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

10/19/2018 1

HRT: New Evidence on a Old Topic

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

Conflict of Interest

• Conflict of Interest

– None

• Off –label drug use

– Mirena IUD – Gabapentin – Effexor – Clonidine

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+P 2004 WHI - ERT 2015 ELITE

WHI vs. Observational studies

Manson JE, et al. 2006; 13:139

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

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

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DOPS - 2012

Schierbeck LL, BMJ 2012

DOPS - 2012

• At 10 years, reduced overall mortality
• Reduced heart failure, MI
• No “apparent” increased risk cancer,

VTE

Breast Cancer

Risk Factors

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

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

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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

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

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

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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

Verbal Memory

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

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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

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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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

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

U.S Preventative Task Force

Gartlehner, JAMA 2017 Gross D, JAMA 2017

Long-term risk/benefit

Holm M, BJOG 2018

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Endocrine Society 2010 Endocrine Society 2010 Current Thinking

• Estrogen most effective treatment
• Bio-identical hormones

– no more effective – no evidence for improved safety

• BZA/CE comparative efficacy

– Thromboembolic risk comparative – Long-term data lacking

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)

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“Lowest Dose”

• Start low

– Decreased stroke risk – Positive effects on symptoms

• May take longer to document benefit

– Positive effects on bone – Safety re: endometrial protection when unopposed not confirmed – Safety re: CVD not confirmed

Route/Type

• Blood pressure – impaired endothelial function

– Small impact of oral; no impact for transdermal – beneficial impact suggested with estradiol and drospirenone

• Metabolic syndrome – menopause diabetogenic

– Reduced DM and insulin resistance with estrogen – Advantage of natural progesterone/non-androgenic progestins (drospeirenone, dydrogesterone)

Route/Type

• CVD

– CRP – increased with oral and not transdermal; worsening affect with MPA – MMP-9 – increased by oral and not by transdermal – “first pass” effect on the liver (lipids) – endothelial function - improved with both (inhibited by MPA and NET)

• Thromboembolic events (case-control study)

– Increased risk with oral – No increase with transdermal

Route/Type

• Neuroprotection

– No differences available between oral and transdermal

• Breast cancer

– No differences available between oral and transdermal – Increased risk with combined progestational agent

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Route

• Transdermal

– Less negative effect on surrogate markers

• Clotting factors, TG, CRP

– Decrease stroke risk – Decreased CV risk – not well documented

• Vaginal

– For local symptoms

Type

• Progestogen

– Daily combined vs. cyclical

• Improved protection re: endometrial cancer
• Increased breast cancer risk

– MPA vs. progesterone

• Stroke risk: Progesterone < MPA

Mirena for Uterine Protection

Jareid M, Gynecol Oncol 2018

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

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Impact of Stopping HT

MikolaTS 2015 JCEM

Impact of Stopping HT

MikolaTS 2015 JCEM Venetkoski M 2017 Menopause

Non-hormonal Alternatives

• SSRI and SNRI have modest effect

– Avoid paroxetine with tamoxifen

• Gabapentin equally effective to estrogen

– ER may have less side effects

• Clonidine

– No comparative trials with estrogen – High side effect profile

Vaginal Relief – new alternatives

• Ospemifene

– SERM – local effect on vaginal tissue – Minimal increase endometrial thickness – no histological changes – Neutral breast – Possible positive bone effect (bone markers) – Possible increased stroke risk

Archer DF, Menopause 2014

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Behavioral therapy

• Yoga appears in early studies to have

some benefit

• Mindfulness, avoidance of triggers and

relaxation may offer benefit to some

• New studies evaluating cognitive

behavioral therapy with reduction in sleep disturbances and depression

Individualization

• Risk profile
• Symptom profile
• Patient preferences

Assess Risk

• CV Risk

– http://my.americanheart.org/cvriskcalculator

• Stroke Risk

– Bushnell, Annals Int Med 2014

• Breast Cancer Risk

– http://www.cancer.gov/bcrisktool/ – Discuss SERM if 5-year risk > 3% – First degree relative, BRCA+, personal history of biopsy with atypia

Assess Risk

• Osteoporosis Risk

– http://www.shef.ac.uk/FRAX/tool.aspx?country=9

• NAMS decision support tool

– Menopause 22(3): 247-253, 2014 – MenoPro App

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Type – new alternatives

• Combination – estrogen + SERM

– CEE 0.45mg + Bazedoxifene (BZA) 20mg – Vasomotor symptom relief – Vaginal symptom relief – Bone protection – albeit < MHT – Favorable lipid profiles – No adverse risk to bone/endometrium – No long-term studies of events

Lobo RA, Fertil Steril Pinkerton JV, J Women’s Health 2014 Pinkerton JV, JCEM 2014

Type – New combination therapies

• Activella: E2 1mg + NETA 0.5mg daily
• Femhrt: EE 5 mcg + NET 1mg daily
• Ortho-prefest: E2 1mg + norgestimate

0.09mg

– Alternate 3 days unopposed E2 with combination

• Combi-patch

– E2 with LVG or NETA