Part IV, Chapter 2: Hormone Replacement Therapy - Weighing the Benefits and Risks

By Leslie Shimp, Pharm.D., M.S. Associate Professor of Pharmacy, College of Pharmacy, University of Michigan Consultant pharmacist, Department of Family Practice, Medical School, University of Michigan

This article is excerpted from two articles originally published in The Rx Consultant, Vol. VI, No. 9 and Vol. VI, No. 11 (Copyright 1997, Continuing Education Network, Inc.) and is reprinted with permission. To receive a complimentary, full text copy of Vol. VI, No. 9, "Menopause and Hormone Replacement Therapy," call 1-800-798-3353.

Overview

In the United States today there are about 40 million women who are postmenopausal; every year another 3.5 million women reach the age of menopause. With an average life span of 81 years, women live about one-third of their lives after menopause occurs. The estrogen deficiency of menopause causes early symptoms such as hot flashes, irregular menstrual cycles, sleep disturbances, vaginal dryness and urinary incontinence. Long-term consequences of estrogen deficiency include an increased risk for heart disease and osteoporosis.

"Should I take estrogen at menopause?"

Every year millions of women ask this question, only to lean there is no simple yes or no answer. Hormone replacement therapy (HRT), which is a combination of estrogen and progestin therapy, can have both positive and negative consequences, and many women are confused about the potential benefits and risks.

One reason for this confusion is the lack of accurate information about HRT. A study of female college graduates found that most did know HRT could reduce the risk of heart disease and osteoporosis, and increase the risk of breast cancer. However, twice as many women were worried about breast cancer as were worried about heart disease. For most of these women, the relative lack of concern about heart disease is in sharp contrast to the facts. Only 1 % of the women described themselves as being at risk for heart disease, when in reality 20% develop it by the age of 70.¹ The result of confusion about the benefits and risks of estrogen replacement is that few women opt to use it. Even though the benefits are widely publicized, only 15-25% of American women start HRT, and even fewer continue it long-term.²

The decision to use HRT is a personal one, in which each woman must weigh her potential benefits against the possible risks. An abundance of ongoing research in this area further complicates the decision for many women.

This article discusses what is currently known about the benefits of HRT for early menopausal symptoms, heart disease and osteoporosis. Intriguing preliminary data about the role of estrogen in Alzheimer's disease is included. We then present up-to-date information on the major risks of HRT: breast cancer and endometrial cancer.

What do we know about the positive long-term effects of HRT?

Current information suggests that many postmenopausal women benefit from therapy. One study has shown a 40% reduction in death from all causes among women who had taken estrogen for 15 or more years.⁴ However, data from population studies cannot be directly applied to the individual.

What should a woman consider when deciding for or against HRT?

In deciding about hormone use, each woman should consider her own risk for heart disease, osteoporosis and breast cancer. Clarifying the goal(s) of therapy also helps. For example, if the goal is to relieve menopausal symptoms

like hot flashes, HRT will be short-term, and breast cancer can be largely disregarded as a concern. However, if hormone replacement is being considered for prevention of heart disease or bone fractures, therapy must be long-term, md the risk of breast cancer is greater.

Can HRT prolong life?

In general, current evidence suggests that most women will live longer with HRT. It has been estimated that less than 1% of healthy perimenopausal women would not benefit from HRT.³

Do some women have more to gain from HRT than others?

Women who have had a hysterectomy and those who are at risk for heart disease are most likely to benefit from HRT. Women who are at low risk for heart disease but have an increased risk for breast cancer are poor candidates for HKT. However, most women do not fit into these categories, and the benefits/risks are less clear.

How can a woman get additional information about HRT?

Reliable information can be obtained from several books and a variety of organizations. Telephone numbers and internet addresses of organizations that provide useful information are listed in the inset on page 37. Additionally, two texts diat may be useful for pharmacists, as well as for individuals, are:

• Dr. Susan Love's Hormone Book (Susan Love, M.D., Random House, New York, 1997)
  
  
• A Woman Doctor's Guide to Hormone Therapy: How to Choose What is Right for You (Nananda Col, M.D., Tatnucic Booksellers Press, 1997)

Symptoms and Consequences of Menopause

A decline in circulating levels of estrogen is associated with the classic symptoms of menopause: disturbances of menstrual pattern, hot flashes/hot flushes, sleep disturbances, psychological symptoms and atrophy of the urinary and genital tracts. Hot flashes occur in up to 75-85% of U.S. women and commonly persist for 2-5 years.^5,6 Urogenital atrophy is a common result of estrogen deficiency which eventually affects most women. Symptoms of vaginal atrophy include vaginal dryness, itching and burning, and discomfort with sexual intercourse. Atrophy of the urinary tract may lead to urinary urgency and stress incontinence. The two conditions associated with a decline in circulating estrogen which have the greatest impact on women's health are osteoporosis and coronary heart disease. Over 90% of people with osteoporosis are post-menopausal women. It is estimated that 25-44% of women experience osteoporotic bone fractures after menopause. Cardiovascular disease is the leading cause of death for women in the United States, and the incidence of cardiovascular disease increases markedly after menopause. Over 53% of postmenopausal women will die of cardiovascular disease.⁷

Hormone Replacement Therapy

The primary benefits of postmenopausal hormone therapy are derived from estrogen (estrogen replacement therapy, or ERT). Estrogen is the hormone associated with the relief of menopausal symptoms, increased bone density, and reduction in me risk for heart disease. A progestin is added to protect against the increased risk of endometrial cancer caused by the use of estrogen alone in women with a uterus. The combination of estrogen and progestin is what is referred to as HRT. Progestin therapy is not necessary if a woman has had a hysterectomy.

Therapeutic Uses

Disturbances in Menstrual Patterns

Perimenopausal irregularities in menses may sometimes be managed with oral contraceptives^8,9 or intermittent regimens of a progestin (e.g., medroxyprogesterune acetate).

Hot Flashes/Hot Flushes

Estrogen is effective for the treatment of hot flashes, with a 95% success rate after 3-4 weeks of therapy.⁵ If hot flushes during the night and sleep disturbances occur, estrogen therapy will decrease night sweats and increase REM sleep. Usually, a daily dose of 0.625 mg of conjugated equine estrogen (CEE) will alleviate hot flashes; occasionally a higher dose may be required.^{10, 11} If estrogen is contraindicated, progestin therapy may be used. Both oral (10-20 mg/day) and depo (50-150 mg/month) medroxyprogesterone acetate (MPA) and oral megestrol acetate (40 mg/day) have been effective.

Clonidine has been used as a nonhormonal therapy for hot flashes. Both oral and transdermal dosage forms have been used, usually in doses of 0.1-0.2 mg/day. Some information suggests that doses above 0.1 mg/day are necessary.¹² The effectiveness of clonidine is controversial, and, at best, a modest improvement in the frequency or severity of hot flashes. Clonidine is less effective than either estrogen or a progestin. Transdermal therapy is likely to be better tolerated than oral therapy.¹³ There is little evidence to support the use of Bellergal™ (phenobarbital, ergotamine and belladonna alkaloids), an agent with many potential adverse effects.¹²

Recently, plant estrogen sources (phytoestrogens or isoflavones) have become popular as a way of managing hot flashes. Many plants, such as citrus fruits, grapes, and red clover sprouts contain phytoestrogens but in unknown and generally small quantities. The two food products most advocated as dietary sources of estrogen are soy products (tofu, soy flour, soy milk, soy beans) and flaxseed; a recipe book utilizing these products is available.¹⁴ Although these plants may be useful for managing hot flashes, it is unclear if any of estrogen's other benefits will be gained by ingesting phytoestrogens. Additionally, while phytoestrogens might stimulate the endometrium, increasing a woman's risk for endometrial cancer, it has been suggested that soy products offer some protection against breast cancer.¹⁴

Cognitive Symptoms and Dementia

Evidence is accumulating that changes in estrogen levels with menopause may affect cognitive function. Estrogen has been found to promote the growth and survival of cholinergic neurons,^15,16 promote regeneration or repair of damaged neurons,^{15, 17} increase cerebral glucose utilization,¹⁸ prevent amyloid deposition,¹⁶ increase cerebral blood flow,^{17, 18} and increase cholinergic function.¹⁹ The cholinergic system, including the neurotransmitter acetylcholine, is the most important system for memory and cognitive functions. Studies comparing the performance of postmenopausal women using estrogen to nonusers found that users performed better on some tests, such as those of verbal memory, conceptualization, and the capacity for learning new information.^{20 22} Other mental functions (e.g., visual memory) were not affected by estrogen use.²¹ The effects of estrogen were modest, and there is no evidence that women who do not take estrogen are “impaired” to the extent that daily functioning is affected.¹⁵

Women make up the majority of persons with Alzheimer's disease.^{18, 23} It is hypothesized that the decrease in estrogen with menopause may increase a woman's risk for dementia.^{17, 18, 24} Several effects of estrogen within the brain may prevent or delay the onset of dementia.^{16, 18} Aside from familial Alzheimer's disease, dementia is uncommon in the first two decades after menopause, but by the third decade up to half of women have some clinical signs of dementia.¹⁵ Two studies suggest that the risk of Alzheimer's disease is lower (by 30% in one study and 60% in the other) among estrogen users than nonusers.^{16, 24} In addition, several small studies of patients with Alzheimer's disease have shown that estrogen therapy improves cognitive test scores and cognitive function in some patients.^{25, 26} While the information accumulated to date is intriguing, it is also limited. Further study is necessary to determine whether estrogen protects against dementia or is useful for persons with dementia.

Urogenital Atrophy

In general, the vaginal and urinary symptoms of menopause are very responsive to estrogen therapy, improving 50-70%.⁵ The dosage of estrogen required to treat these symptoms is usually less than that required for the management of hot flashes. Therapy can be either oral (0.3-0.625 mg CEE) or vaginal (cream or vaginal ring). Topical therapy with a vaginal cream is initiated with daily application for 4 to 8 weeks, then tapered to several times per week or just several rimes per month. In many cases, women can stop therapy after six months. A progestin is generally not prescribed with intermittent use of estrogen cream. If use is more frequent or continued long term, a progestin should be added for endometrial protection.²⁷ Estring™, a new vaginal delivery system, is inserted into the upper third of the vagina where it remains for 90 days. Minimal systemic absorption occurs with Estring™, and progestin therapy is not required. During the perimenopausal period. when pregnancy protection may still be needed, low dose oral contraceptives may relieve symptoms.⁹

Non-hormonal therapy for uro-genital symptoms also exists. Vaginal lubricants (e.g.. GyneMoistrin™, Replens™) can be used to manage dryness and/or discomfort with sexual intercourse. The initial dosage of lubricant is two table-spoonfuls inserted vaginally, then the application frequency and quantity can be adjusted according to patient needs. Pelvic floor exercises may be useful for the management of urinary incontinence.²⁸

Osteoporosis

Estrogen therapy reduces the risk of osteoporosis and related fractures. The risk for spinal fractures is reduced 50%, and the risk for fractures of the hip and forearm is reduced 25%.⁷ Estrogen prevents bone loss, primarily by suppressing bone resorption. In women with osteoporosis, this allows bone building cells to "catch up" with bone resorbing cells, and bone mineral density increases by 5-10%.

Bone loss occurs as a result of aging, and there is also an accelerated phase of bone loss at the time of menopause. Estrogen is the only agent which has been documented to protect against the accelerated phase of bone loss.^{29, 30} The effect of estrogen on bone resorption is lost if therapy is stopped. Women who stop taking estrogen within several years of menopause may revert to a hip fracture risk similar to that of women who never took postmenopausal estrogen.⁷ The majority of bone fractures occur in women over the age of 80, and most hip fractures occur very late in life. In order to sustain a bone protective effect into late life, at least 7 years of postmenopausal estrogen therapy is required.³¹Optimal protection of bone occurs when estrogen is started at the time of menopause and continued long-term.

However, even if estrogen therapy is started 15 years after menopause, the protection against osteoporosis-related fractures may be very close to that seen for women who began therapy at menopause and continued it into old age.^{31, 32} Bone loss and the beneficial effect of estrogen on bone continue into late life.^{30, 32} Estrogen therapy can be initiated to prevent or treat osteoporosis many years after menopause. In fact, recent data suggest that older women may show a greater response to estrogen in terms of increased bone density than do perimenopausal women.

Any estrogen therapy which achieves adequate circulating levels of estrogen (a serum estradiol level of about 40-60 pg/ml)⁵ will protect against osteoporosis and bone fractures. This requires a daily dose of 0.625 mg CEE or the equivalent. A dose of 0.3 mg partially inhibits bone loss, and a dose of 1.25 mg offers no additional protection. Transdennal therapy (50-100 mcg estradiol) also has protective effects.³⁴ The combination of estrogen and progestin has a similar effect on bone to estrogen taken alone.⁷ While estrogen replacement is considered the mainstay for osteoporosis prevention and treatment, nonhormonal measures also reduce the risk of this disease. These include adequate calcium and vitamin D intake, weight bearing exercise, and avoiding cigarette smoking and excessive alcohol intake. Recently, the FDA approved alen-dronate (Fosamax™), which inhibits bone resorprion, for use as a preventive agent. The dose of alendronate for preventive use is 5 mg per day.

Coronary Heart Disease

Many observational studies have reported a cardio-protective effect from estrogen. It is estimated that estrogen therapy reduces the risk of heart disease 40-50% in postmenopausal women. The greatest benefit appears to be for current users, although some risk reduction persists for at least three years after stopping estrogen therapy.^{35, 36} A recent report from the Nurses Health Study (a large, long term observational study of hormone use) suggests that women with at least one major risk factor for coronary heart disease (CHD) benefit more from estrogen therapy than women with no risk factors.³⁷ Among those at risk for CHD, a 49% decrease in death from all causes was seen, while women at little risk for heart disease had only an 11% reduction in mortality. Women who have diagnosed coronary heart disease and atherosclerosis may have an even more impressive 80% reduction in the risk of further disease or coronary death." Evidence suggests that women with severe CHD are the most likely to benefit from estrogen therapy.^35,38 A recent International Consensus Conference of Postmenopausal Hormone Replacement Therapy and the Cardiovascular System stated that the cardiovascular benefits of estrogen replacement would likely outweigh any risks for most postmenopausal women. This group advocated the use of estrogen therapy for most women, based on the prevalence of cardiovascular disease and death.³⁸

Estrogen has several effects which contribute to its cardioprotective action. The positive effect of estrogen on cholesterol levels—about a 15% decrease in LDL-cholesterol and a 15% increase in HDL-cholesterol—is thought to account for about 50% of its cardioprotective action.³⁹ Other cardioprotective mechanisms involve blood vessels and the heart: increased vasodilation, increased cardiac contractility, decreased accumulation of LDL-C in arteries and increased blood flow.³⁵

The dose of estrogen used in most of the studies demonstrating a reduced risk of heart disease was 0.625-1.25 mg daily.⁷ As a result, the dose currently recommended for cardioprotection is the same as that recommended for the prevention of osteoporosis—0.625 mg CEE/day. The estrogen delivery system and the addition of a progestin to me regimen both have a significant influence on the cardioprotective effects of estrogen. Transdennal estrogen does not appear to be as potent as oral estrogen in improving lipid levels. At this time, there are not enough data to demonstrate a cardioprotective effect from any non-oral estrogen formulation, and they are not recommended for the prevention of CHD.^{37, 38}

Progestins have an adverse effect on lipids—increasing LDL-C and decreasing HDL-C. There is some variation among progestins, with the more androgenic agents having a greater adverse lipid effect. While medroxyproges-terone acetate is the least androgenic of the synthetic progestins, it does decrease HDL-C in common therapeutic doses (e.g., 10 mg).³⁵ In women, HDL-C is more strongly related to heart disease than LDL-C. The concern with adding a progestin to estrogen therapy is that the cardioprotective effects might be diminished or lost. The recent PEPI trial, which compared the effect of estrogen alone and three estrogen-progestin regimens, showed that the addition of MPA reduced, but did not eliminate, the positive effect of estrogen on lipid levels. All hormone regimens decreased LDL-C and increased HDL-C to an extent that should be clinically beneficial.⁴⁰ The Nurses Health Study reported in 1996 that women taking estrogen and progestin had at least as great a reduction in heart disease risk as women taking estrogen alone.³⁶

Estrogen therapy is one of several effective methods recommended to reduce the risk for heart disease. Nonhormonal approaches generally address risk factors such as high blood pressure, undesirable cholesterol levels, cigarette smoking, and obesity. Both drug (antihypertensives, cholesterol lowering agents) and nondrug (dietary changes, exercise) measures can be used, but compliance may be a problem.

Contraindications & Adverse Effects

Contraindications

The potential risks of HRT can range from relatively minor to grave, and based on their medical histories and/or conditions, some women should not use it. The absolute contraindications to postmenopausal estrogen therapy are: estrogenrelated cancers (uterine, breast), undiagnosed abnormal vaginal bleeding, active liver disease or chronic severe liver dysfunction, active thrombophlebitis or thromboembolic disorder, malignant melanoma, and prior complications from estrogen therapy (e.g., cholestatic jaundice, migraine headache).^{41, 42} Additionally, there are clinical situations where the risks from the therapy might outweigh its potential benefits. These include an increased risk for thromboembolic disease (estrogen increases the risk for thromboem-bolism),^{43, 44} a history of gallstones (estrogen reduces the solubility of cholesterol),⁴⁵ conditions aggravated by fluid retention (e.g., congestive heart failure, seizure disorders, asthma),^{45, 46} and active endometriosis and benign uterine tumors (estrogen use inhibits postmenopausal resolution of these conditions).⁴¹

HRT has generally been avoided in women with a history of breast cancer, but an assessment of the effect of estrogen exposure (e.g., pregnancy, oral contraceptive use, HRT use) on prognosis showed that estrogen exposure did not confer a worse prognosis.⁴⁷ The American College of Obstetricians and Gynecologists' Committee on Gynecologic Practice and the Eastern Cooperative Oncology Group have both suggested that estrogen replacement therapy (ERT) may be appropriate for some women previously treated for breast cancer.^{47, 48}

Endometrial Cancer

Endometrial cancer is the third most common cancer among women in the U.S. Unopposed (taken alone) estrogen substantially increases the risk for development of endometrial cancer. Based on the pooled results of 35 studies, the risk of endometrial cancer is 2.3 times greater among women who have used ERT than among those who have never used estrogen.⁷ Women who used ERT for 10 years or longer were almost ten times more likely to develop endometrial cancer than women who never used estrogen. The increased risk also persists for five or more years after stopping estrogen therapy.⁴⁹

The PEPI trial reported that within 3 years, 62% of women on unopposed estrogen developed some type of endometrial hyperplasia, which is considered a possible precursor to endometrial cancer. In contrast, the rate of hyperplasia among women on estrogen/progestin regimens was similar to that in women taking a placebo. ⁵⁰ Therefore, women who take postmenopausal estrogen and have an intact uterus should use it in conjunction with a progestin to avoid the increased-risk for endometrial hyperplasia and' cancer. If a woman cannot tolerate progestins, an annual endometrial biopsy is recommended. If hyperplasia develops, estrogen therapy should be stopped and prolonged progestin therapy administered in an attempt to cause the endometrium to revert to normal. ⁵⁰

Breast Cancer

Breast cancer is the most common cancer in women. A 50 year old white woman has a 10% chance and a 50 year old African American woman a 7% chance of developing breast cancer during the remainder other life. Among women with a mother or sister who has had breast cancer, the risk is increased to about 20%. The median age for breast cancer diagnosis is 69 years.^{4, 7} Prolonged exposure to endogenous estrogen (as may occur in women who begin menstruation at a young age, bear no children, or experience a late menopause) is associated with an increased risk for breast cancer. Thus, it is possible that postmenopausal hormone therapy also increases the risk of breast cancer. Recent studies have shown that long-term users of postmenopausal hormones (>9 years) have a 1.3-1.5 times greater risk of breast cancer than women who do not use HRT. ^{4, 51, 52} In addition, there is some evidence that the combination of estrogen and progestin may increase the risk for breast cancer more than unopposed estrogen.⁴ Short-term therapy (less than 5 years of use) is associated with little increase in risk. Previous use also seems to result in little increase in risk, once therapy has been discontinued for several years.

Common Adverse Effects

Side effects are not uncommon with HRT, but are severe in only 8-14% of women.⁵³ Side effects can often be related to one of the hormones.⁵⁴ Common estrogen-related adverse effects are nausea, breast tenderness, heavy withdrawal bleeding, and headaches. Side effects related to progestins include bloating and mood changes. A decreased libido may result from insufficient androgen. Modification of the hormonal components is the usual technique for managing common adverse effects (see Table 1).

Transdermal patches can cause skin irritation and itching. Rotating the site of patch application helps minimize this problem. If skin irritation occurs, applying the patch to a less sensitive area (e.g., buttocks or thighs rather than abdomen) or air-drying the patch for a minute prior to application may help.⁵⁴ Education about common side effects and the need to adjust therapy can help decrease patient frustration and ensure long-term use. When HRT is stopped, the dosages should be tapered slowly over several months to avoid an increase in menopausal symptoms.⁵⁵

Summary

Postmenopausal hormone therapy has the potential to provide significant health benefits, but those benefits are accompanied by several health risks. It is dear that HRT does not benefit all women to the same extent. In particular, women at low risk for CHD gain less benefit than those at high risk or women with diagnosed CHD. Identifying women for whom the potential benefits exceed the risks is the challenge of ERT/HRT utilization. Risk-benefit assessment must evaluate each woman's health information in conjunction with the data available from observational studies and clinical trials. Pharmacists can help women faced with this decision by explaining the data in the medical literature so that it is meaningful to them. In addition, pharmacists can help women and prescribers tailor therapy in order to minimize side effects. Finally, pharmacists should encourage women to follow the national recommendations for breast cancer screening and discuss any unexpected side effects of HRT, including bleeding, with their prescriber.

References

1. Pilote L, HIatky MA. "Attitudes of women toward hormone therapy and prevention of heart disease." Am Heart J, 1995: 129:1237-38.
   
   
2. Weinstein S. "New attitudes towards menopause." FDA Consumer, 1997(March);26-29.
   
   
3. Col NF, Eckman MH, Karas RH, et al. "Patient-specific decisions about hormone replacement therapy in post-menopausal women." JAMA, 1997: 277:1140-47.
   
   
4. Lindsay R, Bush TL, Grady D, et al. "Therapeutic controversy: estrogen replacement in menopause." - J Clin Endocrinol Metab, 1996: 81:3829-38.
   
   
5. Smith RP. "Menopause (Chapter 12)." Gynecotogy in Primary Care. 1997; Baltimore, William and Wilkins.
   
   
6. Walsh BW, Schiff I. "Menopause and Ovarian Hormone Therapy (Chapter 83)." In: Abrams AJ, et al. eds. Merck Manual of Geriatrics (2nd edition), 1995: Pathway, NJ.
   
   
7. Grady D, et al, "Hormone therapy to prevent disease and prolong life in postmenopausal women." Ann Intern Mod, 1992; 117:1016-37.
   
   
8. Upton GV, et al. "Contraception for the transitional years of women older than 40 years of age." Clin Obstet Gynecol, 1992; 35:855-864.
   
   
9. Bachmann GA. "The changes before the change." Postgrad Med, 1994; 95:113-124.
   
   
10. Lomax P, et al. "Postmenopausal hot flushes and their management." Pharmacol Ther, 1993: 57:347-58.
    
    
11. Ginsberg ES. "Hot flashes - physiology, hormonal therapy and alternative therapies." Obstet Gyneco! Clin North Am, 1994: 21:381-90.
    
    
12. Lucero MA, et al. "Alternatives to estrogen for the treatment of hot flashes." Ann Pharmacother, 1997:31:915-17.
    
    
13. Miller KL. "Alternatives to estrogen for menopausal symptoms," Clin Obstet Gynecol, 1992; 35:884-93.
    
    
14. Shandler N, Estrogen the Natural Way, 1997;Villard Books. New York.
    
    
15. Birge SJ. "Is there a role for estrogen replacement therapy in the prevention and treatment of dementia?" J Am Geriatr Soc. 1996: 44:865-70.
    
    
16. Tang MX, Jacobs D, Stern Y, et al. "Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease." Lancet, 1996; 348(9025):429-32.
    
    
17. Birge SJ- "The role of estrogen in the treatment of Alzheimer's disease." Neurology. 1997: 48(5 suppi 7):S36-41.
    
    
18. Henderson VW. "The epidemiology of estrogen replacement therapy and Alzheimer's disease." Neurology. 1997; 48(5 suppi 7):S27-35.
    
    
19. Kaufman H. Vadasz C, Lajtha A. "Effects of estradiol and dexamethasone on choline acetyltransferase activity in various brain regions," Brain Res, 1988: 453:389-92.
    
    
20. Schmidt R, et al. "Estrogen replacement therapy in older women: a neuropsychological and brain MRI study." J Am GeriatrSoc, 1996; 44:1307-13.
    
    
21. Sherwin BB. "Estrogen effects on cognition in menopausal women." Neurology, 1997; 48(5 suppi 7):s21-26.
    
    
22. Phillips SM, et a). "Effects of estrogen in surgically menopausal women." Psychoneuroendocinology. 1992: 17:485-95.
    
    
23. Filley CM. "Alzheimer's disease in women." Am J Obstet Gynecol, 1997; 176(1 pt1):1-7.
    
    
24. Paganini-Hill A, Henderson VW. "Estrogen deficiency and risk of Alzheimer's disease in women." Am J Epidemiol, 1994: 140:256-61.
    
    
25. Ohkura T, et al. "Long-term estrogen replacement therapy in female patients with dementia of the Alzheimer's type: 7 case reports." Dementia, 1995: 6:99-107.
    
    
26. Filit H, et al. "Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer's type." Psychoneuroendocrinology, 1986: 11:337-45.
    
    
27. DuBeau C, et al- "Urinary Incontinence." Abrams AJ, et al. ed. Merck Manual of Geriatrics (2nd edition) 1995, Pathway, NJ.
    
    
28. Rosenfeld JA. "Menopause (Chapter 21)." In: Rosenfeld JA ed. Women's Health in Primary Care, 1997; Baltimore, William and Wilkins.
    
    
29. Recker RR, et al. "Patient care of osteoporosis." Clin Geriatr Med, 1995: 11:625-40.
    
    
30. Prestwood KM, et al. "Treatment of osteoporosis." Ann Rev Med, 1995: 46:249-56.
    
    
31. Felson DT, et al. "The effect of postmenopausal estrogen therapy on bone density in elderly women." N Engl J Med, 1993: 329:1141-6.
    
    
32. Schneider DL, et al. "Timing of postmenopausal estrogen for optimal bone mineral density: the Rancho Bernardo study" JAMA, 1997: 277:543-47.
    
    
33. Ettinger B, Grady D, "Maximizing the benefit of estrogen therapy for prevention of osteoporosis." Menopause, 1994: 1:19-24.
    
    
34. Jones KP. "Estrogen and Progestins: what to use and how to use it." Clin Obstet Gynecol. 1992: 35:871-83.
    
    
35. Schwartz J, et al. "Clinical pharmacology of estrogens: cardiovascular actions and cardioprotective benefits of replacement therapy in postmenopausal women." J Clin Pharmacol, 1995: 35:1-16.
    
    
36. Grodstein F, et al. "Postmenopausal estrogen and prog-estin use and the risk of cardiovascular disease." New Engl J Med, 1996; 335: 453-61.
    
    
37. Grodstein F. et al. "Postmenopausal hormone therapy and mortality." New Engl J Med, 1997: 1769-75.
    
    
38. Lobo RA, Speroff L. "International consensus conference on postmenopausal hormone therapy and the cardiovascular system." Fertil Steril, 1994: 62(suppl 2):176S-795.
    
    
39. Lindsay R, Bush TL, Grady D, Speroff L, Lobo RA. "Therapeutic Controversy: estrogen replacement in menopause." J Clin Endocrinol Metab, 1996: 81:3829-38.
    
    
40. Writing Group for the PEPI Trial. "Effects of Estrogen or Estrogen/Progestin Regimens on Heart Disease Risk Factors in Postmenopausal Women." The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA, 1995: 273:199-208.
    
    
41. Walsh BW. Schiff I. "Menopause and Ovarian Hormone Therapy." In: Abrams AJ, Beers MH, Berkow R, eds. Merck Manual of Geriatrics (2nd ed), 1995. Pathway. NJ.
    
    
42. Leach RE, Hendrix SL. "Hormone Replacement Therapy." In: Hajj SN, Evans WJ, eds. Clinical Postreproductive Gynecology, 1993: Nowalk. CT, Appleton & Lange.
    
    
43. Daly E, et al. "Risk of venous thromboembolism in users of hormone replacement therapy." Lancet 1996; 348:977-80.
    
    
44. Jick H, et al. "Risk of hospital admission for idiopathic venous throboembolism among users of postmenopausal oestrogens." Lancet 1996: 348:981-83.
    
    
45. Berga SL. "Hormonal management of the sick menopausal woman." Obstet Gynecol Clin North Am 1994; 21:231-44.
    
    
46. Lieberman D, Kopernik G, Porath A, et al. "Sub-clinical worsening of bronchial asthma during ERT in asthmatic post-menopausal women." Maturitas, 1995; 21:153-57.
    
    
47. Cobleigh MA, Berris RF. Bush T. et al. "Estrogen replacement therapy in breast cancer survivors." JAMA. 1994 272:540-545.
    
    
48. ACOG Committee Opinion: Committee on Gynecotogic Practice. "Estrogen replacement therapy in women with previously treated breast cancer." Int J Gynecol Obstet. 1994: 45:184-188.
    
    
49. Grady D, Gebretsadik T. Kerlikowske K. et al. "Hormone replacement therapy and endometrial cancer risk: a meta-analysis." Obsret Gynecol. 1995: 85:304-13.
    
    
50. Writing Group for the PEPI Trial. "Effects of hormone replacement therapy on endometrial histology in postmenopausal women." JAMA, 1996; 275:370-75.
    
    
51. Colditz GA, Hankinson SE, Hunter DJ. et al. "The use of estrogens and progestins and the risk of breast cancer in postmenopausal women." N EngI J Med. 1995 332:1589-93.
    
    
52. Hulka BS. "Links between hormone replacement therapy and neoplasia." Fertil Sterit, 1994: 62(suppl 2);168S-75S.
    
    
53. Gambrell Jr RD. "Guidelines for choosing the regimen -managing attending problems." Consultant, 1994:34:1047-57.
    
    
54. Evans MP, Fleming KC, Evans JM. "Hormone replacement therapy: management of common problems." Mayo Clin Proc, 1995: 70:800-805.
    
    
55. Bysshe H. "Hormone replacement therapy: Women s need for information." Prof Care Of Mother and Child. 1996: 6(1 ):3-5.