Conflict of Interest HRT: New Evidence on a Old Topic Conflict of - PowerPoint PPT Presentation

10/19/2018 Conflict of Interest HRT: New Evidence on a Old Topic • Conflict of Interest – None • Off –label drug use – Mirena IUD – Gabapentin Marcelle I. Cedars, M.D. – Effexor Professor and Director Division of Reproductive Endocrinology and Infertility – Clonidine UCSF Problems in Peri- Postmenopausal Women • Abnormal uterine bleeding • Vasomotor symptoms • Genital atrophy • Decrease in skin collagen • Rapid bone loss • Increase in coronary heart disease • Increase in Alzheimer’s disease 1

10/19/2018 2002 1966 WHI – E+P “Feminine Forever” WHI vs. Observational studies 1992 – American College of Physicians Recommends MHT to prevent CHD Menopausal Hormone Therapy (MHT) over the decades 1980’s – cohort and case/control Studies – support MHT reduces CHD and osteoporosis 2004 2015 1995 PEPI trial WHI - ERT ELITE Manson JE, et al. 2006; 13:139 Patient Characteristics: Age Danish Osteoporosis the “timing” hypothesis Prevention Study (DOPS) • Grodstein et al. J Womens Health 2006 • 1006 women – Nurse’s Health Study: evaluating time from • Randomized 45-58 years, last vaginal menopause – women near menopause reduced CV bleeding 3-24 months prior to enrollment risk (RR 0.66 CI: 0.54-0.80) and increased FSH • Manson et al. NEJM 2007 • Randomized, open-label, trial of estrogen – WHI: coronary calcium – women 50-59, coronary calcium score lower in women on ET vs. placebo (2mg daily), triphasic estradiol + (OR 0.69 CI: 0.48-0.98) norethisterone (uterus) vs. no treatment • ELITE Trial – Hodus HN 2015 Schierbeck LL, BMJ 2012 – Protection from CIMT changes in younger women 2

10/19/2018 DOPS - 2012 DOPS - 2012 • At 10 years, reduced overall mortality • Reduced heart failure, MI • No “apparent” increased risk cancer, VTE Schierbeck LL, BMJ 2012 Breast Cancer Breast Cancer Risk Factors Risk Factors • Was there truly a “protective” effect of • Low body weight estrogen in the E-only arm – WHI? • High mammographic breast density • Late menopause • Estrogen – Role of estrogen deprivation • Whether natural or via anti-estrogens (tamoxifen/aromatase inhibitors) – Estrogen as a pro-apoptotic 3

10/19/2018 Breast Cancer Breast Cancer The ‘Gap’ Hypothesis Risk Factors • Starting estrogen remote from menopause • Low body weight decreases risk while treatment within 2 • High mammographic breast density years increases breast cancer risk • Late menopause • Starting close to menopause • The ‘gap hypothesis’ and the ‘timing hypothesis’ are thus in conflict • 2 years after stopping HRT – risk equivalent to never users The “Menopausal Syndrome” Role of Progestational Agents • Epidemiological Studies: proximity to • Gompel, Climacteric 2018 menopause, not associated with aging, – Estrogen alone lowest risk relieved with estrogen • Not indicated with uterus in situ – Vasomotor Symptoms – Synthetic progestins higher risk – Vaginal dryness/dyspareunia • Higher affinity for glucocorticoid receptor – Difficulty sleeping/insomnia • Also androgen receptor and mineralocorticoid – Mood and depression – Natural progesterone risk lowest – Changes in cognitive function 4

10/19/2018 Trouble Sleeping by Cycle Day Hot Flashes worsen Sleep • 20 healthy premenopausal women receiving GnRHa • 80% concordance between subjective/objective VMS (sVMS/oVMS) • Sleep efficiency (actigraphy) worse with oVMS, quality worse with sVMS (questionnaire) Joffe H, Menopause 2013 PMID 23481119 Kravitz, H. M. et al. Arch Intern Med Verbal Duration of VMS Memory Decrement in immediate (A) and delayed (B) verbal recall Epperson JCEM 2013 Avis, NE: JAMA Int Med 2015 5

10/19/2018 Adjusted OR for CES-D > 16 Estradiol and Depressive Disorders Across Menopausal Transition (Soares et al., Arch Gen Psychiatry 2001;58:529) • 50 perimenopausal women aged 40-55 with irregular menstrual periods and FSH > 25 IU/L meeting Pre Early Peri Late Peri Post HT Users criteria for major depressive, dysthymic, or minor depressive disorder by DSM-IV blindly randomized 1.8 1.6 to transdermal estradiol (0.1 mg) or placebo for 12 1.4 wks 1.2 • Remission of depression observed in 17 of 25 (68%) 1 on E 2 and 5% on placebo 0.8 0.6 • Regardless of DSM-IV diagnosis, subjects responded 0.4 similarly to E 2 0.2 0 Bromberger, J Affect Disord 2007 Estrogen for Depression Estrogen and the Brain Prevention • Direct effects – Enhances synaptic plasticity, neurite growth, hippocampal neurogenesis and long-term potentiation (memory) – Protects against apoptosis and neural injury Gordon, J – Stimulates aceytlcholine (memory), serotonin, JAMA Psychiatry noradrenalin 2018 – Decrease deposition of b -amyloid – Promotes morphological and electrophysiological correlates of learning and memory • Indirect effects – Vasculature – Immune system NIA – Frontiers proposal – Bench to Bedside Estrogen as a case-study (2009) 6

10/19/2018 Estrogen and the Brain Estrogen and the Brain Alzheimer Disease • Observational studies suggest protection • Alzheimer Disease • Meta-analyses suggest risk reduction of – Early and consistent symptom – loss of approximately 1/3 episodic memory (failing to recall • Contradicted by the WHIMS trial (ages 65-79) appointments and events) – Risk of dementia increased two-fold with combined HRT – In the laboratory: estrogen reduces the – Impact noted within a few years, suggesting impact formation of b -amyloid formation and primarily on the vasculature diminishes hyperphosphorylation of tau – Past history of use associated with lowered incident risk of dementia (including Alzheimer Disease) protein • Initiation in older women WITH disease is not beneficial Long-term risk/benefit U.S Preventative Task Force Holm M, BJOG 2018 Gartlehner, JAMA 2017 Gross D, JAMA 2017 7

10/19/2018 Endocrine Society 2010 Endocrine Society 2010 Current Thinking Current Thinking • Best treatment population • Estrogen most effective treatment – Young women < 60 years of age • Bio-identical hormones – < 10 years from menopause – no more effective • Individualization – no evidence for improved safety – Personal preference • BZA/CE comparative efficacy – Baseline risk – Thromboembolic risk comparative – Characteristics of MHT (route, type, dose) – Long-term data lacking 8

10/19/2018 “Lowest Dose” Route/Type • Start low • Blood pressure – impaired endothelial function – Small impact of oral; no impact for transdermal – Decreased stroke risk – beneficial impact suggested with estradiol and – Positive effects on symptoms drospirenone • May take longer to document benefit – Positive effects on bone • Metabolic syndrome – menopause diabetogenic – Safety re: endometrial protection when – Reduced DM and insulin resistance with estrogen unopposed not confirmed – Advantage of natural progesterone/non-androgenic – Safety re: CVD not confirmed progestins (drospeirenone, dydrogesterone) Route/Type Route/Type • CVD • Neuroprotection – CRP – increased with oral and not transdermal; – No differences available between oral and worsening affect with MPA – MMP-9 – increased by oral and not by transdermal transdermal – “first pass” effect on the liver (lipids) • Breast cancer – endothelial function - improved with both (inhibited by MPA and NET) – No differences available between oral and transdermal • Thromboembolic events (case-control study) – Increased risk with combined progestational – Increased risk with oral agent – No increase with transdermal 9

10/19/2018 Route Type • Transdermal • Progestogen – Less negative effect on surrogate markers – Daily combined vs. cyclical • Clotting factors, TG, CRP • Improved protection re: endometrial cancer – Decrease stroke risk • Increased breast cancer risk – MPA vs. progesterone – Decreased CV risk – not well documented • Stroke risk: Progesterone < MPA • Vaginal – For local symptoms Duration Mirena for Uterine Protection • 3-5 years • Stopping guidelines – Breast cancer risk after combined continuous for 7 years – Bone loss will resume – Vasomotor and vaginal symptoms may return • Long-term treatment Jareid M, Gynecol Oncol 2018 10

10/19/2018 Impact of Stopping HT Impact of Stopping HT MikolaTS 2015 JCEM MikolaTS 2015 JCEM Venetkoski M 2017 Menopause Vaginal Relief – new Non-hormonal Alternatives alternatives • SSRI and SNRI have modest effect • Ospemifene – Avoid paroxetine with tamoxifen – SERM – local effect on vaginal tissue – Minimal increase endometrial thickness – no • Gabapentin equally effective to estrogen histological changes – ER may have less side effects – Neutral breast • Clonidine – Possible positive bone effect (bone markers) – No comparative trials with estrogen – Possible increased stroke risk – High side effect profile Archer DF, Menopause 2014 11