Menopause - Post WHI Jessie Chan 27th Sept 2012
Women’s Health Initiative15 year project - 1991-20103 components: Randomized clinical trial 68,132 postmenopausal women between the ages of 50-79. Hormone Therapy (HT): Effect of HT on the prevention of heart disease and osteoporosis, and any associated risk for breast cancer. Women participating in this component took hormone pills or a placebo (inactive pill). Dietary Modification: Effect of a low-fat, high fruit, vegetable and grain diet on the prevention of breast and colorectal cancer and heart disease. Study participants followed either their usual eating pattern or a low-fat eating program. Calcium/Vitamin D: Effect of calcium and vitamin D supplementation on the prevention of osteoporosis-related fractures and colorectal cancer. Women in this component took calcium and vitamin D pills or a placebo. Observational study examined the relationship between lifestyle, health and risk factors and specific disease outcomes Community prevention study
WHI - Hormone trialTwo studies The estrogen-plus- progestin study (women with a uterus) The estrogen-alone study (women without a uterus)
WHI - Hormone trialCompared with the placebo, Compared with the placebo,estrogen plus progestin resulted in: estrogen alone resulted in: Increased risk of heart attack No difference in risk for heart Increased risk of stroke attack Increased risk of blood clots Increased risk of stroke Increased risk of breast cancer Increased risk of blood clots Reduced risk of colorectal cancer Fewer fractures Uncertain effect for breast cancer No protection against mild cognitive No difference in risk for colorectal impairment and increased risk of dementia cancer (study included only women 65 and older) Reduced risk of fracture (Findings about memory and
WHI - LimitationsAddressed the value of long-term HT in the prevention of major chronic conditions ofwomen after menopause, not intended to explore treatment of menopausal symptoms.E+P trial was stopped after 5.6 years because of an increased risk of breast cancer andbecause overall risks, including increased risks for heart attack, stroke, and blood clots,outnumbered benefitsThe E-alone study was stopped after 6.8 years because of an increased risk of stroke andno reduction in risk of CHD. The estrogen-alone study also found an increased risk ofblood clots.Difference between results of E+P and E-alone, progestin (medroxyprogesteroneacetate) may be responsible? Two trials populations dissimilar - E-alone participants had a higher mean body massindex and more years of prior exposure to HT than E + P participants, so interpretationof trial differences must be cautious.
Recent Debates:HRT and CVDHRT and CVDWomen’s Health Initiative (WHI) (Rossouw et al, JAMA 2007; 297: 1465-77) Younger women (50 -59) taking HRT over a period of 10 years have shown no increased risk of developing CVD - previous WHI study which stated an opposite findingThe womens international study of long duration estrogen and progestinafter menopause (WISDOM) Women starting or restarting combined HRT have increased cardiovascular and thromboembolic risk when treatment begins many years after the menopause (Vickers et al, BMJ, July 2007, doi:10.1136/bmj.39266.425069.AD) Decreased risk of osteoporotic fracture and no difference in the risk of stroke or cancers.
Recent Debates:HRT and Breast CaHRT and Breast CaStudies have shown an association between E+P with breast cancer - but related to certaintypes of HRT and certain types of breast cancer for women of a particular age group.The recorded risks are statistically small and appear to be linked with the duration of therapy(Ravdin et al, NEJM 2007; 356: 1670-4)Postmenopausal women who take E+P for at least 5 years are increasing their risk of breastcancer. Researchers also found that women can quickly reduce their risk of breast cancerby stopping HRT (Chlebowski et al., NEJM 2009; 360(6): 573-587).In considering these findings, women should be aware that only a small percentage ofcombined estrogen plus progestin users continue use for more than five years (Brett &Reuben, Obstet Gynecol 2003; 102:1240-9).The Society of Obstetricians and Gynaecologists of Canada has noted that risk factors forbreast cancer, such as hormones, should be evaluated in light of equally important riskfactors related to lifestyle (Reid et al, JOGC 2009; 31(1): S5-S8)Research suggests that 34% of breast cancers could be avoided by making lifestylechanges at the time of menopause (Sprague et al, Am J Epidemiol 2008; 168(4): 404-11).
Recent Debates:HRT and Ovarian CaHRT and Ovarian CaMillion Women Study - increased incidence of developing ovarian cancer inwomen on HRT, compared to women who have never used HRT (MillionWomen Study Collaborators, Lancet 2007; 369:1703-10). However, theserisks are statistically small. Researchers report that the risk of developingovarian cancer returns to pre-use levels once users stop using HRT.
Recent Debates:HRT and Colon CaHRT and Colon CaSmall reduction in the risk of colonic cancer (Johnson JR et al, CancerEpidemiology Biomarkers Prev 2009;18(1):196-203).Evidence from the WHI and other trials suggests that current HRT usershave a 40% reduction in colorectal cancers.? too early to consider HRT use in the prevention of colon cancer (Barnesand Long)
Recent Debates:HRT and VTEHRT and VTEThere is an increased risk of venous thromboembolism with oral HRT. Thismay be increased with age and obesity, and may vary by the progestogenused. Observational studies suggest that it may not be associated withtransdermal HRTs (patches), but this needs confirmation (Archer and Ogar).
Recent Debates:HRT and strokeHRT and strokeThere is a modest increase in stroke risk with HRT use if stated near themenopause. This risk rises considerably in women who start at older ages.There is some evidence that use of HRT patches (as opposed to pills) maynot increase stroke risk, but this needs to be confirmed (Henderson andLobo).
Recent Debates:HRT and boneHRT and boneTaking HRT confers some benefit to bone strength (Farquhar C et al,Cochrane Database Syst Rev. 2009 Apr 15;(2):CD004143)Fractures The WHI "Global Index", which looked at the balance of risks andbenefits, inappropriately downgraded the importance of fractures.HRT gives more bone benefits than many other drugs (e.g.bisphosphonates), and so restrictions on HRT use as a first-line therapy arenot appropriate (de Villiers and Stevenson)
HRT and UG + sexualhealthHRT and UG + sexualhealthAround 50% of postmenopausal women will suffer urogenital atrophy.Studies indicate that locally applied hormone therapy is generallymore effective than systemic HRT for urogenital symptoms, includingdyspareunia, which can be a critical determinant of a woman’sinterest in sex.(Nappi & Davis)E-P is effective for relief of lower urinary tract symptoms related toestrogen deficiencyMost studies show that in post menopausal women with urinaryincontinence, E-alone and E-P are not beneficial and may worsen thecondition
Recent Debates:HRT and QoLHRT and QoLWHI - HRT use led to minimal improvement in qualityof lifeWHI study wasn’t designed to look at wemen goingthrough the menopause - underestimated the realextent of effect of HRT on QoL - hence suffering tomany womenSome studies indicate that E-P improves many domainof QoL - mental health and depressive symptoms,physical functioning, bodily pain and sleep.
Recent Debates:HRT and dementiaHRT and dementiaInitial WHI results showed an increase in dementiafor both E+P and E alone users. ? may be influenced by the timing of the HRT initiation, with benefits for those starting nearer the menopause, but increased risks for women starting at older ages (Maki and Henderson).
CurrentrecommendationsThe risks associated with the use of HRT are low and duration of use may, if necessary, beextended, as the use of HRT for many women provides welcome relief from distressingpostmenopausal symptoms (Grady & Barrett-Connor, BMJ 2007; 334:860-1).Start early, use the lowest dose which gives symptom control, for the shortest period of time(Benefit outweighs the risks)‘window-of-opportunity - before the age of 60 and/or within 10 years of the menopause. This reduces the risk of coronary heart disease and overall mortality. HRT is more effective for this than other medicines such as statins and aspirin, and is cost-effective. Starting HRT later than this increases risks to women (Hodis et al).All women commencing HRT should be advised of type, dose, mode of delivery anddurationTailor treatment to individual patients
ReferencesEffect of Hormone Therapy on Risk of Heart Disease May Vary by Age andYears Since Menopause. Additional analyses from the Women’s HealthInitiative. NHI News April 2007The Women’s Health Initiative study and Hormone Therapy – what have welearned 10 years on? International Menopause Society. May 2012Wallace, Robert. The Women’s Health Initiative: The Role of HormonalTherapy in Disease PreventionWomen’s Health Initiative. http://www.nhlbi.nih.gov/whi/Hormone Therapy During Menopause in Malaysian Women. Clinical PracticeGuidelines July 2010.