3. 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
4. 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. 4. Lenton et al. J Clin Endocrinol Metab. 1991;73:1180.
2. Burger. Hum Reprod. 1993;8(suppl 2):129. 5. Santoro et al. J Clin Endocrinol Metab. 1996;81:1495.
3. Burger et al. J Clin Endocrinol Metab. 1995;80:3537. 6. Bancroft et al. Clin Endocrinol. 1996;45:577.
5. 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.
6. Management for Selected
Symptoms
Sleep
GU Changes & Sex
Memory and Cognition
Vasomotor Symptoms
9. 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
10. 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
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.
12. Genitourinary Changes After
Menopause
Genitourinary Atrophy*
Vaginal Dysfunction Urinary Dysfunction
(pain with penetration/
sexual dysfunction)
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.
13. Sexual Physiologic Changes with
Aging
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
Bachmann et al. In: Lobo, ed. Treatment of the Postmenopausal Woman:
Basic and Clinical Aspects. 2nd ed. New York: Lippincott Williams & Wilkins; 1999:195.
14. Sexual Function Declines with
Menopause and Aging
Sexual libido
Sexual responsivity
Sexual activity
Vaginal dyspareunia
partner
Dennerstein et al. Fertil Steril. 2001;76:456.
15. 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.
17. 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
18. 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
19. Efficacy of Low-‐dose Vaginal Estriol on
Urogenital Symptoms
Treatment Group (n = 44) Control Group (n = 44)
Before After Before After P-
Variables Treatment Treatment Treatment Treatment Value*
Clinical
Vaginal dryness 100% 20.5% 100% 90.9% <.001
Dyspareunia 86.4% 20.5% 84.1% 86.4% <.001
Urogenital atrophy 100% 27.3% 100% 93.2% <.01
Urodynamic
MUP (cm H20) 50.82 6.15 62.15 8.64 52.35 6.30 49.40 6.54 <.05
MUCP (cm H20) 45.25 7.20 56.87 9.23 44.77 6.86 43.32 6.32 <.05
PTR (%) 72.52 10.31 88.85 9.66 70.75 9.08 70.77 9.04 <.05
*P-value is comparison between treatment and control groups. MUP = maximum urethral pressure; MUCP =
mean maximum urethral closure; PTR = abdominal pressure transmission ratio.
Adapted from Dessole S, et al. Menopause. 2004;11:49-56.
20. Vaginal Epithelium & Estrogen
6 weeks of
estrogen
Without estrogen - atrophic With estrogen1
Vagina/urethra highest concentration of estrogen receptors2
Most efficient response with local application3,4
1. Freedman. Unpublished data. 3. Elia et al. Obstet Gynecol Surv. 1993;48:509.
2. Losif et al. Am J Obstet Gynecol. 1981;141:817. 4. Weinberger. Am Clin Obstet Gynecol. 1995;38:175.
21. 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.
22. Comparative Efficacy of Oral Esterified Estrogen
With or Without MTestosterone in Postmenopausal Women
With Hypoactive Sexual Desire
Mean Change in Sexual Desire Scores
1.0
EE/MT
Mean Change
0.8 EE
0.6 *
0.4
0.2
0.0
Baseline 4 8 12 16
MT = methyltestosterone.
*P < .02. Study Week
Lobo RA, et al. Fertil Steril. 2003;79:1341-52.
23. Testosterone Transdermal Patch vs Placebo:
Total Satisfying Sexual Activity
3.0 Testosterone
Placebo *
*
4-Week Mean Change
2.5 *
*
from Baseline
2.0 *
1.5
1.0
0.5
0.0
0 4 8 12 16 20 24
Weeks
*P
Simon J, et al. J Clin Endocrinol Metab. 2005;90:5226-33.
24. Testosterone Transdermal Patch vs
Placebo: Personal Distress
0 Testosterone
Placebo
4-Week Mean Change
-5
from Baseline
-10
-15
*
-20
*
-25
* *
-30
0 4 8 12 24
Weeks
*P
Simon J, et al. J Clin Endocrinol Metab. 2005;90:5226-33.
26. Physiology of Memory Changes
Frequently due to sleep interruptions
Stress is a powerful mediator
Forgetfulness among women and men
similar at midlife
27. Cognitive Changes With Age
60 Verbal meaning
Spatial orientation
55 Inductive reasoning
Mean T score
Number
50 Word fluency
45
40
35
25 32 39 46 53 60 67 74 81 88
Age (years)
Longitudinal estimates of mean T scores for single markers of the primary mental ability in men and women
Schaie. Am Psychol. 1994;49:304.
28. 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 + / -‐
29. Effects of Estrogen on
Neuronal Function
Neurotransmission
Neuroprotection
Neurite Branching
Synaptogenesis
Trophic
Factor
Cerebral Blood Flow Expression
Adapted from Birge SJ. Menopause Management. 2000;July/August:13-21.
30. CEE Promotes Cellular Mechanisms
of Memory
Neuronal outgrowth Synapse formation
No CEE Prior to CEE
After CEE
CEE
treatment
treated
Brinton et al. Neurobiol Aging. 2000;21:475.
31. 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.
32. 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.
33. 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.
34. WHIMS Outcomes
Outcome E+P Placebo RR (95%CI)
n = 2,229 n = 2,303
Probable dementia 40 21 2.05 (1.21-3.48)
Mean (SD) F/U yrs 4.01 (1.21) 4.06 (1.18)
Rate per 10,000 woman
yrs 45 22
Mild Cognitive Impairment 56 55 1.07 (0.74-1.55)
Mean (SD) F/U yrs 3.99 (1.23) 4.04 (1.20)
Rate per 10,000 woman
yrs 63 59
Shumaker S et al. JAMA. 2003;289:2651-2662
35. 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
37. SWAN Study: Reported Prevalence
of Vasomotor Symptoms
Ages 40 to 55 Years African American
50 Hispanic
Hot Flushes/Night Sweats
Caucasian
% of Women Reporting
Chinese
40
Japanese
30
20
10
0
Race/Ethnicity
Gold EB, et al. Am J Epidemiol. 2000;152:463-73.
38. Hot Flushes May Continue Years
After Menopause
50 Number of years women report having hot flushes as
45 estimated by a survey of 501 self-‐selected women who
have experienced hot flushes.1
40
Number of subjects
35
30
25
20
15
10
5
0
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
Hot flushes are reported in 58% to 93% of postmenopausal women 2,3
1Kronenberg. Ann NY Acad Sci. 1990;592:52; 2Thompson et al. J Biosoc Sci. 1973;5:71;
3Berg et al. Maturitas. 1988;10:192.
39. 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.
40. 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
41. Could Hot Flashes be Protective?
Hazard Ratio
Ductal carcinoma1
Inv Lobular carcinoma1 OR
Inv Ductal-Lobular carc1
Stroke2
CVD2 HR
Death2
0.5 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
42. Vasomotor Management Strategies
Complementary and Alternative Medicine
Lifestyle Strategies
Behavioral Therapies
Paced respirations
Mindfulness Program
Acupuncture
Non-‐hormonal Medications
Hormone Therapy: ET EPT
43. Lifestyle Strategies
Diet Exercise
Avoidance of Regular Frequency
caffeine Aerobic
sugar
Breathable Fabrics
alcohol
Cotton
Increase Water
Linen
Low Fat
Layers
Vegetables, Protein
Avoid High Neck
Stress Management
Air flow / Fans
Alexander, et al. Menopause. 2003:10(6), 601; Irvin. Mind, Body & Menopause Study. 1996; Kronenberg & Fugh-‐
Berman. Ann Intern Med. 2002;137:805-‐813.
44. 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
45. 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.
46. 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.
47. 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.
48. Phytoestrogens for HFs
Efficacy Side-effects & Cautions
Isoflavones Not effective or mixed results in six Generally well tolerated
trials of red clover1 Long-term use of soy
Effective or mixed results in four of 11 extracts (>5 years) can
trials of soy extract1 increase risk for
Not effective in meta-analysis of five endometrial hyperplasia3
trials of red clover extract and not No increase in
effective in additional trial of red clover proliferation seen with 6
extract (not in meta-analysis due to months use4,5
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
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.)
49. 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 Can cause photosensitivity
(combo w/ chamomile)2 May interact with warfarin
Not effective in 1 trial3
Oil of evening No significant decrease May potentiate seizure side effects in
primrose in one trial4 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.)
50. 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
51. Non-hormonal Medications for
Treating Hot Flushes
Drug Starting Dose % Reduction in Cost, $
Flushes*
Estrogen 0.625mg/d oral 80-100 23
conjugated estrogen
or equivalent
Megestrol 20mg/d 80 25
Venlafaxine or 75mg/d 60 78
Paroxetine 10mg/d (12.5 CR)
Clonidine 0.1mg/d 40 10
*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.
52. E and E+P Reduce Hot Flashes
HOPE Study)
Placebo Placebo
10 10
0.625 mg 0.625/2.5 mg
0.45 mg 0.45/2.5 mg
0.3 mg 0.45/1.5 mg
Adjusted Mean Number*
Adjusted Mean Number*
8 8
0.3/1.5 mg
6 6
4 4
2 2
0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4 5 6 7 8 9 10 11 12 13
Cycle Cycle
*Adjusted for baseline
Mean hot flushes at baseline = 12.3 (range 11.3 13.8)
Utian et al. FETil Steril. 2001;75:1065.
54. Milestones in Hormone Therapy
1940-‐2000
Breast cancer risk
Identified (Berkquist)
1989
Robert Wilson and Endometrial cancer
Feminine forever 1962 risk defined HERS WHI CEE arm
1975 1998 halted 2004
1940 1950 1960 1970 1980 1990 2000
DES approved 1941 DES banned for Wyeth files for CVD WHI CEE +
Conjugated equine human use 1975 prevention indication for MPA halted
estrogens (CEE) 1942 Premarin 2002
* HERS = Heart and Estrogen/Progestin Replacement Study
55. 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
57. 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.
58. Effect of HT vs Placebo on Second CHD
Events (HERS I and II)
HT Placebo
50
40
30
20
10 HERS HERS II
0
1 2 3 4 5 6 to 8
Years
Writing group for the Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) JAMA.
2002;288:49.
59. 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.
60. CEE/MPA Arm
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.
62. 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.
63. 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.
64. 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.
65. 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)
No. Additional
No. of Patients Breast Cancer
(Annualized %) Cases per 10,000
Hazard Women per Year
Study Placebo Statin Ratio 95% CI of Stain Use
Statins meta4 64 (0.23) 81 (0.30) 1.33 (0.79-2.26) 7
Statins meta5 124 (0.29) 132 (0.31) 1.04 (0.81-1.33) 2
WHI-EP6 150 (0.33) 199 (0.42) 1.24 (adj 0.97-1.59) 9
WHI-E7* 161 (0.42) 129 (0.34) 0.82 (0.65-1.04) -8
*Adherence adjusted = 0.67 (0.47-0.97) 1Salpeter S, et al. J Gen Intern Med 2004;19:791-804.
*Ductal carcinoma = 0.71 (0.52-0.99) 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.
66. 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
67. 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.
68. 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
69. 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.
71. Weighing the Benefits vs Risks
of HT
Barriers
Examples
Tolerability Benefits
Fears Examples
Misperceptions Vasomotor
Risks Sexuality
QOL
Osteoporosis
72. 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
73. Acknowledgements
Some slides courtesy of:
NAMS (purchased slide set)
NOF
NPWH
Council on Hormone Education
Colleagues
Used with permission, copyright held by
original authors
