Pharmacology Update: Menopause and Hormone Therapy North American Menopause Society Meeting 2015 Disclosure The faculty and planners for this activity, as well as the CME staff, do not have any relevant financial relationships with commercial interests or affiliations to disclose. 1
Menopause signs/symptoms Bone loss Hot flashes Night sweats Disturbed sleep Mood changes Genitourinary syndrome/vaginal atrophy Decreased Libido 2
Menopause Treatment Lifestyle changes first Nonprescription remedies/herbals Hormone Therapy-the most effective treatment for bothersome hot flashes Not all women are good candidates for Hormones Contraindications include: breast or uterine cancer, heart attack, blood clots, stroke, severe liver disease high triglycerides, thromboembolic disease, undiagnosed vaginal bleeding Hormone Therapy Systemic: usually patch or pill form Estrogen Therapy (ET) for women without a uterus Estrogen-progesterone therapy (EPT or HRT) Lowest dose/shortest duration, max effect 4-12 wks Local estrogen therapy: vaginal creams, gels, rings, tablets, *risks/benefits are very different between forms 3
Women s Health Initiative NIH study initiated in 1991 to investigate the long-term benefits and risks of hormone therapy: More than 160,000 postmenopausal women, aged 50-79-average age 63.3! (ave age menopause 51.4)- treatment phase ended early, d/t increased risk of breast cancer, CHD, stroke and thomboembolic disease in the EPT group and increased risk of thromboembolic disease in the estrogen only group. WHI results 4
WHI results WHI 10 yrs later Patients are individuals with unique health risks, concerns and symptoms- A one size fits all recommendation for HT is not appropriate Timing Hypothesis More benefit, less risk when HT started within 5-10 yrs of last menstrual period or younger than 60- *starting hormone therapy in early menopause shows lower cardiovascular risk Increased breast cancer risk with combined therapy at 5 yrs of use No increase risk in breast cancer with estrogen alone 5
Beers Criteria The American Geriatrics Society Identifies potentially inappropriate medication use in older adults (over 65) Estrogens with or without progestins is included on list Newer research documents moderate to severe hot flashes lasting into the mid 60s for some women Nams position: HRT after age 65 is appropriate in some situations, with the decision to be made by the patient and provider, considering the risks and benefits, and possible alternative treatments 6
Contraception in the Perimenopause A Top 10 List DEPARTMENT NAME PLACEHOLDER (OPTIONAL) #10 No contraceptive is contraindicated based solely on age. Can a nulliparous teenager have an IUD placed? Yes! Can a perimenopausal woman be given combined oral contraceptive pills? Yes! 7
#9 Overall Risk of any cancer in women who used COC is lower than in nonusers 12% lower for all cancers 29% lower for all gyn cancers #8 The Mirena IUD is an ideal choice for contraception after the age of 45. If placed after the age of 45 the Mirena IUD will be effective for up to 7 years. If placed after the age of 45 the Mirea IUD can be continued until menopause if the woman remains amenorrheic These are proven but off label uses for the Mirena IUD. 8
#7 The copper IUD (Paraguard) is the only reliable non hormonal method of contraception. Cyclic NSAIDS may be used to counteract the increase in bleeding and cramping associated with the copper iud. Daily ibuprofen 2-3 times daily starting 2-3 days prior to menses through the first 3 days of the menstrual flow. 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 17 September 20, 2016 #6 Tubal ligation with Filshie clips or Essure have the lowest pregnancy rates of all methods. There is a 40% decrease in ovarian cancer rates after tubal sterilization. 9
#5 The Essure method of tubal sterilization is an office procedure. Despite media coverage of patient complaints, there is only a 2.7% complication rate for the Essure procedure. #4 Eventually you can take your patients off contraception If they are between the ages of 40-50 and have amenorrhea > 2 yr If they are >=50 and have amenorrhea >1 yr Or if they are age 55-60 10
#3 If you must, you can use lab values to determine when to stop contraception No need for contraception if FSH >30 measured on 2 occasions at least 6 weeks apart. #2 FSH levels are not suppressed with use of depoprovera or progestin only pills. Therefore can check FSH levels while using progestin only methods. May check FSH 1-2 wk after stopping combined OCP. 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 22 September 20, 2016 11
Perimenopausal Contraception: Top Ten List #1 Most interesting fact Guinness Book of World records shows oldest spontaneous pregnancy leading to live birth in a woman age 59 while on estrogen! 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 23 September 20, 2016 Menopause, Cardiovascular disease and diabetes A Top 10 List 12
10: Menopause, Cardiovascular Disease and Diabetes: Loss of estrogen at menopause increases visceral fat and insulin resistance, impairs insulin secretion and increases incidence of Type 2 Diabetes 9: Menopause, Cardiovascular Disease and Diabetes Menopausal hormone therapy containing estrogens significantly decreases the incidence of diabetes in placebo-controlled randomized trials 13
8 Menopause, Cardiovascular Disease and Diabetes HT has an anti-diabetic effect Estrogen decreases abdominal fat, decreases insulin resistance and increases insulin sensitivity Decreased risk is independent of adiposity 7 Menopause, Cardiovascular Disease and Diabetes 20% decrease in diabetes with 5 years of HT- Almost 30% decrease in 50-59 age group- *timing of and length of treatment important 14
Menopause, Cardiovascular Disease and Diabetes 6 *Oral Estrogen works better at decreasing diabetes risk than transdermal Oral may increase other risks (stroke) vs. transdermal (possible dose response, lower levels in transdermal) 5 Menopause, Cardiovascular Disease and Diabetes Estradiol based HT used in Finland Observational study shows protective effect of HT on Cardiovascular disease. Increased CVD mortality after stopping HT, protective effect while on HT 15
Menopause, Cardiovascular Disease and Diabetes 4 TIMING IS EVERYTHING: No benefits in HRT for cardiovascular disease in those over 60 Longer exposure, initiation closer to menopause more benefit Increased risk of cardiac death in first year post discontinuation of HT (<60) 3 Menopause, Cardiovascular Disease and Diabetes Cumulated data shows that HT consistently reduces CHD and total mortality when initiated in women less than 10 years since menopause and/or less than age 60 (Over all ages, there is a null effect on CHD and total mortality in women with HT) 16
2 Menopause, Cardiovascular Disease and Diabetes There are gender specific differences in primary prevention therapies for CV disease Aspirin-decreased CVA in women, no effect on MI (opposite in men) Statin-No effect on CHD in women, but decreased CHD in men Ace I-no CHD decrease in women, decrease in CHD and mortality in men HT+Statin-50% decrease in total mortality in women Menopause 1 17
Estrogen Replacement Therapy after TAHBSO A Top 10 List 18
#10 Transdermal estrogen may be safer than oral Transdermal estrogen skips the first pass effect on the liver, therefore does not increase the production of clotting factors. A study of 1000 menopausal French women showed a 4.5 fold increase in venous thromboembolism on oral estrogen compared to a 0.9 fold increase on transdermal estrogen. #9 Rates of global index of disease are the same for ERT users vs non-users Although this is true for the global index of disease, specific diseases may be effected either positively or negatively. 19
#8 The Timing Hypothesis states that early ERT is beneficial to cardiovascular health. In extended f/u from WHI, ERT after TAHBSO ages 50-59 Significant decrease in CVD Significant decrease in MI Significant decrease in overall mortality #7 Estrogen Replacement Therapy after Hysterectomy and BSO shows a decreased incidence of breast cancer 20
#6 Recurrence of pelvic pain 3.5% in endometriosis pt given ERT after TAHBSO #5 If ERT given after TAHBSO, there is no increase risk of cognitive decline, CVD, overall mortality. 21
#4 ERT post TAHBSO does improve emotional symptoms If ERT given after TAHBSO there Is NO reduction in menopause induced anxiety, depression, parkinsonism 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 43 September 20, 2016 #3 In younger women ERT is protective of their health after BSO Mayo clinic study of oophorectomy at/before age 45 BSO with no ERT showed significant decrease in overall survival rate BSO with ERT showed increase in overall survival rate compared to both no BSO and BSO with no treatment 22
#2 Beneficial effects of BSO before age 50 90% decrease risk ovarian cancer 50% decrease risk breast cancer 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 45 September 20, 2016 ERT after BSO: Top Ten List #1 Most Interesting : NAMS says Don t castrate your patients Deleterious effects of BSO before the age of 50 include increased risk of: All cause mortality Lung cancer CHD Stroke Parkinsonism Psychiatric d/o Cognitive impairment Sexual dysfunction 46 2011 Kaiser Foundation Health Plan, Inc. For internal use only. September 20, 2016 23
Compounded HRT: Top Ten List 24
#10 The term Bioidentical is not a scientific term and has no definition in the medical dictionary. The term Compounded is more appropriate #9 Compounded HT has never been shown to be safer or more effective than commercial HT. 25
#8 Brand and generic drugs must conform to GMP Good Manufacturing Practices are the Federal requirements for identity, quality, potency, and purity of the drugs. Compounded drugs do not follow nor are held accountable for GMP #7 Morbidity and mortality have occurred related to infections from compounded drugs. In 2014 hundreds of deaths occurred from contaminated steroids used for epidural injections from a compounding pharmacy. 26
#6 The AMA Counsel on Science and Public Health issued the following statement No credible scientific evidence exists on the value of so called bioidentical hormones and there are concerns about their purity, potency, and quality because they are not FDA approved. #5 In one study 25% of compounded HT failed quality control testing versus 2% of commercial HT 27
#4 There may be an increased risk of endometrial cancer with compounded HRT The variable absorption of creams/mists etc as well as the variation in actual amount of hormone may cause insufficient progesterone to protect the endometrium from the proliferative effects of estrogen. #3 The amount of progesterone cream that would be needed for endometrial protection is unknown, but would most probably require the majority of the leg to be covered on a daily basis. 28
#2 The provider who prescribes the compounded HT will be found liable if there is any harm to the patient Compounded HRT: Top Ten List #1: We need a consistent response to patient demands for bioidentical/compounded hormone replacement therapy. 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 58 September 20, 2016 29
Questions:??? References, Citations and Resources The Compounded Hormone : NAMS Lecture 2013 Wulf H. Utian MB BCh PhD DSc(Med) FRCOG FACOG FICS, Professor Emeritus, Case Western Reserve University, Executive Director, NAMS 3 Cases on bioidentical HRT: Eden et al, MJA 2007;187:244-5 2 cases on bioidentical HRT: Jessel et al, Menopause 2009;16:1247 4 cases in NAMS survey: 2011 Kaiser Foundation Health Plan, Inc. For internal use only. Menopause 2015;22:PAP 60 September 20, 2016 30
References, Citations, and Resources Hysterectomy: Issues, Challenges, Risks/Benefits : NAMS 2015 Lecture Case School of Medicine Case Research Institute University Hospitals UH Medical Group; James H. Liu, M.D., Arthur H. Bill Professor, Chair of Reproductive Biology, Dept of Obstetrics and Gynecology 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 61 September 20, 2016 References, Citations, and Resources The Contraceptive Needs of Older Reproductive Age Women NAMS lecture 2015 Amanda Black, MD, MPH, FRCSC Vice Chair Research, Department of Obstetrics & Gynecology, The Ottawa Hospital Co-Medical Director, Shirley E. Greenberg Women s Health Centre Dr. Elaine Jolly Chair in Women s Health Research Associate Professor, The University of Ottawa, Ottawa, Canada 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 62 September 20, 2016 31
Citations: Cardiovascular Disease and Postmenopausal Hormone Therapy: Tomi S Mikkola, MD, NAMS plenary Symposium10/2015 Primary Prevention of Coronary Heart Disease in Women: New updates: Howard N. Hodis, MD, NAMS plenary symposium, 10/2015 Estrogen Therapy After Postmenopausal Hysterectomy-Issues, Challenges, Risks and Benefits: James H Liu, MD, NAMS plenary symposium 10/2015 Citations: Understanding the Emerging Evidence from the WHI Estrogen-Alone study: Wyeth Pharmaceuticals, Sept, 2006 Understanding the WHI Estrogen plus Progestin study: Assessing the results: Wyeth Pharmaceuticals, Sept 2006 The Menopause Guidebook: North American Menopause Society, 8 th Edition 2015 Menopause Hormone Replacement Therapy: Kanchan Kaur, MBBS, Scott Lucidi, MD, et al Medscape: updated Mar 17, 2016 32