Learning Objectives Differentiate early, premature and surgical - PDF document

9/26/2016 Learning Objectives   Differentiate early, premature and surgical menopause from age-appropriate menopause in terms of symptoms and risks for subsequent disease Nanette Santoro, MD  Enumerate the ways in which estrogen loss early Professor and E Stewart Taylor Chair of Ob/Gyn in the life course alters the risk to benefit University of Colorado School of Medicine equation of menopause hormone therapy  Adjust hormone therapy approaches in the absence of RCT evidence for women < age 50 When Menopause Is Disclosures Sudden, or Too Early…    Surgical menopause, early (<45 yrs) or primary  Investigator-initiated grant support: Bayer ovarian insufficiency/premature ovarian failure Womens Health Inc (POF/POI; <40 yrs)  Symptoms are similar but appear to be overall  Stock options: Menogenix more severe and may be prolonged compared to women undergoing natural menopause  Disease susceptibility is increased for several conditions 1

9/26/2016 Premenopausal POF/POI: Symptoms May Oophorectomy or POF/POI Last For Many Years    Many years of life without hormones  Sample of 290 women from iPOFA website  Worse menopausal symptoms  Symptoms persist for decades in many  Likely long-term consequence: bone resorption women  Possible long-term consequences:  ‘Usual symptoms*’ plus:  Mortality (RR=1.5 [.97,2.34]), cancer (RR=2.34 [1.52,  Brain fog, mood swings (>75%) 4.98]; Cooper)  Hair loss, dry eyes, joint clicking (>50%)  Adverse mood (Rocca)  Only modest improvements in MenQOL  Dementia (Rocca) sexual and physical domains over up to 4  Cardiovascular disease (RR=1.17 [1.02, 1.35]; Parker) decades after diagnosis *hot flashes, poor sleep, adverse mood, vaginal dryness Cooper, Am J Epi 1998; 8:229; Rocca, Mol Cell Endo 2014; Rocca, Neurodeg Dis 2012; 10:175; Parker WH, Ob/Gyn 2009; 113:1027 Allshouse, Menopause 2015; 22: 166 Early Menopause and Symptoms and Premenopausal Oophorectomy Health Risks    Early withdrawal of estrogen  Believed to be more severe  Sleep  Net reduction in breast cancer risk—fewer lifetime  Mood (not all studies support risk; see Gibson vs years of estrogen exposure Schuster)  Net increase in osteoporosis risk  Hot flashes  Net increase in CVD risk  vaginal dryness  Independent risk factor for failure to ever wean off of  No known consequences to early withdrawal of hormones (Grady) progesterone Gibson, Ob/Gyn 2012; 119: 935; Schuster, Menopause Int 2008; 14:111; Grady, Ob/Gyn 2003; 102:1233 2

9/26/2016 How Does Menopause Populations at Risk for Early Affect CVD Risk? Heart Disease    Renin-angiotensin-aldosterone system  POF/POI (1-2%) upregulated in women after menopause  Early menopause (<age 45; 5%)  Salt sensitivity upregulated in women after  Surgical menopause < age 65 menopause  Atherogenicity of lipid profile increases with  Elective risk reducing menopause; CIMT increases oophorectomy (any age)  Endothelial function may be adversely affected by estrogen withdrawal Mass A Neth Heath J 2010; 18:598; El Khoudary Eur J Prev Cardiol 2016; 23: 694 Hypoestrogenemia Predicts CAD in Cardiovascular Mortality Increased Premenopausal Women After BSO   Significant Predictors of CAD (logistic Oophorectomy HR mortality P value regression) Predictor OR 95% CI P Unilateral 0.82 (.67-.99) 0.04 Hypoestrogenemia* 7.4 1.7, 33.3 0.008 Bilateral 1.44 (1.01-2.05) 0.001 Aspirin Use in Past 7.6 1.7, 33.7 0.008 Reference 1 -- Week ATP-III 10 Yr Risk 8.3 1.2, 59.6 0.04 *defined as < 50 pg/ml Rivera CM, et al Menopause 2009; 16:15-23 Bairey Merz, J Am Coll Cardiol 2003; 41:413 3

9/26/2016 Some Statistics Newest Risk Pool    Women with risk factors for ovarian carcinoma  National Center for Health Statistics (2004): 617,000  Susceptibility genes estimated to be detectable in 10% of hysterectomies in the USA women who get ovarian cancer (1.4% lifetime risk)  73% of these entailed oophorectomy  BrCA  52% are performed on women <44 years old  Two relatives with the disease  Breast cancer prior to age 45  Only 10% for cancer indications  Other pedigree analysis  617,000 x .9 x .52 x .73= 210,792 women per year who  More than 1/1000 women, numbers likely to increase over are surgically castrated at age 44 or earlier! time as genetic testing gets better  151,963,000 women x 0.14=21,274,820 additional premenopausal oophorectomies for cancer risk reduction! Premenopausal Premenopausal Oophorectomy: More Depression and Anxiety Oophorectomy   Olmsted County Study: --Women interviewed by phone for  1,274 women with unilateral depression/anxiety (666 oophorectomy and oophorectomy 673 referent)  1,091 women with bilateral oophorectomy  HR 1.54 (1.04-2.26) for depression  2,383 referent women age matched  HR 2.29 (1.33-3.93) for anxiety  All surgeries performed 1950-1987 --Estrogen treatment to age 50 did not modify risk Rocca WA, Menopause 2008; 15:1050 4

9/26/2016 Mortality Risk: Greater After Premenopausal Oophorectomy: Oophorectomy Up to Age 65 Worse Cognition    Parker, et al: Survival advantage of 8.6% in women --Risks following oophorectomy greater for who had conservation of the ovaries up to age 65  Parkinsonism  NO AGE GROUP showed a survival disadvantage with ovarian conservation  Cognitive impairment  Nurses Health Study: RR of mortality 1.12 (1.03,  Dementia 1.21) with oophorectomy  NO AGE GROUP showed a survival --Risks modified by estrogen treatment disadvantage with ovarian conservation Rocca WA, Neurodegen Dis 2008; 5:257 Parker, Ob/Gyn 2005; 106:219; and Ob/Gyn 2009; 113:1027 Attributable risks premenopausal Attributable Risks of Premenopausal oophorectomy Oophorectomy—Current Standard of Care   Number at Disease Lifetime Relative Excess Cases risk* Prevalence Risk Number Disease Lifetime Relative Excess 21,485,612 CHD- 16.6% 1.44 1,569,309 mortality at risk Prevalence Risk Cases 21,485,612 Depression 10%-25 1.54 2,900,558 21,485,612 Anxiety 6.6% 2.29 1,829,285 210,792 CHD- 16.6% 1.44 15,396 mortality *assumes that all women who are candidates for risk 210,792 Depression 10%-25 1.54 28,454 reduction oophorectomies undergo the procedure. 210,792 Anxiety 6.6% 2.29 17,945 5

9/26/2016 Summary: Extended MHT for Women Summary: Premenopausal Oophorectomy With POF/POI and EM    NO available data from RCTs to define long term use of MHT  Clearly not a benign intervention in this population  Should be performed for distinct clinical  Extrapolation from clinical studies, clinical series and other indication (e.g., endometriosis, cancer risk available information favors the use of MHT in women with reduction) POF/POI and EM up to the age at ‘natural menopause’ (51.4  Estrogen ‘replacement’ may be insufficient to yrs) reverse all of the adverse outcomes  After app age 50, risks and benefits should be individualized as they are for naturally menopausal women  Many women do not adhere to estrogen  Not all risks associated with POF/POI and EM may be treatment regimens reversed with MHT 6