 or 10 micrograms of ethinyl estradiol improved bone mineral density by an additional 3-4%, demonstrating that estrogens and certain progestins may give additive benefit to bone mineral density.
There are also differences between combination therapies, as seen in the international EPIC study that included both European and American participants. The European women used norethindrone acetate as a progestin, and had significantly greater BMD than the American users of conjugated estrogen and MPA. However, it is important to note that norethindrone acetate and MPA were not compared directly in the same study. A large observational study from Sweden has demonstrated hip fracture prevention in women using estrogens and mostly 19-norsteroids as progestin therapy. One could therefore assume that the BMD changes seen in prospective studies translate into fracture prevention.
Because there are few randomized trials confirming estrogen's benefits on fracture prevention, the Osteoporosis Research Advisory Group (ORAG) group convened and studied 57 published randomized trials and confirmed that there is 50% reduction in vertebral and nonvertebral fractures with estrogen and progestin users.
"It is important to screen the menopausal population for bone mineral density," Dr. Portman emphasized, "and encourage preventive therapies such as HRT as well as new available alternatives."
Individualizing Treatment Options for Menopausal Women
"The physician's role should be to facilitate the menopausal patient's wishes for symptom control and long-term disease prevention," said Nanette F. Santoro, MD, Pro-fessor and Director, Division of Reproductive Endocrinology, Albert Einstein College of Medicine, Bronx, NY. "Frequently, these discussions are best held sequentially, since a woman will often present first with symptoms, requesting relief, and secondarily with questions concerning the long-term safety and effectiveness of hormone replacement therapy (HRT) in disease prevention."
Symptoms should be prioritized, and approached one by one. Some, like hot flashes, are readily amenable to HRT and have few alternatives, noting that it takes about 8-12 weeks to get maximum effect. Other symptoms, such as vaginal dryness, can be treated with HRT in combination with local estrogen therapy or nonhormonal lubricants. However, sleep and mood shifts may be related in part to the changing hormonal milieu and be totally resolved with replacement.
"When approaching the symptomatic patient," added Santoro, "it is helpful to point out that HRT usage for 5 years or less carries little known risk. In addition, with the large variety of HRT regimens available, most patients can find one that is convenient and relatively side-effect free."
The risks of long-term HRT emerge as more dominant factors in the decision-making process. While current HRT has been convincingly associated with increased risk of deep vein thrombosis and gall bladder disease, other long-term risks, such as breast cancer, remain to be well defined. The long-term preventive benefit of HRT in delaying the onset of coronary heart disease, as well as Alzheimer's disease, remains to be proven in randomized clinical trials. However, to the extent that there is even a small influence of HRT in preventing heart disease, it makes a major impact on the overall risk-benefit equation for the average woman.
In order to determine if a patient is at excess risk for disease and to help her make decisions about HRT choices, it is necessary to conduct an adequate risk assessment. Both the Gail Breast Cancer Risk Assessment Model and the Col Algorithm for HRT Use are extremely helpful office tools to assist in establishing a patient's personal risk profile. For instance, if a patient has very high systolic blood pressures, left ventricular hypertrophy, and thus is at high cardiac risk, she is probably likely to benefit from HRT. A woman who is exceptionally dyslipidemic may do well with a statin drug, with or without HRT, depending on clinical judgment. Women who are at higher risk for breast cancer may be better candidates long term for a selective estrogen receptor modulator (SERM), as might someone at very high fracture risk. In contrast, women at low or very low fracture risk, with minimal degrees of cardiovascular risk, may not need HRT at all. Santoro observed that many women are pleasantly surprised by the relatively small risks associated with HRT in their particular profile.
A combined approach to patient management that takes into account her short- and long-term objectives and prepares her overall for a healthy lifestyle is likely to be the most successful. Only a minority of women choose a long-term preventive model, but for those who do, it is important to make it convenient for them. The symptom treatment for many women will be short term, but be adaptable. "Clinicians must keep in mind that a woman's goals may change throughout menopause," concluded Santoro. "Treatment needs to be tailored to the individual and, with time and thought, many of the regimens can be customized."
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