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- Laboratory testing is not indicated to initiate treatment of perimenopausal symptoms.
- While estrogens are the best established of the options to treat vasomotor symptoms at perimenopause, they are not a proven treatment for major depression or poor libido.
- Little evidence exists regarding the benefits and risks of androgens for perimenopausal women, suggesting a cautious approach to their use.
- Routine use of hormone replacement therapy, especially beyond 5 years’ duration, is not recommended because of uncertainties regarding risks and benefits.
Menopause has been successfully promoted as an estrogen-deficient state. Prescriptions in the United States for noncontraceptive estrogen formulations increased from 16 million to 39 million between 1982 and 1992; progestin sales reached 4.7 million by 1992 after their introduction in 1986.1 A condition for which half of the population becomes eligible for pharmacologic treatment for 30 years or more of their life spans is worthy of family physicians’ attention. Counseling of women regarding menopause has also been incorporated into the Health Employer Data Information Set (HEDIS) for measuring the quality of care provided by health care plans.
The women of the generation born from 1946 to 1965 are now 36 to 55 years old. About half will at some time seek medical attention for relief of symptoms believed to be related to the menopausal transition.2 The clinical picture, however, can be confusing: women at midlife are susceptible to diseases that may affect or be affected by the menopausal transition. Life cycle changes can also provoke dysphoric symptoms similar to those of menopause or aggravate symptoms that already exist.
Natural history
A woman’s hormonal rhythm changes gradually, usually in the early to middle forties. Ovarian mass decreases progressively; production of ovarian hormones decreases as well. The menstrual cycles tend to be somewhat shorter. Follicle-stimulating hormone (FSH) and estrogen levels fluctuate. Estrogen levels may be transiently higher than in former years in response to higher FSH levels, recruiting more ovarian follicles. Anovulatory cycles are more frequent. Perimenopausal menstrual irregularity typically lasts for approximately 4 years; the large majority of women experience such irregularity for 1 to 7 years.2 For 10% of women, menses simply cease without prior menstrual irregularity.
The best estimate of mean age at menopause in the United States, based on a cohort of primarily Caucasian women, is 51.3 years.2 Smokers experience menopause 1.8 years earlier than nonsmokers (50.2 versus 52.0 years). Less than 10% of women reach menopause before age 46, while approximately 30% do so before age 50.2 A recent review3 concluded that the lifetime number of ovulatory cycles is predictive of age at menopause: earlier for women with shorter cycles and nulliparous women, later for multigravid women and those with a history of oral contraceptive use. A familial tendency toward similarity in age at menopause has been noted.
Premature menopause or premature ovarian failure is defined as cessation of menstrual periods before 40 years of age. The prevalence of premature ovarian failure is approximately 1% by age 40 and 0.1% by 30 years of age.4 Premature ovarian failure is frequently an autoimmune disorder.5
Diagnosis of menopause
The gold standard for diagnosing menopause is to do so retrospectively, 1 year after the last menstrual period. In general, a diagnosis of menopause based on menstrual history or hormone levels is not considered necessary to begin treatment for perimenopausal symptoms, which often begin several years before the onset of menopause.
Laboratory diagnosis
The extent to which FSH or other serologic markers can be used to diagnose menopause is controversial. The most important clinical reason to do so is to discontinue contraceptive methods safely. Some consider an FSH level greater than 40 mIU/mL to be diagnostic. This value was chosen because it is about 2 standard deviations above the periovulatory peak in FSH levels in regularly cycling women. However, longitudinal studies6,7 during the perimenopausal years have demonstrated that hormonal patterns that include FSH values greater than 40 mIU/mL often abruptly revert to premenopausal patterns and are accompanied by ovulatory cycles. For the individual patient, hormone levels do not appear to rule out fertility reliably.8 Studies defining test characteristics (sensitivity, specificity, likelihood ratios) of hormone assays for the diagnosis of menopause are needed.
History and physical examination
A large population-based survey of Swedish women9 found that the most common climacteric symptoms are, in order of frequency, vasomotor symptoms (hot flashes), mood disturbances, sleep disturbances, decreased libido, and vaginal dryness. Several observational studies10-13 have shown that vasomotor symptoms have the clearest temporal association with the menstrual cycle changes of the climacteric. These symptoms result from a sudden change in the hypothalamic control of temperature regulation,14 although the precise triggers have not been elucidated. Hot flashes occur commonly among women in their late thirties and forties who have regular menstrual cycles.15 Several studies2,10,13,16 have shown that the prevalence of hot flashes peaks in the year immediately following the final menstrual period. A typical pattern prevalence of hot flashes is 25% in premenopausal women, 69% in perimenopausal women, and 39% in late-postmenopausal women (more than 4.5 years).17 Fifteen years after menopause, 10% of women may continue to have moderate to severe hot flashes,18 which can be lifelong.
Irritability and mood swings are common climacteric complaints. Women often compare them with their earlier premenstrual symptoms. Studies of depressive symptoms in menopausal women indicate that menopause is not associated with increased rates of major depression.19 Stressful life context and poor health status appear to be more important risk factors for depression than symptoms of menopause in climacteric women.20
Many perimenopausal women complain of poor sleep, often attributed to nocturnal hot flashes. Subjective impairment of sleep quality that is associated with climacteric vasomotor symptoms does not manifest as abnormalities in polysomnographic sleep recordings.21 It does not appear to be related to sleep apnea.
Sexual dysfunction is common in women at midlife and beyond. Dyspareunia, associated with vaginal dryness, increases in frequency with increasing time after menopause.9 The other complaint is decreased libido. Multiple factors may contribute to lack of sexual interest. Both aging and the menopause are independently associated with decreases in sexual responsiveness.22 The roles of declining endogenous sex steroid hormones in this process have not been elucidated.
Treatment
Vasomotor symptoms
Table 1 summarizes treatment options for vasomotor symptoms. Numerous well-designed clinical trials have demonstrated the effectiveness of oral or transdermal estrogen replacement therapy (ERT) for hot flashes.18,23-25 Low-dose oral contraceptive formulations are approved until 50 years of age for nonsmoking women.26 In a well-designed randomized controlled trial (RCT) of 93 women, low-dose estrogen (0.625 mg conjugated equine estrogens daily) plus 1.25 mg methyltestosterone daily was shown to be more effective than low-dose estrogen only and as effective as high-dose estrogen (1.25 mg conjugated estrogens daily).27
Phytoestrogens may be helpful, but have not yet been studied extensively. One RCT28 of 104 postmenopausal women comparing ingestion of 60 g soy protein daily with that of 60 g casein (placebo) daily showed a 45% relative reduction of hot flashes at 12 weeks in the group taking soy versus the control group. A second RCT29 of 51 women comparing soy protein with carbohydrate placebo showed a decrease in severity, but not frequency, of hot flashes. Another well-designed RCT30 including 69 women treated with 40 g soy daily versus whey protein for 24 weeks showed no difference between treatment groups and improvement in symptom scores over time in both groups. It is difficult to include a 40-g to 60-g protein supplement in the daily diet because of the accompanying caloric intake required. Recent reports of randomized placebo-controlled trials of black cohosh31 and dong quai32 and a systematic review33 of controlled trials of red clover have found no benefit.
Alternatives to estrogen for treatment of hot flashes include methyldopa, clonidine, transdermal progesterone, and megestrol acetate. Megestrol, which reduces symptoms by 70%, appears to be the most effective of these.34 Although long-term use of megestrol acetate by cancer survivors for the treatment of hot flashes has been demonstrated to be effective and well tolerated,35 it is not customarily used at menopause. A 20% reduction in hot flashes can be expected with clonidine at a dose of 0.1 to 0.2 mg daily,34,36 although this regimen may cause an increase in difficulty sleeping37 as well as dry mouth, constipation, and low blood pressure. Transdermal progesterone cream alone has been shown to improve vasomotor symptoms, although without protective effect regarding bone loss.38 One small study39 of behavioral approaches showed symptom reduction with deep-breathing relaxation techniques. Pilot studies of sertraline,40 venlafaxine,41 and paroxetine42 show promise in the treatment of hot flashes.
The remainder of this article focuses on hormonal treatment effects and risks for menopausal women. A summary appears in Table 2.
TABLE 1
TREATMENT OF VASOMOTOR SYMPTOMS
| Strength of Recommendation | Treatment | Comment |
|---|---|---|
| A | Estrogens | Many preparations with both oral and transdermal delivery have been studied |
| A | Estrogen + MPA | Other progestins not well studied |
| B | Transdermal progesterone | One RCT38 |
| B | Estrogen + testosterone | One RCT27; long-term safety is a theoretical concern |
| B | Megasterol | Cohort35; long experience with cancer patients gives some assurance of safety |
| C | Behavioral approaches | One small RCT39; deep breathing was beneficial |
| C | Clonidine | Small RCTs36,37 with important loss of subjects because of side effects |
| D | Antidepressants | Pilot studies of sertraline,40 venlafaxine,41 and paroxetine42 |
| D | Phytoestrogens | Conflicting RCT results |
| D | Exercise | Weak observational studies suggest benefit74,76 |
| No benefit seen | ||
| B | Black cohosh | No benefit seen in one RCT31 |
| B | Dong quai | No benefit seen in one RCT32 |
| B | Red clover | No benefit seen in systematic review33 |
| Grades of recommendation are based on Oxford Centre for Evidence-Based Medicine guidelines. | ||
| MPA denotes medroxyprogesterone; RCT, randomized clinical trial. | ||
TABLE 2
SUMMARY OF RISKS AND BENEFITS OF TREATMENTS FOR PERIMENOPAUSAL SYMPTOMS
| Treatment | VMS | Mood | Libido | Bone | CAD | Breast CA |
|---|---|---|---|---|---|---|
| Estrogens | Benefit | Benefit | No benefit | Benefit | Uncertain | Risk |
| Estrogen + MPA | Benefit | ? benefit | No benefit | Benefit | Uncertain* | Risk† |
| Progesterone | Benefit | Risk | No benefit | NS | Uncertain | NS |
| Testosterone | Benefit | NS | ? benefit | Benefit | NS | NS |
| Phytoestrogens | ? benefit | NS | NS | No benefit | NS | NS |
| DHEA | NS | ? benefit | ? benefit | NS | NS | NS |
| * Not beneficial for secondary prevention. † Increased risk over estrogen alone. | ||||||
| CA denotes cancer; CAD, coronary artery disease; DHEA, dihydroepiandrosterone; MPA, medroxyprogesterone acetate; NS, not studied; VMS, vasomotor symptoms. | ||||||
Mood disorders
In a meta-analysis43 including 26 RCTs of the effects of hormone replacement therapy (HRT) on depressed mood, estrogen showed limited effectiveness in improving mood. The addition of synthetic progestins reduced the estrogen effect. More recent short trials of unopposed transdermal estrogen showed benefit.44,45 Other reviews46,47 have concluded that ERT or HRT has little effect in the treatment of psychological symptoms, including anxiety, cognitive, and affective symptoms. As an adjuvant to psychotropic therapy, it may have limited effect. There is insufficient evidence to support prophylactic ERT or HRT to prevent depression in women whose medical history includes prior postpartum depression.47 Estrogens do not affect the ability of a woman with moderate to severe vasomotor symptoms to cope with stress.48 Clinical trials reporting the effects of testosterone treatment on mood in women were not identified.
Women with mild psychological and predominantly vasomotor symptoms may benefit from a trial of HRT before psychotropic medication. For women who meet criteria for a diagnosis of major depression, initial treatment with an antidepressant alone or concurrent with HRT is advisable.
Sleep disturbance
In a survey of more than 6000 women aged 40 to 64 years, 30% of HRT users reported sleep improvement that they attributed to therapy.49 Other standard approaches to insomnia, such as sleep hygiene measures and progressive relaxation techniques, can also be used. If sleep apnea is suspected, a sleep study may be indicated.
Sexual dysfunction
In a systematic review50 of HRT for climacteric sexual dysfunction, vaginal dryness improved with ERT in 7 of 8 studies. Dyspareunia improved in only 1 of 6 studies using transdermal 17-beta-estradiol. Orgasm increased in only 1 of 5 trials using ethinyl estradiol. Sexual interest increased in none of 7 studies that used conjugated estrogens. However, taking testosterone appeared to increase sexual interest. The evidence regarding the safety and efficacy of androgens (testosterone and dehydroepiandrosterone [DHEA]) for the treatment of sexual dysfunction in perimenopause is incomplete; therefore, these drugs should not routinely be prescribed.51
Bone
Although HRT prevents the rapid bone loss observed in the early menopausal period, this effect is lost when treatment is stopped. The positive effect of estrogen alone on bone mineral density was not diminished by medroxyprogesterone acetate (MPA) or micronized progesterone over a 3-year follow-up period.52 The long-term effects of MPA on fracture risk in postmenopausal women have not been reported. Use of transdermal progesterone alone does not prevent bone loss.38
Cancer
Estrogen alone for women with an intact uterus is currently considered unacceptable because adding the hormone poses endometrial cancer risk. An exception is low-dose estrogen administered intravaginally; this method does not alter the endometrium.53
Estrogen alone or in combination with progestins has been associated with an increased risk of breast cancer in many observational studies and meta-analyses. A comprehensive reanalysis54 of 51 mostly observational studies, including 52,705 cases of breast cancer and more than 100,000 controls, examined the association of breast cancer with HRT, predominantly unopposed estrogen. These authors concluded that there is an increase in incidence of breast cancer of 0.2%, 0.6%. and 1.2% with 5, 10, and 15 years of use, respectively. Thus, 1 additional case of breast cancer occurs for every 167 women treated for 10 years (number needed to harm [NNH] = 167). Two recent observational studies have documented up to a fourfold increase in breast cancer with estrogen plus progesterone over estrogen alone.55,56
Cardiovascular disease
HRT has been widely advocated for prevention of coronary artery disease (CAD), based on many observational studies. A meta-analysis57 of 25 studies published through 1997 gave a relative risk (RR) of 0.7 (CI 0.65-0.75) for coronary events in women using HRT. However, a consistent bias in these studies of selecting healthy, compliant women for inclusion may explain the observed benefit.
A meta-analysis58 of 22 trials of 4124 women comparing HRT with placebo, no therapy, or vitamins, in which cardiovascular events were secondary endpoints, revealed that there was no benefit regarding cardiac events and there were small increases in absolute risk of stroke and venous thromboembolism (VET). In the Heart and Estrogen/Progestin Replacement (HERS) study,59 conjugated equine estrogens (CEE) plus MPA, administered to women with established CAD for a mean of 4.1 years, did not reduce risk of cardiovascular events. An increase in events, particularly VET and stroke,60 occurred in the first year of use. Small increases in the absolute risks of stroke61,62 and VTE63,64 have also been described in observational studies.
Randomized trial evidence is currently lacking for a role of HRT in the primary prevention of cardiovascular disease. A large study of low-risk postmenopausal women, the Women’s Health Initiative,65 is currently under way. Its objective is to investigate strategies for the prevention and control of some of the most common causes of morbidity and mortality in postmenopausal women. The study includes 27,000 women randomized to CEE plus MPA or placebo. Results are expected in 2007. The American Heart Association now recommends against estrogen therapy with or without progestin solely for the prevention of heart disease.66 Long-term effects of androgens on cardiovascular risk have not been studied; concerns exist about their use.51
Other effects
A meta-analysis67 of trials of HRT for urinary incontinence showed no benefit. The HERS study68 showed an increase in urinary incontinence episodes with combined HRT for women with incontinence at baseline (NNH = 8). HRT also increases the risk of gallbladder disease69 and may worsen cognitive function for women with mild to moderate dementia.70
Prognosis
The symptoms of perimenopause are not life threatening and are usually limited in time. Climacteric symptoms are generally more severe and difficult to treat in women who have undergone bilateral oophorectomy before experiencing natural menopause.71 Women with multiple chronic medical conditions,13,72,73 psychiatric illnesses,15,74 or a history of premenstrual syndrome11,12,75 are also likely to experience more difficulty with symptoms attributed to the menopausal transition. Table 3 provides a list of resources for patient education regarding menopause.
TABLE 3
RESOURCES FOR PATIENT EDUCATION ABOUT MENOPAUSE
| Organization | Contact Information | Description |
|---|---|---|
| Ottawa Health Decision Centre | ldrake@civich.Ottawa.on.ca 613-798-5555 | Making Choices: Hormones After Menopause (audiotape and workbook) |
| American Academy of Family Physicians | www.aafp.org 1-800-274-2237 | Brochures: “Menopause: What to Expect When Your Body Is Changing”; “Osteoporosis: Keeping Your Bones Healthy and Strong” |
| American College of Obstetricians and Gynecologists | www.acog.org 1-800-410-ACOG | Brochures: “Midlife Transitions: A Guide to the Menopause Years”; “Hormone Replacement Therapy” |
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2. McKinlay S, Brambilla PJ, Posnere JG. The normal menopause transition. Maturitas 1992;14:13-5.
3. Harlow B, Signorello LB. Factors associated with early menopause. Maturitas 2000;35:3-9.
4. Coulam C, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol 1986;67:604-6.
5. Kalantaridou S, Nelson LM. Premature ovarian failure is not premature menopause. Ann NY Acad Sci 2000;900:393-402.
6. Hee J, MacNaughton J, Bangah M, Burger HG. Perimenopausal patterns of gonadotropins, immunoreactive inhibin, oestradiol and progesterone. Maturitas 1993;18:9-20.
7. Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone moneral density. Maturitas 1995;21:103-13.
8. Burger H. Diagnostic role of follicle-stimulating hormone (FSH) measurements during the menopausal transition—an analysis of FSH, oestradiol and inhibin. Eur J Endocrinol 1994;130:38-42.
9. Stadberg E, Mattson LA, Milsom I. The prevalence and severity of climacteric symptoms and the use of different treatment regimens in a Swedish population. Acta Obstet Gynecol Scand 1997;76:442-8.
10. Holte A, Mikkelsen A. The menopausal syndrome: a factor analytic replication. Maturitas 1991;13:193-203.
11. Hunter M. The South-East England Longitudinal Study of the climacteric and postmenopause. Maturitas 1992;14:217-28.
12. Collins A, Landgren BM. Reproductive health, use of estrogen and experience of symptoms in perimenopausal women: a population-based study. Maturitas 1995;20:101-11.
13. Dennerstein L, Smith AMA, Morse C, Burger H, Green A, Hopper J, et al. Menopausal symptoms in Australian women. Med J Aust 1993;159:232-6.
14. Mashchak C, Kletsky QA, Artel R, et al. The relation of physiological changes to subjective symptoms in postmenopausal women with and without hot flushes. Maturitas 1985;6:301-8.
15. Grisso J, Freeman EW, Maurin E, Garcia-Espans B, Berlin JA. Racial differences in menopause information and the experience of hot flashes. J Gen Intern Med 1999;14:98-103.
16. Oldenhave A, Jaszmann LJB, Haspels AA, et al. Impact of climacteric on well-being. Am J Obstet Gynecol 1993;168:772-80.
17. Barentsen R, Groeneveld FP, Bareman FP, et al. Women’s opinion on withdrawal bleeding with hormone replacement therapy. Eur J Obstet Gynecol Reprod Biol 1993;51:203-7.
18. Bachman G. Vasomotor flushes in menopausal women. Am J Obstet Gynecol 1999;180:S312-6.
19. Pearlstein T, Rosen K, Stone AB. Mood disorders and menopause. Endocr Metab Clin North Am 1997;26:279-94.
20. Woods N, Mitchell ES. Pathways to depressed mood for midlife women: observations from the Seattle midlife women’s health study. Res Nurs Health 1997;20:119-29.
21. Polo-Kantola P, Erkkola R. Climacteric symptoms and sleep quality. Obstet Gynecol 1999;94:219-24.
22. Dennerstein L, Dudley E, Burger H. Are changes in sexual functioning during midlife due to aging or menopause? Fertil Steril 2001;76:456-60.
23. Notelovitz M, Cassel D, Hille D, et al. Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with menopause. Am J Obstet Gynecol 2000;182:7-12.
24. Utian W, Burry KA, Archer DF, et al. Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. Am J Obstet Gynecol 1999;181:71-9.
25. Greendale G, 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;92:982-8.
26. World Health Organization. Improving access to quality care in family planning:medical eligibility criteria for contraceptive use. Geneva, Switzerland; 1996.
27. Simon J, Kaiber E, Wiita B, Bowen YHA. Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women. Menopause 1999;6:138-46.
28. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, de Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998;91:6-11.
29. Washburn S, Burke GL, Morgan T, Anthony M. Effect of soy protein on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women. Menopause 1999;6:7-13.
30. St Germaine A, Peterson CT, Robinson JG. Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause 2001;8:17-26.
31. Jacobson J, Troxel AB, Evans J. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 2001;19:2739-45.
32. Hirata J, Swiersz LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertil Steril 1997;68:981-6.
33. Fugh-Berman A, Kronenberg F. Red clover (trifolium pratense) for menopausal women: current state of knowledge. Menopause 2001;8:333-7.
34. Greendale G, Lee NP, Arriola ER. The menopause. Lancet 1999;353:571-80.
35. Quella S, Loprinzi CL, Sloan JA, et al. Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes. Cancer 1998;82:1784-8.
36. Laufer L, Erlik Y, Meldrum DR, Judd HL. Effect of clonidine on hot flashes in postmenopausal women. Obstet Gynecol 1982;60:583-6.
37. Pandya K, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Int Med 2000;132:788-93.
38. Leonetti H, Longo S, Anasti JN. Transdermal progresterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999;94:225-8.
39. Freedman R, Woodward S. Behavioral treatment of menopausal hot flushes: evaluation by ambulatory monitoring. Am J Obstet Gynecol 1992;167436-9.
40. Roth A, Sacher HI. Sertraline relieves hot flashes secondary to medical castration as treatment of advanced prostate cancer. Psychooncology 1998;7:129-32.
41. Loprinzi C, Pisansky TM, Fonseca R, et al. Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 1998;16:2377-81.
42. Stearns V, Isaacs C, Rowland J, et al. A pilot trial of paroxetine hydrochloride in controlling hot flashes in breast cancer survivors. Ann Oncol 2000;11:17-22.
43. Zweifel J, O’Brien WH. Meta-analysis of the effect of hormone replacement therapy on depressed mood. Psychoneuroendocrinology 1997;22:189-212.
44. Soares C, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001;58:529-34.
45. Schmidt P, Neiman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000;183:414-20.
46. Bech P, Munk-Jensen N, Obel EB, et al. Combined versus sequential hormonal replacement therapy: a double-blind, placebo-controlled study on quality of life-relationed outcome measures. Psychother Psychosom 1998;7:259-65.
47. Joffe H, Cohen LS. Estrogen, serotonin and mood disturbance: where is the therapeutic bridge? Biol Psychiatry 1998;44:798-811.
48. Nedstrand E, Wijma K, Lindgren M, Hammar M. The relationship between stress-coping and vasomotor symptoms in postmenopausal women. Maturitas 1998;31:29-34.
49. Asplund R, Aberg HE. Body mass index and sleep in women aged 40-64 years. Maturitas 1995;22:1-8.
50. McCoy N. Sexual issues for postmenopausal women. Top Geriatr Rehab 1997;12:28-39.
51. American College of Obstetricians and Gynecologists Committee on Gyecologic Practice. Androgen treatment of decreased libido. Obstet Gynecol 2000;96:244-5.
52. Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineral density. JAMA 1996;276:1389.-
53. Botsis D, Kassanos D, Kalogiro D, et al. Vaginal ultrasound of the endometrium in postmenopausal women with symptoms of uro genital atrophy on low-dose estrogen or tibolone treatment: a comparison. Maturitas 1997;26:57-62.
54. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047-59.
55. Ross R, Paganini-Hill A, Wan PC, et al. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328-32.
56. Schairer C, Lubin J, Triosi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-91.
57. Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other conditions. Ann Rev Public Health 1998;19:55-72.
58. Hemminki E, McPherson K. Impact of postmenopausal therapy on cardiovascular events and cancer: pooled data from clinical trials. BMJ 1997;315:149-53.
59. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13.
60. Simon J, Hsia J, Cauley JA, et al. Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen/Progestin Replacement Study (HERS). Circulation 2001;103:638-42.
61. Wilson P, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. N Engl J Med 1985;313:1038-45.
62. Oger E, Scarabin PY. Risk of stroke among users of hormone replacement therapy. Ann d’Endocrinol 1999;60:232-41.
63. Gutthann S, Rodriguez LA, Castellsague J, Oliart AD. Hormone replacement therapy and risk of thromboembolism: population based case-control study. BMJ 1997;314:796-800.
64. Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977-80.
65. Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998;19:61-109.
66. Mosca L, Grundy SM, Judelson D, King K, Limacher M, Oparil S. AHA/ACC scientific statement: consensus panel statement. Guide to preventive cardiology for women. J Am Coll Cardiol 1999;33:1751-5.
67. Fantl J, Cardozo L, McClish DK. Estrogen therapy in the management of urinary incontinence in postmenopausal women: a meta-analysis. Obstet Gynecol 1994;83:12-8.
68. Grady D, Brown JS, Vittinghoff E, Applegate W, Warner E, Snyder T. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol 2001;97:116-20.
69. Uhler M, Marks JW, Judd HL. Estrogen replacement therapy and gallbladder disease in postmenopausal women. Menopause 2000;7:162-7.
70. Mulnard R, Cotman CW, Kawas C, et al. Estrogen replacement therapy for mild to moderate Alzheimer’s disease: a randomized controlled trial. JAMA 2000;283:1007-15.
71. Langenberg P, Kjerulff KH, Stolley PD. Hormone replacement and menopausal symptoms following hysterectomy. Am J Epidemiol 1997;146:870-80.
72. Kuh D, Wadsworth M, Hardy R. Women’s health in midlife: the influence of the menopause, social factors and health in earlier life. Br J Obstet Gynaecol 1997;104:923-33.
73. Kirchengast S. Relations between anthropometric characteristics and degree of severity of the climacteric syndrome in Austrian women. Maturitas 1993;17:167-80.
74. Stadberg E, Mattson LA, Milsom I. Factors associated with climacteric symptoms and the use of hormone replacement therapy. Acta Obstet Gynecol Scand 2000;79:286-92.
75. Guthrie J, Dennerstein L, Hopper JL, Burger HG. Hot flushes, menstrual status, and hormone levels in a population-based sample of midlife women. Obstet Gynecol 1996;88:437-42.
76. Hammar M, Berg G, Lindgren R. Does physical exercise influence the frequency of postmenopausal hot flushes? Acta Obstet Gynecol Scand 1990;69:409-12.
- Laboratory testing is not indicated to initiate treatment of perimenopausal symptoms.
- While estrogens are the best established of the options to treat vasomotor symptoms at perimenopause, they are not a proven treatment for major depression or poor libido.
- Little evidence exists regarding the benefits and risks of androgens for perimenopausal women, suggesting a cautious approach to their use.
- Routine use of hormone replacement therapy, especially beyond 5 years’ duration, is not recommended because of uncertainties regarding risks and benefits.
Menopause has been successfully promoted as an estrogen-deficient state. Prescriptions in the United States for noncontraceptive estrogen formulations increased from 16 million to 39 million between 1982 and 1992; progestin sales reached 4.7 million by 1992 after their introduction in 1986.1 A condition for which half of the population becomes eligible for pharmacologic treatment for 30 years or more of their life spans is worthy of family physicians’ attention. Counseling of women regarding menopause has also been incorporated into the Health Employer Data Information Set (HEDIS) for measuring the quality of care provided by health care plans.
The women of the generation born from 1946 to 1965 are now 36 to 55 years old. About half will at some time seek medical attention for relief of symptoms believed to be related to the menopausal transition.2 The clinical picture, however, can be confusing: women at midlife are susceptible to diseases that may affect or be affected by the menopausal transition. Life cycle changes can also provoke dysphoric symptoms similar to those of menopause or aggravate symptoms that already exist.
Natural history
A woman’s hormonal rhythm changes gradually, usually in the early to middle forties. Ovarian mass decreases progressively; production of ovarian hormones decreases as well. The menstrual cycles tend to be somewhat shorter. Follicle-stimulating hormone (FSH) and estrogen levels fluctuate. Estrogen levels may be transiently higher than in former years in response to higher FSH levels, recruiting more ovarian follicles. Anovulatory cycles are more frequent. Perimenopausal menstrual irregularity typically lasts for approximately 4 years; the large majority of women experience such irregularity for 1 to 7 years.2 For 10% of women, menses simply cease without prior menstrual irregularity.
The best estimate of mean age at menopause in the United States, based on a cohort of primarily Caucasian women, is 51.3 years.2 Smokers experience menopause 1.8 years earlier than nonsmokers (50.2 versus 52.0 years). Less than 10% of women reach menopause before age 46, while approximately 30% do so before age 50.2 A recent review3 concluded that the lifetime number of ovulatory cycles is predictive of age at menopause: earlier for women with shorter cycles and nulliparous women, later for multigravid women and those with a history of oral contraceptive use. A familial tendency toward similarity in age at menopause has been noted.
Premature menopause or premature ovarian failure is defined as cessation of menstrual periods before 40 years of age. The prevalence of premature ovarian failure is approximately 1% by age 40 and 0.1% by 30 years of age.4 Premature ovarian failure is frequently an autoimmune disorder.5
Diagnosis of menopause
The gold standard for diagnosing menopause is to do so retrospectively, 1 year after the last menstrual period. In general, a diagnosis of menopause based on menstrual history or hormone levels is not considered necessary to begin treatment for perimenopausal symptoms, which often begin several years before the onset of menopause.
Laboratory diagnosis
The extent to which FSH or other serologic markers can be used to diagnose menopause is controversial. The most important clinical reason to do so is to discontinue contraceptive methods safely. Some consider an FSH level greater than 40 mIU/mL to be diagnostic. This value was chosen because it is about 2 standard deviations above the periovulatory peak in FSH levels in regularly cycling women. However, longitudinal studies6,7 during the perimenopausal years have demonstrated that hormonal patterns that include FSH values greater than 40 mIU/mL often abruptly revert to premenopausal patterns and are accompanied by ovulatory cycles. For the individual patient, hormone levels do not appear to rule out fertility reliably.8 Studies defining test characteristics (sensitivity, specificity, likelihood ratios) of hormone assays for the diagnosis of menopause are needed.
History and physical examination
A large population-based survey of Swedish women9 found that the most common climacteric symptoms are, in order of frequency, vasomotor symptoms (hot flashes), mood disturbances, sleep disturbances, decreased libido, and vaginal dryness. Several observational studies10-13 have shown that vasomotor symptoms have the clearest temporal association with the menstrual cycle changes of the climacteric. These symptoms result from a sudden change in the hypothalamic control of temperature regulation,14 although the precise triggers have not been elucidated. Hot flashes occur commonly among women in their late thirties and forties who have regular menstrual cycles.15 Several studies2,10,13,16 have shown that the prevalence of hot flashes peaks in the year immediately following the final menstrual period. A typical pattern prevalence of hot flashes is 25% in premenopausal women, 69% in perimenopausal women, and 39% in late-postmenopausal women (more than 4.5 years).17 Fifteen years after menopause, 10% of women may continue to have moderate to severe hot flashes,18 which can be lifelong.
Irritability and mood swings are common climacteric complaints. Women often compare them with their earlier premenstrual symptoms. Studies of depressive symptoms in menopausal women indicate that menopause is not associated with increased rates of major depression.19 Stressful life context and poor health status appear to be more important risk factors for depression than symptoms of menopause in climacteric women.20
Many perimenopausal women complain of poor sleep, often attributed to nocturnal hot flashes. Subjective impairment of sleep quality that is associated with climacteric vasomotor symptoms does not manifest as abnormalities in polysomnographic sleep recordings.21 It does not appear to be related to sleep apnea.
Sexual dysfunction is common in women at midlife and beyond. Dyspareunia, associated with vaginal dryness, increases in frequency with increasing time after menopause.9 The other complaint is decreased libido. Multiple factors may contribute to lack of sexual interest. Both aging and the menopause are independently associated with decreases in sexual responsiveness.22 The roles of declining endogenous sex steroid hormones in this process have not been elucidated.
Treatment
Vasomotor symptoms
Table 1 summarizes treatment options for vasomotor symptoms. Numerous well-designed clinical trials have demonstrated the effectiveness of oral or transdermal estrogen replacement therapy (ERT) for hot flashes.18,23-25 Low-dose oral contraceptive formulations are approved until 50 years of age for nonsmoking women.26 In a well-designed randomized controlled trial (RCT) of 93 women, low-dose estrogen (0.625 mg conjugated equine estrogens daily) plus 1.25 mg methyltestosterone daily was shown to be more effective than low-dose estrogen only and as effective as high-dose estrogen (1.25 mg conjugated estrogens daily).27
Phytoestrogens may be helpful, but have not yet been studied extensively. One RCT28 of 104 postmenopausal women comparing ingestion of 60 g soy protein daily with that of 60 g casein (placebo) daily showed a 45% relative reduction of hot flashes at 12 weeks in the group taking soy versus the control group. A second RCT29 of 51 women comparing soy protein with carbohydrate placebo showed a decrease in severity, but not frequency, of hot flashes. Another well-designed RCT30 including 69 women treated with 40 g soy daily versus whey protein for 24 weeks showed no difference between treatment groups and improvement in symptom scores over time in both groups. It is difficult to include a 40-g to 60-g protein supplement in the daily diet because of the accompanying caloric intake required. Recent reports of randomized placebo-controlled trials of black cohosh31 and dong quai32 and a systematic review33 of controlled trials of red clover have found no benefit.
Alternatives to estrogen for treatment of hot flashes include methyldopa, clonidine, transdermal progesterone, and megestrol acetate. Megestrol, which reduces symptoms by 70%, appears to be the most effective of these.34 Although long-term use of megestrol acetate by cancer survivors for the treatment of hot flashes has been demonstrated to be effective and well tolerated,35 it is not customarily used at menopause. A 20% reduction in hot flashes can be expected with clonidine at a dose of 0.1 to 0.2 mg daily,34,36 although this regimen may cause an increase in difficulty sleeping37 as well as dry mouth, constipation, and low blood pressure. Transdermal progesterone cream alone has been shown to improve vasomotor symptoms, although without protective effect regarding bone loss.38 One small study39 of behavioral approaches showed symptom reduction with deep-breathing relaxation techniques. Pilot studies of sertraline,40 venlafaxine,41 and paroxetine42 show promise in the treatment of hot flashes.
The remainder of this article focuses on hormonal treatment effects and risks for menopausal women. A summary appears in Table 2.
TABLE 1
TREATMENT OF VASOMOTOR SYMPTOMS
| Strength of Recommendation | Treatment | Comment |
|---|---|---|
| A | Estrogens | Many preparations with both oral and transdermal delivery have been studied |
| A | Estrogen + MPA | Other progestins not well studied |
| B | Transdermal progesterone | One RCT38 |
| B | Estrogen + testosterone | One RCT27; long-term safety is a theoretical concern |
| B | Megasterol | Cohort35; long experience with cancer patients gives some assurance of safety |
| C | Behavioral approaches | One small RCT39; deep breathing was beneficial |
| C | Clonidine | Small RCTs36,37 with important loss of subjects because of side effects |
| D | Antidepressants | Pilot studies of sertraline,40 venlafaxine,41 and paroxetine42 |
| D | Phytoestrogens | Conflicting RCT results |
| D | Exercise | Weak observational studies suggest benefit74,76 |
| No benefit seen | ||
| B | Black cohosh | No benefit seen in one RCT31 |
| B | Dong quai | No benefit seen in one RCT32 |
| B | Red clover | No benefit seen in systematic review33 |
| Grades of recommendation are based on Oxford Centre for Evidence-Based Medicine guidelines. | ||
| MPA denotes medroxyprogesterone; RCT, randomized clinical trial. | ||
TABLE 2
SUMMARY OF RISKS AND BENEFITS OF TREATMENTS FOR PERIMENOPAUSAL SYMPTOMS
| Treatment | VMS | Mood | Libido | Bone | CAD | Breast CA |
|---|---|---|---|---|---|---|
| Estrogens | Benefit | Benefit | No benefit | Benefit | Uncertain | Risk |
| Estrogen + MPA | Benefit | ? benefit | No benefit | Benefit | Uncertain* | Risk† |
| Progesterone | Benefit | Risk | No benefit | NS | Uncertain | NS |
| Testosterone | Benefit | NS | ? benefit | Benefit | NS | NS |
| Phytoestrogens | ? benefit | NS | NS | No benefit | NS | NS |
| DHEA | NS | ? benefit | ? benefit | NS | NS | NS |
| * Not beneficial for secondary prevention. † Increased risk over estrogen alone. | ||||||
| CA denotes cancer; CAD, coronary artery disease; DHEA, dihydroepiandrosterone; MPA, medroxyprogesterone acetate; NS, not studied; VMS, vasomotor symptoms. | ||||||
Mood disorders
In a meta-analysis43 including 26 RCTs of the effects of hormone replacement therapy (HRT) on depressed mood, estrogen showed limited effectiveness in improving mood. The addition of synthetic progestins reduced the estrogen effect. More recent short trials of unopposed transdermal estrogen showed benefit.44,45 Other reviews46,47 have concluded that ERT or HRT has little effect in the treatment of psychological symptoms, including anxiety, cognitive, and affective symptoms. As an adjuvant to psychotropic therapy, it may have limited effect. There is insufficient evidence to support prophylactic ERT or HRT to prevent depression in women whose medical history includes prior postpartum depression.47 Estrogens do not affect the ability of a woman with moderate to severe vasomotor symptoms to cope with stress.48 Clinical trials reporting the effects of testosterone treatment on mood in women were not identified.
Women with mild psychological and predominantly vasomotor symptoms may benefit from a trial of HRT before psychotropic medication. For women who meet criteria for a diagnosis of major depression, initial treatment with an antidepressant alone or concurrent with HRT is advisable.
Sleep disturbance
In a survey of more than 6000 women aged 40 to 64 years, 30% of HRT users reported sleep improvement that they attributed to therapy.49 Other standard approaches to insomnia, such as sleep hygiene measures and progressive relaxation techniques, can also be used. If sleep apnea is suspected, a sleep study may be indicated.
Sexual dysfunction
In a systematic review50 of HRT for climacteric sexual dysfunction, vaginal dryness improved with ERT in 7 of 8 studies. Dyspareunia improved in only 1 of 6 studies using transdermal 17-beta-estradiol. Orgasm increased in only 1 of 5 trials using ethinyl estradiol. Sexual interest increased in none of 7 studies that used conjugated estrogens. However, taking testosterone appeared to increase sexual interest. The evidence regarding the safety and efficacy of androgens (testosterone and dehydroepiandrosterone [DHEA]) for the treatment of sexual dysfunction in perimenopause is incomplete; therefore, these drugs should not routinely be prescribed.51
Bone
Although HRT prevents the rapid bone loss observed in the early menopausal period, this effect is lost when treatment is stopped. The positive effect of estrogen alone on bone mineral density was not diminished by medroxyprogesterone acetate (MPA) or micronized progesterone over a 3-year follow-up period.52 The long-term effects of MPA on fracture risk in postmenopausal women have not been reported. Use of transdermal progesterone alone does not prevent bone loss.38
Cancer
Estrogen alone for women with an intact uterus is currently considered unacceptable because adding the hormone poses endometrial cancer risk. An exception is low-dose estrogen administered intravaginally; this method does not alter the endometrium.53
Estrogen alone or in combination with progestins has been associated with an increased risk of breast cancer in many observational studies and meta-analyses. A comprehensive reanalysis54 of 51 mostly observational studies, including 52,705 cases of breast cancer and more than 100,000 controls, examined the association of breast cancer with HRT, predominantly unopposed estrogen. These authors concluded that there is an increase in incidence of breast cancer of 0.2%, 0.6%. and 1.2% with 5, 10, and 15 years of use, respectively. Thus, 1 additional case of breast cancer occurs for every 167 women treated for 10 years (number needed to harm [NNH] = 167). Two recent observational studies have documented up to a fourfold increase in breast cancer with estrogen plus progesterone over estrogen alone.55,56
Cardiovascular disease
HRT has been widely advocated for prevention of coronary artery disease (CAD), based on many observational studies. A meta-analysis57 of 25 studies published through 1997 gave a relative risk (RR) of 0.7 (CI 0.65-0.75) for coronary events in women using HRT. However, a consistent bias in these studies of selecting healthy, compliant women for inclusion may explain the observed benefit.
A meta-analysis58 of 22 trials of 4124 women comparing HRT with placebo, no therapy, or vitamins, in which cardiovascular events were secondary endpoints, revealed that there was no benefit regarding cardiac events and there were small increases in absolute risk of stroke and venous thromboembolism (VET). In the Heart and Estrogen/Progestin Replacement (HERS) study,59 conjugated equine estrogens (CEE) plus MPA, administered to women with established CAD for a mean of 4.1 years, did not reduce risk of cardiovascular events. An increase in events, particularly VET and stroke,60 occurred in the first year of use. Small increases in the absolute risks of stroke61,62 and VTE63,64 have also been described in observational studies.
Randomized trial evidence is currently lacking for a role of HRT in the primary prevention of cardiovascular disease. A large study of low-risk postmenopausal women, the Women’s Health Initiative,65 is currently under way. Its objective is to investigate strategies for the prevention and control of some of the most common causes of morbidity and mortality in postmenopausal women. The study includes 27,000 women randomized to CEE plus MPA or placebo. Results are expected in 2007. The American Heart Association now recommends against estrogen therapy with or without progestin solely for the prevention of heart disease.66 Long-term effects of androgens on cardiovascular risk have not been studied; concerns exist about their use.51
Other effects
A meta-analysis67 of trials of HRT for urinary incontinence showed no benefit. The HERS study68 showed an increase in urinary incontinence episodes with combined HRT for women with incontinence at baseline (NNH = 8). HRT also increases the risk of gallbladder disease69 and may worsen cognitive function for women with mild to moderate dementia.70
Prognosis
The symptoms of perimenopause are not life threatening and are usually limited in time. Climacteric symptoms are generally more severe and difficult to treat in women who have undergone bilateral oophorectomy before experiencing natural menopause.71 Women with multiple chronic medical conditions,13,72,73 psychiatric illnesses,15,74 or a history of premenstrual syndrome11,12,75 are also likely to experience more difficulty with symptoms attributed to the menopausal transition. Table 3 provides a list of resources for patient education regarding menopause.
TABLE 3
RESOURCES FOR PATIENT EDUCATION ABOUT MENOPAUSE
| Organization | Contact Information | Description |
|---|---|---|
| Ottawa Health Decision Centre | ldrake@civich.Ottawa.on.ca 613-798-5555 | Making Choices: Hormones After Menopause (audiotape and workbook) |
| American Academy of Family Physicians | www.aafp.org 1-800-274-2237 | Brochures: “Menopause: What to Expect When Your Body Is Changing”; “Osteoporosis: Keeping Your Bones Healthy and Strong” |
| American College of Obstetricians and Gynecologists | www.acog.org 1-800-410-ACOG | Brochures: “Midlife Transitions: A Guide to the Menopause Years”; “Hormone Replacement Therapy” |
- Laboratory testing is not indicated to initiate treatment of perimenopausal symptoms.
- While estrogens are the best established of the options to treat vasomotor symptoms at perimenopause, they are not a proven treatment for major depression or poor libido.
- Little evidence exists regarding the benefits and risks of androgens for perimenopausal women, suggesting a cautious approach to their use.
- Routine use of hormone replacement therapy, especially beyond 5 years’ duration, is not recommended because of uncertainties regarding risks and benefits.
Menopause has been successfully promoted as an estrogen-deficient state. Prescriptions in the United States for noncontraceptive estrogen formulations increased from 16 million to 39 million between 1982 and 1992; progestin sales reached 4.7 million by 1992 after their introduction in 1986.1 A condition for which half of the population becomes eligible for pharmacologic treatment for 30 years or more of their life spans is worthy of family physicians’ attention. Counseling of women regarding menopause has also been incorporated into the Health Employer Data Information Set (HEDIS) for measuring the quality of care provided by health care plans.
The women of the generation born from 1946 to 1965 are now 36 to 55 years old. About half will at some time seek medical attention for relief of symptoms believed to be related to the menopausal transition.2 The clinical picture, however, can be confusing: women at midlife are susceptible to diseases that may affect or be affected by the menopausal transition. Life cycle changes can also provoke dysphoric symptoms similar to those of menopause or aggravate symptoms that already exist.
Natural history
A woman’s hormonal rhythm changes gradually, usually in the early to middle forties. Ovarian mass decreases progressively; production of ovarian hormones decreases as well. The menstrual cycles tend to be somewhat shorter. Follicle-stimulating hormone (FSH) and estrogen levels fluctuate. Estrogen levels may be transiently higher than in former years in response to higher FSH levels, recruiting more ovarian follicles. Anovulatory cycles are more frequent. Perimenopausal menstrual irregularity typically lasts for approximately 4 years; the large majority of women experience such irregularity for 1 to 7 years.2 For 10% of women, menses simply cease without prior menstrual irregularity.
The best estimate of mean age at menopause in the United States, based on a cohort of primarily Caucasian women, is 51.3 years.2 Smokers experience menopause 1.8 years earlier than nonsmokers (50.2 versus 52.0 years). Less than 10% of women reach menopause before age 46, while approximately 30% do so before age 50.2 A recent review3 concluded that the lifetime number of ovulatory cycles is predictive of age at menopause: earlier for women with shorter cycles and nulliparous women, later for multigravid women and those with a history of oral contraceptive use. A familial tendency toward similarity in age at menopause has been noted.
Premature menopause or premature ovarian failure is defined as cessation of menstrual periods before 40 years of age. The prevalence of premature ovarian failure is approximately 1% by age 40 and 0.1% by 30 years of age.4 Premature ovarian failure is frequently an autoimmune disorder.5
Diagnosis of menopause
The gold standard for diagnosing menopause is to do so retrospectively, 1 year after the last menstrual period. In general, a diagnosis of menopause based on menstrual history or hormone levels is not considered necessary to begin treatment for perimenopausal symptoms, which often begin several years before the onset of menopause.
Laboratory diagnosis
The extent to which FSH or other serologic markers can be used to diagnose menopause is controversial. The most important clinical reason to do so is to discontinue contraceptive methods safely. Some consider an FSH level greater than 40 mIU/mL to be diagnostic. This value was chosen because it is about 2 standard deviations above the periovulatory peak in FSH levels in regularly cycling women. However, longitudinal studies6,7 during the perimenopausal years have demonstrated that hormonal patterns that include FSH values greater than 40 mIU/mL often abruptly revert to premenopausal patterns and are accompanied by ovulatory cycles. For the individual patient, hormone levels do not appear to rule out fertility reliably.8 Studies defining test characteristics (sensitivity, specificity, likelihood ratios) of hormone assays for the diagnosis of menopause are needed.
History and physical examination
A large population-based survey of Swedish women9 found that the most common climacteric symptoms are, in order of frequency, vasomotor symptoms (hot flashes), mood disturbances, sleep disturbances, decreased libido, and vaginal dryness. Several observational studies10-13 have shown that vasomotor symptoms have the clearest temporal association with the menstrual cycle changes of the climacteric. These symptoms result from a sudden change in the hypothalamic control of temperature regulation,14 although the precise triggers have not been elucidated. Hot flashes occur commonly among women in their late thirties and forties who have regular menstrual cycles.15 Several studies2,10,13,16 have shown that the prevalence of hot flashes peaks in the year immediately following the final menstrual period. A typical pattern prevalence of hot flashes is 25% in premenopausal women, 69% in perimenopausal women, and 39% in late-postmenopausal women (more than 4.5 years).17 Fifteen years after menopause, 10% of women may continue to have moderate to severe hot flashes,18 which can be lifelong.
Irritability and mood swings are common climacteric complaints. Women often compare them with their earlier premenstrual symptoms. Studies of depressive symptoms in menopausal women indicate that menopause is not associated with increased rates of major depression.19 Stressful life context and poor health status appear to be more important risk factors for depression than symptoms of menopause in climacteric women.20
Many perimenopausal women complain of poor sleep, often attributed to nocturnal hot flashes. Subjective impairment of sleep quality that is associated with climacteric vasomotor symptoms does not manifest as abnormalities in polysomnographic sleep recordings.21 It does not appear to be related to sleep apnea.
Sexual dysfunction is common in women at midlife and beyond. Dyspareunia, associated with vaginal dryness, increases in frequency with increasing time after menopause.9 The other complaint is decreased libido. Multiple factors may contribute to lack of sexual interest. Both aging and the menopause are independently associated with decreases in sexual responsiveness.22 The roles of declining endogenous sex steroid hormones in this process have not been elucidated.
Treatment
Vasomotor symptoms
Table 1 summarizes treatment options for vasomotor symptoms. Numerous well-designed clinical trials have demonstrated the effectiveness of oral or transdermal estrogen replacement therapy (ERT) for hot flashes.18,23-25 Low-dose oral contraceptive formulations are approved until 50 years of age for nonsmoking women.26 In a well-designed randomized controlled trial (RCT) of 93 women, low-dose estrogen (0.625 mg conjugated equine estrogens daily) plus 1.25 mg methyltestosterone daily was shown to be more effective than low-dose estrogen only and as effective as high-dose estrogen (1.25 mg conjugated estrogens daily).27
Phytoestrogens may be helpful, but have not yet been studied extensively. One RCT28 of 104 postmenopausal women comparing ingestion of 60 g soy protein daily with that of 60 g casein (placebo) daily showed a 45% relative reduction of hot flashes at 12 weeks in the group taking soy versus the control group. A second RCT29 of 51 women comparing soy protein with carbohydrate placebo showed a decrease in severity, but not frequency, of hot flashes. Another well-designed RCT30 including 69 women treated with 40 g soy daily versus whey protein for 24 weeks showed no difference between treatment groups and improvement in symptom scores over time in both groups. It is difficult to include a 40-g to 60-g protein supplement in the daily diet because of the accompanying caloric intake required. Recent reports of randomized placebo-controlled trials of black cohosh31 and dong quai32 and a systematic review33 of controlled trials of red clover have found no benefit.
Alternatives to estrogen for treatment of hot flashes include methyldopa, clonidine, transdermal progesterone, and megestrol acetate. Megestrol, which reduces symptoms by 70%, appears to be the most effective of these.34 Although long-term use of megestrol acetate by cancer survivors for the treatment of hot flashes has been demonstrated to be effective and well tolerated,35 it is not customarily used at menopause. A 20% reduction in hot flashes can be expected with clonidine at a dose of 0.1 to 0.2 mg daily,34,36 although this regimen may cause an increase in difficulty sleeping37 as well as dry mouth, constipation, and low blood pressure. Transdermal progesterone cream alone has been shown to improve vasomotor symptoms, although without protective effect regarding bone loss.38 One small study39 of behavioral approaches showed symptom reduction with deep-breathing relaxation techniques. Pilot studies of sertraline,40 venlafaxine,41 and paroxetine42 show promise in the treatment of hot flashes.
The remainder of this article focuses on hormonal treatment effects and risks for menopausal women. A summary appears in Table 2.
TABLE 1
TREATMENT OF VASOMOTOR SYMPTOMS
| Strength of Recommendation | Treatment | Comment |
|---|---|---|
| A | Estrogens | Many preparations with both oral and transdermal delivery have been studied |
| A | Estrogen + MPA | Other progestins not well studied |
| B | Transdermal progesterone | One RCT38 |
| B | Estrogen + testosterone | One RCT27; long-term safety is a theoretical concern |
| B | Megasterol | Cohort35; long experience with cancer patients gives some assurance of safety |
| C | Behavioral approaches | One small RCT39; deep breathing was beneficial |
| C | Clonidine | Small RCTs36,37 with important loss of subjects because of side effects |
| D | Antidepressants | Pilot studies of sertraline,40 venlafaxine,41 and paroxetine42 |
| D | Phytoestrogens | Conflicting RCT results |
| D | Exercise | Weak observational studies suggest benefit74,76 |
| No benefit seen | ||
| B | Black cohosh | No benefit seen in one RCT31 |
| B | Dong quai | No benefit seen in one RCT32 |
| B | Red clover | No benefit seen in systematic review33 |
| Grades of recommendation are based on Oxford Centre for Evidence-Based Medicine guidelines. | ||
| MPA denotes medroxyprogesterone; RCT, randomized clinical trial. | ||
TABLE 2
SUMMARY OF RISKS AND BENEFITS OF TREATMENTS FOR PERIMENOPAUSAL SYMPTOMS
| Treatment | VMS | Mood | Libido | Bone | CAD | Breast CA |
|---|---|---|---|---|---|---|
| Estrogens | Benefit | Benefit | No benefit | Benefit | Uncertain | Risk |
| Estrogen + MPA | Benefit | ? benefit | No benefit | Benefit | Uncertain* | Risk† |
| Progesterone | Benefit | Risk | No benefit | NS | Uncertain | NS |
| Testosterone | Benefit | NS | ? benefit | Benefit | NS | NS |
| Phytoestrogens | ? benefit | NS | NS | No benefit | NS | NS |
| DHEA | NS | ? benefit | ? benefit | NS | NS | NS |
| * Not beneficial for secondary prevention. † Increased risk over estrogen alone. | ||||||
| CA denotes cancer; CAD, coronary artery disease; DHEA, dihydroepiandrosterone; MPA, medroxyprogesterone acetate; NS, not studied; VMS, vasomotor symptoms. | ||||||
Mood disorders
In a meta-analysis43 including 26 RCTs of the effects of hormone replacement therapy (HRT) on depressed mood, estrogen showed limited effectiveness in improving mood. The addition of synthetic progestins reduced the estrogen effect. More recent short trials of unopposed transdermal estrogen showed benefit.44,45 Other reviews46,47 have concluded that ERT or HRT has little effect in the treatment of psychological symptoms, including anxiety, cognitive, and affective symptoms. As an adjuvant to psychotropic therapy, it may have limited effect. There is insufficient evidence to support prophylactic ERT or HRT to prevent depression in women whose medical history includes prior postpartum depression.47 Estrogens do not affect the ability of a woman with moderate to severe vasomotor symptoms to cope with stress.48 Clinical trials reporting the effects of testosterone treatment on mood in women were not identified.
Women with mild psychological and predominantly vasomotor symptoms may benefit from a trial of HRT before psychotropic medication. For women who meet criteria for a diagnosis of major depression, initial treatment with an antidepressant alone or concurrent with HRT is advisable.
Sleep disturbance
In a survey of more than 6000 women aged 40 to 64 years, 30% of HRT users reported sleep improvement that they attributed to therapy.49 Other standard approaches to insomnia, such as sleep hygiene measures and progressive relaxation techniques, can also be used. If sleep apnea is suspected, a sleep study may be indicated.
Sexual dysfunction
In a systematic review50 of HRT for climacteric sexual dysfunction, vaginal dryness improved with ERT in 7 of 8 studies. Dyspareunia improved in only 1 of 6 studies using transdermal 17-beta-estradiol. Orgasm increased in only 1 of 5 trials using ethinyl estradiol. Sexual interest increased in none of 7 studies that used conjugated estrogens. However, taking testosterone appeared to increase sexual interest. The evidence regarding the safety and efficacy of androgens (testosterone and dehydroepiandrosterone [DHEA]) for the treatment of sexual dysfunction in perimenopause is incomplete; therefore, these drugs should not routinely be prescribed.51
Bone
Although HRT prevents the rapid bone loss observed in the early menopausal period, this effect is lost when treatment is stopped. The positive effect of estrogen alone on bone mineral density was not diminished by medroxyprogesterone acetate (MPA) or micronized progesterone over a 3-year follow-up period.52 The long-term effects of MPA on fracture risk in postmenopausal women have not been reported. Use of transdermal progesterone alone does not prevent bone loss.38
Cancer
Estrogen alone for women with an intact uterus is currently considered unacceptable because adding the hormone poses endometrial cancer risk. An exception is low-dose estrogen administered intravaginally; this method does not alter the endometrium.53
Estrogen alone or in combination with progestins has been associated with an increased risk of breast cancer in many observational studies and meta-analyses. A comprehensive reanalysis54 of 51 mostly observational studies, including 52,705 cases of breast cancer and more than 100,000 controls, examined the association of breast cancer with HRT, predominantly unopposed estrogen. These authors concluded that there is an increase in incidence of breast cancer of 0.2%, 0.6%. and 1.2% with 5, 10, and 15 years of use, respectively. Thus, 1 additional case of breast cancer occurs for every 167 women treated for 10 years (number needed to harm [NNH] = 167). Two recent observational studies have documented up to a fourfold increase in breast cancer with estrogen plus progesterone over estrogen alone.55,56
Cardiovascular disease
HRT has been widely advocated for prevention of coronary artery disease (CAD), based on many observational studies. A meta-analysis57 of 25 studies published through 1997 gave a relative risk (RR) of 0.7 (CI 0.65-0.75) for coronary events in women using HRT. However, a consistent bias in these studies of selecting healthy, compliant women for inclusion may explain the observed benefit.
A meta-analysis58 of 22 trials of 4124 women comparing HRT with placebo, no therapy, or vitamins, in which cardiovascular events were secondary endpoints, revealed that there was no benefit regarding cardiac events and there were small increases in absolute risk of stroke and venous thromboembolism (VET). In the Heart and Estrogen/Progestin Replacement (HERS) study,59 conjugated equine estrogens (CEE) plus MPA, administered to women with established CAD for a mean of 4.1 years, did not reduce risk of cardiovascular events. An increase in events, particularly VET and stroke,60 occurred in the first year of use. Small increases in the absolute risks of stroke61,62 and VTE63,64 have also been described in observational studies.
Randomized trial evidence is currently lacking for a role of HRT in the primary prevention of cardiovascular disease. A large study of low-risk postmenopausal women, the Women’s Health Initiative,65 is currently under way. Its objective is to investigate strategies for the prevention and control of some of the most common causes of morbidity and mortality in postmenopausal women. The study includes 27,000 women randomized to CEE plus MPA or placebo. Results are expected in 2007. The American Heart Association now recommends against estrogen therapy with or without progestin solely for the prevention of heart disease.66 Long-term effects of androgens on cardiovascular risk have not been studied; concerns exist about their use.51
Other effects
A meta-analysis67 of trials of HRT for urinary incontinence showed no benefit. The HERS study68 showed an increase in urinary incontinence episodes with combined HRT for women with incontinence at baseline (NNH = 8). HRT also increases the risk of gallbladder disease69 and may worsen cognitive function for women with mild to moderate dementia.70
Prognosis
The symptoms of perimenopause are not life threatening and are usually limited in time. Climacteric symptoms are generally more severe and difficult to treat in women who have undergone bilateral oophorectomy before experiencing natural menopause.71 Women with multiple chronic medical conditions,13,72,73 psychiatric illnesses,15,74 or a history of premenstrual syndrome11,12,75 are also likely to experience more difficulty with symptoms attributed to the menopausal transition. Table 3 provides a list of resources for patient education regarding menopause.
TABLE 3
RESOURCES FOR PATIENT EDUCATION ABOUT MENOPAUSE
| Organization | Contact Information | Description |
|---|---|---|
| Ottawa Health Decision Centre | ldrake@civich.Ottawa.on.ca 613-798-5555 | Making Choices: Hormones After Menopause (audiotape and workbook) |
| American Academy of Family Physicians | www.aafp.org 1-800-274-2237 | Brochures: “Menopause: What to Expect When Your Body Is Changing”; “Osteoporosis: Keeping Your Bones Healthy and Strong” |
| American College of Obstetricians and Gynecologists | www.acog.org 1-800-410-ACOG | Brochures: “Midlife Transitions: A Guide to the Menopause Years”; “Hormone Replacement Therapy” |
1. Wysowski D, Golden L, Burke L. Use of menopausal estrogens and medroxyprogesterone in the United States, 1982-1992. Obstet Gynecol 1995;85:6-10.
2. McKinlay S, Brambilla PJ, Posnere JG. The normal menopause transition. Maturitas 1992;14:13-5.
3. Harlow B, Signorello LB. Factors associated with early menopause. Maturitas 2000;35:3-9.
4. Coulam C, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol 1986;67:604-6.
5. Kalantaridou S, Nelson LM. Premature ovarian failure is not premature menopause. Ann NY Acad Sci 2000;900:393-402.
6. Hee J, MacNaughton J, Bangah M, Burger HG. Perimenopausal patterns of gonadotropins, immunoreactive inhibin, oestradiol and progesterone. Maturitas 1993;18:9-20.
7. Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone moneral density. Maturitas 1995;21:103-13.
8. Burger H. Diagnostic role of follicle-stimulating hormone (FSH) measurements during the menopausal transition—an analysis of FSH, oestradiol and inhibin. Eur J Endocrinol 1994;130:38-42.
9. Stadberg E, Mattson LA, Milsom I. The prevalence and severity of climacteric symptoms and the use of different treatment regimens in a Swedish population. Acta Obstet Gynecol Scand 1997;76:442-8.
10. Holte A, Mikkelsen A. The menopausal syndrome: a factor analytic replication. Maturitas 1991;13:193-203.
11. Hunter M. The South-East England Longitudinal Study of the climacteric and postmenopause. Maturitas 1992;14:217-28.
12. Collins A, Landgren BM. Reproductive health, use of estrogen and experience of symptoms in perimenopausal women: a population-based study. Maturitas 1995;20:101-11.
13. Dennerstein L, Smith AMA, Morse C, Burger H, Green A, Hopper J, et al. Menopausal symptoms in Australian women. Med J Aust 1993;159:232-6.
14. Mashchak C, Kletsky QA, Artel R, et al. The relation of physiological changes to subjective symptoms in postmenopausal women with and without hot flushes. Maturitas 1985;6:301-8.
15. Grisso J, Freeman EW, Maurin E, Garcia-Espans B, Berlin JA. Racial differences in menopause information and the experience of hot flashes. J Gen Intern Med 1999;14:98-103.
16. Oldenhave A, Jaszmann LJB, Haspels AA, et al. Impact of climacteric on well-being. Am J Obstet Gynecol 1993;168:772-80.
17. Barentsen R, Groeneveld FP, Bareman FP, et al. Women’s opinion on withdrawal bleeding with hormone replacement therapy. Eur J Obstet Gynecol Reprod Biol 1993;51:203-7.
18. Bachman G. Vasomotor flushes in menopausal women. Am J Obstet Gynecol 1999;180:S312-6.
19. Pearlstein T, Rosen K, Stone AB. Mood disorders and menopause. Endocr Metab Clin North Am 1997;26:279-94.
20. Woods N, Mitchell ES. Pathways to depressed mood for midlife women: observations from the Seattle midlife women’s health study. Res Nurs Health 1997;20:119-29.
21. Polo-Kantola P, Erkkola R. Climacteric symptoms and sleep quality. Obstet Gynecol 1999;94:219-24.
22. Dennerstein L, Dudley E, Burger H. Are changes in sexual functioning during midlife due to aging or menopause? Fertil Steril 2001;76:456-60.
23. Notelovitz M, Cassel D, Hille D, et al. Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with menopause. Am J Obstet Gynecol 2000;182:7-12.
24. Utian W, Burry KA, Archer DF, et al. Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. Am J Obstet Gynecol 1999;181:71-9.
25. Greendale G, 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;92:982-8.
26. World Health Organization. Improving access to quality care in family planning:medical eligibility criteria for contraceptive use. Geneva, Switzerland; 1996.
27. Simon J, Kaiber E, Wiita B, Bowen YHA. Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women. Menopause 1999;6:138-46.
28. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, de Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998;91:6-11.
29. Washburn S, Burke GL, Morgan T, Anthony M. Effect of soy protein on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women. Menopause 1999;6:7-13.
30. St Germaine A, Peterson CT, Robinson JG. Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause 2001;8:17-26.
31. Jacobson J, Troxel AB, Evans J. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 2001;19:2739-45.
32. Hirata J, Swiersz LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertil Steril 1997;68:981-6.
33. Fugh-Berman A, Kronenberg F. Red clover (trifolium pratense) for menopausal women: current state of knowledge. Menopause 2001;8:333-7.
34. Greendale G, Lee NP, Arriola ER. The menopause. Lancet 1999;353:571-80.
35. Quella S, Loprinzi CL, Sloan JA, et al. Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes. Cancer 1998;82:1784-8.
36. Laufer L, Erlik Y, Meldrum DR, Judd HL. Effect of clonidine on hot flashes in postmenopausal women. Obstet Gynecol 1982;60:583-6.
37. Pandya K, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Int Med 2000;132:788-93.
38. Leonetti H, Longo S, Anasti JN. Transdermal progresterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999;94:225-8.
39. Freedman R, Woodward S. Behavioral treatment of menopausal hot flushes: evaluation by ambulatory monitoring. Am J Obstet Gynecol 1992;167436-9.
40. Roth A, Sacher HI. Sertraline relieves hot flashes secondary to medical castration as treatment of advanced prostate cancer. Psychooncology 1998;7:129-32.
41. Loprinzi C, Pisansky TM, Fonseca R, et al. Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 1998;16:2377-81.
42. Stearns V, Isaacs C, Rowland J, et al. A pilot trial of paroxetine hydrochloride in controlling hot flashes in breast cancer survivors. Ann Oncol 2000;11:17-22.
43. Zweifel J, O’Brien WH. Meta-analysis of the effect of hormone replacement therapy on depressed mood. Psychoneuroendocrinology 1997;22:189-212.
44. Soares C, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001;58:529-34.
45. Schmidt P, Neiman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000;183:414-20.
46. Bech P, Munk-Jensen N, Obel EB, et al. Combined versus sequential hormonal replacement therapy: a double-blind, placebo-controlled study on quality of life-relationed outcome measures. Psychother Psychosom 1998;7:259-65.
47. Joffe H, Cohen LS. Estrogen, serotonin and mood disturbance: where is the therapeutic bridge? Biol Psychiatry 1998;44:798-811.
48. Nedstrand E, Wijma K, Lindgren M, Hammar M. The relationship between stress-coping and vasomotor symptoms in postmenopausal women. Maturitas 1998;31:29-34.
49. Asplund R, Aberg HE. Body mass index and sleep in women aged 40-64 years. Maturitas 1995;22:1-8.
50. McCoy N. Sexual issues for postmenopausal women. Top Geriatr Rehab 1997;12:28-39.
51. American College of Obstetricians and Gynecologists Committee on Gyecologic Practice. Androgen treatment of decreased libido. Obstet Gynecol 2000;96:244-5.
52. Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineral density. JAMA 1996;276:1389.-
53. Botsis D, Kassanos D, Kalogiro D, et al. Vaginal ultrasound of the endometrium in postmenopausal women with symptoms of uro genital atrophy on low-dose estrogen or tibolone treatment: a comparison. Maturitas 1997;26:57-62.
54. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047-59.
55. Ross R, Paganini-Hill A, Wan PC, et al. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328-32.
56. Schairer C, Lubin J, Triosi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-91.
57. Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other conditions. Ann Rev Public Health 1998;19:55-72.
58. Hemminki E, McPherson K. Impact of postmenopausal therapy on cardiovascular events and cancer: pooled data from clinical trials. BMJ 1997;315:149-53.
59. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13.
60. Simon J, Hsia J, Cauley JA, et al. Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen/Progestin Replacement Study (HERS). Circulation 2001;103:638-42.
61. Wilson P, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. N Engl J Med 1985;313:1038-45.
62. Oger E, Scarabin PY. Risk of stroke among users of hormone replacement therapy. Ann d’Endocrinol 1999;60:232-41.
63. Gutthann S, Rodriguez LA, Castellsague J, Oliart AD. Hormone replacement therapy and risk of thromboembolism: population based case-control study. BMJ 1997;314:796-800.
64. Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977-80.
65. Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998;19:61-109.
66. Mosca L, Grundy SM, Judelson D, King K, Limacher M, Oparil S. AHA/ACC scientific statement: consensus panel statement. Guide to preventive cardiology for women. J Am Coll Cardiol 1999;33:1751-5.
67. Fantl J, Cardozo L, McClish DK. Estrogen therapy in the management of urinary incontinence in postmenopausal women: a meta-analysis. Obstet Gynecol 1994;83:12-8.
68. Grady D, Brown JS, Vittinghoff E, Applegate W, Warner E, Snyder T. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol 2001;97:116-20.
69. Uhler M, Marks JW, Judd HL. Estrogen replacement therapy and gallbladder disease in postmenopausal women. Menopause 2000;7:162-7.
70. Mulnard R, Cotman CW, Kawas C, et al. Estrogen replacement therapy for mild to moderate Alzheimer’s disease: a randomized controlled trial. JAMA 2000;283:1007-15.
71. Langenberg P, Kjerulff KH, Stolley PD. Hormone replacement and menopausal symptoms following hysterectomy. Am J Epidemiol 1997;146:870-80.
72. Kuh D, Wadsworth M, Hardy R. Women’s health in midlife: the influence of the menopause, social factors and health in earlier life. Br J Obstet Gynaecol 1997;104:923-33.
73. Kirchengast S. Relations between anthropometric characteristics and degree of severity of the climacteric syndrome in Austrian women. Maturitas 1993;17:167-80.
74. Stadberg E, Mattson LA, Milsom I. Factors associated with climacteric symptoms and the use of hormone replacement therapy. Acta Obstet Gynecol Scand 2000;79:286-92.
75. Guthrie J, Dennerstein L, Hopper JL, Burger HG. Hot flushes, menstrual status, and hormone levels in a population-based sample of midlife women. Obstet Gynecol 1996;88:437-42.
76. Hammar M, Berg G, Lindgren R. Does physical exercise influence the frequency of postmenopausal hot flushes? Acta Obstet Gynecol Scand 1990;69:409-12.
1. Wysowski D, Golden L, Burke L. Use of menopausal estrogens and medroxyprogesterone in the United States, 1982-1992. Obstet Gynecol 1995;85:6-10.
2. McKinlay S, Brambilla PJ, Posnere JG. The normal menopause transition. Maturitas 1992;14:13-5.
3. Harlow B, Signorello LB. Factors associated with early menopause. Maturitas 2000;35:3-9.
4. Coulam C, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol 1986;67:604-6.
5. Kalantaridou S, Nelson LM. Premature ovarian failure is not premature menopause. Ann NY Acad Sci 2000;900:393-402.
6. Hee J, MacNaughton J, Bangah M, Burger HG. Perimenopausal patterns of gonadotropins, immunoreactive inhibin, oestradiol and progesterone. Maturitas 1993;18:9-20.
7. Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone moneral density. Maturitas 1995;21:103-13.
8. Burger H. Diagnostic role of follicle-stimulating hormone (FSH) measurements during the menopausal transition—an analysis of FSH, oestradiol and inhibin. Eur J Endocrinol 1994;130:38-42.
9. Stadberg E, Mattson LA, Milsom I. The prevalence and severity of climacteric symptoms and the use of different treatment regimens in a Swedish population. Acta Obstet Gynecol Scand 1997;76:442-8.
10. Holte A, Mikkelsen A. The menopausal syndrome: a factor analytic replication. Maturitas 1991;13:193-203.
11. Hunter M. The South-East England Longitudinal Study of the climacteric and postmenopause. Maturitas 1992;14:217-28.
12. Collins A, Landgren BM. Reproductive health, use of estrogen and experience of symptoms in perimenopausal women: a population-based study. Maturitas 1995;20:101-11.
13. Dennerstein L, Smith AMA, Morse C, Burger H, Green A, Hopper J, et al. Menopausal symptoms in Australian women. Med J Aust 1993;159:232-6.
14. Mashchak C, Kletsky QA, Artel R, et al. The relation of physiological changes to subjective symptoms in postmenopausal women with and without hot flushes. Maturitas 1985;6:301-8.
15. Grisso J, Freeman EW, Maurin E, Garcia-Espans B, Berlin JA. Racial differences in menopause information and the experience of hot flashes. J Gen Intern Med 1999;14:98-103.
16. Oldenhave A, Jaszmann LJB, Haspels AA, et al. Impact of climacteric on well-being. Am J Obstet Gynecol 1993;168:772-80.
17. Barentsen R, Groeneveld FP, Bareman FP, et al. Women’s opinion on withdrawal bleeding with hormone replacement therapy. Eur J Obstet Gynecol Reprod Biol 1993;51:203-7.
18. Bachman G. Vasomotor flushes in menopausal women. Am J Obstet Gynecol 1999;180:S312-6.
19. Pearlstein T, Rosen K, Stone AB. Mood disorders and menopause. Endocr Metab Clin North Am 1997;26:279-94.
20. Woods N, Mitchell ES. Pathways to depressed mood for midlife women: observations from the Seattle midlife women’s health study. Res Nurs Health 1997;20:119-29.
21. Polo-Kantola P, Erkkola R. Climacteric symptoms and sleep quality. Obstet Gynecol 1999;94:219-24.
22. Dennerstein L, Dudley E, Burger H. Are changes in sexual functioning during midlife due to aging or menopause? Fertil Steril 2001;76:456-60.
23. Notelovitz M, Cassel D, Hille D, et al. Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with menopause. Am J Obstet Gynecol 2000;182:7-12.
24. Utian W, Burry KA, Archer DF, et al. Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. Am J Obstet Gynecol 1999;181:71-9.
25. Greendale G, 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;92:982-8.
26. World Health Organization. Improving access to quality care in family planning:medical eligibility criteria for contraceptive use. Geneva, Switzerland; 1996.
27. Simon J, Kaiber E, Wiita B, Bowen YHA. Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women. Menopause 1999;6:138-46.
28. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, de Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998;91:6-11.
29. Washburn S, Burke GL, Morgan T, Anthony M. Effect of soy protein on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women. Menopause 1999;6:7-13.
30. St Germaine A, Peterson CT, Robinson JG. Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause 2001;8:17-26.
31. Jacobson J, Troxel AB, Evans J. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 2001;19:2739-45.
32. Hirata J, Swiersz LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertil Steril 1997;68:981-6.
33. Fugh-Berman A, Kronenberg F. Red clover (trifolium pratense) for menopausal women: current state of knowledge. Menopause 2001;8:333-7.
34. Greendale G, Lee NP, Arriola ER. The menopause. Lancet 1999;353:571-80.
35. Quella S, Loprinzi CL, Sloan JA, et al. Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes. Cancer 1998;82:1784-8.
36. Laufer L, Erlik Y, Meldrum DR, Judd HL. Effect of clonidine on hot flashes in postmenopausal women. Obstet Gynecol 1982;60:583-6.
37. Pandya K, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Int Med 2000;132:788-93.
38. Leonetti H, Longo S, Anasti JN. Transdermal progresterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999;94:225-8.
39. Freedman R, Woodward S. Behavioral treatment of menopausal hot flushes: evaluation by ambulatory monitoring. Am J Obstet Gynecol 1992;167436-9.
40. Roth A, Sacher HI. Sertraline relieves hot flashes secondary to medical castration as treatment of advanced prostate cancer. Psychooncology 1998;7:129-32.
41. Loprinzi C, Pisansky TM, Fonseca R, et al. Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 1998;16:2377-81.
42. Stearns V, Isaacs C, Rowland J, et al. A pilot trial of paroxetine hydrochloride in controlling hot flashes in breast cancer survivors. Ann Oncol 2000;11:17-22.
43. Zweifel J, O’Brien WH. Meta-analysis of the effect of hormone replacement therapy on depressed mood. Psychoneuroendocrinology 1997;22:189-212.
44. Soares C, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001;58:529-34.
45. Schmidt P, Neiman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000;183:414-20.
46. Bech P, Munk-Jensen N, Obel EB, et al. Combined versus sequential hormonal replacement therapy: a double-blind, placebo-controlled study on quality of life-relationed outcome measures. Psychother Psychosom 1998;7:259-65.
47. Joffe H, Cohen LS. Estrogen, serotonin and mood disturbance: where is the therapeutic bridge? Biol Psychiatry 1998;44:798-811.
48. Nedstrand E, Wijma K, Lindgren M, Hammar M. The relationship between stress-coping and vasomotor symptoms in postmenopausal women. Maturitas 1998;31:29-34.
49. Asplund R, Aberg HE. Body mass index and sleep in women aged 40-64 years. Maturitas 1995;22:1-8.
50. McCoy N. Sexual issues for postmenopausal women. Top Geriatr Rehab 1997;12:28-39.
51. American College of Obstetricians and Gynecologists Committee on Gyecologic Practice. Androgen treatment of decreased libido. Obstet Gynecol 2000;96:244-5.
52. Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineral density. JAMA 1996;276:1389.-
53. Botsis D, Kassanos D, Kalogiro D, et al. Vaginal ultrasound of the endometrium in postmenopausal women with symptoms of uro genital atrophy on low-dose estrogen or tibolone treatment: a comparison. Maturitas 1997;26:57-62.
54. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047-59.
55. Ross R, Paganini-Hill A, Wan PC, et al. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328-32.
56. Schairer C, Lubin J, Triosi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-91.
57. Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other conditions. Ann Rev Public Health 1998;19:55-72.
58. Hemminki E, McPherson K. Impact of postmenopausal therapy on cardiovascular events and cancer: pooled data from clinical trials. BMJ 1997;315:149-53.
59. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13.
60. Simon J, Hsia J, Cauley JA, et al. Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen/Progestin Replacement Study (HERS). Circulation 2001;103:638-42.
61. Wilson P, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. N Engl J Med 1985;313:1038-45.
62. Oger E, Scarabin PY. Risk of stroke among users of hormone replacement therapy. Ann d’Endocrinol 1999;60:232-41.
63. Gutthann S, Rodriguez LA, Castellsague J, Oliart AD. Hormone replacement therapy and risk of thromboembolism: population based case-control study. BMJ 1997;314:796-800.
64. Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977-80.
65. Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998;19:61-109.
66. Mosca L, Grundy SM, Judelson D, King K, Limacher M, Oparil S. AHA/ACC scientific statement: consensus panel statement. Guide to preventive cardiology for women. J Am Coll Cardiol 1999;33:1751-5.
67. Fantl J, Cardozo L, McClish DK. Estrogen therapy in the management of urinary incontinence in postmenopausal women: a meta-analysis. Obstet Gynecol 1994;83:12-8.
68. Grady D, Brown JS, Vittinghoff E, Applegate W, Warner E, Snyder T. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol 2001;97:116-20.
69. Uhler M, Marks JW, Judd HL. Estrogen replacement therapy and gallbladder disease in postmenopausal women. Menopause 2000;7:162-7.
70. Mulnard R, Cotman CW, Kawas C, et al. Estrogen replacement therapy for mild to moderate Alzheimer’s disease: a randomized controlled trial. JAMA 2000;283:1007-15.
71. Langenberg P, Kjerulff KH, Stolley PD. Hormone replacement and menopausal symptoms following hysterectomy. Am J Epidemiol 1997;146:870-80.
72. Kuh D, Wadsworth M, Hardy R. Women’s health in midlife: the influence of the menopause, social factors and health in earlier life. Br J Obstet Gynaecol 1997;104:923-33.
73. Kirchengast S. Relations between anthropometric characteristics and degree of severity of the climacteric syndrome in Austrian women. Maturitas 1993;17:167-80.
74. Stadberg E, Mattson LA, Milsom I. Factors associated with climacteric symptoms and the use of hormone replacement therapy. Acta Obstet Gynecol Scand 2000;79:286-92.
75. Guthrie J, Dennerstein L, Hopper JL, Burger HG. Hot flushes, menstrual status, and hormone levels in a population-based sample of midlife women. Obstet Gynecol 1996;88:437-42.
76. Hammar M, Berg G, Lindgren R. Does physical exercise influence the frequency of postmenopausal hot flushes? Acta Obstet Gynecol Scand 1990;69:409-12.