Learning Objectives Differentiate early, premature and surgical - - PDF document

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Nanette Santoro, MD Professor and E Stewart Taylor Chair of Ob/Gyn University of Colorado School of Medicine

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Differentiate early, premature and surgical menopause from age-appropriate menopause in terms of symptoms and risks for subsequent disease Enumerate the ways in which estrogen loss early in the life course alters the risk to benefit equation of menopause hormone therapy Adjust hormone therapy approaches in the absence of RCT evidence for women < age 50

Learning Objectives 

Investigator-initiated grant support: Bayer Womens Health Inc Stock options: Menogenix

Disclosures 

Surgical menopause, early (<45 yrs) or primary

• varian insufficiency/premature ovarian failure

(POF/POI; <40 yrs) Symptoms are similar but appear to be overall more severe and may be prolonged compared to women undergoing natural menopause Disease susceptibility is increased for several conditions

When Menopause Is Sudden, or Too Early…

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 Many years of life without hormones  Worse menopausal symptoms  Likely long-term consequence: bone resorption  Possible long-term consequences:

 Mortality (RR=1.5 [.97,2.34]), cancer (RR=2.34 [1.52, 4.98]; Cooper)  Adverse mood (Rocca)  Dementia (Rocca)  Cardiovascular disease (RR=1.17 [1.02, 1.35]; Parker)

Premenopausal Oophorectomy or POF/POI

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

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Sample of 290 women from iPOFA website Symptoms persist for decades in many women ‘Usual symptoms*’ plus:

 Brain fog, mood swings (>75%)  Hair loss, dry eyes, joint clicking (>50%)  Only modest improvements in MenQOL sexual and physical domains over up to 4 decades after diagnosis

POF/POI: Symptoms May Last For Many Years

Allshouse, Menopause 2015; 22: 166 *hot flashes, poor sleep, adverse mood, vaginal dryness

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 Believed to be more severe

 Sleep  Mood (not all studies support risk; see Gibson vs Schuster)  Hot flashes  vaginal dryness

 Independent risk factor for failure to ever wean off of hormones (Grady)

Symptoms and Premenopausal Oophorectomy

Gibson, Ob/Gyn 2012; 119: 935; Schuster, Menopause Int 2008; 14:111; Grady, Ob/Gyn 2003; 102:1233

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Early withdrawal of estrogen

 Net reduction in breast cancer risk—fewer lifetime years of estrogen exposure  Net increase in osteoporosis risk  Net increase in CVD risk

No known consequences to early withdrawal of progesterone

Early Menopause and Health Risks

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Renin-angiotensin-aldosterone system upregulated in women after menopause Salt sensitivity upregulated in women after menopause Atherogenicity of lipid profile increases with menopause; CIMT increases Endothelial function may be adversely affected by estrogen withdrawal

How Does Menopause Affect CVD Risk?

Mass A Neth Heath J 2010; 18:598; El Khoudary Eur J Prev Cardiol 2016; 23: 694

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POF/POI (1-2%) Early menopause (<age 45; 5%) Surgical menopause < age 65 Elective risk reducing

• ophorectomy (any age)

Populations at Risk for Early Heart Disease

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Significant Predictors of CAD (logistic regression) Predictor OR 95% CI P Hypoestrogenemia* 7.4 1.7, 33.3 0.008 Aspirin Use in Past Week 7.6 1.7, 33.7 0.008 ATP-III 10 Yr Risk 8.3 1.2, 59.6 0.04

Hypoestrogenemia Predicts CAD in Premenopausal Women

Bairey Merz, J Am Coll Cardiol 2003; 41:413 *defined as < 50 pg/ml

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Oophorectomy HR mortality P value Unilateral 0.82 (.67-.99) 0.04 Bilateral 1.44 (1.01-2.05) 0.001 Reference 1

• Cardiovascular Mortality Increased

After BSO

Rivera CM, et al Menopause 2009; 16:15-23

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National Center for Health Statistics (2004): 617,000 hysterectomies in the USA 73% of these entailed oophorectomy 52% are performed on women <44 years old Only 10% for cancer indications 617,000 x .9 x .52 x .73=210,792 women per year who are surgically castrated at age 44 or earlier!

Some Statistics 

 Women with risk factors for ovarian carcinoma  Susceptibility genes estimated to be detectable in 10% of women who get ovarian cancer (1.4% lifetime risk)

 BrCA  Two relatives with the disease  Breast cancer prior to age 45  Other pedigree analysis

 More than 1/1000 women, numbers likely to increase over time as genetic testing gets better  151,963,000 women x 0.14=21,274,820 additional premenopausal oophorectomies for cancer risk reduction!

Newest Risk Pool 

Olmsted County Study:

1,274 women with unilateral

• ophorectomy

1,091 women with bilateral oophorectomy 2,383 referent women age matched All surgeries performed 1950-1987

Premenopausal Oophorectomy

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• -Women interviewed by phone for

depression/anxiety (666 oophorectomy and 673 referent)

HR 1.54 (1.04-2.26) for depression  HR 2.29 (1.33-3.93) for anxiety

• -Estrogen treatment to age 50 did not

modify risk

Premenopausal Oophorectomy: More Depression and Anxiety

Rocca WA, Menopause 2008; 15:1050

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• -Risks following oophorectomy greater for

Parkinsonism Cognitive impairment Dementia

• -Risks modified by estrogen treatment

Premenopausal Oophorectomy: Worse Cognition

Rocca WA, Neurodegen Dis 2008; 5:257

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Parker, et al: Survival advantage of 8.6% in women who had conservation of the ovaries up to age 65 NO AGE GROUP showed a survival disadvantage with ovarian conservation Nurses Health Study: RR of mortality 1.12 (1.03, 1.21) with oophorectomy NO AGE GROUP showed a survival disadvantage with ovarian conservation

Mortality Risk: Greater After Oophorectomy Up to Age 65

Parker, Ob/Gyn 2005; 106:219; and Ob/Gyn 2009; 113:1027

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Number at risk Disease Lifetime Prevalence Relative Risk Excess Cases 210,792 CHD- mortality 16.6% 1.44 15,396 210,792 Depression 10%-25 1.54 28,454 210,792 Anxiety 6.6% 2.29 17,945

Attributable Risks of Premenopausal Oophorectomy—Current Standard of Care

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Attributable risks premenopausal

• ophorectomy

Number at risk* Disease Lifetime Prevalence Relative Risk Excess Cases 21,485,612 CHD- mortality 16.6% 1.44 1,569,309 21,485,612 Depression 10%-25 1.54 2,900,558 21,485,612 Anxiety 6.6% 2.29 1,829,285 *assumes that all women who are candidates for risk reduction oophorectomies undergo the procedure.

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 NO available data from RCTs to define long term use of MHT in this population  Extrapolation from clinical studies, clinical series and other available information favors the use of MHT in women with POF/POI and EM up to the age at ‘natural menopause’ (51.4 yrs)  After app age 50, risks and benefits should be individualized as they are for naturally menopausal women  Not all risks associated with POF/POI and EM may be reversed with MHT

Summary: Extended MHT for Women With POF/POI and EM

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Clearly not a benign intervention Should be performed for distinct clinical indication (e.g., endometriosis, cancer risk reduction) Estrogen ‘replacement’ may be insufficient to reverse all of the adverse outcomes Many women do not adhere to estrogen treatment regimens

Summary: Premenopausal Oophorectomy