OB/GYN Update: Menopausal Management What Does The Evidence Show? Rebecca Levy-Gantt D.O. PremierObGyn Napa Inc.

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1 OB/GYN Update: Menopausal Management What Does The Evidence Show? Rebecca Levy-Gantt D.O. PremierObGyn Napa Inc.

2 Napa, California

3 IMPORTANT SAFETY INFORMATION ABOUT EVAMIST: WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER, PROBABLE DEMENTIA and UNINTENTIONAL SECONDARY EXPOSURE TO ESTROGEN. *INCREASED RISK OF ENDOMETRIAL CANCER IN WOMEN USING UNOPPOSED ESTROGEN. *ESTROGEN SHOULD NOT BE USED FOR PREVENTION OF CARDIOVASCULAR DISEASE OR DEMENTIA *THE WOMEN S HEALTH INITIATIVE REPORTED INCREASED RISK OF STROKE AND DVT WITH ESTROGEN USE *THE WHI ESTROGEN PLUS PROGESTIN STUDY REPORTED INCREASED RISKS OF INVASIVE BREAST CANCER

4 Transdermal Estrogen Is used to treat symptoms, not for prevention of cardiac disease Is NOT the same type of Estrogen used in the WHI Is NOT the type of Estrogen that increases risk for DVT and stroke

5 GOALS: (1): To be able to clearly define menopause, and the most common changes likely to occur as well as symptoms menopausal women are likely to have (2): To define the hormonal changes that occur, and what treatments are available for menopausal symptoms (3): To become familiar with some of the older and the more recent studies on the safety and success rates of various menopausal treatments (4): To compile a list of alternatives to hormones to manage symptoms

6 WHAT IS MENOPAUSE?: TWELVE CONSECUTIVE MONTHS AROUND THE AGE OF FIFTY with NO PERIODS WITH or WITHOUT SYMPTOMS

7 ALWAYS ALWAYS ALWAYS EVALUATE POST-MENOPAUSAL BLEEDING

8 WHAT HAPPENS IN MENOPAUSE?: Progesterone levels decline (lack of ovulation) Estrogen levels decline (ovaries shut down) Irregular periods > fewer periods No periods/ Hot flashes/ Insomnia/symptoms Ultimately, NO periods

9 MENOPAUSE PLANNING: LACK OF ESTROGEN: INSOMNIA HOT FLASHES MOOD SWINGS BLADDER PROBLEMS DEPRESSION/ANXIETY VAGINAL DRYNESS PAINFUL INTERCOURSE LACK OF ENERGY THINNING HAIR,DRY SKIN

10 LACK OF PROGESTERONE: BREAST TENDERNESS BLOATING PMS-LIKE FEELING INSOMNIA,POOR SLEEP ANXIETY

11 LACK OF TESTOSTERONE: LOW ENERGY LOW LIBIDO ACHES AND PAINS IN THE JOINTS WEAK MUSCLES FATIGUE

12 WHO CANNOT USE ESTROGEN? History of an Estrogen-related cancer History of an Estrogen-related blood clot Previous bad side effects or allergic reaction to an Estrogen-related product Unexplained vaginal bleeding Clotting abnormality/liver issues/hypercoagulable...smokers?

13 HORMONES are FOR SYMPTOMS In the N.I.H. -sponsored State of the Science Conference on the Management of Menopausal Symptoms in March of 2005, it was concluded that for vasomotor symptoms, night sweats and vaginal dryness only Estrogen therapy is conclusively associated with benefit.

14 The Women s Health Initiative Launched in 1991 Clinical trials and observational over 160,000 women oral conjugated equine Estrogen and Medroxyprogesterone, a Progestin Looking for cardiovascular benefit.

15 The WOMEN S HEALTH INITIATIVE One arm stopped in 2002 (CEE+P) Cardiovascular events outweighed benefits Other arm (CEE only) stopped due to increased stroke risk (no increase in breast ca or heart disease)

16 WOMEN s HEALTH INITIATIVE: Concluded that the long-standing opinion that supplementation with Estrogen would REDUCE cardiovascular risk was WRONG There was an increase in cardiovascular events in this study (which used only Conjugated Equine Estrogen and Medroxyprogesterone orally) The study was abruptly halted because of these findings.

17 After The WHI Most women discontinued their hormones They were then looking for other ways to treat their symptoms Many new studies came out looking at different types of hormones MANY OF THEIR CONCLUSIONS WERE INCORRECT

18 What was wrong with the WHI? enopause is 51, but average age in the WHI was 63; distant f The study did not address menopausal symptoms Large dropout rate dy was disease prevention but most women take hormones

19 WHI conclusions: No increase in all-cause mortality in women on HRT during either the treatment period or the long-term follow up 29% fewer hip fractures in women on hormone replacement, with 21% fewer hip fractures in women age 60 & above ONE more breast cancer case per 1000 women in the E+P arm of the study

20 The K.E.E.Ps Trial 2012 The KRONOS Early Estrogen Prevention Study Presented at the North American Menopause Society s 2012 meeting. Studied by the Kronos Longevity Research Institute. Multicenter, randomized study >700 women over 4 years double-blinded placebo-controlled Low dose oral Premarin or Transdermal Estradiol and cyclic monthly Progesterone

21 KEEPS Three Arms Oral Premarin Transdermal Estradiol Estrogen groups received cyclic Placebo Progesterone

22 EEPS Both hormone therapy groups had reduced symptoms of menopause, including hot flashes and night sweats Also had favorable effects on bone density compared to the placebo group. Improvements in lubrication and decreased pain with intercourse In the Transdermal group: improved arousal and desire but not in the oral Conjugated Estrogens group Coronary artery calcium and carotid ultrasounds showed a trend toward less progression of deposits in the groups on HT compared to placebo

23 K.E.E.P.s Study --No differences in the rates of Breast Cancer, Endometrial Cancer, M.I., Stroke or DVT --Small study Population, difficult to make definitive conclusions --Younger population may have been key since this study population were all between 42 and 59 years of age when they entered the study. --TYPE of Estrogen and Progesterone were different than what had been used in the WHI

24 Effect of Hormone Replacement Therapy on Cardiovascular Events in Recently Postmenopausal Women Randomized controlled trial of >1000 Danish women Recently menopausal, age Half received Hormone replacement, (17-B estradiol/norethistrone); half none (controls) After 10 yrs of treatment women on HRT had a significantly reduced risk of mortality, heart failure and MI British Medical Journal 2012:345:e6409 October 9

25 Danish study: Hormone therapy started in recently menopausal women and continued for a long period of time (>10 yrs) does not increase or provoke adverse cardiovascular events

26 STANFORD Medical School 2014 Estradiol but not Premarin, Preserves Key Brain Regions in Postmenopausal Women at risk for Dementia ---several dozen San Francisco Bay area women ---under 60, in robust health ---Initiated hormone therapy within a year of their last menstrual cycle ---at heightened risk for dementia PLOS 1: March 12, 2014

27 Stanford Medical School Study CONCLUSIONS: ---When women who started on ESTRADIOL therapy within a year of menopause stayed on the regimen, metabolic activity in regions of the brain was preserved ---It declined significantly in those who stopped using the Estradiol ---PREMARIN appeared to accelerate the brain regions metabolic decline ---If a PROGESTIN (as in the WHI) was added to the beneficial Estradiol regimen, it seemed to negate the beneficial effect of the Estradiol

28 CHOIICE STUDY: 2011 Dr Kenna Stephenson Compounded Bioidentical Hormones: Immune, Inflammatory and Cardiovascular Effects ---A 3-year study undertaken to look at the effects of transdermal hormones on: ~Fasting Glucose ~Triglycerides ~C-Reactive Protein levels Found Improvement in all of these, concluding that Bioidentical hormones through the skin may have a benefit in reducing cardiovascular risk and prevention of cardiovascular disease. Although there is MUCH controversy about the use of Compounded products, there may be some benefit. Small study, 75 in intervention, 75 in control University of Texas Health Science Center

29 The ESTHER Study HORMONE THERAPY AND VENOUS THROMBOEMBOLISM AMONG POSTMENOPAUSAL WOMEN Published in the Journal CIRCULATION --Multicenter case controlled study --VTE among postmenopausal women age between 1999 and 2005 in France who were on various hormonal regimens --CONCLUSION: Oral, but NOT Transdermal Estrogen was associated with an increased risk for VTE ---NO significant increase in VTE with Micronized, BioIdentical Progesterone Circulation:2007, Feb 20;115(7):840-5

30 ESTHER Study Multicenter, case control study 271 cases of VTE from hospital records & 610 controls, matched for age and admission date NO significant association of VTE with transdermal Estrogens, or with Micronized Progesterone, but positive association with oral Estrogen Circulation:2007, Feb 20;115(7):840-5

31 ELITE TRIAL Early vs Late Intervention Trial with Estradiol >600 healthy postmenopausal women, stratified according to time since menopause Either 17B-estradiol + progesterone or placebo Primary outcome: rate of change of carotid artery intimate-media thickness Secondary outcome: assessment of coronary atherosclerosis by cardiac CT NEJM 2016; 374:

32 ELITE TRIAL Early vs Late Intervention Trial with Estradiol Among women who were less than 6 years from menopause, mean intimal thickness was statistically less in the estrogen group vs placebo (.0078 vs.0044mm, p=.008) Among women who were >10 years past menopause, rates of intimal thickening were similar in placebo vs estrogen group NEJM 2016; 374:

33 ELITE TRIAL Early vs Late Intervention Trial with Estradiol In conclusion, we found that the effects of estradiol (with or without progesterone) on the progression of atherosclerosis differed according to the time of initiation of therapy, with benefit noted when it was initiated in women who were less than 6 years past menopause but not when it was initiated in women who were 10 or more years past menopause. NEJM 2016; 374:

34 THE RULES of Hormone Replacement HORMONE THERAPY IS FOR SYMPTOMS IF A PATIENT HAS AN INTACT UTERUS, PROGESTERONE MUST BE PRESCRIBED ALONG WITH ESTROGEN ESTROGEN SHOULD GO THROUGH THE SKIN IF POSSIBLE KNOW IF YOUR PATIENT IS IN MENOPAUSE

35 The Rules: IF THE SYMPTOMS ARE ONLY VAGINAL, TREAT VAGINALLY (VAGIFEM, ESTRACE cream, ESTRING, Vaginal DHEA, oral Osphena, CO2 laser for the vagina) TAKE A GOOD HISTORY AND DO AN EXAM Evaluate all bleeding (IS THERE A REASON THIS PATIENT CANNOT USE HRT?) PAY ATTENTION TO THE TIME THEORY

36 Treatment forvaginal symptoms 1-Estrogen products: Premarin cream, Estrace cream, Vagifem and Yuvafem Pills and Estring vaginal ring 2-OSPHENA- S.E.R.M. 60 mg PO Qday 3-Vaginal/vulvar CO2 fractionated laser 4- Vaginal DHEA: Intrarosa Recently FDA approved 5-Lubricants, ph correctors, Protectants

37 NORTH AMERICAN MENOPAUSE SOCIETY on CONTINUING USE of SYSTEMIC HORMONE THERAPY AFTER AGE NAMS stated that hormone therapy is the most effective treatment for symptoms of menopause Initiate within 10 yrs of menopause (Ideally 5-7) No contraindications, no reason to stop Benefits of menopause symptom relief outweigh the risks..

38 ALTERNATIVES BRISDELLE--SSRI low dose 10 mg for flashes VENLAFAXINE SSNRI for hot flashes ESTROVERA- Rhubarb plant, studies have shown hot flash relief CATAPRES--patch or pill; many incremental doses RELIZEN- Bee pollen OSPHENA--SERM for vaginal dryness/dyspareunia

39 Conclusions: Evidence shows the benefits of using HRT often outweigh the risks. Most women are candidates for HRT to treat their symptoms; rule out those who are not and offer alternatives Time Theory-must initiate near menopause Vaginal symptoms require vaginal treatment

40 THANK YOU Dr Rebecca Levy-Gantt Premier ObGyn Napa Inc premierobgynnapa.com

Women s Health: Managing Menopause. Jane S. Sillman, MD Assistant Professor of Medicine Harvard Medical School

Women s Health: Managing Menopause Jane S. Sillman, MD Assistant Professor of Medicine Harvard Medical School Disclosures I have no conflicts of interest. Learning Objectives 1. Apply strategies to help