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Obstetrics and Gynecology Clinics
Volume 27 • Number 3 • September 2000
Copyright © 2000 W. B. Saunders Company
HORMONE REPLACEMENT FOR THE NEW MILLENNIUM
Margery Gass MD
Robert Rebar MD
Department of Obstetrics and Gynecology, The University of Cincinnati College of Medicine, Cincinnati, Ohio
Research in the area of menopause has greatly expanded in recent years. Topics of investigation include estrogen and progestin therapy, selective estrogen receptor modulators (SERMs), androgen supplementation, quality of life, cognitive function, and the role of complementary and alternative medicine. Major health concerns associated with aging, such as osteoporosis and cardiovascular disease, are being studied because of their potential relationship to decreased estrogen levels. This article reviews recent advances and trends in hormone replacement therapy (HRT).
PERIMENOPAUSE
Menopause is permanent amenorrhea resulting from the cessation of follicular development and the consequent decrease in ovarian estrogen and progesterone production. The years immediately preceding and following the actual cessation of menstruation have been called the perimenopause. Clinically, the several years leading up to menopause may be more challenging to a woman than the postmenopausal state. The erratic hormone levels may be associated with unpredictable menses, labile mood, anxiety, insomnia, breast tenderness, intermittent bouts of hot flushes, sleep disruption, and the exacerbation of migraine headaches.
Women may begin to experience hot flushes well before actual menopause when estrogen levels occasionally drop below the threshold necessary to prevent them. Hot flushes and poor sleep quality 1 to 2 days before and during the menses are frequently reported in the perimenopause because estrogen levels are lowest at that time. Women may become amenorrheic and have estrogen and follicle-stimulating hormone (FSH) levels in the menopausal range only to return to premenopausal function with resumption of normal menstrual cycling. Although FSH levels are useful to fertility specialists in considering the probability of pregnancy, they are not useful in predicting prospectively the timing of the last menstrual period.
Several options now exist for women having difficulty during the perimenopause. In the past, clinicians often resorted to initiating HRT before menopause in women who were highly symptomatic with hot flushes. HRT successfully alleviates hot flushes but may not always provide cycle control at a time in life when irregular cycles are common. Low-dose oral contraceptives can be an excellent choice for regulating irregular or heavy bleeding unrelated to other causes. Hot flushes and mood lability frequently improve as well. Awareness of the safety of low-dose oral contraceptives in this age group has gradually increased. Reports of the low incidence of cardiovascular events in nonsmoking women aged more than 35 years who take oral contraceptives have challenged the adage that these agents should not be used in the older woman. Such women should be normotensive; should be nonsmokers; and have a negative history for venous thromboembolic disease, hypertriglyceridemia, or liver disease.
The additional benefit of using oral contraceptives for perimenopausal symptoms is that the medication provides contraception. This contraceptive benefit is especially important for women in this age group because they have the highest unplanned pregnancy rate among women aged more than 20 years. For perimenopausal women using oral contraceptives, the question becomes when to discontinue their use because withdrawal bleeding can occur indefinitely and obscure the occurrence of menopause. Determining when a patient becomes menopausal while taking oral contraceptives can be a challenge. The woman can be instructed to call her physician when she is routinely experiencing hot flushes the week she is taking the placebo pills in the package. In the absence of hot flushes, a FSH level can be obtained at the end of the week of placebo pills starting at age 50 to 51 years. A level greater than 30 IU/mL indicates menopausal status. The higher the level, the more convincing the result; however, neither method is foolproof. The oral contraceptive may continue to suppress FSH even in the presence of low endogenous estradiol levels. There is little published information documenting the validity of this approach, and it may become expensive to measure FSH levels on several occasions; consequently, some clinicians merely stop the oral contraceptives at an arbitrary age such as 52 or 55 years and warn patients of a very low risk of pregnancy. Such a decision may depend on how important it is for an individual woman to avoid any possibility of pregnancy. One year without menses is still the safest guideline despite the fact that fecundity after age 50 years is very low. Even though the spontaneous abortion rate over the age of 40 years approaches 50%, most women do not want to risk the possibility of pregnancy at that age.
The real difficulty in treating perimenopausal women stems from how little is understood about the causes of menopause or the changes associated with menopause. The Study of Women's Health across the Nation (SWAN) sponsored by the National Institutes of Health is intended to characterize the changes occurring during the perimenopausal years so that future studies can investigate the causes and the best approaches to therapy. As an example, it remains unclear why some women are symptomatic (e.g., sustaining hot flushes) at this time in life, whereas others are not.
ESTROGEN AND EARLY MENOPAUSAL SYMPTOMS
Once a woman is menopausal, it is appropriate to consider hormone replacement. Contraindications include a history of an estrogen-dependent cancer, venous thromboembolic events, uncontrolled hypertension, and active liver disease. Relative contraindications, such as endometriosis, leiomyomata, and atypical cells on breast biopsy, merit a discussion of the low but potential risk of exacerbating these conditions. The woman should weigh these risks against the benefit she desires to obtain.
For the classic menopausal symptoms of hot flushes and vaginal dryness, estrogen is the most effective treatment. In fact, only estrogen reliably eliminates hot flushes. Once the mechanism behind hot flushes is understood, other effective therapies may be developed. A wide variety of estrogen regimens are available. With various modes of delivery and a range of doses, it is usually possible to find a regimen that will be acceptable to the woman. The new vaginal ring provides long-lasting delivery of a low dose of estradiol directly to the vaginal mucosa. The dose of 7 mug/day does not raise serum estradiol levels above the menopausal range. The estradiol-containing ring improves the maturation index and symptoms of vaginal dryness without necessitating use of a progestin but will not improve hot flushes. Low doses of estrogen cream administered vaginally would probably serve the same purpose, but the exact dose that would provide the benefit without stimulating the endometrium has not been clearly established. Standard vaginal cream doses, the equivalent of 1 g of conjugated estrogens, are no different from oral estrogen use in that a progestin is required to protect the endometrium from the higher systemic levels of estrogen that ensue. This dose of unopposed estrogen can cause endometrial hyperplasia and adenocarcinoma when used long term. Estrogens are actually absorbed better through the vaginal mucosa than through the gastrointestinal tract.
In addition to the creams, the estradiol-containing ring, and oral estrogens, a variety of transdermal patches are available. The dose of estradiol in patches ranges from 0.025 to 0.1 mg. Some patches are changed once a week and others twice a week. Until recently, these patches have had greater appeal to the woman who had a hysterectomy and did not have to take an oral progestogen along with transdermal estrogen. The advent of combination patches that contain estrogen and progestogen has increased their convenience for the woman who needs both hormones.
Continuous dosing is another option that is attractive to some patients. For many women, continuous dosing of the estrogen and progestogen eliminates cyclic bleeding; however, there is a high incidence of breakthrough bleeding during the first year on this method. Only 60% of women achieve amenorrhea by the end of the first year. [3] Evidence suggests that the further one is from menopause, the greater the likelihood of amenorrhea. [39]
The continuous dosing regimen is especially beneficial for women with a history of menstrual migraines. Eliminating the fluctuations in hormone levels can reduce the number of migraine headaches a woman experiences. [5] [29] Other methods of reducing or eliminating withdrawal bleeding include reducing the dose of estrogen or administering the progestogen less frequently than monthly. Administering progestogen every 3 months may result in heavier, longer withdrawal bleeding, with more breakthrough bleeding when compared with the effects of monthly progestogen. [14] Long-term safety data on this method are being gathered.
ANDROGENS
Decreased libido is a common complaint at menopause. Sexual function is a complex issue wherein many factors interact. The practitioner must rule out other causes of sexual dysfunction before attributing the problem to declining testosterone levels. Common causes of sexual dysfunction include relationship dissatisfaction, depression, self-image problems associated with aging or weight gain, and use of the following medications:
Selective serotonin reuptake inhibitors
Tricyclic antidepressants
Antihypertensives (especially alpha-methyldopa and reserpine)
Antipsychotics
Thiazide diuretics
Fenfluramine
Metronidazole
Naproxen
Phenytoin
Digoxin
Less is known about sexual dysfunction in women taking medications because the dysfunction may not be so obvious as it is in men. Nonetheless, if no apparent cause of sexual dysfunction is identified, testosterone supplementation can be considered. Women who have undergone bilateral oophorectomy experience a 50% reduction in circulating testosterone levels. It is not mandatory that testosterone levels be measured before supplementing with low-dose testosterone; however, a lipid profile may be in order because of the potential adverse effect on the lipid profile. Relative contraindications to using testosterone include liver disease or an unfavorable lipid profile, especially a very low high-density lipoprotein (HDL) level, because methyltestosterone could decrease the HDL further. Methyltestosterone given orally and in combination with esterified estrogens has been found to decrease triglyceride levels. [40] Methyltestosterone counters the beneficial effect of estrogen on HDL and the adverse effects of estrogen on triglycerides.
Although the data on testosterone and sexual function in women are limited, reports suggest a correlation between levels of free testosterone and libido, [4] [18] as well as improvement in sense of well-being and sexual fantasy. [37] The wide variety of choices available for estrogen supplementation do not exist for testosterone. The oral preparation approved by the Food and Drug Administration (FDA) is an esterified estrogen/methyltestosterone combination available in two doses. Even the low-dose preparation probably provides more androgen than is usually present in premenopausal women. Testosterone creams are available from compounding pharmacies; however, few data are available regarding serum levels produced by the different doses. Further research is needed, and new products are under investigation.
ALTERNATIVES TO HORMONE REPLACEMENT THERAPY
Some women are philosophically opposed to HRT. They view menopause as a natural phenomenon and prefer to use supplemental therapies that they consider natural. Other women turn to these therapies because they have a medical history that precludes HRT. Still other women try HRT but are unwilling to endure the side effects. Many alternatives are available. The most simple approach is to live a healthy lifestyle through nutritious food, a balanced exercise program, and elimination of unhealthy behaviors such as smoking.
Many individuals in the United States are going beyond a healthy lifestyle in their search for good health. An increasing number of men and women are turning to megavitamins, expensive vitamins, massage therapy, homeopathy, self-help groups, energy healing, therapeutic touch, and herbal remedies. In 1990, 33% of Americans had used 1 of 16 different alternative therapies. That figure rose to 42.1% in 1997. Out-of-pocket expenditures related to these therapies were estimated at $27 billion, an amount thought to be equivalent to the out-of-pocket expenditures for physician services in the same year. [10] Although a discussion of all of these alternative therapies as they relate to menopause is beyond the scope of this article, a few comments about herbal supplements are in order because of the phytoestrogens contained in many plants.
Despite the absence of supporting data, many women view herbal supplements as a safe and natural way to obtain an estrogenic effect. Plants contain phenolic phytoestrogens that are similar in molecular structure to steroidal estrogens and have potencies 1/50 to 1/20,000 that of estradiol. There are many different kinds of phytoestrogens (e.g., flavones, flavanones, flavonols, lignans, and isoflavones). Most plants contain several types of phytoestrogens, but some plants contain only one type. Isoflavones seem to be the most potent in terms of estrogenic activity. They are common in legumes such as soy, lentils, chickpeas, and beans. Among the stronger isoflavones are genistein and daidzein, both of which are found in soy.
Soy has been the subject of numerous studies because it is consumed in large quantities by cultures that have less cardiovascular disease and less breast, prostate, and lung cancer than populations in which less soy is consumed. A meta-analysis of the effects of soy on lipoproteins concluded that soy produced a significant decrease in total cholesterol, low-density lipoprotein (LDL), and triglycerides. [2] The authors have recently reported that 60 mg of isoflavone decreases total cholesterol and the oxidation of LDL-cholesterol when consumed daily for 3 months. [34] Soy has been reported to decrease hot flushes, [1] but the effect is only modest. An inverse association between soy intake and breast cancer has been suggested in observational studies in premenopausal women. [23] [25] These findings are consistent with the possibility that some phytoestrogens may act similarly to SERMs.
None of the phytoestrogens has been subjected to the large and extensive studies performed on estrogens. The effects of phytoestrogens on the uterus and breast have not been well documented. These products may provide a convenient alternative to HRT; however, more data are required in this age of evidence-based medicine.
Some herbal preparations, such as dong quai, also have been used for hot flushes with less documentation. One controlled prospective study found no significant benefit. [21] Black cohosh and red clover have been marketed extensively for menopausal symptoms, but some of these preparations may actually contain harmful substances.
LONG-TERM HEALTH CONCERNS
Menopause and aging are intertwined so tightly that it is often difficult to determine which physiologic processes are predominantly related to menopause. The early sequelae of menopause, such as vasomotor symptoms and vaginal atrophy, are undoubtedly related to a sharp decline in estrogen. Other conditions, such as osteoporosis, are not solely under the control of estrogen but seem to be accelerated by the reduced levels of estrogen that occur at menopause.
Osteoporosis
Substantial evidence supports the correlation of low estrogen levels with bone loss. Although men and women lose bone with aging, for women, there is a more rapid phase of bone loss in the years immediately following menopause. The rapid loss that occurs preferentially in trabecular bone can be arrested by estrogen therapy.
For many years, it has been widely accepted that the minimum effective dose for preventing bone loss is 0.625 mg of conjugated estrogens or the equivalent in other estrogen products. [27] A growing body of evidence now suggests that lower doses of estrogen may be adequate for many women. Oral estradiol, 0.5 mg; transdermal estradiol, 0.025 mg; esterified estrogens, 0.3 mg; and conjugated estrogens, 0.3 mg, have been found to halt bone loss. [12] [16] [19] [33] One small study using an estradiol vaginal ring that did not raise systemic estrogen levels above the menopausal range reported a 2.1% increase in bone mineral density (BMD) of the forearm compared with a 2.7% loss in nonusers. [30] It is possible that, in the very elderly, a small increase in estrogen could produce a benefit in bone density, whereas the same small dose would not be so effective during the rapid bone loss phase of early menopause.
Lower doses of estrogen for bone protection have the potential benefit of reducing adverse side effects, a feature that can be crucial to estrogen compliance. Continuation rates for HRT are conspicuously low. It is estimated that as few as one third of the women who begin HRT continue it long-term. [32] A higher compliance rate was found for the 0.3-mg dose in a study comparing three different doses of esterified estrogens. [31]
In addition to fewer side effects with lower doses, the safety of using estrogens may be enhanced. Conjugated estrogens and esterified estrogens have been shown to have a greater adverse effect on triglycerides with higher oral doses. [19] [41] Pancreatitis resulting from hypertriglyceridemia apparently induced by oral estrogen has been reported. [20] In the esterified estrogen study, the 0.3-mg dose did not produce a significant increase in triglycerides. Caution should be exercised when prescribing estrogen for a woman who has hypertriglyceridemia. Despite the negligible effect on triglycerides, it is unknown whether these low doses of estrogens are cardioprotective, and studies examining this question need to be conducted.
Endometrial safety is another issue related to dose. Many studies have confirmed a dose-dependent occurrence of hyperplasia. Although the use of a progestogen will usually offset the risk of cancer, a lower dose of estrogen may increase the margin of safety. In one study, the incidence of hyperplasia after 2 years in women receiving 0.3 mg of unopposed esterified estrogens was no different from the incidence in women taking placebo. [31]
Questions often arise regarding (1) how long one should take estrogen for bone protection or (2) how late one can start estrogen and still obtain benefit. Studies show that once a woman stops HRT, bone loss accelerates, and BMD rapidly falls to the level of a peer group who never used HRT. [13] These observational data suggest that a woman may need to use HRT indefinitely to maintain bone density.
Observational data indicate that women may be able to start HRT 10 years after menopause and achieve a BMD almost equal to women using HRT continuously since menopause. [13] [35] This observation is good news for the woman who has no symptoms at menopause and is not interested in using HRT and for the woman who is concerned about breast cancer and wants to minimize that risk by not using HRT. Both groups of women can reconsider their decision at 60 to 65 years of age and, if they elect to begin HRT, can still obtain significant benefit. Studies using HRT in the very elderly population indicate that improvement in BMD can be achieved in that age group. [33] The amounts of estrogen mentioned earlier may be beneficial, and the lower doses may be better tolerated. Many elderly women are not willing to accept uterine bleeding or breast tenderness, and these side effects may be reduced with lower doses of estrogen.
For women who cannot or will not use HRT, there are several other options for preventing and treating osteoporosis. The bisphosphonate alendronate has been shown to increase BMD and reduce the risk of fractures at the spine and hip. [26] Side effects are generally minimal, but the patient needs to be willing to adhere to a strict dosing regimen that requires taking the medication on arising in the morning on an empty stomach with a full glass of water. She must not eat or drink anything else for one-half hour and not recline or lie back down. Because the one serious side effect with this medication is esophageal irritation or ulceration, patients who already have significant gastroesophageal reflux disease may not be good candidates for this treatment option. Other bisphosphonates are available outside the United States, and additional agents are being developed. A second bisphosphonate, risechonate, was approved by the FDA in April 2000.
Calcitonin presents a third option for the treatment of osteoporosis. This medication has shown BMD improvement and vertebral fraction reduction. [28] It is recommended for women who will not be using HRT and who are at least 5 years beyond menopause. The nasal spray formulation is easy to use.
The newest drugs approved by the FDA for the prevention of osteoporosis are SERMs. These agents have the unique feature of functioning as estrogen agonists at some sites in the body and estrogen antagonists at other sites. SERMs already on the market for other purposes include tamoxifen and clomiphene citrate. Different SERMs and estrogens bind with different affinities to the two identified estrogen receptors.
The one SERM approved for the prevention of osteoporosis is raloxifene. This drug produces an increase in BMD and has a mildly beneficial effect on the lipid profile. The reports on fracture prevention suggest a 30% to 50% reduction in vertebral fractures. [11] Unlike estrogen, raloxifene does not seem to stimulate the breast or the uterus. One study indicated a 76% reduction in the incidence of invasive breast cancers in raloxifene users when compared with a placebo group, [7] making it an attractive alternative for women concerned about breast cancer.
Raloxifene will not alleviate hot flushes or vaginal dryness. This feature makes it a less attractive option for newly menopausal women who are symptomatic. Side effects associated with the drug include leg cramps and venous thromboembolic events. The latter are no more common with raloxifene than they are with estrogen, with approximately a three to four fold increase over the background rate of venous thromboembolic events. A personal history of a venous thromboembolic event is a contraindication to the use of this drug.
No matter what therapy is used for osteoporosis, adequate calcium and vitamin D are essential. Standard recommendations are 1000 mg/day of elemental calcium for the woman using estrogen and 1500 mg/day of elemental calcium for the woman not using HRT. The recommended adequate intake for vitamin D is 400 IU/day. The Food and Nutrition Board uses the term adequate intake for calcium and vitamin D instead of recommended daily allowance because it is thought that there are not enough data to use the stronger recommendation.
Studies indicate that many people over 65 years old in the United States are vitamin D deficient. [9] [38] Furthermore, it has been shown that postmenopausal women with a hip fracture are more likely to have occult vitamin D deficiency than their peers without a hip fracture. [24] The skin does not process vitamin D efficiently in the older person. In addition, the elderly may not spend as much time in the sun. For these reasons, it has been recommended that persons aged more than 65 years take an oral supplement of 600 IU of vitamin D per day. Vitamin D and calcium supplementation has been shown to have beneficial effects even without the use of other drugs, with two studies reporting a decrease in fractures in an elderly population given vitamin D and calcium supplements. [6] [8]
All of these treatments for osteoporosis have produced varying degrees of improvement in bone density and a reduction in fracture rate. The reduction in fracture does not always correlate with the amount of improvement in bone density.
Regardless of whether a woman uses HRT or any of the other osteoporosis treatment options, she needs to maintain a healthy lifestyle that includes adequate calcium, vitamin D, and exercise. Exercise is essential for preserving muscle tone and balance, both of which are thought to be important for preventing the falls that are responsible for most fractures. The role of gonadal steroids in maintaining muscle mass in postmenopausal women has not been well studied.
Cardiovascular Effects: no benefits; see WHI study (section on this and on cognitive function edited out from original article, since new studies have shown either increased risk (heart attacks and strokes) or no benefits (cognitive function)
CONCLUSIONS
It is likely that the treatment offered to postmenopausal women in the years ahead will continue to evolve. Because there seems to be no increased risk of breast cancer with use of estrogen replacement therapy for less than 5 years, various drugs may be offered at different times in the life of an individual. An estrogen may be offered in the perimenopausal years to alleviate symptoms, followed by a SERM, a "statin" together with a bisphosphonate for women with hypercholesterolemia, or a healthy lifestyle alone. Based on current knowledge, individualization is clearly required.
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