MENOPAUSE

 

General information

  • Clinically diagnose menopause based upon amenorrhea for 6 months, symptoms such as vasomotor flushes, vaginal dryness, and insomnia.
  • Regarding symptoms associated with menopause, a panel convened by the NIH concluded that evidence establishes causality only for vasomotor symptoms and vaginal dryness, with some positive evidence for causality with regards to sleep disturbances.  Evidence does NOT establish causality for mood symptoms (depression, anxiety, and irritability), cognitive disturbances, somatic symptoms (back pain, tiredness, and stiff joints), urinary incontinence, or sexual dysfunction (Ann Intern Med. 2005. 142. 1003-1013).

·         A meta-analysis of 2 longitudinal and 8 cross sectional studies with >80% follow up showed that vasomotor symptoms on average start to increase 2 years before the final menstrual period, peak at 1 year after the final menstrual period, and return to baseline 8 years after the final menstrual period. 50% of women continue to report vasomotor symptoms 4 years after the final menstrual period and 10% report symptoms up to 12 years after the final menstrual period (J Gen Intern Med. 2008. 23. 1507-1513).

  • Confirm a diagnosis of menopause with FSH greater than 40 pg/nl, and serum pregnancy test negative. An alternative to a FSH level is measurement of vaginal pH – a value greater than 4.5 in women without vaginitis is diagnostic (Am J Obstet Gynecol. 2004. 190. 1272-1277).
  • Confirm that symptoms are indeed due to estrogen deficiency by checking estradiol level to see if it is low.  BE AWARE that many perimenopausal symptoms are associated with a low progesterone level, and not a low estrogen level.

 

Hormone replacement therapy (HRT)

  • Historically, three indications for hormone replacement therapy (HRT).
    • Relief of symptoms of menopause (hot flashes, urogenital atrophy, moodiness, insomnia). Therapy is effective in controlling symptoms in more than 90% of women (Acta Obstet Gynecol Scand. 1997. 76. 442-448).  As of 7/02, this is considered the only indication for HRT.
    • Prevention of osteoporosis/hip fractures. NO LONGER CONSIDERED A GOOD INDICATION AS OF JULY, 2002 BECAUSE THERE ARE OTHER PHARMACEUTICAL AGENTS WITH FEWER RISKS.  SEE BELOW FOR DETAILS.
    • Prevention of coronary artery disease (CAD). AS OF JULY, 2002 BASED ON NEW DATA, NO LONGER CONSIDERED AND INDICATION.  SEE BELOW FOR DETAILS.
  • Contraindications to estrogen use include pregnancy, breast cancer, estrogen-dependent cancer of any kind, unexplained vaginal bleeding, history of deep venous thrombosis, and active hepatocellular (liver) disease.
    • A17 year observational cohort study which evaluated data from 2755 breast cancer survivors, of whom 174 had used HRT after diagnosis, the mortality rate was actually lower in the group of HRT users (16 per 1000 women years versus 30 per 1000 women years), suggesting that HRT use in self-selected symptomatic breast cancer survivors may actually be safe (J Natl Cancer Inst. 2001. 93. 754-762).
    • HOWEVER, an open randomized trial which had enrolled 434 women was terminated early on 12/17/03 after 6 years when investigators determined that 26 women in the treatment group experienced recurrence, compared with only 7 in the control group.  At this point in the study, 345 of the 434 women had at least one follow up visit and the recurrence occurred at a median of 2.1 years after initiation of HRT (Lancet. 2004. 363. 453-455).
  • The risks of hormone replacement therapy include breast cancer, heart disease, stroke, thromboembolic events, Alzheimer’s disease, biliary tract surgery, ovarian cancer, urinary incontinence, and endometrial cancer if unopposed estrogen is used in women with an intact uterus.
    • Breast cancer:
      • Analysis of data from 46,355 postmenopausal women who participated from 1980-1995 in the Breast Cancer Detection Demonstration Project, a prospective observational study, shows a 1% increase in the relative risk of breast cancer with each year of estrogen use alone, but an 8% increase in the relative risk of breast cancer with each year of estrogen-progesterone use (JAMA. 2000. 283. 485-491). The increased risk of breast cancer is largely limited to current or recent users of hormone replacement therapy.
      • In the Women's Health Initiative estrogen plus progestin trial, a prospective, randomized trial of 16,608 postmenopausal women aged 50-79 with an intact uterus, the relative risk of breast cancer in women on combined HRT arm (Premarin 0.625 mg per day plus Provera 2.5 mg per day) was 1.26 (1.00-1.59) at 5.2 years of follow up, which translates into an absolute increase in risk of 8 cases of breast cancer per year in 10,000 women taking combined HRT. There were 38 cases in the treatment group versus 30 cases in the control group per 10,000 woman years.  The mean age of the women in the study was 63 (JAMA. 2002. 288. 321-333). 
        • Further analysis of the WHI data showed that the cancers in the combined HRT group were diagnosed at a more advanced stage, despite nearly 90% compliance with annual mammography screening in both the treatment and placebo groups.  There were 199 invasive cancers in the treatment group compared with 150 in the placebo group (p=0.003).  In the treatment group, average tumor diameter of the invasive cancers was 1.7 cm compared to 1.5 cm in the placebo group (p=0.04).   In the treatment group, 25.9% of the cancers showed regional spread compared to 15.8% of the cancers in the placebo group (p=0.04).  The histology and grade of the invasive tumors were similar in the treatment versus placebo group.  The incidence of breast cancer in the treatment group was actually lower in the first two years of the study, but this may be due to the decreased sensitivity of mammography in this group (see below). There were not any easily identified subgroups at higher risk (JAMA. 2003. 289. 3243-3253).
        • Adjustment of the relative risk of breast cancer for baseline risk factors for breast cancer, including age, race/ethnicity, BMI, physical activity level, smoking, alcohol use, parity, OC use, family history of breast cancer, frequency of screening mammography, and vasomotor symptoms changed the relative risk slightly from 1.26 to 1.20 (0.94-1.53). This adjusted 95% confidence interval indicates that the increased risk of breast cancer in the Women's Health Initiative estrogen plus progestin trial is not statistically significant (Maturitas. 2006. 55. 103-115).
        • Data analyzed after a total mean follow-up of 11.0 years shows that cumulative breast cancer incidence was higher in the treatment arm, the cancers associated with HRT were more often invasive (p=0.004), more commonly node positive (p=0.03), and mortality from breast cancer in the treatment arm of the WHI appeared to be increased, as compared with the placebo arm (p=0.049). All cause mortality also appeared increased in the treatment arm (p=0.045) [JAMA. 2010. 304. 1684-1692 and editorial 1719-1720).
      • In the HERS II trial, the increased relative risk of breast cancer in the combined HRT group at 6.8 years of follow-up was comparable in magnitude to the increased risk seen in the WHI (JAMA. 2002. 288. 58-66).
      • In the U.K. Million Women Study, a fair quality study, the relative risk of breast cancer in current users of combined HRT was 2.00 (1.91-2.09) compared with those who never used HRT (Lancet. 2003. 362. 419-427).
      • In the Black Women’s Health Study, a prospective epidemiologic study, data on 32,559 women over age 40, collected through biennial questionnaires, showed that use of estrogen alone and also estrogen plus progesterone was associated with an increased risk of breast cancer. The magnitude of risk increased with duration of use, and the association was stronger among leaner women (Arch Intern Med. 2006. 166. 760-765).
      • A population-based case-control study in three counties in western Washington state indicate that the increased risk of breast cancer associated with combined hormone replacement therapy is due primarily to an increase in invasive lobular cancers, and is independent of whether the progesterone component was taken in a continuous or a sequential manner  (JAMA. 2003. 289. 3254-3263).
      • Hormone replacement therapy increases breast density in some women, and decreases both the sensitivity and the specificity of mammography screening for breast cancer (J Natl Cancer Inst. 1996. 88. 643-649; Ann Intern Med. 2003. 138. 168-175).
        • In the PEPI trial, the 16% to 26% of women taking estrogen plus progesterone who experienced an increase in breast density did so within the first year (Ann Intern Med. 1999. 130. 262-269).
        • Combinations of estrogen and progesterone increase breast density more than estrogen alone, and continuous combined regimens increase the density more than sequential combined regimens (J Clin Oncol. 1997. 15. 3201-3207).
        • A study of 103,770 women from Australia showed that the sensitivity of two year mammographic screening in women aged 50-69 given hormone replacement therapy was 64.3% whereas in those not given HRT it was 79.8% (Lancet. 2000. 355. 270-274).
        • In the WHI combined treatment arm, after 1 year 9.4% of women in the treatment group had an abnormal mammogram compared to 5.4% in the placebo group (p<0.001)  [JAMA. 2003. 289. 3243-3253]. At 5.6 years of follow up, 35% of women in the treatment group had an abnormal mammogram compared to 23% in the placebo group (p<0.001). Furthermore, the breast biopsy rate (for abnormal mammograms) was 10% in the treatment group compared to 6.1% in the placebo group (p<0.001) [Arch Intern Med. 2008. 168. 370-377].
        • Discontinuing HRT 1 month or 2 months prior to screening mammography does NOT increase detection rates of breast cancer, based on data from a RCT, even though it is associated with decreased mammographic breast density. In this study, hot flashes recurred in 85% of those randomized to discontinue HRT in advance of screening mammography
      • In the WHI estrogen-alone arm, a prospective, randomized trial in 10,739 postmenopausal women aged 50-79, with prior hysterectomy, Premarin 0.625 mg per day was not associated with an increased risk of breast cancer at 6.8 years of follow up. There was actually a strong trend in this trial toward a decreased risk of breast cancer in the treatment group, with a relative risk of 0.77 (0.59-1.01).  There were 7 fewer cases of breast cancer per 10,000 woman years in the treatment group, but this did not reach statistical significance (JAMA. 2004. 291. 1701-1712).
        • Further analysis of the data came to the same conclusion, but did show a significant increase in abnormal mammograms requiring ‘short-interval’ mammographic follow-up in the treatment group, compared with the control group (36.2% vs. 28.1%, p<0.001) [JAMA. 2006. 295. 1647-1657].
        • At the cessation of this arm of the trial, 7645 surviving participants (78%) who completed the intervention phase gave consent for continued observational follow up through a mean of 10.7 years. Median Premarin use in this subgroup was 5.9 years (but as per an accompanying editorial, median adherent time of women in this arm of the study was only 3.5 years). The decreased risk of breast cancer did persist in users of Premarin, with a relative risk at 10.7 years of follow up of 0.77 (0.62-0.95) [JAMA. 2011. 305. 1305-1314 and editorial 1354-1355].
      • In the E3N-EPIC study, a prospective population study of 54,548 women in France born between 1925 and 1950, at an average follow up of 5.8 years, the relative risk of breast cancer in women using estrogens and synthetic progestins was 1.4 whereas the risk for those using estrogen plus micronized progesterone was 0.9. The risk for those using estrogen alone was 1.1 (not statistically significant). This data would suggest that micronized progesterone is safer from a breast health standpoint (Int J Cancer. 2005. 114. 448-454).
      • The USPSTF III update (2005) concluded that there is good quality evidence that combined HRT increases incidence of breast cancer, but its effects on breast cancer mortality remain uncertain, with the results of 2 good-quality cohort studies conflicting.  Results are also conflicting in the two studies of estrogen alone and effects on breast cancer incidence (Ann Intern Med. 2005. 142. 855-860).
      • Data in Finland obtained by cross-referencing cancer diagnosis in the comprehensive registry with pharmacy data (to identify women older than age 50 who filled at least one prescription for estrogen-only hormone therapy and then eliminating women who took CEE) showed that estradiol use for 5 or more years was associated with an increased relative risk of breast cancer of 1.44, which translates into 20-30 additional cases of breast cancer per 10,000 women during 10 years of follow up. This data encompassed 648,022 patient-years of observation (Obstet Gynecol. 2006. 108. 1354-1360).
    • Heart disease:
      • Historically, prospective, observational data suggested that estrogen reduces the risk of heart disease by 35-50%.  The most convincing of the observational studies was the Nurses Health Study which is methodologically sound and has followed 70,533 postmenopausal women over 20 years (Ann Intern Med.  2000. 133. 933-941). Premarin 0.625 mg daily increases HDL cholesterol 10-15% and decreases LDL cholesterol by 10-15%. Thus, there was a seemingly strong theoretic rationale to support the conclusion of a cardioprotective effect of HRT.
      • However, the combination HRT arm of the Women's Health Initiative estrogen plus progestin trial, a prospective, randomized trial of 16,608 postmenopausal women aged 50-79 with an intact uterus but without heart disease, was terminated two years early, in 2002, because an independent review board actually found an increase in the risk of heart disease!   At 5.2 years the relative risk in the active treatment group was 1.29 (1.02-1.63) for heart attacks, which translates into an absolute risk of 7 additional heart attacks per 10,000 women per year.  There were 37 events in the treatment group versus 30 events in the control group per 10,000 woman years.  The mean age of the women in the study was 63 (JAMA. 2002. 288. 321-333). NOTE the subgroup analysis by years from menopause described just below (JAMA. 2007. 297. 1465-1477).
      • Furthermore, a randomized, prospective secondary prevention trial of postmenopausal women with established heart disease, the HERS Trial, which followed 2763 postmenopausal women for 4.1 years, found no overall difference in cardiovascular endpoints between the women treated with a combination of daily Premarin 0.625 mg and Provera 2.5 mg versus women treated with placebo (JAMA. 1998. 280. 605-613). In the HERS trial, an increase in cardiovascular risk was noted in the first year, postulated to be due to the thrombotic effects of  hormone replacement therapy, with a trend noted of decreased risk of CHD events with increased duration of use of HRT.  However, the HERS II, which was unblinded and followed the women in the HERS trial for an additional 2.7 years, found that those who chose to take HRT did not sustain the lower rates of CHD noted in the final years of the HERS trial, such that after 6.8 total years of combined hormone replacement therapy, there was no reduction in CHD events in women with pre-existing CHD (JAMA. 2002. 288. 49-57).
      • Finally, another secondary prevention trial, the Estrogen Replacement in Atherosclerosis Trial, in which 309 women with angiographically verified coronary artery disease, followed for a mean of 3.2 years, had baseline and follow-up quantitative angiograms, showed no benefit of estrogen alone or estrogen plus progesterone on the progression of coronary artery disease (N Engl J Med. 2000. 343. 522-529).
      • The USPSTF III (2002) concluded that HRT does not decrease and may in fact increase the risk of CHD, but its effects on CHD mortality remain uncertain (Ann Intern Med. 2002. 137. 834-839).
      • In the WHI estrogen-alone arm,  a prospective, randomized trial in 10,739 postmenopausal women aged 50-79, with prior hysterectomy, the risk of heart disease was identical at 6.8 years of follow up in the treatment and control groups, with a relative risk in the treatment group of 0.91 (0.75-1.12) [JAMA. 2004. 291. 1701-1712].
        • A more detailed analysis of the same data concluded that there was no protection against either MI or coronary death, (Arch Intern Med. 2006. 166. 357-365), but subgroup analysis (described just below) showed a strong trend toward protection in the subgroup of women age 50-59 (Arch Intern Med. 2006. 166. 399-404).
        • Data at a mean of 10.7 years in the 7645 surviving participants (78%) who completed the intervention phase gave consent for continued observational follow up continued to show a lack of protective benefit of Premarin, with a relative risk in the intervention group of 0.97 (0.75-1.25). However, as reported in the 2006 paper looking at subgroup analysis of women age 50-59 at trial onset, data suggested a net reduction in heart disease in this younger subgroup of women (JAMA. 2011. 305. 1305-1314 and editorial 1354-1355).
      • Esterified estrogen (EE) might be safer than conjugated equine estrogen (CEE), based on a case-control study conducted in GHC, a staff-model HMO in which there was a formulary change – there was a trend in the first 6 months on estrogen toward a higher risk of MI with CEE (odds ratio 2.33, 95% confidence interval 0.93-5.82) [Arch Intern Med. 2006. 166. 399-404].
      • Estrogen and heart disease – there is data to support the concept that estrogen has different effects on blood vessels in younger postmenopausal women (50-59 years old), as compared with older postmenopausal women (NOTE the average age of women in the WHI study was 63 years old) [Editorial. HRT and the young heart. N  Engl J Med. 2007. 356. 2639-3641].
        • Basic research and animal research on the vascular biology of estrogen supports this concept of a differential effect of estrogen in younger versus older postmenopausal women (Curr Opin Cardiol. 1994. 9. 619-626; N Engl J Med. 1999. 340. 1801-1811).
        • This concept of a differential effect of estrogen in younger versus older postmenopausal women can help to explain the discrepancy between observational data showing a protective effect of estrogen and the WHI showing no protective effect.
        • Subgroup analysis of the WHI estrogen-alone arm showed that there was a trend toward a lower risk of heart disease in women age 50-59 at baseline, with a relative risk of 0.63, but a confidence interval of 0.36-1.08. The number of women 50-59 in this study who received Premarin was 1637 and the number who received placebo was 1673. The relative risk in women age 60-69 was 0.94 and the relative risk in women age 70-79 was 1.11 (Arch Intern Med. 2006. 166. 399-404).
        • Subgroup analysis in which data from the WHI estrogen-alone arm and the WHI estrogen plus progesterone arm was combined and analyzed by decade after menopause found that (1) in women less than 10 years since menopause, the hazard ratio for CHD was 0.78, (2) in women 10-19 years since menopause, the hazard ratio for CHD was 1.10, and (3) in women greater than 20 years since menopause, the hazard ratio for CHD was 1.35 (JAMA. 2007. 297. 1465-1477).
        • However, re-analysis of the WHI data looking at the subgroup of women who initiated either Premarin alone or Premarin + Provera within 5 years of menopause found that the risk of CHD was slightly increased regardless of whether hormone therapy was instituted within 5 years of menopause or more than 5 years after menopause (Am J Epidemiol. 2009. 170. 12). This study differed from the above studies published in JAMA and Archives of Internal Medicine in that this study analyzed the time between menopause and first use of hormone therapy, whereas the above studies published in JAMA and Archives of Internal Medicine analyzed the time between menopause and study entry into the WHI (Commentary by Tori Hudson. Townsend Letter. 4/10. Pg 114).
        • In the WHI-CASS, an ancillary substudy of the WHI in which 28 of the 40 centers participated, coronary artery calcium scores were determined in 1064 women age 50-59, after a mean of 7.4 years of treatment and 1.3 years after the trial was completed. Surgically induced menopause occurred a mean of 11 years prior to the entry of this cohort of women in the WHI. Mean scores were lower in women receiving Premarin (83.1) than in women receiving placebo (123.1), and this 42% difference was statistically significant (p=0.02). In the subset of women adherent to estrogen treatment, calcium scores were 61% lower (N Engl J Med. 2007. 356. 2591-2602).
        • 2007 Consensus statements of the North American Menopause Society and the IMS endorse the timing hypothesis and recognize the potential beneficial cardiovascular effects of estrogen in younger menopausal women (Menopause. 2007. 2. 168-182; Climacteric. 2007. 10. 181-194).
    • Stroke:
      • In the Women's Health Initiative estrogen plus progestin trial, the relative risk of stroke in women on combined HRT was 1.41 (1.07-1.85) at 5.2 years, which translates into an absolute increase in risk of 8 strokes per year in 10,000 women taking combined HRT.  There were 29 strokes in the treatment group and 21 strokes in the control group per 10,000 woman years (JAMA. 2002. 288. 321-333).
      • Further analysis of the WHI data showed that the increased risk was for ischemic strokes, with a nonstatistically significant decrease in the risk of hemorrhagic stroke.  Subgroup analysis indicated that the increased risk of stroke was present in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin.  Other risk factors for stroke, including smoking, high blood pressure, diabetes, lower use of vitamin C, and blood-based biomarkers of inflammation did not modify the effect of estrogen plus progesterone on stroke risk (JAMA. 2003. 289. 2673-2684).
      • In the Nurses Health Study involving 70,533 postmenopausal women, the risk for ischemic stroke was increased among hormone users compared with never-users (Ann Intern Med. 2000. 133. 933-941).
      • The USPSTF III (2002) concluded there is fair evidence that HRT increases the risk for stroke (Ann Intern Med. 2002. 137. 834-839).
      • In the WHI estrogen-alone arm, a prospective, randomized trial in 10,739 postmenopausal women aged 50-79, with prior hysterectomy, the study was terminated approximately one year early at 6.8 years of follow up because of an increased relative risk of stroke, 1.39 (1.10-1.77).  This translates into 12 additional strokes per 10,000 woman years (JAMA. 2004. 291. 1701-1712). Recalculation of the hazard ratio in a subsequent publication yielded a result of 1.33, with a nominal 95% confidence interval of 1.05-1.66, but an adjusted  95% confidence interval of 0.97-1.99 (JAMA. 2007. 297. 1465-1477).
      • Esterified estrogen (EE) might be safer than conjugated equine estrogen (CEE), based on a case-control study conducted in GHC, a staff-model HMO in which there was a formulary change – there was a trend toward a higher risk of ischemic stroke with CEE (odds ratio 1.57, 95% confidence interval 0.98-2.53) [Arch Intern Med. 2006. 166. 399-404].
    • Thromboembolic events:
      • In the Women's Health Initiative estrogen plus progestin trial, the relative risk of thromboembolic events in women on combined HRT was 2.13 (1.39-3.25) at 5.2 years of follow-up, which translates into an absolute increase in risk of 18 thromboembolic events per year in 10,000 women taking combined HRT.   There were 34 events in the treatment group versus 16 events in the control group per 10,000 woman years. The absolute increase in the risk of pulmonary embolus, a subcategory of thromboembolic events, was 8 per year (JAMA. 2002. 288. 321-333).
      • In the HERS trial of 2763 postmenopausal women on combined HRT, the relative risk of thromboembolic events was 2.66 at 4.1 years of follow-up (JAMA. 1998. 280. 605-613).  In HERS II it dropped to 1.40, so the overall risk at 6.8 years of follow up was 2.08 (JAMA. 2002. 288. 49-57).
      • A meta-analysis of 12 studies demonstrate that current use of postmenopausal estrogen is associated with a relative risk of venous thromboembolism of 2.14, based on an additional 1.5 events per 10,000 women each year, from a baseline risk of 1.3 events per 10,000 woman-years.  Six studies that reported risk according to duration of use found the highest risk in the first year of use, with a relative risk of 3.49 (Ann Intern Med. 2002. 136. 680-690).  As an aside, tamoxifen (Nolvadex) is associated with a threefold increased risk of pulmonary embolism (J Natl Cancer Inst. 1998. 90. 1371-1388) and raloxifene (Evista) is associated with a threefold increased risk of venous thromboembolism (JAMA. 1999. 281. 2189-2197).
      • The USPSTF III (2002) concluded there is good evidence that HRT increases the risk for venous thromboembolism (Ann Intern Med. 2002. 137. 834-839).
      • Transdermal estradiol does NOT appear to increase the risk of thromboembolic events, based on data from a case-control study.  This may be due to the reduced plasma estrone-to-estradiol ratios achieved by transdermal preparations, or it may be due to less alteration of clotting factors (Lancet. 2003. 362. 428-432).
      • Esterified estrogen does NOT appear to increase risk of thromboembolic events, based on data from a case control study (JAMA. 2004. 292. 1581-1587).
      • In the WHI estrogen-alone arm, there was a nonsignificant increase in the risk of pulmonary embolus, with a relative risk of 1.34 (0.87-2.06) [JAMA. 2004. 291. 1701-1712]. Further analysis of the data showed that there was a significant increased risk of DVT of 1.47 (1.06-2.06), and that the risk venous thromboembolism (DVT + pulmonary embolus) was highest in the first two years on conjugated estrogens (Arch Intern Med. 2006. 166. 772-780).
    • Alzheimer's disease:
      • Historically, epidemiologic data subjected to a systematic review and meta-analysis (JAMA. 2001. 285. 1489-1499) and prospective, observational data (Lancet. 1996. 348. 429-432; Neurology. 48. 1517-1521; JAMA. 2002. 288.  2123-2129) suggested a benefit.  The magnitude of the benefit appeared to be about a 30% reduced risk.  In the most recent prospective study (JAMA) only former users and long time current users (>10 years) appeared to benefit, suggesting that there may be a critical period for use prior to the onset of preclinical disease.
      • Additionally, strong biological evidence supports the beneficial effects of estrogen on the brain, including neurotrophic effects, reductions in beta-amyloid accumulation, enhanced neurotransmitter release and action, and protection against oxidative damage (J Clin Endocrinol Metab. 1999. 84. 1790-1797; Nat Med. 1998. 4. 447-451).  Estrogen receptors are located throughout the brain, especially in areas involved in learning and memory (J Comp Neurol. 1997. 388. 507-525).
      • The USPSTF III (2002) concluded there is insufficient evidence to determine whether HRT reduces the risk for dementia or cognitive dysfunction in otherwise healthy women (Ann Intern Med. 2002. 137. 834-839).
      • However, in the Women's Health Initiative Memory Study (WHIMS), a RCT of women over age 65 and free of probable dementia, recruited from 39 of the 40 WHI clinical centers, hormone replacement therapy was associated with an increased risk of dementia and a more rapid deterioration in cognitive function.  The results are as follows:
        • In the Premarin plus Provera group, in which 4532 community-dwelling women aged 65-79 were enrolled, at 4.05 years of follow up the relative risk for probable dementia was 2.05 (1.21-3.48, p=0.01).  This translates into an absolute risk of 23 additional cases of dementia per 10,000 women per year (45 cases vs. 22 cases per 10,000 women per year).  Alzheimer disease was the most common classification of dementia in both the treatment group and the placebo group.  Subgroup analysis found similar results among multiple subgroups evaluated.  Treatment effects on mild cognitive impairment did not differ between the treatment group and the placebo group, with 63 cases per 10,000 women per year in the treatment group compared with 59 cases in the placebo group, for a relative risk 1.07 (0.74-1.55) [JAMA. 2003. 289. 2651-2662].
        • In the Premarin group, in which 2947 community-dwelling women aged 65-79 were enrolled, at 5.4 years of follow up the relative risk for probable dementia was 1.49 (0.83-2.66).  This translates into an absolute risk of 9 additional cases of dementia per 10,000 women per year (28 cases vs. 19 cases per 10,000 women per year).    Mild cognitive impairment was more common in the treatment group, with 76 cases vs. 58 cases, for a relative risk of 1.34 (0.95-1.89) [JAMA. 2004. 291. 2947-2958].
        • When data from the Premarin plus Provera trial were pooled with data from the Premarin trial, as per the original WHIMS protocol, the relative risk for probable dementia was 1.76 (1.19-2.60, p=0.005).  Re-analysis of the data after excluding participants with baseline low Modified MMSE scores did not change the statistical outcomes.  The relative risk for mild cognitive impairment when the data was pooled was 1.25 (0.97-1.60) [JAMA. 2004. 291. 2947-2958].
        • In the Premarin plus Provera group, at 4.2 years of follow up, there was no difference in global cognitive function between the treatment group and the placebo group, as measured by the Modified MMSE exam.  The scores tended to improve in the treatment and placebo group, actually with slightly greater improvement in the placebo group which was statistically significant (p=0.03) but not considered to be clinically significant (JAMA. 2003. 289. 2663-2672).
        • In the Premarin group, at 5.4 years of follow up, global cognitive function deteriorated more in the treatment group than the placebo group (p=0.04) [JAMA. 2004. 291. 2959-2968].
        • When the data from the Premarin plus Provera trial were pooled with data from the Premarin trial, global cognitive function deteriorated more in the treatment group than the placebo group (p=0.006) [JAMA. 2004. 291. 2959-2968].
      • Randomized trials of Premarin 0.625 mg a day or higher for 4-12 months in women diagnosed with mild to moderate Alzheimer’s showed no benefit and possible harm, as per an editorial (JAMA. 2004. 291. 3005-3007). These results were all reported after the initiation of  WHIMS (Neurology. 2000. 54. 295-301; JAMA. 2000. 283. 1007-1015; Neurology. 2000. 54. 2061-2066; Cochrane Database Syst Rev. 2002. CD0031220.
    • Gallbladder disease:
      • Risk is increased by a factor of 1.8 in the short term and 2.5 in the long term (Obstet Gynecol. 1994. 83. 5-11).
      • In HERS II the relative risk of biliary tract surgery was 1.48 at 6.8 years of follow up (JAMA. 2002. 288. 49-57).
      • The Women's Health Initiative estrogen plus progestin trial at 5.6 years of follow-up found that the relative risk of a gallbladder event (hospitalization for gallbladder disease or gallbladder-related procedure) was 1.59 (1.28-1.97) which translates to an excess of 20 events per 10,000 person years (55 vs. 35).  In the WHI estrogen-alone arm, the relative risk of a gallbladder event was 1.67 (1.35-206) which translates to an excess of 31 events per 10,000 person years (78 vs. 47) [JAMA. 2005. 293. 330-339].
      • The USPSTF III (2002) concluded there is fair evidence that HRT increases the risk for cholecystitis (Ann Intern Med. 2002. 137. 834-839).
    • Ovarian cancer:
      • One study found no effect of HRT on ovarian cancer mortality (Int J Cancer. 1996. 67. 327-332).
      • However, a good-quality cohort study reported an increased risk of ovarian cancer mortality in women who had taken hormone replacement therapy for 10 years or more (JAMA. 2001. 285. 1460-1465).
      • Analysis of data from 46,355 postmenopausal women who participated from 1979-1998 in the Breast Cancer Detection Demonstration Project, a prospective observational study, shows an increased risk of ovarian cancer with estrogen-only replacement therapy, but no increased risk in women taking combined estrogen-progesterone hormone replacement therapy.   The relative risk of ovarian cancer in women who took estrogen-only  replacement therapy for 10-19 years was 1.8, and the relative risk of ovarian cancer in women who took estrogen-only  replacement therapy for 20 or more years was 3.2 (JAMA. 2002. 288. 334-341).
      • The Women's Health Initiative estrogen plus progestin trial at 5.6 years of follow-up found a trend toward an increased incidence of invasive ovarian cancer in women on estrogen/progesterone, with a hazard ration of 1.58 [0.77-3.24] (JAMA. 2003. 290. 1739-1748).
      • In a prospective observational study of 910,000 women over age 50 in Denmark followed for an average of 8 years, current users of HRT had a RR of ovarian cancer of 1.38 and previous users had a RR of 1.15 (JAMA. 2009. 302. 298).
      • The USPSTF III (2002) concluded evidence was insufficient to determine the effect of HRT on ovarian cancer (Ann Intern Med. 2002. 137. 834-839).
    • Urine incontinence (UI):
      • In women continent at baseline in the WHI, the relative risk of stress UI at one year was1.87 (1.61-2.18) in women on estrogen plus progesterone and 2.15 (1.77-2.62) in women on estrogen alone (JAMA. 2005. 293. 935-948)..
      •  In women continent at baseline in the WHI, the relative risk of mixed UI at one year was1.49 (1.10-2.01) in women on estrogen plus progesterone and 1.79 (1.26-2.53) in women on estrogen alone (JAMA. 2005. 293. 935-948)..
      • In women continent at baseline in the WHI, the relative risk of urge UI at one year was neutral at 1.15 (0.99-1.34) in women on estrogen plus progesterone but 1.32 (1.10-1.58) in women on estrogen alone (JAMA. 2005. 293. 935-948)..
      • Among women experiencing urine incontinence at baseline in the WHI, the frequency worsened at one year in both the estrogen plus progesterone group and the estrogen alone group (JAMA. 2005. 293. 935-948)..
      • Women receiving either estrogen plus progesterone or estrogen alone were more likely than women receiving placebo to report at one year that urine incontinence limited their daily activities and bothered them (JAMA. 2005. 293. 935-948).
    • Endometrial cancer:
      • Results of a meta-analysis of 29 good-quality observational studies reported a relative risk of 2.3 for users of unopposed estrogen (Obstet Gynecol. 1995. 85. 304-313).  However, the risk of death is probably not increased because of early detection. Hysterectomy is usually curative - women on unopposed estrogen probably face a lifetime probability of 20% of requiring hysterectomy; addition of progesterone eliminates the risk. In women on unopposed estrogen, yearly endometrial biopsy is quite effective for early detection. Transvaginal ultrasound may eliminate the need for many endometrial biopsies.
      • The Women's Health Initiative estrogen plus progestin trial (JAMA. 2002. 288. 321-333) and the HERS II trial (JAMA. 2002. 288. 58-66) showed that combined estrogen/progestin treatment does not increase the risk of endometrial cancer.
      • The USPSTF III (2002) concluded that unopposed estrogen, but not estrogen-progestin therapy, increases the risk for endometrial cancer (Ann Intern Med. 2002. 137. 834-839).
    • Lung cancer: Post hoc analysis of the Women's Health Initiative estrogen plus progestin trial showed that at a mean of 7.9 years of follow up, estrogen plus progesterone increased lung cancer mortality but not incidence in postmenopausal women. Incidence was increased, but this increase did not reach statistical significance. The increased deaths were specifically detected for non-small cell lung cancer and women over age 60 (Lancet. 2009. 374. 1243-1251).
    • Cataract surgery: In a 98 month study in 30,861 postmenopausal women, those who had ever used HRT had a 14% higher risk for cataract extraction, and current users of HRT had a18% higher risk, compared with women who never used HRT (Lindblad E. Ophthalmology. Epub 1/4/10).
    • Nephrolithiasis – in the Women’s Health Initiative, Premarin was associated with a RR of nephrolithiasis of 1.21, relative to placebo (39 events per 10,000 person years as compared with 34 events per 10,000 person years). When the data was analyzed for the subgroup of women who adhered to therapy, RR was 1.39. The increased risk was independent of coadministration of Provera (Arch Intern Med. 2010. 170. 1678-1685).
  • The benefits of hormone replacement therapy include relief of symptoms of menopause, prevention of hip fracture, a decreased risk of colon cancer, and a decreased risk of diabetes.
    • Mortality in younger women – Bayesian meta-analysis of 19 RCT’s (n=16,283; mean follow up 5 years) and 8 observational studies (n=212,171; mean follow up 14 years) concluded that consistent evidence from randomized and observational studies shows that hormone therapy reduces mortality in younger (age < 60) postmenopausal women. The absolute risk reduction was 0.75%, NNT 134 (Am J Med. 2009. 122. 1016-1022).
    • Hip fracture:
      • In the Women's Health Initiative estrogen plus progestin trial, the relative risk of hip fracture in women on combined HRT was 0.66 (0.45-0.98) at 5.2 years of follow up, which translates into an absolute risk reduction of 5 hip fractures per year in 10,000 women taking combined HRT.  There were 10 cases in the treatment group versus 15 cases in the control group per 10,000 woman years (JAMA. 2002. 288. 321-333).
      • Further analysis of data in the Women's Health Initiative estrogen plus progestin trial determined at 5.6 years of follow-up that estrogen plus progesterone increased bone mineral density and decreased the risk of fracture (hip + vertebrae + wrist) independent of baseline risk. The relative risk for any fracture was 0.76 in the treatment group (0.69-0.83). There were 47 fewer total fractures per 10,000 women per year in the treatment group (JAMA. 2003. 290. 1729-1738).
      • The HERS II trial surprisingly found no reduction in fractures in HRT users (JAMA. 2002. 288. 58-66).
      • Historical note - in terms of effect on bone density, some studies suggest that the response to estrogens may be greatest in those women furthest from menopause (Obstet Gynecol. 1990. 76. 290-295; J Clin Endocrinol Metab. 1995. 80. 776-782).
        • In a RCT of 40 women with a mean age of 62 and with established osteoporosis, BMD at the lumbar spine increased by 10.6% (p<0.01) and BMD at the hip increased by 5.5% (p<0.1) after two years of conjugated estrogen 0.625 mg daily (Obstet Gynecol. 1990. 76. 290-295).
        • In a RCT of 75 women with a mean age of 65 and with established osteoporosis, BMD at the lumbar spine increased by 5.3% (p<0.001) after one year of transdermal estradiol 0.1mg/week (Ann Intern Med. 1992. 117. 1-9).
      • Ultra-low dose micronized 17 beta-estradiol, 0.25 mg/day shown in a 3 year RCT in 167 healthy, community-dwelling women over age 65 to increase density in the hip, spine, and total body, and to reduce bone turnover, as measured by metabolic markers.  This lower dose is presumably safer, although this is unknown.  The effect of this low dose on osteoporotic fractures is also unknown (JAMA. 2003. 290. 1042-1048).
      • In the WHI estrogen-alone arm, the relative risk of hip fracture was decreased with treatment, relative risk 0.61 (0.41-0.91).  This translated into 6 fewer hip fractures per 10,000 women treated per year. The relative risk of any fracture was 0.70 (0.63-0.79), translating into 56 fewer fractures per 10,000 women treated per year (JAMA. 2004. 291. 1701-1712).
      • The USPSTF III update (2005) concluded that there is good quality evidence that combined HRT increases bone density (Ann Intern Med. 2005. 142. 855-860).
    • Colorectal cancer:
      • In the Women's Health Initiative estrogen plus progestin trial, the relative risk of colon cancer in women on combined HRT was 0.63 (0.43-0.92) at 5.2 years of follow up, which translates into an absolute risk reduction of 6 cases of colon cancer per year in 10,000 women taking combined HRT.  There were 10 cases in the treatment group versus 16 cases in the control group per 10,000 woman years (JAMA. 2002. 288. 321-333).
      • In the HERS II trial, the relative risk of colon cancer was reduced but not statistically significant at 0.81 [0.46-1.45] (JAMA. 2002. 288. 58-66).
      • The USPSTF III (2002) concluded there is fair evidence that HRT reduces colorectal cancer incidence (Ann Intern Med. 2002. 137. 834-839).
      • In the WHI estrogen-alone arm, the risk of colon cancer was unchanged with treatment, relative risk 1.08 (0.75-1.55) [JAMA. 2004. 291. 1701-1712].
    • Diabetes:
      • In the HERS Trial, a secondary prevention trial in 2763 postmenopausal women, HRT was protective in the subgroup of 2029 women who did not have diabetes at baseline, reducing the risk of onset of diabetes by 35% from 9.5% in the placebo group to 6.2% in the HRT group.  The number needed to treat to prevent one case of diabetes was 30 (Ann Intern Med. 2003. 138. 1-9).
      • A subanalysis of the Women's Health Initiative estrogen plus progestin trial found that women on HRT had a relative risk of 0.79 (0.67-0.93) for development diabetes after 5 years (277 cases vs. 324 cases). This translates into 15 fewer cases of diabetes per 10,000 women per year in the treatment group. In the subgroup of women compliant with HRT throughout the follow up period, the decreased risk was 33% (Diabetologia. 2004. 47. 1175-1187).
      • A subanalysis of the WHI estrogen-alone arm found that women on estrogen had a relative risk of  0.88 (0.77-1.01) for development of diabetes after 6 years, a difference which was not significant. In the subgroup of women compliant with estrogen throughout the follow up period, the decreased risk was 27%, a difference which was significant (Diabetologia. 2006. 49. 459-468).
  • Historical note - estrogen was historically considered advisable in women after a hysterectomy because of observational data showing that estrogen therapy post-hysterectomy adds an average of 1.1 years of life.  However, in the WHI estrogen-alone arm, the estimated excess risk for all monitored events in the global index was 2 events per 10,000 woman years, indicating neither harm nor benefit from estrogen monotherapy (JAMA. 2003. 289. 2663-2672).
  • Side effects of hormone replacement therapy:
    • Side effects of estrogen include bloating, headaches, and breast tenderness in 5-10% women. Symptoms are often self limited after a few months. If intolerance, try half dose for 2 months, then increase to full dose.
    • Side effects of progesterone include breast tenderness, bloating, weight gain, irritability, and depression.  If side effects occur with one formulation, then try a different formulation.
  • Modes of administration of hormone replacement therapy:
    • Estrogen can be given by mouth, by patch, or by injection.
      • Injections are expensive, inconvenient, and produce unnecessarily high blood levels.
      • The advantage of a patch is that it avoids “first pass” metabolism of estrogen in the liver.
    • Progesterone historically was always given by mouth, is now also available in patch form.
  • Formulations of estrogen (and usual replacement doses) include:
    • Conjugated estrogens (Premarin) 0.625 mg
    • Estropipate (Ogen, Orto-Est) 0.625 mg
    • Micronized estradiol (Estrace) 0.5 mg
    • Transdermal estradiol (Climara, Estraderm, Vivelle) 0.5 mg
    • Ethinyl estradiol 0.05 mg
    • Esterified estrogens 0.3 mg
  • Formulations of progesterone include:
    • Provera (medroxyprogesterone) 2.5-10 mg/day
    • Norethindrone 0.35mg/day
    • Norgestrol 0.075 mg/day
    • Micronized progesterone (Prometrium) 200 mg/day
  • Dosage options if a decision is made to treat (trend toward decreased doses and increased duration of Provera treatment).
    • Premarin 0.625 mg days 1-25, Provera 5-10 mg days 14-25.
    • Premarin 0.625 mg days 1-31, Provera 5-10 mg days 1-12.
      • Withdrawal bleeding is acceptable from days 5-15.
      • If bleeding occurs before day 10, increase progesterone dose.
    • Premarin 0.625 mg + Provera 2.5 mg every day.
      • There is no long term withdrawal bleeding, but 1/3 of patients have unpredictable bleeding for the first year.
      • Data in diabetics indicates that this regimen causes more disruption of insulin levels and blood sugar control.
    • Premarin 0.3 mg + Provera 1.5 mg every day.
      • The Women's HOPE Study, which enrolled over 2600 healthy but symptomatic postmenopausal women with an intact uterus showed both an improvement in vasomotor symptoms and vaginal atrophy at 3 weeks (Fertil Steril. 2001. 75. 1065-1079) and an increase in bone mineral density of the spine, hip, and total body at 24 months, compared to baseline (JAMA. 2002. 287. 2668-2676). The lower dose provided endometrial protection similar to standard doses despite higher rates of amenorrhea (Fertil Steril. 2001. 75. 1080-1087).
      • Older, less rigorous studies had shown no benefit from doses of conjugated equine estrogen this low.
  • HRT and quality of life:
    • In the Postmenopausal Estrogen/Progesterone Intervention Trial, HRT was not associated with an improvement in quality of life (Obstet Gynecol. 1998. 92. 982-988).
    • In the HERS trial, a RCT with 2763 patients with known coronary artery disease, women with the symptom of flushing or hot flashes showed a measurable improvement in emotional quality of life on HRT, but women without flushing at baseline showed a measurable deterioration in quality of life on HRT.
    • In the Women's Health Initiative estrogen plus progestin trial, in which only 12% of women reported symptoms of menopause at baseline, HRT did not have a clinically meaningful effect on health-related quality of life, except in the subgroup with symptoms (New Engl J Med. 2003. 348. 1839-1854).
    • In the Women’s Health Initiative estrogen only arm in postmenopausal women with hysterectomy, oral conjugated equine estrogens (Premarin) did not improve any of the HRQOL variables at one year (Arch Intern Med. 2005. 165. 1976-1986).
  • HRT discontinuation and quality of life: (JAMA. 2005. 294. 183-193 and 245-246)
    • Data below based on information collected in surveys mailed 8-12 months after the stop date of the estrogen + progesterone arm of the WHI to each of the 8405 women who were still taking study pills (either HRT or placebo) when the study was terminated 7/8/02.  9351 women were enrolled in this arm of the study; 89.9% were still taking pills on the study termination date. Mean age of these women at trial stop date was 69.1 years, and women had been taking pills on average for 5.7 years.
    • In women who discontinued estrogen + progesterone, 21.2% experienced moderate to severe vasomotor symptoms. In this group, 55.5% of the women with these symptoms at baseline reported them upon withdrawal of estrogen + progesterone.
    • In women who discontinued placebo, 4.8% experienced moderate to severe vasomotor symptoms. In this group, 21.3% of the women with these symptoms at baseline reported them upon withdrawal of placebo.
    • In women who discontinued placebo, 38.3% reported pain or stiffness – note these symptoms may not be caused by an estrogen-deficient state.
    • Among women who did not have vasomotor symptoms at baseline, only 6.4% reported symptoms upon discontinuation of estrogen + progesterone.
    • Among the 63.3% of WHI participants who reported at least one moderate or severe symptom after discontinuation of estrogen + progesterone, lifestyle changes such as increasing exercise, practicing yoga, meditation, or breathing exercises, and using fans were perceived as helpful.
    • One can speculate that part of the reason for symptoms upon withdrawal of estrogen + progesterone is due to abrupt discontinuation and that tapering the dose may decrease the likelihood of withdrawal symptoms.

 

Bio-identical hormone replacement therapy

·        By definition, this refers to administration of synthetic estrogen or progesterone which is identical in biologic structure to what the body produces. 

o       Bio-identical hormone replacement therapy is a more accurate term than natural hormone replacement therapy.

o       Bio-identical hormones are synthesized from beta-sitosterol, which is derived from soybean, or from diosgenin, which is extracted from wild yam

·        Some individuals will experience fewer side effects with bio-identical HRT, compared with Premarin and Provera.

·        Effectiveness of bio-identical HRT:

o        A systematic review and meta-analysis of 32 treatment trials found that the use of Premarin (conjugated equine estrogens) and oral and transdermal 17-beta-estradiol have consistent and comparable effects on the treatment of hot flashes in menopausal women with symptoms (JAMA. 2004. 291. 1610-1620).

o       Bio-identical progesterone should be as effective as synthetic progestins at prevention of endometrial cancer as long as an adequate serum level is achieved.

§         Micronized oral progesterone shown to be effective in the PEPI trial.

§         Three studies have shown that if progesterone cream is used instead of oral progesterone along with estrogen replacement therapy, serum levels of progesterone are insufficient to prevent estrogenic stimulation of the uterus (Lancet. 1998. 351. 1255-1256; Lancet. 1999. 354. 1447-1448; Maturitas. 2002. 41.1-6).

§         Wild yam products which contain only diosgenin, a precursor to progesterone, are not effective because diosgenin cannot be converted to hormonally active progesterone in the human body.

·        Safety of bio-identical HRT:

o       Hypothesized as safer than Premarin and Provera, and there are some in-vitro studies to indicate greater safety (J Complem Med. 2004. 3[5]. 44-45), but no clinical trial data comparing bio-identical HRT to Premarin and Provera.

o       Micronized oral progesterone has been shown in the PEPI trial to have a less adverse effect on lipid profiles than Provera, but this is a surrogate endpoint.

o       There was no increase in risk of breast cancer in the estrogen arm of the French MISSION study, at an average follow up of 8 years. This is a prospective observational study (Gynecologic Endocrinology. 2007. 23. 391-397).

·        Progesterone cream

o       Dr. John Lee published data on transdermal progesterone cream and osteoporosis reversal (Lancet. 1991. 336. 1327).

o       A one year RCT in 102 postmenopausal women looking at the efficacy of 1/4 teaspoon or 20 grams of progesterone cream per day, rubbed on the skin, found that 83% of treatment subjects noted improvement or resolution of vasomotor symptoms compared with 19% of placebo control subjects(p<0.001).  Eight women in this study had induction of postmenopausal bleeding by progesterone cream. There was no benefit in terms of bone density.  Both placebo and control groups took a multivitamin and calcium 1200 mg per day (Obstet Gynecol. 1999. 94. 225-228). 

o       Proponents of progesterone creams recommend using only those creams which contain at least 400 mg of progesterone per ounce of cream. Over the counter creams contain 50 mg/ounce or less.

o       Until there is further research into the risks of progesterone cream in terms of induction of postmenopausal bleeding, some advocates suggest 3 weeks on and one week off as a safer regimen. 

o       NOTE that wild yam preparations contain diosgenin, which can be converted to progesterone in a laboratory, but not in the human body.

 

Alternatives to hormone replacement therapy for treatment of symptoms of menopause – research ongoing at Columbia University

  • Acupuncture
    • Ineffective in one small trial with 24 menopausal women (Menopause. 1995. 2. 3-12).
    • Effective in reducing the severity of nocturnal hot flashes compared with placebo, in a randomized, controlled pilot study in 29 women in which the treatment group received 9 acupuncture treatments over 7 weeks (Fertil Steril. 2006. 86. 700-710).
    • Effective in a 12 week trial comparing acupuncture to venlafaxine for the management of hot flashes in breast cancer patients. Acupuncture was equally effective, with fewer adverse effects (Walker EM et al. J Clin Oncol. Epub 12/28/09).
    • Effective in several placebo controlled RCTs for hot flashes in breast cancer patients (J Clin Oncol. 2010. 28. 634-640; Breast Cancer Res Treat. 2009. 116. 311-316; J Clin Oncol. 2007. 25. 5584-5590).
    • There are additional published studies showing a benefit of acupuncture or electroacupuncture. Most of these are observational studies (J Tradit Chin Med. 2005. 25(1):3-6; Holist Nurs Pract. 2003.17(6):295-299; Acupunct Med. 2005. 23(4):171-180; Climacteric. 2004. 7(2):153-164; Tumori. 2002. 88(2):128-130; J Altern Complement Med. 2001. 7(6):651-658).
  • Alternate nostril breathing
  • Aromatherapy with clary sage.
  • Avoid triggers - alcohol, caffeine, chocolate, foods high in arachadonic acid (commercial dairy foods, commercial red meat), refined carbohydrates, spicy foods, and sugar because they can worsen hot flashes. 
  • Dress in layers of clothing.
  • Exercise
    • Observational studies show that women who exercise regularly are less likely than sedentary women to experience severe hot flashes (Acta Obstet Gynecol Scand. 2000. 79. 286-292; Maturitas. 2005. 52. 374-385).
    • In one study in 793 women age 55-56 who had reached natural menopause, the relative risk for severe hot flashes was 0.26 in the highly physically active women, versus those with little or no exercise (Maturitas. 1998. 29. 139).
  • Fish oil – anti-inflammatory
  • Paced respiration (slow, deep breathing) - shown effective in 2 controlled trials. 
    • In one trial with 33 postmenopausal women, paced respiration training for 4 months significantly reduced the frequency of hot flashes by 39% (p<0.02) compared to control groups with progressive muscle relaxation or nontherapeutic alpha-wave EEG biofeedback (Am J Obstet Gynecol. 1992, 167, 436-439). 
    • In another trial with 24 postmenopausal women with >5 hot flashes per day, those assigned to paced respiration had a 44% decrease in hot flashes (p<0.001) compared to biofeedback controls who had no change in hot flash frequency (Menopause. 1995. 2. 211-218).
  • Positive attitude toward menopause – associated with reduced intensity of symptoms and improved psychological outcomes.
  • Probiotics and prebiotics - bacteria in the large intestine convert lignans (a class of phytoestrogens) into their active metabolites.  Probiotics decrease microbial deconjugation and enterohepatic reuptake of estrogen analogues.  Prebiotic foods nourish these bacteria (IMCJ. 2005. 4[1]. 20-27).
  • Relaxation response technique - A 7 week RCT with 45 women (33 completed the study) who were experiencing > 5 hot flashes daily in which the treatment group practiced the relaxation response 20 minutes daily and the control group charted symptoms showed no change in the frequency of hot flashes in either group, but a decrease in intensity of hot flashes only in the relaxation group [p<0.05] (J Psychosom Obstet Gynaecol. 1996. 17. 202-207).
  • Stop smoking.
  • Weight loss if overweight
  • Yoga (hatha) beneficial in a 10 week pilot study in 12 perimenopausal women (Maturitas. 2007. 57. 286-295).

 

  • Black cohosh
    • Initially thought to contain phytoestrogens, but current consensus is that it does NOT have estrogenic activity; benefit may be mediated by an effect on the hypothalamus.
    • Clinical trial data – MIXED, with reviews published including HerbalGram, winter, 1999; Lieberman S. A review of the effectiveness of Cimicifuga racemosa for the symptoms of menopause. J Womens Health. 1998. 7. 525-529; Kligler B. Black cohosh. Am Fam Physician. 2003. 68. 114-116; Kiefer D. Alt Med Alert. 2006. 9. 133-137.
      • Many of the early clinical trials were published in German, and most of these were open trials rather than RCT's.
      • Positive study - a 3 month randomized, open, treatment-controlled trial in 60 women aged 45-60 (48 were menopausal, 55 completed the study) comparing Remifemin 40 drops twice daily with conjugated estrogens 0.25 mg daily with diazepam 2 mg daily showed "highly significant reductions" with all 3 treatments, with no statistical calculations reported (Med Welt. 1985. 36. 871-874).
      • Positive study - a 3 month RCT in 80 women aged 46-58 (41 were menopausal, 75 completed the study) comparing Remifemin tablets 40 mg twice a day versus conjugated estrogens 0.625 mg per day versus placebo showed significant benefit in the Remifemin group, but the lack of difference between estrogen and placebo in this study calls into question the validity of the study (Therapeutikon. 1987. 1. 23-31).
      • Positive study - a 6 month randomized, treatment-controlled trial in 60 women (41 menopausal) comparing Remifemin tablets 40 mg twice a day versus estriol versus conjugated estrogens versus estrogen/progesterone showed improvement in all groups with no significant differences amongst groups (Zentralbl Gynakol. 1988. 110. 611-618).
      • Negative study - a 2 month RCT in 85 women with breast cancer (59 were using tamoxifen concurrently and only 68 of the 85 completed the study) comparing Remifemin 40 mg/day with placebo showed no benefit in the treatment group with regard to either frequency or intensity of hot flashes (J Clin Oncol. 2001. 19. 2739-2745).
      • Negative study - a methodologically rigorous study in which 351 perimenopausal women were randomized to one of four groups failed to show any benefit from the black cohosh in terms of frequency or intensity of vasomotor symptoms (Maturitas. 2005. 52. 134-146).
      • Positive study - a 12 week RCT in 304 patients using 40 mg/day showed improvement in a variety of menopausal symptoms, as measured by the Menopause Rating Scale (Obstet Gynecol. 2005. 105. 1074-1083).
      • As of 2005, there were 8 RCTs of black cohosh and 5 of the 8 were positive.  However, a systematic review of the literature identified only 4 black cohosh trials which met inclusion criteria, and only 1 of these 4 showed benefit (Arch Intern Med. 2006. 166. 1453-1465). Negative trials may be the result of an inadequate dose or duration of the trial. Subsets of women such as those early in menopause or those with more severe symptoms may benefit to a greater extent.
      • Negative study - the HALT trial, a large, well designed, rigorous 12 month study in 351 women age 45-55 with 2 or more vasomotor symptoms per day (average of 6 vasomotor symptoms per day) who were randomized to one of 5 arms, with the black cohosh arm receiving 160 mg/day or a 70% ethanol extract containing 2.5% triterpene glycosides (i.e. 4 mg triterpene glycosides/day). The product was provided by Pure World, Inc and independently tested for content by Consumerlab. There was a 92% completion rate. Most subjects were predominantly Caucasian and well educated. (Ann Intern Med. 2006. 145. 869-879 and editorial 924-925).
        • NOTE this study used an ethanol extract whereas most studies have used an isopropanolic extract.
        • A secondary analysis showed that at 3 months, there were no statistically significant treatment effects of black cohosh on TC, HDL, LDL, TG, fibrinogen, glucose, or insulin (Maturitas. 2007. 57. 195-204).
        • Another secondary analysis showed that at 12 months, black cohosh had no effects on vaginal dryness or dyspareunia, also had no effect on bleeding, endometrial thickening, or reproductive hormone levels (Menopause. 2008. 15. 51-58).
      • Negative study – a 4 week crossover RCT in 132 patients, using Remifemin 20 mg twice a day (J Clin Oncol. 2006. 24. 2836-2841).
      • Positive study – a 16 week RCT in 301 women, using a combination formula of black cohosh and St John’s wort reported improvements in hot flashes and depression symptoms (Obstet Gynecol. 2006. 107. 247-255).
      • Positive study – a 12 week study in 77 Korean women, using a combination formula of black cohosh and St John’s wort reported improvements in hot flashes, but no improvement in vaginal dryness or libido (Yonsei Med J. 2007. 48. 289-294).
      • Positive study - a multi-site observational study in which 6141 women from 1287 outpatient gynecology offices were treated with black cohosh alone or in combination showed that black cohosh was effective in controlling symptoms of menopause; the combination was even more effective (Maturitas. 2007. 57. 405-414).
      • Positive study - a 12 week RCT in 244 menopausal Chinese women treated with 40 mg per day of Remifemin or 2.5 mg of Tibolone, a STEAR not available in the US as of 2008, found significant benefit with Remifemin treatment, using the KMI score. The Remifemin was equivalent to Tibolone in terms of efficacy, and better tolerated using a combination formula of black cohosh and St John’s wort reported improvements in hot flashes (Maturitas. 2007. 58. 31-41).
      • Negative study – a 1 year, 4 arm RCT in 89 perimenopausal women, using an ethanolic extract of black cohosh in one arm and an ethanolic extract of red clover in a second arm, and conventional HRT in the third arm found HRT beneficial but neither black cohosh or red clover beneficial at reduction of hot flashes (Geller S. Menopause. Epub 7/15/09).
      • Negative study – a 20 week RCT in 93 women showed no benefit of a formula containing Chinese herbs and black cohosh (Menopause. 2009. 16.336-344).
      • A meta-analysis of 9 RCts reported that 6 showed improvement in the black cohosh group, with overall improvement in symptoms of 26% as compared with placebo, but with significant heterogeneity between trials (Alt Ther Health Med. 2010. 16[1]. 36-44).
      • Positive study – prospective observational study in 50 breast cancer patients who were on tamoxifen (Ronstock M et al. Gynecol Endocrinol. Epub 1/13/11).
    • Safety in women with a personal or family history of breast cancer is unknown, with conflicting published data.
      • There is data that black cohosh does NOT increase breast cell cancer division (Arch Gynecol Obstet. 1993. 254. 817-818).
      • One tissue culture study showed no stimulation of estrogen receptor positive cell lines, and found that black cohosh increased the inhibitory effect of the prescription drug tamoxifen on breast cancer cell lines (Altern Ther Health Med. 2001. 7. 93-100).
      • HOWEVER, one study found that black cohosh significantly increased breast cancer cell growth (Wei Sheng Yan Jiu. 2001. 30. 77-80).
      • Another study found that black cohosh does NOT promote breast cancer cell growth (Int J Oncol. 2003. 23. 1407-1412).
      • A case control study found use of black cohosh associated with a 61% reduction in the risk of breast cancer (Int J Cancer. 2007. 120. 1523-1528).
    • Long term safety unknown
      • As of 2003, no clinical trials longer than 6 months. The German Commission E monograph published in 1989 recommends a maximum of 6 months of use due to concern about possible estrogenic effects on the breast.
      • There are case reports of hepatotoxicity – pre-existing liver disease is a relative contra-indication
    • Adverse effects are infrequent. GI upset is the most common adverse effect.
    • Dose - the therapeutic dose is generally considered 2 tablets (20 mg each) twice a day, but some data suggests that 1 tablet twice a day may be as effective as 2 tablets twice a day.  Each tablet is standardized to contain 1 mg of triterpene glycosides calculated as 27-deoxyactein.  Most studies of the liquid extract have used 40 drops twice a day, for a total dose of 4 mg of triterpene glycosides a day.
    • Remifemin is the brand name product used in most clinical trials. BNO 1055 is a second brand name for which there is published outcomes data.
  • Dong quai
    • Contrary to conventional wisdom, there is no good data that dong quai has estrogenic effects.
    • Dose is 500-900 mg or 30 drops of tincture three times a day with meals, ideally standardized to contain 0.8% to 1.1% ligustilide.
    • A 6 month RCT of dong quai 3 capsules 3 times a day (4.5 grams of dong quai root per day, standardized to 0.5 mg/kg ferulic acid) in 71 women with menopausal symptoms (61 completed the study) showed no benefit (Fertil Steril. 1997. 68. 981-986).
    • In traditional Chinese medicine, dong quai is always used in combination with other herbs, and it is conceivable that dong quai would have efficacy in combination products, but this has not been scientifically studied.
  • Evening primrose oil - studied in only one randomized trial, and found to be no more effective than placebo. Of the 56 postmenopausal women with >3 hot flashes daily who started the 6 month trial, only 35 completed it.  The treatment group received 2000 mg of evening primrose oil with 20 mg Vitamin E twice daily (BMJ. 1994. 308. 501-503).
  • Fish oil – beneficial in reducing the frequency of hot flashes in an 8 week RCT in 120 women, but did not alter the severity of hot flashes or quality of life scores. The treatment group received one capsule three times a day, with each capsule containing 350 mg of EPA and 50 mg of DHA. The baseline hot flash frequency of 2.8 per day decreased by 58% in the treatment group, compared with 25% in the placebo group (Menopause. 2009. 16. 357-366).
  • Ginkgo biloba.  No controlled study data available.
  • Ginseng – a 4 month RCT of Ginsana (Panax Ginseng standardized to contain 100 mg of G115) in 384 postmenopausal women found no improvements in hot flashes, but improvements in mood.  (Int J Clin Pharmacol Res. 1999. 19. 89-99).
  • Hops (Humulus lupulus) – a 3 arm, 12 week RCT in 67 menopausal women reported mixed results, with the 100mcg/day dose superior to placebo at 6 weeks for hot flash reduction, but no longer statistically significantly better than placebo at the end of the 12 week trial. The high (250 mcg/day) dose was no more effective than the lower dose (Maturitas. 2006. 54. 164-175).
  • Kudzu (Pueraria mirafica) – contains phytoestrogens, and in a 24 week RCT in 71 postmenopausal women, those randomized to various doses of kudzu did show improvement in symptoms of vaginal dryness (Menopause. 2007. 14. 919-924). Usual supplemental dose is 20-100 mg/day.
  • Maca (Lepidium peruvianum) specifically from the highlands of Peru. Mechanism of action hypothesized to be stimulation of hypothalamus, pituitary, adrenal, and ovarian glands by plant sterols in Masa; herb does NOT appear to contain phytoestrogens. As per Dr Low Dog (April 2011 presentation), may be more effective at increasing libido than decreasing hot flashes.

o        1 gm bid of a proprietary extract (Maca GO) was beneficial in a 3 month multicenter RCT in 168 early postmenopausal women. A limitation of this study is that only 124 of the 168 women completed the study (Int J Biomedical Sci. 2006. 2. 360-374).

o        1 gm bid of a proprietary extract (Maca GO) was beneficial in a 4 month crossover RCT in 34 postmenopausal women. Menopausal symptoms were assessed using Kupperman’s Index and Greene’s Score. In this study, maca consumption was associated with a rise in estrogen levels and a drop in cortisol levels and ACTH (Int J Biomedical Sci. 2006. 2. 375-394).

o        3.5 gm daily of powdered maca beneficial in a 6 week crossover RCT in 14 postmenopausal women – treatment associated with beneficial effects on anxiety, depression, and sexual dysfunction. In this study, the beneficial effects were independent of any androgenic or alpha estrogenic effects (Menopause. 2008. 15. 1157-1162).

  • Nutrafem – combination of botanical extracts shown more effective than placebo in a RCT in 159 postmenopausal women with at least 21 hot flashes per week, with an average 46% reduction in the number of hot flashes in the treatment group, as compared with 26% in the placebo group (Menopause. 2010. 17. 303-308).
  • Phytoestrogens - nonsteroidal plant compounds with estrogen-like biologic activity.
    • Include three classes of compounds - isoflavones (genistein and daidzein), lignans (enterolactone and enterodiol), and coumestrans (coumestrol). At least 20 different compounds have been identified in at least 300 plants from 16 different plant species.
      • Isoflavones are found in lentils, chickpeas, red clover, raw soybeans, soy milk, soy nuts, tempeh, and tofu (but NOT soy sauce, soy oil, and many brands of soy burgers, soy cheese, or soy hotdogs).
      • Lignans are found in rye grains, linseeds, flaxseeds, carrots, spinach, broccoli, and tea.
      • Coumestrans are found in bean sprouts, alfalfa, and clover.
    • When compared to estradiol (equivalent to 1), the relative potencies of genistein, daidzein, and coumestans are 0.084, 0.013, and 0.202 respectively.
    • These can function as estrogens and anti-estrogens, much like a new class of prescription drugs named SERM's.
    • NOTE phytosterols (beta-sitosterol, campesterol, stigmasterol), found in vegetable oils, grains, and some fruits and vegetables are also believed to have estrogenic properties.
    • EFFICACY - or clinical studies, see ‘red clover’ and ‘soy’ just below. A systematic review of the literature identified 15 trials on phytoestrogen which met inclusion criteria, and only 4 of these showed benefit (Arch Intern Med. 2006. 166. 1453-1465).
    • SAFETY – A meta-analysis which identified 174 RCTs and found that side effects were reported in 92 of the 174 RCTs (n=9629 participants in the 92 RCTs) found that “phytoestrogen supplements have a safe side-effect profile with moderately elevated rates of gastrointestinal side effects. Rates of vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly increased among phytoestrogen users in the investigated studies” Studies in this meta-analysis were variable in length, with a median duration of 6.2 months. Subgroup analysis showed that side effects were less common in women younger than age 55, with a RR of 0.97 as compared with placebo; slightly more common in women older than age 55, with a RR of 1.14 (Am J Med. 2009. 122. 939-946).
  • Pycnogenol (pine bark extract) – benefit seen with 100 mg twice a day in a well-conducted 6 month RCT in 230 perimenopausal Taiwanese women, with improvement reported in hot flashes, memory, anxiety, depression, and sleep (Acta Obstet Gynecol Scand. 2007. 86. 978-985).
  • Red clover (Alt Med Alert. 2008. 11. 90-93).
    • Contains isoflavones – biochanin A and formononetin
    • Clinical trial data - MIXED – based on current data, consider an 8 week trial of proprietary extracts used in clinical trials, using the higher dose (i.e. Promensil 80 mg/day or Rimostil 57 mg/day), in women who are not at high risk of breast cancer (Alt Med Alert. 2008. 11. 90-93).
      • A 2007 review identified 6 studies of red clover, and concluded that the results were inconsistent, with 3 positive trials and 3 negative trials (Arch Gynecol Obstet. 2007. 276. 463-469).
      • A 2007 meta-analysis of 5 trials in which Promensil was used found that  red clover groups had 1.45 less hot flashes per day than the placebo group (p<0.05) [Phytomedicine. 2007. 14. 153-159].
      • Negative study - the ICE study, a 12 week RCT in which 252 participants were randomly assigned to Promensil (derived from red clover, 82 mg of per day), Rimostil (derived from red clover, 57 mg of per day), or placebo.  This was conducted at 3 U.S. medical centers, and included women experiencing an average of 8.1 hot flashes per day.  There was a 2 week placebo run-in, and 98% completed the study.  At the end of 12 weeks, there were no differences amongst the groups with regard to mean hot flash count or quality of life (JAMA. 2003. 290. 207-214).
    • Unknown whether long term use may be harmful in terms of a possible estrogenic effect on the uterus and the breast – preliminary results suggest a lack of harm, though (See ‘Safety’ of phytoestrogens, just above).
    • In published reports, all adverse effects are mild.
  • Siberian rhubarb (Rheum rhaponticum) root extract – used widely in Germany since 1993. A limitation of the ‘independent’ RCTs showing efficacy is that both have been carried out by the same contract research organization (Guest Editorial. Alt Ther Health Med. 2009. 15[1]. 16-17). Relatively contra-indicated in women with a history of breast cancer.
    • In a 12 week multicenter RCT in 112 women, those who received one enteric coated tablet (250 mg) per day of an extract of Rheum rhaponticum (ERr 731) showed significant improvement in menopausal symptoms. No adverse events in this trial (Menopause. 2006. 13. 744-759). Improvements in anxiety were noted in this same cohort in a subsequent publication (Menopause. 2007. 14. 270-283).
    • A subsequent 6 month observational trial in 363 women enrolled from 70 gynecologic practices in Germany showed that ERr 731 at a dose of one tablet daily was effective in reducing the Menopause Rating Scale score from baseline (p<0.0001) and was safe and well tolerated. Only 252 of the 363 women completed the study (Alt Ther Health Med. 2008. 14[6]. 32-38).
    • In a confirmatory 12 week multicenter RCT in 109 women, those who received one enteric coated tablet per day of an extract of Rheum rhaponticum (ERr 731) showed significant improvement in menopausal symptoms (Alt Ther Health Med. 2009. 15[1]. 24-34).
  • Soy - data is MIXED, with most high quality studies negative
    • Soy foods have been consumed in Asia for thousands of years and may be presumed safe, but the safety of isolated often high dose isoflavone supplements sold over the counter is really still unknown.
    • Diets rich in soy foods (45-80 grams per day) have been shown to decrease vasomotor symptoms of menopause (J Clin Endocrinol Metab. 1998. 83. 297-303). Furthermore, a recent cohort study in Japan found that hot flashes in menopausal women were inversely associated with consumption of soy foods (Am J Epidemiol. 2001. 153. 790-793). However, in the HALT trial, benefit was NOT seen (and in fact at 12 months symptom intensity was significantly worse than in the placebo group, P=0.016) in the group randomized to increase intake of soy-containing foods to 2 portions per day, in conjunction with taking a multibotanical with black cohosh and 9 other ingredients. Of note, this group did NOT achieve the target level of dietary soy intake though (Ann Intern Med. 20006. 145. 869-879 and editorial 924-925). One cup of fresh soybeans, 1/3 cup of soy nuts, or 3.5 cups of soy milk provide 25 grams of soy protein, which contains approximately 70-140 mg of isoflavones.
    • A literature review identified 11 clinical trials that examined soy or isoflavone supplementation for hot flashes.  Of the 8 studies with treatment phases which lasted longer than 6 weeks, only 3 studies showed benefit.  Placebo response in many of these studies was 50-60% (Ann Intern Med. 2002. 137. 805-813).
    • A systematic review of 13 randomized, controlled trials of soy extracts for menopausal symptoms found that there is some evidence of efficacy, but the data overall is inconclusive (Maturitas. 2004. 47. 1-9).
    • A systematic review of 22 clinical trials comparing phytoestrogen supplementation with placebo concluded that phytoestrogens are no more effective than placebo in relieving symptoms of menopause, regardless of the type of dose of phytoestrogen used. The 22 trials included in the analysis were chosen from a larger group of 40 trials identified by a literature search, and included a total of 2069 participants.  Ten studies investigated soy products, 7 investigated soy extract, and 5 investigated red clover (Obstet Gynecol. 2004. 104. 824-836).
    • A 3 month RCT in 64 postmenopausal women who were breast cancer survivors and had symptoms of menopause found that 114 mg of soy isoflavones daily did not improve vaginal dryness (Fertil Steril. 2005. 83. 137-142).
    • A systematic review of CAM therapies for menopause found that of 15 fair to good quality studies of soy isoflavones, only 4 showed a benefit (Arch Intern Med. 2006. 166. 1453-1465).
    • A meta-analysis of 19 RCTs concluded that there was a statistically significant improvement in hot flashes with soy treatment, but the difference (0.39 fewer hot flashes per day) was not clinically significant (Menopause. 2010. 17. 660-666).
    • The SPARE study, a NIH-funded 2 year RCT of 248 women aged 45-60 and within 5 years of menopause found that 200 mg/day of soy isoflavones were actually associated with an INCREASED incidence of hot flashes. Menopausal symptoms in this study were a secondary outcome, and measured using the Women’s Health Questionnaire (Arch Intern Med. 2011. 171. 1363-1369 and Invited Commentary 1369-1370).
    • Possible explanations for conflicting clinical trial results
      • Equol, a metabolic product of daidzein, is thought to be more metabolically active and only 25-50% of women are equol producers (Am J Clin Nutr. 2009. 89. 16645-16675). Benefits might be seen in the subgroup of equol producers.
      • Analysis of 11 studies that used similar soy isoflavone doses (30-114 mg/day of isoflavone equivalents) found that in the 5 studies which used > 15 mg of genistein per treatment (n=177), there was a significant reduction in hot flashes in the active treatment group; whereas in the 6 studies which used <15 mg of genistein, only 1 showed a significant reduction in hot flashes. These results suggest it is the amount of genistein present in the dose of isoflavones which may be important (Menopause. 2006. 13. 831-839).
    • Safety
      • Soy isoflavones bind primarily to estrogen beta receptors involved in antiproliferative and reparative processes, rather than the alpha receptors involved in proliferative and reproductive functions.
      • Data on whether soy isoflavones induce endometrial hyperplasia is mixed. It may be that long term (5 years of more) exposure to high dose isoflavones (150 mg/day) is associated with a proliferative effect on the endometrium.
      • A 3 month RCT showed that 114 mg of soy isoflavones daily did not affect vaginal maturation index or endometrial thickness (Fertil Steril. 2005. 83. 137-142). 
      • A meta-analysis which identified 174 RCTs and found that side effects were reported in 92 of the 174 RCTs (n=9629 participants in the 92 RCTs) found that “phytoestrogen supplements have a safe side-effect profile with moderately elevated rates of gastrointestinal side effects. Rates of vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly increased among phytoestrogen users in the investigated studies” (Am J Med. 2009. 122. 939-946).
  • St. John's wort 300 mg 3 times a day with meals. The data is mixed
    • A 2 month RCT of St John’s wort in 100 Iranian women showed benefit, but not until the second month of treatment (Menopause. 2010. 17. 326-331).
    • A 12 week RCT in 47 symptomatic perimenopausal women reported that quality of life scores were better in those administered St John’s wort. Sleep disturbance was less common in those administered St John’s wort (Menopause. 2009. 16. 307-314).
    • In an uncontrolled 12 week study, about 75% of women reported symptomatic improvement (Adv Ther. 1999. 16. 177).
    • Benefit reported in 2 RCTs using a combination of black cohosh and St John’s wort (Obstet Gynecol. 2006. 107. 247-255; Yonsei Med J. 2007. 48. 289-294) and an open label observational study in 6141 women (Maturitas. 2007. 57. 405-414).
  • Vitamin E
    • In a double-blind, 3 year study in 1953 which compared Vitamin E 50-100 mg per day with two estrogen preparations, phenobarbital, and placebo in 658 women, Vitamin E was no more effective than placebo (Arch Intern Med. 1953. 91. 792-796). 
    • In a more recent 4 week crossover RCT using Vitamin E 400 IU twice a day in 125 breast cancer survivors, Vitamin E was associated with one less hot flash per day, but patients did not prefer Vitamin E over placebo (J Clin Oncol. 1998. 16. 495-500).
  • Vitex
    • Dose is 400-500 mg a day.  Best taken before a meal. 
    • A standardized extract with 0.5% agnuside is considered ideal. 
    • No controlled trial data for symptoms of menopause.
    • Based on the current understanding of mechanism of action (i.e. increase secretion of LH, and thus increase progesterone levels), it is likely beneficial in the management of dysfunctional uterine bleeding in perimenopausal women.

 

  • Dr Andrew Weil recommends dong quai, vitex, and damiana, two capsules or one dropperful of each, once a day. Dr Weil states that dong quai does not have estrogenic activity and therefore does not increase the risk of uterine cancer.  

 

References

  • National Institutes of Health State-of-the-Science Conference Statement: Management of Menopause-Related Symptoms. Ann Intern Med. 2005. 142. 1003-1013.
  • Complementary and Alternative Therapies for Management of Menopause-Related Symptoms: A Systemic Evidence Review. Arch Intern Med. 2006. 166. 1453-1465.

 

  • Berman L and Berman J. For Women Only
  • Corio, Laura. The Change Before the Change
  • Lee JR. What Your Doctor May Not Tell You About Premenopause
  • Sommers, Suzanne. The Sexy Years

 


[Last Updated November 15, 2011] [Return to List of Topics]