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West J Med. 2001 June; 174(6): 400–404. | PMCID: PMC1071429 |
Copyright © Copyright 2001 BMJ Publishing Group Menopause and hormone replacement Part 1. Evaluation and treatment Shari Ratner1 and Danielle Ofri1 1 New York University School of Medicine Bellevue Hospital 462 First Ave, Rm 2W42 New York, NY 10016 - Menopause marks the end of spontaneous menstruation. It occurs as a result of the natural loss of ovarian follicular function and is a stage of life, rather than a disease
- The average age at menopause is 51 years, with most women have several years of gradual menstrual irregularity, hormonal fluctuation, and varying degrees of menopausal symptoms before the menses stop (perimenopause)1
- Women who undergo surgical menopause (bilateral oophorectomy) often experience abrupt symptoms
- The average woman may spend a third of her life in the postmenopausal period; hence, the perimenopausal period provides an opportunity for education about preventive health care
- Hormone replacement therapy (HRT) can alleviate perimenopausal symptoms and both treat and prevent osteoporosis. It may protect against coronary artery disease (CAD), but the data are conflicting
- Menopause is usually obvious by history alone. If the diagnosis is in question (eg, early age or hysterectomy without oophorectomy), a follicle-stimulating hormone level of more than 25 to 30 IU/L is confirmatory
- Although pregnancy is unlikely in the perimenopause, a β-human chorionic gonadotropin level should be checked if pregnancy is suspected
- Other causes of hot flashlike symptoms, such as thyroid and infectious disease, should be assessed, if appropriate
- Symptoms of menopause include hot flashes, flushing, sweating, urogenital atrophy, sleeplessness, early morning awakenings, stress incontinence, dyspareunia, changes in libido, emotional lability, perception of memory loss, or changes in cognitive function
- Perimenopausal evaluation includes mammography, breast examination, pelvic examination, and Papanicolaou test, in addition to assessing risk for cardiovascular disease, osteoporosis, and breast cancer
INDICATIONS FOR SHORT-TERM HRT Short-term HRT is indicated to treat menopausal symptoms. The decision to use HRT depends on the extent to which symptoms are disabling and the patient's willingness to tolerate side effects. Other treatments should also be considered. Contraindications to HRT The true risks of HRT are unknown because women with these conditions have traditionally been excluded from clinical trials Absolute contraindications - Breast, ovarian, or endometrial cancer
- Active thromboembolism or thrombophlebitis
- Undiagnosed vaginal bleeding
- Pregnancy
- History of thromboembolism
Relative contraindications - Gallbladder disease
- Liver disease
- Hypertriglyceridemia
- Severe fibroid disease
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Hot flashes - Hot flashes and flushing are thought to be related to the rate of estrogen withdrawal and resultant vasomotor instability
- Episodes generally last from 30 seconds to 5 minutes and occur to some degree in most perimenopausal women. They can be disabling in 10% to 15% due to frequent occurrence, particularly at night, leading to insomnia and fatigue
- Hot flashes generally regress spontaneously; they may persist for as long as 6 years
- Precipitants to avoid include large meals, alcohol, caffeine, hot pepper, hot drinks, coffee, and tea. Wearing loose-fitting clothes and keeping ice water nearby can be helpful
- HRT given continuously or cyclically is extremely effective against hot flashes2
- Clonidine hydrochloride, a centrally acting α-agonist, has been shown to decrease symptoms.3 It can be used orally or transdermally. Side effects include drowsiness, dry mouth, and dizziness
- Megestrol acetate, a progestin, has shown some efficacy in women who have had breast cancer and in men with prostate cancer who have been treated with androgen-deprivation therapy4
- Alternative therapies are used by many women who do not wish to take HRT, but the few trials that have been undertaken have shown weak, if any, effects on menopausal symptoms
- Isoflavones in soy products are estrogenlike compounds that bind to estrogen receptors.5,6 Consumption of whole soy foods (soy milk, tofu, soy nuts) has not been shown consistently to relieve symptoms but is probably not harmful
- Vitamin E and vitamin B complex are frequently used, but there are no studies evaluating them
- Sage, black cohosh, fennel, ginseng, and dong quai are herbs that have been used in various preparations, but the few trials available do not support their effectiveness
Urogenital atrophy - The vulva, vagina, urethra, and trigone of the bladder all have large numbers of estrogen receptors. Menopause-related symptoms can include vulvovaginal pruritus, bleeding, dyspareunia, incontinence, and increased frequency of cystitis
- Intravaginal estrogen cream can provide relief,7 as can oral and transdermal preparations
- Sterile water-soluble lubricants (Replens, K-Y Jelly) can also be helpful, especially for dyspareunia. Petroleum-based products should not be used because they can break down latex condoms and form a barrier against endogenous lubricants. Natural lubricants include vitamin E oil, olive oil, and sesame oil
- Kegel exercises of the pelvic diaphragm and bladder training can help alleviate incontinence
Mood, cognitive function, and libido Although estrogen-binding sites exist in various areas of the central nervous system (CNS), whether declining hormone levels contribute directly to the CNS symptoms of menopause is controversial - Symptoms seen during the perimenopausal period include depression, emotional lability, irritability, memory loss, inability to concentrate, and decreased libido. Frequent hot flashes and resultant insomnia, as well as underlying clinical depression, can contribute to many of these symptoms
- Although observational studies have reported some improvement with HRT, the results of randomized controlled trials with HRT2 or raloxifene hydrochloride8 have been inconclusive
- The addition of testosterone may offer added benefits in psychological and sexual function when estrogen therapy alone is not adequate. In a randomized trial of 75 women, transdermal administration of testosterone at 300 μg added to estrogen, 0.625 mg, improved sexual function as measured by a standardized questionnaire.9 This is theoretically important in women who have had oophorectomy and thus have much less testosterone than those with natural menopause
The decision to use long-term HRT depends on a woman's risks for osteoporosis, heart disease, and breast cancer. Prevention and treatment of osteoporosis - Bone mineral density (BMD) declines most rapidly within 2 years of menopause, when estrogen deficiency causes increased trabecular bone resorption
- HRT halts the increased resorption of trabecular bone, creating an increase in BMD and continued protection from further loss as long as it is used. In the PEPI trial, BMD increased by 3.5% to 5.0% in the hip and 1.7% in the spine in all 3 HRT arms over 3 years. BMD decreased by 1.8% (spine) and 1.7% (hip) in controls10
- Although no large randomized trials assessing clinical outcomes have been completed to date, observational studies show an association between estrogen use and reduced risk for osteoporotic hip, wrist, and vertebral fractures11
- Bone densitometry is useful if the decision to use long-term HRT is based solely on fracture risk. Screening recommendations for BMD were published in 1998 by the National Osteoporosis Foundation and are outlined in the chapter on osteoporosis
- For maximal prevention of fracture, HRT should probably be initiated within 5 years after the menopause and continued indefinitely.11 A minimum therapy duration of 7 years is required to confer some benefit to women aged 75 years and older,12 when the risk of fracture is greatest
- Standard oral or transdermal HRT doses are used for prevention and treatment of osteoporosis. No trials of low-dose HRT with fracture as an end point have been published to date
- Raloxifene is a selective estrogen-receptor modulator that has estrogenic effects in bone and liver and antiestrogenic effects in the breast and uterus. Raloxifene increases BMD and reduces vertebral, but not hip, fractures.13 Side effects include hot flashes and leg cramps. Progestins are not needed because there is no endometrial hyperplasia
- Alternatives to hormone-based therapies are biphosphonates. Alendronate sodium and risedronate sodium have been approved for both prevention and treatment of osteoporosis14,15
- In 1 study, biphosphonates added to HRT increased BMD by 2% to 3% compared with placebo, but there is no evidence for a decreased fracture rate16
Primary prevention of CAD - CAD is the leading cause of death in American women, and the risk of CAD increases substantially after menopause, suggesting that estrogen may have some protective effect
- Possible cardioprotective mechanisms of estrogens include beneficial changes in lipid levels,17 a decrease in fibrinogen levels, direct antiatherosclerotic effects in arteries, direct inotropic actions on the heart, and endothelium-dependent vasodilatory and antiplatelet-aggregating effects
- The Women's Health Initiative, the only large randomized trial evaluating HRT for primary prevention of CAD, osteoporosis, breast cancer, and stroke, is under way
- The Nurses' Health Study is the largest observational study.18,19 In multiple analyses, it has demonstrated a consistent reduction in CAD and cardiovascular mortality. On average, current users of HRT have a relative risk (RR) of 0.5 for CAD compared with never users, regardless of the dose of estrogen or the addition of progesterone
- The major criticism of this cohort study is that women who choose to use estrogen do not represent all women. On average, they are healthier, better educated, and in a higher socioeconomic class
- The reduction in CAD risk may come at the expense of an increased risk for stroke (see below)
- Raloxifene has been shown in clinical trials to decrease total cholesterol and low-density-lipoprotein (LDL) concentrations, but no trials with CAD as an end point have been completed to date
Secondary prevention of CAD: the HERS - The Heart and Estrogen/Progestin Replacement Study (HERS) is the only randomized, blinded, placebo-controlled trial evaluating combination HRT (Prempro) in the secondary prevention of CAD20
- 2,763 women with CAD were randomly allocated to combination HRT or placebo and observed for nearly 5 years. 172 events (myocardial infarction [MI] or cardiac death) occurred in the treatment group compared with 176 in the placebo group
- 34 thromboembolic events occurred in the treatment group (13 in year 1) versus 12 in the placebo group
- There was a pattern of early harm (year 1) and later benefit (years 3-5)
- Overall, there was no reduction in the incidence of MI or CAD death at 4.1 years of average follow-up
- Given the disappointing results of the HERS, HRT for the secondary prevention of CAD cannot be routinely recommended. However, because of the trend toward later benefit, it may be appropriate to continue therapy in women already receiving it
- Reducing well-known risk factors for CAD—hypertension, smoking, diabetes, and obesity—should take priority
Risk of stroke No clinical trials evaluating raloxifene and stroke risk have been published to date. |
• Initial data from the Nurses' Health Study showed no significant association between stroke risk and use of HRT. In the most recent follow-up, 19 however, a significant increase in stroke risk (RR=1.5) was found for combined HRT (estrogen, 0.625 mg, plus progestin). Estrogen use alone at all doses showed no significant association with stroke. No data were presented for the use of estrogen, 0.3 mg, plus progestin Risk of breast cancer - Results from many observational studies of breast cancer risk with estrogen therapy are inconsistent. Studies vary considerably in design, dosage, and duration
- The best estimate of risk comes from the Nurses' Health Study,21 which shows an RR of 1.4 among those currently using HRT (estrogen or estrogen plus progestin) for 5 or more years. This risk increases with increasing age (RR of 1.7 for women aged 60-64 years). Use for less than 5 years was not associated with increased risk
- Data from the MORE trial showed a 75% reduction in invasive breast cancer during 3 years of raloxifene therapy.22 To prevent 1 case of breast cancer, 126 women would need to be treated
Risk of venous thromboembolic disease - For the average healthy menopausal woman, the absolute risk of venous thromboembolism is small (about 1/10,000 women per year), but estrogens appear to increase this risk
- In the PEPI trial of healthy women,17 a nonsignificant increase occurred with estrogen use
- In the HERS of women with CAD,23 the use of combined estrogen and progesterone gave an RR of 2.8, causing 1 case of deep venous thrombosis for every 339 women treated. 75% of cases were in women who had an underlying increased risk: recent lower extremity fracture, surgery, hospitalization, heart failure exacerbation, MI, stroke, or cancer
- In the MORE trial,22 healthy raloxifene users had an RR of 3.1 for thromboembolic disease
Risk of endometrial cancer - The use of unopposed estrogen, at doses of 0.625 mg or more, carries an RR of endometrial cancer of close to 8
- The addition of progesterone negates this risk. Women with a uterus are advised to take progestin along with estrogen
- Raloxifene use has not been shown to increase the risk of endometrial cancer
1. Greendale GA, Lee NP, Arriola ER. The menopause. Lancet 1999;353: 571-580. [PubMed] 2. Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions trial. Obstet Gynecol 1998;92: 982-988. The PEPI trial is the largest randomized controlled trial of HRT to date. 875 postmenopausal women were observed for 3 years while on estrogen, placebo, or 1 of 3 estrogen-progesterone regimens. In this analysis, all treatment groups had relief of vasomotor symptoms. Only those taking progesterone experienced breast tenderness. Anxiety and cognitive symptoms were not significantly affected. [PubMed] 3. Nagamani M, Kelver ME, Smith ER. Treatment of postmenopausal hot flashes with transdermal administration of clonidine. Am J Obstet Gynecol 1987;156: 561-565. After 8 weeks of treatment with clonidine or placebo (n=29) more women in the treatment group reported a decrease in frequency (80% vs 36%) and severity (73% vs 39%) of hot flashes. [PubMed] 4. Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994;331: 347-352. In this crossover trial of 97 women with breast cancer and 66 men with prostate cancer, the use of megestrol (20 mg orally twice a day) decreased hot flashes by 85% versus 20% with placebo. [PubMed] 5. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter double-blinded randomized placebo controlled trial. Menopause 2000;7: 236-242. In this trial of 177 women, hot flashes were relieved at 6 weeks but not at 12 weeks. [PubMed] 6. Anderson JJ, Anthony MS, Cline JM, Washburn SA, Garner SC. Health potential of soy isoflavones for menopausal women. Public Health Nutr 1999;2: 489-504. A recent review found no consistent effect of isoflavones on menopausal symptoms. [PubMed] 7. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993;329: 753-756. 93 postmenopausal women with frequent urinary tract infections were randomly allocated to intravaginal estriol versus placebo and observed for 8 months. Women in the treatment group experienced 0.5 versus 5.9 episodes per patient-year compared with women receiving placebo. [PubMed] 8. Strickler R, Stovall DW, Meritt D, Shen W, Wong M, Silfen SL. Raloxifene and estrogen effects on quality of life in healthy postmenopausal women: a placebo controlled randomized trial. Obstet Gynecol 2000;96: 359-365. Overall, little difference was shown. [PubMed] 9. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in postmenopausal women with impaired sexual function after oophorectomy. N Engl J Med 2000;343: 682-688. [PubMed] 10. Effects of hormone therapy on bone mineral density: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 1996;276: 1389-1396. [PubMed] 11. Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D, Cummings SR for the Study of Osteoporotic Fractures Research Group. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1995;122: 9-16. Prospective cohort of 9,704 white women. Current estrogen users (mean duration, 17 years) had an RR of hip, spine, and wrist fractures of 0.3 to 0.5 compared with never-users. There was no difference between combined HRT and estrogen alone. [PubMed] 12. Felson DT, Zhang Y, Hannan MT, Kiel DP, Wilson PW, Anderson JJ. The effect of postmenopausal estrogen therapy on bone density in elderly women. N Engl J Med 1993;329: 1141-1146. [PubMed] 13. Ettinger B, Black DM, Mitlak BH, et al for the Multiple Outcomes of Raloxifene Evaluation (MORE) investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year clinical trial. JAMA 1999;282: 637-645. [PubMed] 14. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280: 2077-2082. This 4-year randomized trial of 4,432 women aged 54 to 81 years demonstrated a significant decrease in risk of fracture at all sites for women with osteoporosis (BMD <2.5) RR = 0.64. [PubMed] 15. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) study group. JAMA 1999;282: 1344-1352. 1,600 women were randomly allocated to receive placebo or risedronate, 5 mg orally daily. 52 women in the control group had fractures versus 33 in the treatment group after 3 years [PubMed] 16. Lindsay R, Cosman F, Lobo RA, et al. Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized controlled clinical trial. J Clin Endocrinol Metab 1999;84: 3076-3081. [PubMed] 17. PEPI Trial Writing Group. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273: 199-208. Women on HRT had a decrease in LDL levels of 16 mg/dL, an increase in high-density lipoprotein levels of 5 mg/dL, and an increase in triglyceride levels of 13 mg/dL. [PubMed] 18. Stampfer M, Colditz G, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease: ten year follow-up from the Nurses' Health Study. N Engl J Med 1991;325: 756-762. A cohort of more than 48,000 healthy postmenopausal women observed prospectively every 2 years. [PubMed] 19. Grodstein F, Manson JE, Graham A, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133: 933-941. 70,500 postmenopausal participants. [PubMed] 20. Hulley S, Grady D, Bush T, et al for the Heart and Estrogen/Progestin Replacement (HERS) research group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280: 605-613. Relative risks for nonfatal MI or CAD death by year of study were as follows: 1 year, 1.5; 2 years, 1.0; 3 years, 0.9; 4 to 5 years, 0.7. [PubMed] 21. Colditz GA, Hawkinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332: 1589-1593. More data from the Nurses' Health Study. There was a possible element of surveillance bias with respect to mammography in users versus nonusers. RR=1.3 for current estrogen use alone, RR=1.4 for current combined HRT use, RR=1.5 for current HRT use for 5 or more years, and RR=1.7 for current HRT use 5 or more years in women aged 60 to 64 years. [PubMed] 22. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. JAMA 1999;281: 2189-2197. Showed a significant decrease in estrogen-receptor-positive breast cancer risk (RR=0.1). Also a significant increase in risk of venous thromboembolic disease (RR=3.1) and no effect on risk of endometrial cancer. One case of estrogen-receptor-positive breast cancer was prevented for every 126 women treated for 40 months with raloxifene. [PubMed] 23. Grady D, Wenger NK, Herrington D, et al for the Heart and Estrogen/Progestin Replacement (HERS) Research Group. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. Ann Intern Med 2000;132: 689-696. RR=2.8 for deep venous thrombosis, 2.8 for pulmonary embolism, and 2.7 for all venous thromboembolic disease. [PubMed]
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TERM HRT
