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Menopause Management: 2012 Update
Ivy M. Alexander, PhD, APRN, ANP-‐BC, FAAN Professor, Yale University School of Nursing
Disclosures
(within past 12 months) for: PDR Network Medscape NPACE, CT APRN Soc, NPWH Engage Amgen Datamonitor Pfizer
Objectives
Following this presentation, participants will be able to:
1. Identify common symptoms women experience related to menopause
2.Differentiate the risks and benefits of various therapies for menopause-‐related symptoms as identified in recent research
3. Apply evidence from recent studies in making individualized clinical decisions for managing menopause-‐related symptoms
Physiologic Changes in the Natural Menopausal Transition
Variable cycle length1
Endocrinologic milieu shifts Inhibin2-‐4
FSH2-‐4
Variable changes in E15
Testosterone: no significant change3,6
1. Treolar et al. Int J Infertil. 1967;12:77. 2. Burger. Hum Reprod. 1993;8(suppl 2):129. 3. Burger et al. J Clin Endocrinol Metab. 1995;80:3537.
4. Lenton et al. J Clin Endocrinol Metab. 1991;73:1180. 5. Santoro et al. J Clin Endocrinol Metab. 1996;81:1495. 6. Bancroft et al. Clin Endocrinol. 1996;45:577.
Dilemma in Diagnosing Menopause
Clinical symptoms are the best guide to diagnosing menopause
Natural menopause can be diagnosed after 12 consecutive months of amenorrhea that has no other obvious pathologic/physiologic cause
Biochemical tests alone are not reliable guides to an accurate diagnosis
FSH levels are not reliable predictors of menopause because FSH levels are variable in perimenopausal women
Creinin MD. Fertil Steril. 1996;66:101; Gebbie AE et al. Contraception. 1995;52:221.
Management for Selected Symptoms
Sleep GU Changes & Sex
Memory and Cognition Vasomotor Symptoms
Approaches
Evaluate risks Stepped approach:
Lifestyle Strategies CAM Therapies
Behavioral Therapies Acupuncture Botanicals
Pharmacotherapeutics
Non-‐hormone Hormone
Sleep Disruption
Management Strategies for Sleep Disturbances
(Frequently related to hot flashes) Reduce hot flashes Keep room cool, fan
Wicking sleepwear Avoid all stimulants Good bedtime practices (sleep hygiene) Sleep retraining Many women use CAMs Estrogen
1Schiff I, et al. Maturitas. 1980;2:179-83. 2Scharf MB, et al. Clin Ther. 1997;19:304-11. 3Erlik Y, et al. JAMA. 1981;245:1741-4. 4Polo-Kantola P, et al. Am J Obstet Gynecol. 1998;178:1002-9. 5Antonijevic IA, et al. Am J Obstet Gynecol. 2000;182:277-82.
Estrogen Improves Sleep
Decreases the frequency of Night sweats1-‐4
Periods of night awakenings3,4
Reduces sleep latency1,2
Improves sleep in menopausal women with insomnia, even in the absence of vasomotor symptoms4
Increases the percentage of REM sleep1,5
May alleviate sleep apnea3,4
GU Changes & Sexual Health
Genitourinary Atrophy*
Genitourinary Changes After Menopause
Most inevitable, least publicized consequence of estrogen loss 100% of women affected not bothersome for all women
Up to 45% of older women suffer from urinary incontinence
High prevalence of sexual dysfunction in menopause clinics
Weinberger. Clin Obstet Gynecol. 1995;38:175; Sarrel. Obstet Gynecol Clin North Am. 1987;14:49; Elia et al. Obstet Gynecol Surv. 1993;48:509.
Vaginal Dysfunction (pain with penetration/
sexual dysfunction)
Urinary Dysfunction
Time to achieve vaginal lubrication, Vaginal lubrication Vaginal elasticity, rugation, color Petechiae and bleeding after minor trauma in lactobacilli
Vaginal pH Vulnerability to urogenital pathogens
Superficial vaginal epithelial cells Collagen and adipose in vulva
Labial involution and clitoral exposure Vagina thinner and paler
Sexual Physiologic Changes with Aging
Bachmann et al. In: Lobo, ed. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. 2nd ed. New York: Lippincott Williams & Wilkins; 1999:195.
Sexual Function Declines with Menopause and Aging
Sexual libido Sexual responsivity Sexual activity Vaginal dyspareunia
partner
Dennerstein et al. Fertil Steril. 2001;76:456.
Sexual Dysfunction in Women
Includes desire, arousal, orgasmic, and pain disorders
Can be caused by: physiological changes of menopause breakdown in interpersonal relationships family, societal and religious beliefs Medications, partner problems, aging
A detailed patient history is required to diagnose sexual dysfunction
Basson R, et al. J Urol. 2000;163:888-93.; Laumann EO, et al. JAMA. 1999;281:537-44; Basson R. Menopause. 2004;11(6 pt 2):714-25; and Dennerstein L, et al. Fertil Steril. 2005;84:174-80.
Prevalence of Male and Female Sexual Complaints
National Health and Social Life Survey Ages 18 to 59 Years
0 5 10 15 20 25 30 35
Women Have Trouble Lubricating
Men Unable to Keep an Erection
Climax Too Early
Anxiety About Performance
Lacked Interest in Sex
Unable to Achieve Orgasm
Sex Not Pleasurable
Experience Pain During Sex
Percentage
Women (n = 1664)
Men (n = 1330)
Laumann EO, et al. The Social Organization of Sexuality: Sexual Practices in the United States. Chicago, Ill: University of Chicago Press; 1994. © 1994 by Edward O. Laumann, Robert T. Michael, CSG Enterprises, Inc., and Stuart Michaels. All rights reserved.
Management Strategies for Sexual Dysfunction/Complaints
Lubricants/moisturizers
Hormone therapy (FDA approved for vaginal dryness, off label use for sexual dysfunction)
Local estrogen cream, ring, tablet
Systemic estrogen ring, patch, cream, gel, mousse, spray, oral tablet
Estrogen + progestin
Estrogen + androgen (+/-‐ progestin)
Androgen
Vaginal Lubricants and Moisturizers
OTC water-‐based vaginal lubricants (short acting) and moisturizers (longer acting)
Women may need both
Vitamin E oil, olive oil
Product selection is based on individual preference
Adapted from Dessole S, et al. Menopause. 2004;11:49-56.
Efficacy of Low-‐dose Vaginal Estriol on Urogenital Symptoms
Variables
Treatment Group (n = 44) Control Group (n = 44) P-
Value* Before Treatment
After Treatment
Before Treatment
After Treatment
Clinical Vaginal dryness Dyspareunia Urogenital atrophy Urodynamic MUP (cm H20) MUCP (cm H20) PTR (%)
100% 86.4% 100%
50.82 6.15 45.25 7.20 72.52 10.31
20.5% 20.5% 27.3%
62.15 8.64 56.87 9.23 88.85 9.66
100% 84.1% 100%
52.35 6.30 44.77 6.86 70.75 9.08
90.9% 86.4% 93.2%
49.40 6.54 43.32 6.32 70.77 9.04
<.001 <.001 <.01 <.05 <.05 <.05
*P-value is comparison between treatment and control groups. MUP = maximum urethral pressure; MUCP = mean maximum urethral closure; PTR = abdominal pressure transmission ratio.
Vaginal Epithelium & Estrogen
Vagina/urethra highest concentration of estrogen receptors2 Most efficient response with local application3,4
6 weeks of estrogen
Without estrogen - atrophic With estrogen1
1. Freedman. Unpublished data. 2. Losif et al. Am J Obstet Gynecol. 1981;141:817.
3. Elia et al. Obstet Gynecol Surv. 1993;48:509. 4. Weinberger. Am Clin Obstet Gynecol. 1995;38:175.
Sexual Function
Population-‐based cohort of 438 Australian women, 45-‐55 years of age, who were still menstruating at baseline Hormonal levels, age, menopausal status, partner status, and feelings for partner were measured and evaluated The authors concluded that prior function and relationship factors are more important than hormonal determinants of sexual function for women in midlife
Dennerstein L, et al. Fertil Steril. 2005;84:174-80.
0.0
0.2
0.4
0.6
0.8
1.0
Baseline 4 8 12 16
EE/MTEE
Mean Change in Sexual Desire Scores
Mea
n C
hang
e
Study Week MT = methyltestosterone. *P < .02. Lobo RA, et al. Fertil Steril. 2003;79:1341-52.
*
Comparative Efficacy of Oral Esterified Estrogen With or Without MTestosterone in Postmenopausal Women
With Hypoactive Sexual Desire
Testosterone Transdermal Patch vs Placebo: Total Satisfying Sexual Activity
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0 4 8 12 16 20 24
Weeks
4-W
eek
Mea
n C
hang
e fr
om B
asel
ine
TestosteronePlacebo
Simon J, et al. J Clin Endocrinol Metab. 2005;90:5226-33.
*
* * *
*
*P
Testosterone Transdermal Patch vs Placebo: Personal Distress
-30
-25
-20
-15
-10
-5
0
0 4 8 12 24
Weeks
4-W
eek
Mea
n C
hang
e fr
om B
asel
ine
TestosteronePlacebo
*
*
* *
*P
Simon J, et al. J Clin Endocrinol Metab. 2005;90:5226-33.
Memory & Cognition
Physiology of Memory Changes
Frequently due to sleep interruptions
Stress is a powerful mediator
Forgetfulness among women and men similar at midlife
Schaie. Am Psychol. 1994;49:304.
Cognitive Changes With Age
35
40
45
50
55
60
25 32 39 46 53 60 67 74 81 88Age (years)
Mea
n T
scor
e
Verbal meaningSpatial orientationInductive reasoningNumberWord fluency
Longitudinal estimates of mean T scores for single markers of the primary mental ability in men and women
Management Strategies for Memory/Cognition
Treatment aimed at restoring sleep, reducing stress
Diet, exercise, relaxation techniques Use of memory aids Maintain mental acuity games, puzzles, etc Stress management strategies ? HT + / -‐
Neurotransmission Neuroprotection
Neurite Branching Synaptogenesis
Cerebral Blood Flow
Trophic Factor
Expression
Effects of Estrogen on Neuronal Function
Adapted from Birge SJ. Menopause Management. 2000;July/August:13-21.
CEE Promotes Cellular Mechanisms of Memory
Brinton et al. Neurobiol Aging. 2000;21:475.
No CEE
CEE treated
Neuronal outgrowth Synapse formation
Prior to CEE
After CEE treatment
Cerebral Blood Flow (SPECT): 48-‐Yr-‐Old Healthy Menopausal Woman
During a Hot Flush CEE
SPECT, single photon emission computed tomography. Greene. Neurobiol Aging. 1998;19:757.
ET/HT May Protect Against Cognitive Decline
ET/HT users perform better than nonusers on tests of memory and other cognitive functions1-‐4
ET/HT modulates brain activation patterns during cognitive testing3-‐5
As women age, ET/HT increases blood flow to cerebral and hippocampal brain structures involved in memory3
May prevent AD with early intervention
ET = estrogen therapy; HT = hormone therapy. 1Jacobs DM, et al. Neurology. 1998;50:368-73. 2Maki PM, et al. Am J Psychiatry. 2001;158:227-33. 3Resnick SM, et al. Horm Behav. 1998;34:171-82. 4Maki PM, Resnick SM. Neurobiol Aging. 2000;21:373-83. 5Shaywitz SE, et al. JAMA. 1999;281:1197-202.
Improved Memory Gerontology Research Center at NIH National Institute on Aging1
50-‐ to 89-‐year-‐old postmenopausal women; n=103 HRT improved verbal learning and memory tests
Cache County Study2
1357 men & 1889 women incidence > after age 80 in women and exceeded risk for men (HR 2.11, 1.22-‐3.86)
>10 years HRT
1Maki et al. Am J Psychiatry. 2001;158:227-233; 2Zandi et al. JAMA. 2002;288:2123-2129.
WHIMS Outcomes
Shumaker S et al. JAMA. 2003;289:2651-2662
RR (95%CI) Placebo n = 2,303
E+P n = 2,229
Outcome
4.06 (1.18) 22
4.01 (1.21) 45
Mean (SD) F/U yrs Rate per 10,000 woman yrs
1.07 (0.74-1.55) 55 56 Mild Cognitive Impairment
4.04 (1.20) 59
3.99 (1.23) 63
Mean (SD) F/U yrs Rate per 10,000 woman yrs
2.05 (1.21-3.48) 21 40 Probable dementia
Critical Window & Dementia?
US HMO Study 26% risk reduction for dementia when HT used during midlife only
48% risk increase for dementia when HT used only later in life
??provide a bridge for observation vs WHIMS results
Whitmer RA, et al (2010). Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol. EPUb
Vasomotor Symptoms
0
10
20
30
40
50African AmericanHispanicCaucasianChineseJapanese
% o
f Wom
en R
epor
ting
H
ot F
lush
es/N
ight
Sw
eats
Gold EB, et al. Am J Epidemiol. 2000;152:463-73.
SWAN Study: Reported Prevalence of Vasomotor Symptoms
Race/Ethnicity
Ages 40 to 55 Years
Hot Flushes May Continue Years After Menopause
Number of years women report having hot flushes as estimated by a survey of 501 self-‐selected women who have experienced hot flushes.1
05
101520253035404550
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 26 28 29 30 32 36 38 41 44
Years
Num
ber o
f sub
ject
s
1Kronenberg. Ann NY Acad Sci. 1990;592:52; 2Thompson et al. J Biosoc Sci. 1973;5:71; 3Berg et al. Maturitas. 1988;10:192.
Hot flushes are reported in 58% to 93% of postmenopausal women 2,3
The Vasomotor Cascade
Night sweats
Interrupted sleep
Fatigue
Irritability, mood changes Kronenberg. Ann NY Acad Sci. 1990;592:52-86. Beers et al, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. 1999. Baker et al. J Psychosom Res. 1997;43:359-369.
Physiology of The Hot Flash
No inherent health hazard
Related to reduced thermoneutral zone
Many women have a prodrome
Aura followed by measurable increase in heat over entire body surface
increase skin temp and conductance
followed by decrease in core body temp
Could Hot Flashes be Protective?
0.5
Hazard Ratio
Ductal carcinoma1 Inv Lobular carcinoma1 Inv Ductal-Lobular carc1 Stroke2 CVD2 Death2
1.0 1.5 Huang, Y et al. (2011). Relationship between menopausal symptoms and risk of postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev; 20(2); 1 10; Szmuilowicz, E. D., J. E. Manson, et al. (2011). Vasomotor symptoms and cardiovascular events in postmenopausal women. Menopause. available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21358352
OR
HR
Vasomotor Management Strategies
Complementary and Alternative Medicine Lifestyle Strategies Behavioral Therapies
Paced respirations Mindfulness Program
Acupuncture
Non-‐hormonal Medications Hormone Therapy: ET EPT
Lifestyle Strategies
Diet Avoidance of
caffeine
sugar
alcohol
Increase Water
Low Fat
Vegetables, Protein
Stress Management
Air flow / Fans
Exercise Regular Frequency Aerobic
Breathable Fabrics Cotton Linen Layers
Avoid High Neck
Alexander, et al. Menopause. 2003:10(6), 601; Irvin. Mind, Body & Menopause Study. 1996; Kronenberg & Fugh-‐Berman. Ann Intern Med. 2002;137:805-‐813.
Relaxation Techniques
Paced respirations
Acupuncture
Mindfulness program1
No difference in frequency of HF Sig decrease in stress, improved sleep, and less bother from HFs in tx group
1Carmody, J. F., S. Crawford, et al. (2011). "Mindfulness training for coping with hot flashes: results of a randomized trial." Menopause. published oinline: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21372745
Paced Respirations
Reduces frequency and severity of HF
Study used elaborate respiration monitoring
4-‐7-‐9 breathing is effective -‐ ??stress mediation
Freedman RR, et al. Biochemical and thermoregulatory effects of treatment for menopausal hot flashes. Menopause. 1995;2:211 218; Freedman RR, Woodward S. Behavioral treatment of menopausal hot flushes: Evaluation by ambulatory monitoring. Am J Obstet Gynecol. 1992;167(2):436 439.; Irvin JH, et al. The effects of relaxation response training on menopausal symptoms. J Psychosom Obstet Gynaecol. 1996;17(4):202 207.; and Carson KM, et al. Yoga program decreases hot flashes in breast cancer survivors: Results from a randomized trial. Presented at the Second IAYT Symposium on Yoga Therapy and Research, March 6-9, 2008, Los Angeles, Calif.
Acupuncture for HFs Well accepted CAM
Known to provide relaxation and pain relief
Of 8 studies published 1995-‐20081-‐8: 3 showed significant decrease in HF severity1, 2, 3
1 showed significant decrease in HF frequency for both tx and sham groups4
3 showed beneficial effects on mood1, 3, 5 1 showed no difference4
1Cohen SM, et al. Can acupuncture ease the symptoms of menopause? Holist Nurs Pract. 2003;17(6):295 299. 2Nir Y, et al. Acupuncture for postmenopausal hot flashes. Maturitas. 2007;56(4):383 395. 3Huang MI, et al. A randomized controlled pilot study of acupuncture for postmenopausal hot flashes: effect on nocturnal hot flashes and sleep quality. Fertil Steril. 2006;86(3):700 710. 4Avis NE, et al. A randomized, controlled pilot study of acupuncture treatment for menopausal hot flashes. Menopause. 2008;15(6):1070 1078. 5Wyon Y, et al. Effects of acupuncture on climacteric vasomotor symptoms, quality of life, and urinary excretion of neuropeptides among postmenopausal women. Menopause. 1995;2:3 12. 6Deng G, et al. Randomized, controlled trial of acupuncture for the treatment of hot flashes in breast cancer patients. J Clin Oncol. 2007;25(35):5584 5590. 7Vincent A, et al. Acupuncture for hot flashes: a randomized, sham-controlled clinical study. Menopause. 2007;14(1):45 52. 8Wyon Y, et al. A comparison of acupuncture and oral estradiol treatment of vasomotor symptoms in postmenopausal women. Climacteric. 2004;7(2):153 164.
Acupuncture for HFs
In head to head trial with venlafaxine Women with hormone receptor-‐positive breast cancer
No difference in HF improvement between two arms
Conclusion: acupuncture as effective as venlafaxine, Possibly safer and with fewer side effects
Walker EM, Rodrigues AI, kohn B et al. Acupuncture versus vanlafaxine for the management of vasomotor symptoms in patietns with hormone receptor-positive breast cancer: a randomized controlled trial. J Clin Oncol 2010;28:634-640.
Phytoestrogens for HFs Efficacy Side-effects & Cautions
Isoflavones Not effective or mixed results in six trials of red clover1
Effective or mixed results in four of 11 trials of soy extract1
Not effective in meta-analysis of five trials of red clover extract and not effective in additional trial of red clover extract (not in meta-analysis due to differences in study design)2
Not effective in seven of nine trials of dietary soy2
Not effective in four of nine trials of soy extracts2
Not effective in six trials using other phytoestrogens2
Generally well tolerated Long-term use of soy
extracts (>5 years) can increase risk for endometrial hyperplasia3
No increase in proliferation seen with 6 months use4,5
1Nelson HD, et al. JAMA. 2006;295(17):2057 2071. 2Lethaby AE, et al. Cochrane Database Syst Rev. 2007(4):CD001395. 3Unfer V, et al. Fertil Steril. 2004;82(1):145 148, 265. 4Balk JL, et al. J Soc Gynecol Investig. 2002;9(4):238 242. 5Kaari C, et al. Maturitas. 2006;53(1):49 58. (table frm: Alexander. Advance for NPs. 2009;17(7):31-36.)
Botanicals for HF Botanical Efficacy Side-effects & Cautions Black cohosh Effective in 5 of 9 trials1 Headache, short-term dizziness,
gastrointestinal symptoms Caution for possible liver toxicity (may
relate to contaminants in product as opposed to black cohosh itself)
Ginseng Not effective in 2 trials1 Headache, gastrointestinal symptoms, sleep disruptions May interact with warfarin
Dong quai Effective in 1 trial (combo w/ chamomile)2
Not effective in 1 trial3
Can cause photosensitivity May interact with warfarin
Oil of evening primrose
No significant decrease in one trial4
May potentiate seizure side effects in some medications (e.g., phenothiazines)
1Ihenacho. Drug Ther Bull. 2009;47(1):2 6. 2Hirata JD, et al. Fertil Steril. 1997;68(6):981 986. 3Kupfersztain C, et al. Clin Exp Obstet Gynecol. 2003;30(4):203 206. 4Chenoy R, et al. Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. BMJ. 1994;308(6927):501 503. (table frm: Alexander. Advance for NPs. 2009;17(7):31-36.)
Non-Hormonal Medications for Hot Flashes
SSRIs or SNRIs effective, 4 of 6 trials
Clonidine effective, 4 of 7 trials
Gabapentin effective, 2 of 2 trials
Isoflavone extracts -‐ mixed results, no difference 6 trials red clover, improvement in 3 of 7 trials soy extracts Effects are less than for Estrogen
Nelson, Vesco, et al. JAMA. 2006;295(17):2057-20716
Non-hormonal Medications for Treating Hot Flushes
10 40 0.1mg/d Clonidine
78 60 75mg/d 10mg/d (12.5 CR)
Venlafaxine or Paroxetine
25 80 20mg/d Megestrol
23 80-100 0.625mg/d oral conjugated estrogen or equivalent
Estrogen
Cost, $ % Reduction in Flushes*
Starting Dose Drug
*Based on published randomized trials in which treatment with placebo reduced the severity and frequency oh hot flushes 20 to 40%
Cost data based on prices from a national chain pharmacy
Other estrogen preparations such as 17B estradiol, 1.0mg orally. And transdermal estradiol, 0.05mg) are equally effective
Grady. JAMA. 2002;287:2130.
E and E+P Reduce Hot Flashes HOPE Study)
0
2
4
6
8
10
1 2 3 4 5 6 7 8 9 10 11 12 13Cycle
Adj
uste
d M
ean
Num
ber*
0
2
4
6
8
10
1 2 3 4 5 6 7 8 9 10 11 12 13Cycle
Adj
uste
d M
ean
Num
ber*
*Adjusted for baseline Mean hot flushes at baseline = 12.3 (range 11.3 13.8)
0.625 mg 0.45 mg 0.3 mg
Placebo 0.625/2.5 mg 0.45/2.5 mg 0.45/1.5 mg 0.3/1.5 mg
Placebo
Utian et al. FETil Steril. 2001;75:1065.
Historical Swings in HT History
1940 1950 1960 1970 1980 1990 2000
DES approved 1941 Conjugated equine
estrogens (CEE) 1942
Robert Wilson and Feminine forever 1962
DES banned for human use 1975
Wyeth files for CVD prevention indication for Premarin
* HERS = Heart and Estrogen/Progestin Replacement Study
Milestones in Hormone Therapy 1940-‐2000
Endometrial cancer risk defined 1975
HERS 1998
WHI CEE + MPA halted 2002
WHI CEE arm halted 2004
Breast cancer risk Identified (Berkquist) 1989
HT and CVD
Meta analysis 1993 (Grady et al)
Application to FDA for CEE as cardiopreventive in healthy women
FDA requested RCT First trial designed 2nd prevention (HERS)
Second designed for primary prevention (WHI)
HERS and WHI designed as statin trials
HT Today: The Evidence-‐base from Prevention
Heart and Estrogen/progestin Replacement Study (HERS)
Study design: Randomized, double-‐blind, placebo-‐ controlled, secondary prevention
Subjects: 2763 postmenopausal women, <80 years old (mean age, 66.7 years) with CAD
Intervention: CEE 0.625 mg + MPA 2.5 mg daily or placebo
Follow-‐up: HERS I 4.1 years HERS II open-‐label 2.7 years
1° end point: Nonfatal MI or CHD death
CAD = coronary artery disease; MI = myocardial infarction; CHD = coronary heart disease. Hulley S, et al. JAMA. 1998;280:605-13. Grady D, et al. JAMA. 2002;288:49-57.
0
10
20
30
40
50
1 2 3 4 5 6 to 8
HT Placebo
Effect of HT vs Placebo on Second CHD Events (HERS I and II)
Writing group for the Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) JAMA. 2002;288:49.
Years
HERS HERS II
Papworth HRT Atherosclerosis Study (PHASE)
RCT of 255 postmenopausal women with angiographically confirmed coronary disease Randomized to 17 -‐estradiol with or without NETA (n=134) or placebo (n=121) for 4 years Primary outcome: hospital admission with unstable angina, proven MI, or death
15.6 / 100 patient-‐years (EPT all) 12.6 / 100 patient-‐years (placebo) RR 1.23 (95% CI: 0.82-‐1.86; p=0.3)
Event rates were highest in first 2 years
Clarke S et al. Abstract. Eur Heart J, 2000; 21:212.
Study design: Randomized, double-‐blind, placebo-‐ controlled, primary prevention trial
Subjects: 16,608 postmenopausal women without vasomotor symptoms 50 to 79 years old (mean age, 63.3 years)
Intervention: CEE 0.625 mg + MPA 2.5 mg daily or placebo
Follow-‐up: 5.2 years (average) terminated early (8.5 years planned)
1° end point: Nonfatal MI or CHD death
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
CEE/MPA Arm
All-‐Cause Mortality Was Not Affected by HT in WHI or HERS
0
0.05
0.1
0.15
0 1 2 3 4 5 6 7Time (years)
Cum
ulat
ive
Haza
rd
Estrogen + ProgestinPlacebo
HR = 0.98 P = NS
WHI (cumulative hazard)
0
5
10
15
0 1 2 3 4 5
Follow-up, Years (number at risk)
Inci
denc
e (%
)
Estrogen + ProgestinPlacebo
HERS (incidence %)
P = NS
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33. ©2002 American Medical Association. All rights reserved. Hulley S, et al. JAMA. 1998;280:605-13. ©1998 American Medical Association. All rights reserved.
Gap Hypothesis: British Million Women Study
ET and EPT use Overall No risk if start 5 yr after menopause ET RR = 1.05, 95% CI = 0.89 to 1.24 EPT RR = 1.53, 95% CI = 1.38 to 1.70 risk if start at or before menopause ET RR =
1.43, 95% CI = 1.35 to 1.51 EPT RR = 2.04, 95% CI = 1.95 to 2.14
Incidence among women aged 50 59 yrs Never users = 0.30 % (95% CI = 0.29% to 0.31%) Current ET* = 0.43% (95% CI = 0.42% to 0.45%) Current EPT* = 0.61% (95% CI = 0.59% to 0.64%)
*initiated use <5 years after menopause
Beral V et al (2011). Breast Cancer Risk in Relation to the Interval Between Menopause and Starting Hormone Therapy. J Natl Cancer Inst 2011;103:296 305.
Breast Cancer Risk is Important
Re-‐analysis of the WHI E-‐only arm data Risk analysis is important
Women at low risk for breast cancer do not have increased risk with ET
Risk factors: family hx (esp 1st or 2nd degree), +BRCA-‐1/2, dense breasts, bx = atypical hyperplasia, radiation, obesity, alcohol use, inactivity
Risk mediators: early age of full-‐term pregnancy, long-‐term breast feeding, +exercise, no hx fibrocystic breast dz.
Archer DF. IMS Press Release, Dec 13, 2010; Ragaz J et al. (2010) Dual estrogen effects on breast cancer: endogenous estrogen stimulates, exogenous estrogen protects. Further investigation of estrogen chemoprevention is warranted. San Antonio Breast Cancer Symposium, abstract # 1410.
WHI ET Arm and Breast CA: 10.7 Yr Follow-‐up Data
23% risk of invasive breast CA in ET group versus placebo after 10.7 years (3.5 yrs use) (HR 0.77, CI 0.62 0.95)
No significant effects overall for CHD, DVT, CVA, hip fx, colorectal ca, or total mortality
LaCroix AZ, Chlebowski RT, Manson JE et al. Health outcomes after stopping conjugated equine estrogen among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;305:1305-1314.
Breast Cancer in Primary CHD Prevention Trials
Hormone Therapy1,2 Lipid Lowering3 CHD 0.68 (0.48-0.96) 0.89 (0.69-1.09) Total Mortality 0.61 (0.39-0.95) 0.95 (0.62-1.46)
7 (0.79-2.26) 1.33 81 (0.30) 64 (0.23) Statins meta4
9 (adj 0.97-1.59) 1.24 199 (0.42) 150 (0.33) WHI-EP6 -8 (0.65-1.04) 0.82 129 (0.34) 161 (0.42) WHI-E7*
95% CI
No. of Patients (Annualized %)
No. Additional Breast Cancer
Cases per 10,000 Women per Year
of Stain Use Hazard Ratio
Statin
Placebo
Study
*Adherence adjusted = 0.67 (0.47-0.97) *Ductal carcinoma = 0.71 (0.52-0.99)
1Salpeter S, et al. J Gen Intern Med 2004;19:791-804. 2Salpeter S, et al. J Gen Intern Med 2006;21:363-366. 3Walsh JME, et al. JAMA 2004;21:363-366. 4Dale KM, et al. JAMA 2006;295:74-80. 5Stefanos, et al. J Clin Oncol 2005;23:8606-8612. 6Chlebowski RT, et al. JAMA 2003;289:3243-3253. 7Stefanick ML, et al. JAMA 2006;295:1647-1657.
2 (0.81-1.33) 1.04 132 (0.31) 124 (0.29) Statins meta5
Latest Epidemiological News on Breast Cancer and EPT:
Breast CA incidence -‐ Canada study:1 incidence 2002 after WHI
incidence again 2005/6,
??EPT promotes tumor growth but not causative
WHI EPT Br CA Mortality, ~ 11 yr follow-‐up (~5 years on therapy):2
of 10,000 women, 1.3 deaths/yr on placebo
of 10,000 women, 2.6 deaths/yr on EPT
1Prithwish et al. Breast cancer incidence and hormone replacement therapy in Canada. J Natl Cancer Inst 2010; 102:1489-1495. 2Chlewbowski et al. (2010). Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304(15): 1684-92
Time Effects of HT and CVD: WHI ET Arm 10.7 Yr Follow-‐up Data
Women aged 50 59: 40% to 50% risks for HD endpoints in tx grp Of 10,000, tx grp had 12 fewer MIs, 13 fewer deaths, 18 fewer AEs
Women aged 70 79: risks for HD endpoints in tx grp
Of 10,000, tx grp had 16 more MIs, 19 more deaths, 48 more AEs
LaCroix AZ, Chlebowski RT, Manson JE et al. Health outcomes after stopping conjugated equine estrogen among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;305:1305-1314.
Time Effect with Estrogen ?? Meta analysis of observational studies beneficial effects on heart disease if ET/HT started at time of menopause (Salpeter, et al, 2004)
WHI data analysis of women initiating therapy at time of menopause had protective cardiovascular effects (Hsia, et al, 2006)
Early versus Late Intervention Trial with Estrogen (ELITE) trial, Kronos Early Estrogen
On the Horizon
Estrogen with Bazedoxifene (BZA) Tissue-‐Selective Estrogen Complex (TSEC)
Protects bone
Reduces menopause-‐related symptoms ( HFs, vaginal dryness, sexual function)
No increase in endometrial or breast cancer
Lewiecki EM. Bazedoxifene and bazedoxifene combined with conjugated estrogens for the management of postmenopausal osteoporosis. Expert Opin Investig Drugs. Oct 2007;16(10):1663-1672. Ronkin et al. Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women. Obstet Gynecol. Jun 2005;105(6):1397-1404.
Individualizing Management for Women with
Menopause-‐related Symptoms
Weighing the Benefits vs Risks of HT
Vasomotor Sexuality QOL Osteoporosis
Examples
Benefits Tolerability Fears Misperceptions Risks
Examples
Barriers
Resources NIH -‐ National Heart, Lung, and Blood Institute
http://www.nhlbi.nih.gov/ The Hormone Foundation
http://www.hormone.org/
http://nccam.nih.gov/ National Osteoporosis Foundation
http://www.nof.org/ Herbal Product Information
http://consumerlabs.com
North American Menopause Society http://www.menopause.com
Acknowledgements
Some slides courtesy of: NAMS (purchased slide set)
NOF
NPWH
Council on Hormone Education
Colleagues
Used with permission, copyright held by original authors
Thank You
Questions?