Conflict of Interest Conflict of Interest Where are we on HRT for - - PowerPoint PPT Presentation

10/18/2019 1

Where are we on HRT for prevention?

Marcelle I. Cedars, M.D. Professor and Director Division of Reproductive Endocrinology and Infertility UCSF

Conflict of Interest

• Conflict of Interest

– KEEPS investigator

Learning Objectives

• At the conclusion of this debate, the

participant should be able to:

– discuss the risks and benefits of hormone therapy – understand the importance of individualization of treatment – develop informed treatment plans

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

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Menopausal Hormone Therapy (MHT) over the decades

1966 “Feminine Forever” 1980’s – cohort and case/control Studies – support MHT reduces CHD and osteoporosis 1992 – American College of Physicians Recommends MHT to prevent CHD 1995 PEPI trial 2002 WHI – E+P2004 WHI - ERT 2015 ELITE 1998 HERS

HRT for Prevention

• A. HRT should be used for

prevention in all women

• B. HRT should be used for

prevention in young women

• C. HRT should not be used for

prevention

H R T s h

• u

l d b e u s e d f

• r

. . . H R T s h

• u

l d b e u s e d f

• r

. . . H R T s h

• u

l d n

• t

b e u s e d f . .

15% 53% 32%

WHI vs. Observational studies

Manson JE, et al. 2006; 13:139

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Patient Characteristics: Age the “timing” hypothesis

• Grodstein et al. J Womens Health 2006

– Nurse’s Health Study: evaluating time from menopause – women near menopause reduced CV risk (RR 0.66 CI: 0.54-0.80)

• Manson et al. NEJM 2007

– WHI: coronary calcium – women 50-59, coronary calcium score lower in women on ET vs. placebo (OR 0.69 CI: 0.48-0.98)

• ELITE Trial – Hodus HN 2015

– Protection from CIMT changes in younger women

Early vs Late Intervention Trial with Estrogen (ELITE)

Hodis H, NEJM 2016

Estrogen and the Brain Alzheimer Disease

• Observational studies suggest protection
• Meta-analyses suggest risk reduction of

approximately 1/3

• Contradicted by the WHIMS trial (ages 65-79)

– Risk of dementia increased two-fold with combined HRT – Impact noted within a few years, suggesting impact primarily on the vasculature – Past history of use associated with lowered incident risk of dementia (including Alzheimer Disease)

• Initiation in older women WITH disease is not

beneficial

Estrogen and the Brain

• Direct effects

– Enhances synaptic plasticity, neurite growth, hippocampal neurogenesis and long-term potentiation (memory) – Protects against apoptosis and neural injury – Stimulates aceytlcholine (memory), serotonin, noradrenalin – 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)

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Verbal Memory

Decrement in immediate (A) and delayed (B) verbal recall Epperson JCEM 2013

Estrogen and the Brain

• Estrogen effect on memory
• Estrogen effect on mood
• Estrogen effect on stress and cognition

– Reduction in cortisol response to stress – Reduction in effect of stress to reduce working memory

Early effects of estrogen

• Girard: Scientific Reports 2017
• Neurocognitive function

– Cognitive control; mental set shifting – Response to environmental context

• Functional MRI

– Prefrontal functions – Cognitive flexibility

• Method to identify effect (pre-behavioral)

Estrogen and the Brain

• Alzheimer Disease

– Early and consistent symptom – loss of episodic memory (failing to recall appointments and events) – In the laboratory: estrogen reduces the formation of b-amyloid formation and diminishes hyperphosphorylation of tau protein 13 14 15 16

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Age-stratified Risk for Alzheimer Disease

OR Adjusted OR Entire Sample (age 50-99) HRT 0.47 (0.35-0.63) 0.70 (0.51-0.95) Ages 50-63 HRT 0.35 (0.19-0.64) 0.35 (0.19-0.66) Ages 64-71 HRT 0.65 (0.39-1.1) 0.86 (0.5-1.5)

Henderson VW MIRAGE 2005

Estrogen effect on verbal recall

Joffe, H Menopause 2006

Amyloid Deposition

Kantarci J J Alzheimer Disease 2016

Cognition and Estrogen

• No risk with early exposure

– KEEPS – ELITE – WHIMSY

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The “Menopausal Syndrome”

• Epidemiological Studies: proximity to

menopause, not associated with aging, relieved with estrogen

– Vasomotor Symptoms – Vaginal dryness/dyspareunia – Difficulty sleeping/insomnia – Mood and depression – Changes in cognitive function

Trouble Sleeping by Cycle Day

Kravitz, H. M. et al. Arch Intern Med

Hot Flashes worsen Sleep

• 20 healthy premenopausal women

receiving GnRHa

• 80% concordance between

subjective/objective VMS (sVMS/oVMS)

• Sleep efficiency (actigraphy) worse with
• VMS, quality worse with sVMS

(questionnaire)

Joffe H, Menopause 2013 PMID 23481119

Duration of VMS

Avis, NE: JAMA Int Med 2015

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Adjusted OR for CES-D > 16 Across Menopausal Transition

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 Pre Early Peri Late Peri Post HT Users

Bromberger, J Affect Disord 2007

Estradiol and Depressive Disorders

(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 criteria for major depressive, dysthymic, or minor depressive disorder by DSM-IV blindly randomized to transdermal estradiol (0.1 mg) or placebo for 12 wks

• Remission of depression observed in 17 of 25 (68%)
• n E2 and 5% on placebo
• Regardless of DSM-IV diagnosis, subjects responded

similarly to E2

Estrogen for Depression Prevention

Gordon, J JAMA Psychiatry 2018

Breast Cancer

Risk Factors

• Low body weight
• High mammographic breast density
• Late menopause

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Severity of Cancer by Treatment Group in WHI Women with Breast Cancer

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With Positive Nodes SEER Stage R or D Not well Differentiated E + P Placebo

Percent of Breast Cancers Tested Severity 81/341 43/263 91/379 53/291 232/332 193/260 p = 0.03 p = 0.07 p = 0.51

Adapted from: Chlebowski RT, et al. JAMA 2010;304:1684

Cumulative Breast Cancer Mortality in WHI Women Taking

E +P vs. Placebo

Cumulative Breast Cancer Mortality in WHI Women Taking E +P vs. Placebo

2.6 vs. 1.3 deaths per 10,000 women per year

Chlebowski RT, et al. JAMA 2010;304:1684

Breast Cancer Risk Factors

• Was there truly a “protective” effect of

estrogen in the E-only arm – WHI?

• Estrogen

– Role of estrogen deprivation

• Whether natural or via anti-estrogens

(tamoxifen/aromatase inhibitors)

– Estrogen as a pro-apoptotic

Breast Cancer The ‘Gap’ Hypothesis

• Starting estrogen remote from menopause

decreases risk while treatment within 2 years increases breast cancer risk

• The ‘gap hypothesis’ and the ‘timing

hypothesis’ are thus in conflict

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Breast Cancer

Risk Factors

• Low body weight
• High mammographic breast density
• Late menopause
• Starting close to menopause
• 2 years after stopping HRT – risk

equivalent to never users

Role of Progestational Agents

• Gompel, Climacteric 2018

– Estrogen alone lowest risk

• Not indicated with uterus in situ

– Synthetic progestins higher risk

• Higher affinity for glucocorticoid receptor
• Also androgen receptor and mineralocorticoid

– Natural progesterone risk lowest

U.S Preventative Task Force

Gartlehner, JAMA 2017 Gross D, JAMA 2017

WHI E+P: During Study and Follow-up: Mortality

Modified from Heiss et al. JAMA 2008;299:1036-45

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Danish Osteoporosis Prevention Study (DOPS)

• 1006 women
• Randomized 45-58 years, last vaginal

bleeding 3-24 months prior to enrollment and increased FSH

• Randomized, open-label, trial of estrogen

(2mg daily), triphasic estradiol + norethisterone (uterus) vs. no treatment

Schierbeck LL, BMJ 2012

DOPS - 2012

Schierbeck LL, BMJ 2012

Long-term risk/benefit

Mikkola TS. Menopause 2015

Menopausal Hormone Therapy Good Prevention Strategy

• Rise in mortality for women - increased

44% compared with 3% for men since 2002

• Only other preventative strategy -

lifestyle

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Menopausal Hormone Therapy Good Prevention Strategy

• Prevention of cardiovascular disease
• Prevention of osteoporosis and fractures
• Reduction in new onset diabetes
• Reduction in dementia
• Reduction in all-cause mortality
• Improved quality of life

Menopausal Hormone Therapy Good Prevention Strategy

• Absolute risks

– Breast cancer: 5-8/10,000 women years – Venous thrombosis: 5/10,000 women years

• Use of non-oral eliminates risk

Modified from Heiss et al. JAMA 2008;299:1036-45

Study Publication Oral Estrogen Transdermal Estrogen

Scarabin, et al (1) 3.5 (1.8-6.8) 0.9 (0.5-1.6) Canonico, et al (2) 4.2 (1.5-11.6) 0.9 (0.4-2.1)

1.Lancet, 2003,362: 428-3 2.Circulation, 2007,115: 840-845

Endocrine Society 2010

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Endocrine Society 2010 Current Thinking

• Best treatment population

– Young women < 60 years of age – < 10 years from menopause

• Individualization

– Personal preference – Baseline risk – Characteristics of MHT (route, type, dose)

Duration

• 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

Impact of Stopping HT

MikkolaTS 2015 JCEM

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Impact of Stopping HT

MikkolaTS 2015 JCEM Venetkoski M 2017 Menopause

Individualization

• Risk profile
• Symptom profile
• Medication selection
• Patient preferences

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