Menopause Update 2014

Menopause 2014
Janet Pregler, M.D., FACP
Director, Iris Cantor-UCLA Women’s Health Center
David Geffen School of Medicine
University of California, Los Angeles
Disclosure of Financial Relationships
Janet Pregler, M.D., FACP
Have no relationships with any proprietary entity
producing health care goods or services consumed
by or used on patients.
Menopause Update
• What new information is available about symptoms during the
menopause transition?
• What are effective hormonal and non-hormonal approaches to the
treatment of vasomotor symptoms and vaginal atrophy? What is
the role of new medications approved for these indications by the
FDA in the last year?
• Do different hormonal preparations, including “bioidentical
hormones” have different risks or benefits?
• What is the role of complementary and alternative medicine in the
treatment of menopausal symptoms?
Presentation of a Case
A.R. is a 52 year old woman who presents with complaints of hot flashes,
irritability, and diffuse muscle aches after stopping her HT when she heard it
causes strokes. However, a friend who lives in San Diego gave her a copy of a
“Harvard Women’s Health Watch” that suggests that since she has a high risk
of heart disease, she should take HT. The same friend gave her a local
newspaper article quoting famous gynecologists who said the same thing.
She asks for your advice.
Presentation of a Case
Allergies: None
PMHx/PSHx: s/p hysterectomy for fibroids, age 40, ovaries intact
Medications: None
Family History: Mother died of an MI at age 55, father died of an MI at
57. One sister, healthy.
Social History: Married, no children. Works as a lawyer. Has smoked
one pack per day for 35 years. Does not drink alcohol. No regular
exercise. Eats few fruits and vegetables.
ROS: Vaginal dryness uncomfortable during sex.
Presentation of a Case
PE: BMI= 27 BP= 139/89 HR= 80, reg.RR=12 T= 37 C, remainder of the
exam unremarkable, except vaginal atrophy.
Labs: TC 244 mg/dL LDL 159 mg/dL HDL 35 mg/dL TG 240 mg/dL, Fasting
glucose= 109 mg/dL, Mammogram, Pap smear, Colonoscopy WNL
Estimated 10 year ASCVD risk 9.7%
Presentation of a Case
When you return to the room after examining her, she presents you with
a list of additional questions, including:
•
I am having trouble with my memory, is it from my menopause?
•
My friend has depression, is it because she is in menopause?
•
If I don’t take estrogen, will my skin look old?
•
Does estrogen cause breast cancer?
•
If I take estrogen, is bioidentical safer?
•
I saw on television that there’s a pill for vaginal dryness, should I take
it?
Menopause
New Information on Natural History and
Associated Symptoms
Epidemiology of Vasomotor
Symptoms
• African American and Latina patients may be more likely to
experience vasomotor symptoms, and experience them for
longer
• Higher BMI is associated with a higher likelihood of vasomotor
symptoms
• Smokers enter the menopausal transition earlier, and are
more likely to experience hot flashes
Freeman Menopause 2014; Gold Am J Pub Health 2006
Meta-analysis of Prevalence of Vasomotor Symptoms by Time
from Menopause
Polti JGIM 2008
60
% of 50
Women 40
with 30
Vasomotor 20
Symptoms 10
0
-2 yrs
+1 yr
+ 5 yrs
+ 12 yrs
Percent of African American and White Women with
Moderate to Severe Hot Flashes:
Penn Ovarian Aging Study
Freeman Menopause 2014
50
45
40
35
% 30
25
20
15
10
5
0
-10 yrs -5 yrs
-1 yr
Final +1 yr
Menses
+ 5 yr
+10 yr
Natural History of Menopause
Systemic symptoms of menopause are not all associated with the
degree of vasomotor symptoms
•
•
Sleep disturbance occurs in women without vasomotor
symptoms
•
Depression is more common during the menopause transition
•
Cognitive changes reported by some women at the time of
menopause relate to the stage of menopause, and improve
when the menopause transition is completed
Greendale Neurology 2009; 72: 1850; Bromberger Psychological Medicine 2011 41:1879;
Kravtiz Obstet Gynecol Clin N Am 2011 38:567
Study of Women’s Health Across the Nation (SWAN):
Major Depression Risk Over 10 Years of Follow-up by
Menopausal Status or Age
Not adjusted for VMS
Adjusted for VMS
Adjusted for
prior major
depression, use
of psychotropic
medications, life
events, BMI
4.5
4
RR 3.5
3
2.5
2
1.5
*Trend toward
decreasing RR
more than 2 yrs
after menopause
1
0.5
0
Peri-menopause
Post-menopause*
Age
Adapted from: Bromberger Psychological Medicine 2011 41:1879
Perimenopause is Bad for Your Brain, but You Bounce Back in
Postmenopause
I
62
60
Premenopaus e
58
Early perimenopaus e
Score
Late perimenopaus e
Pos t menopaus e
56
54
4
5
6
Years
7
8
Illustrations of adjusted trajectories of Symbol Digit Modalities Test scores in
each menopause transition (MT) stage, assuming MT stage fixed for 4 years
Source: Greendale Neurology 2009; 72: 1850
Hormone Treatment
Major Chronic Disease Effects
Treatment of Menopausal Symptoms: Hormone
Therapy
• Hormone therapy remains the most effective treatment for vasomotor
symptoms, with a reduction in symptoms of 80-90%
• Overall risks of hormone therapy are low for otherwise healthy women
at the time of menopause
• For women with a uterus, estrogen without a progestin increases the
risk of endometrial cancer, and is not recommended in most cases
• Both estrogen and estrogen + progestin increased stroke risk in WHI,
whether they were started close to menopause or not. Based on this,
long term use of hormones for chronic disease prevention is not
recommended
Menopause Hormone Therapy
Risk-Benefit Balance 2014
Symptoms/Side Effects
Risks
Breast/Bleeding Side Effects
Urinary incontinence
Kidney stones
Gallstones
Benefits (all while on
therapy)
Vasomotor Symptoms
Vaginal Atrophy
?Skin Preservation
?Depression
ACOG Obstet Gynecol 2004, Chlebowski JAMA 2008; Chlebowski JAMA 2010;
Maalouf Arch Intern Med 2010; Manson JAMA 2013; Grady JAMA 2002
Estrogen + Progestin
Risk-Benefit Balance 2014
Major Chronic Disease Outcomes
Risks
Stroke
Breast Cancer (includes increased
breast cancer mortality, risk persisted
after discontinuation of treatment)
CHD (at initiation, older
women/existing CHD)
Venous thrombosis
Dementia (women over 65 years)
Pancreatitis
?Ovarian Cancer
Benefits
Osteoporosis
Diabetes (taking
therapy)
ACOG Task Force for Hormone Therapy Obstet Gynecol 2004 ; Chlebowski JAMA 2008;
Chlebowski JAMA 2010; Manson JAMA 2013; Grady JAMA 2002
Estrogen Alone
Risk-Benefit Balance 2014
Major Chronic Disease Outcomes
Risks (while on therapy)
Stroke
Dementia (women over 65
years- trend, trial stopped
early)
Venous thrombosis
Endometrial
Hyperplasia/Cancer
Pancreatitis
?Ovarian Cancer
Benefits
Breast Cancer Incidence (5-6 yrs
of therapy, 13 yrs of follow-up)
Osteoporosis (taking therapy)
Diabetes (taking therapy)
ACOG Task Force for Hormone Therapy, Obstet Gynecol 2004; Chlebowski JAMA 2011;
Manson JAMA 2013; U.S. FDA
Principles of Hormone Treatment
• Very important to add progestin in women with a uterus
• In the PEPI trial, 34% of women on unopposed
estrogen developed advanced hyperplasia after 3
years of treatment
Writing Group for the PEPI trial. JAMA 1996
Why avoid estrogen only therapy in breast cancer
survivors? Effect on existing tumor may be
different than prevention:
Data from WHI
• Invasive breast cancers in women assigned to CEE were
larger (1.8 cm compared to 1.5 cm, p=.03)
• Invasive breast cancers in women assigned to CEE
tended to be node positive (36% vs. 23%, p=.07)
Stefanick JAMA 2006;295:1647
Nurses Health Study cohort study: Women who have
oophorectomy compared with ovarian conservation with
hysterectomy for benign disease have higher mortality: Is it
hormones, selection bias, or both?
1.6
1.4
*
*
Mortality
1.2
1
0.8
HR
0.6
0.4
0.2
0
< 50 yrs 50-59 yrs 60 yrs +
Parker Obstet Gyecol 2013
No HT
HT
* Statistically Significant
Nurses Health Study cohort study: Causes of death for women who had
oophorectomy compared to ovarian conservation during hysterectomy for
benign disease
1.6
1.4
*
*
*
*
1.2
1
0.8
Hazard Ratio for
Mortality
0.6
0.4
0.2
0
* Statistically
Breast Lung
CA
CA
Colon
CA
Parker Obstet Gynecol 2013
Total
CA
CVD
Significant
Guidelines about
Hormone Therapy for Chronic Disease
Prevention
• American College of Obstetricians and Gynecologists (ACOG)
• “Menopausal HT should not be used for the primary or secondary
prevention of CHD at the present time.”
• “Recent evidence suggests that women in early menopause who are in
good cardiovascular health are at low risk of adverse cardiac outcomes and
should be considered candidates (for HT) for relief of menopausal
symptoms.”
• U.S. Preventative Services Task Force (USPSTF)
• The USPSTF recommends against the use of combined estrogen and
progestin for the prevention of chronic conditions in postmenopausal
women (Grade D: Evidence of Harm)
• The USPSTF recommends against the use of estrogen for the prevention of
chronic conditions in postmenopausal women who have had a
hysterectomy (Grade D: Evidence of Harm)
ACOG Committee Opinion Hormone Therapy and Heart Disease Obstet Gynecol
2013; USPSTF October 2012
Global Events per 10,000 Women Per Year:
CHD, Invasive Breast, Colon, and Endometrial Cancer,
Hip Fracture, PE, All Cause Mortality
Manson JAMA 2013
Note: In WHI, all
women assigned to
CEE alone were s/p
hysterectomy
50-59 y
60-69 y 70-79 y
Estrogen Therapy in Postmenopausal Women
and Skin Changes
5
4.5
4
Investigator
Global 3.5
Assessment 3
of
2.5
Wrinkling
Placebo
1 mg NA/ 10 ug EE
2
1.5
1
Baseline
Phillips J Am Acad Dermatol 2008
48 Weeks
No statistically
significant
difference
Hormone Treatment
Are Some Formulations Safer/Better?
FDA Takes Action Against Compounded Hormone
Therapy Drugs (“Bioidenticals”)
• Risks of compounded bioidenticals unknown
• No evidence of greater safety, efficacy
• Estriol not FDA approved
• Saliva testing to determine hormone levels is inaccurate
• Hormone levels fluctuate
Source: FDA Press Release, January 9, 2008
American College of Obstetricians and Gynecologists
Committee Opinion August 2012
“Not only is evidence lacking to support superiority claims of
compounded bioidentical hormones over conventional menopausal
hormone therapy, but these claims also pose the additional risks of
variable purity and potency and lack efficacy and safety data”
• Under and overdosage are of concern, eg. endometrial hyperplasia
and cancer are a concern with untested/unreliable doses of
estrogen and progestins
• Estradiol and micronized progesterone are available in proven
formulations, and are preferred given available data
ACOG Committee Opinion #532, August 2012
Breast Cancers and Different HT
Formulations
“Million Woman Study Shows Breast Cancer Risk”
• Prospective cohort study in Britain
• For CURRENT USERS, increased incidence of breast CA for both E
alone (RR = 1.3) and
E + P (RR = 2.0)
• Increased for pills, patches, implants, continuous, and sequential
regimens
Beral Million Women Study Coordinators. Lancet 2003;362:419
ACOG Committee Opinion 2013: Postmenopausal Estrogen
Therapy: Route of Administration and Risk of Venous
Thromboembolism
• Cohort studies of transdermal estrogen in postmenopausal women
have not shown increased risk of venous thromboembolism
compared to non-users
• Some have postulated that this is because transdermal ET does not
effect prothrombotic factors and may have beneficial effects on
proinflammatory markers
Things to consider:
• Multiple cohort studies of Ortho Evra (R) contraceptive patch have
shown increased thrombotic risk, currently Ortho Evra (R)
contraceptive patch carries a black box warning for thrombotic risk,
which is attributed to different pharmacokinetics of estrogen with
patch delivery (lower peaks but higher average levels)
Bottom line: Clinicians are free to counsel that transdermal delivery is
preferred if that is their interpretation of the data, but FDA does not
recognize that patches are safer than oral forms, and use of any
form of estrogen in women at high risk for venous
thromboembolism is relatively contraindicated according to FDA
ACOG Committee Opinion #556 April 2013
Newly FDA approved for Treatment of Vasomotor
Symptoms
• Conjugated equine estrogens/bazedoxifene (Duavee ® )
• Estrogen with new SERM, approved by FDA in 2013 for treatment of
vasomotor symptoms and prevention of osteoporosis in women with a
uterus
• Boxed warning: risk of endometrial cancer, stroke, DVT, dementia, do not
use for prevention of dementia OR CHD. Also, do not use if breast or
other estrogen-dependent cancer, pregnancy.
• 24 months of endometrial safety data, over 24 months increased hip
and spine BMD, effect on hot flashes similar range to estrogen
• Studies lacked power (6200 patients over max 2 years) to adequately
assess stroke and DVT, but increased risk known for HT and other
SERMS; breast cancer effects unknown
• About 15% of patients spotting at one year
• Dose CEE 0.45 mg/bazedoxifene 20 mg, one po daily; given limited data,
an alternative to traditional estrogen plus progestin therapy for hot flashes,
but not proven to be safer/better than estrogen plus progestin although it
might be
FDA 2013
Vasomotor symptoms
Non-Hormonal Treatment
Nonhormonal Pharmaceuticals for Hot Flashes More Effective Than
Placebo in Randomized, Controlled Trials: Lowest Effective Dose, nonFDA Approved Use Unless Noted
• Venlafaxine XR 75 mg/d (37.5 mg/d also effective)
• Desvenlafaxine 100 mg/d
• Paroxetine CR 12.5 mg/d; Paroxetine 10 mg/d; Paroxetine 7.5 mg/ day
(FDA approved 2013, Brisdelle (R) )
• Fluoxetine 20 mg/d
• Sertraline 50 mg/d
• Citalopram 20 mg/d
• Escitalopram 10-20 mg/d
• Note: There is evidence that SSRIs (paroxetine) may interfere with
tamoxifen metabolism, rendering it less effective.
• Gabapentin 300 mg tid (up to 2700 mg/d may increase relief)
• Pregabalin 75 mg bid
• Clonidine 0.1 mg/d
Loprinzi Lancet. Guttuso Obstet Gynecol. Loprinzi J Clin Oncol. Stearns JAMA. Kimmick The Breast Journal 2006
Pandya Ann Intern Med. Sterns J Clin Oncol 2005 Gordon Menopause 2006, Speroff Obstet Gynecol 2008; Kalay
Menopause 2007; Freeman JAMA 2011; Kelly BMJ 2010; FDA 2013
Escitalopram for Hot Flashes in Healthy Menopausal Women:
A Randomized Controlled Trial
Freeman JAMA 2011
10
8
*
Mean # of 6
Hot Flashes 4
2
0
Baseline
Escitalopram
*Statistically fewer hot flashes than placebo
Placebo
“Back to the Future”:
Anxiolytics for Hot Flash-Related Sleep Disturbance
80
70
60
*
50
Zolpidem 10
mg qhs
Placebo
40
% indicating
better sleep
30
20
10
0
Week Week Week Week
1
2
3
4
*p < .001 for each week, improvement in sleep-related
daytime functioning p<0.05 for zolpidem group
Adapted from Dorsey Clin Ther 2004
An Intensive Behavioral Weight Loss Intervention and Hot
Flushes in Women
Haung Arch Intern Med 2010
• 338 overweight or obese women enrolled in a 6 month randomized
controlled trail of an intensive behavioral weight loss intervention
compared to a structured educational program to promote weight loss to
improve urinary incontinence completed a self-administered questionnaire
assessing hot flushes.
• 154 women endorsed that they were bothered by hot flushes at the start
of the study.
• Reductions in weight (OR 1.32, 95% CI 1.08-1.61 per 5 kg decrease), BMI
(OR 1.17, 95% CI 1.05-1.30 per 1 point decrease), and abdominal
circumference (OR 1.32, 95% CI 1.07-1.64 per 5 cm decrease) were
associated with a 1 point improvement in a five point self-reported hot
flush scale.
• Changes in physical activity, calorie intake, blood pressure, and physical and
mental functioning were not associated with a change in hot flush
symptoms
Vasomotor symptoms
Alternative and Complementary Therapies
Common Complementary Treatments for Vasomotor Symptoms
Studied in at Least One Randomized, Controlled Trial
•
•
•
•
•
•
•
•
•
Soy
Vitamin E
Black Cohosh
Oil of Primrose
“Yam Progesterone”
Dong Quai
Red Clover
Ginseng
Acupuncture
Treatment of Vasomotor Symptoms with Black Cohosh,
Multibotanicals, Soy, Hormone Therapy, or Placebo: Selected
Results at 3 Months Compared to Baseline
7
6
5
4
3
2
# hot
flashes
1
0
Baseline
Placebo
Black
cohosh
Adapted from Newton Ann Intern Med 2006
Estrogen
The Placebo Effect and Hot Flashes
• Efficacy of alternative and complementary therapies is similar to
placebo
• Placebo benefit is a 25%-50% reduction in vasomotor symptoms
• “ We feel that some of the dramatic results achieved with
preparations such as vitamin E and a famous vegetable compound
now on the market must be attributed to the psychological effect of
a placebo…”
Kupperman, et al, JAMA 1959, as quoted by Nancy King Reame,
Menopause 2005
Menopause Facts:
Hot Flashes and Associated Symptoms
0
10
-25%
20
-35%
30
40
-65%
-85%
50
Decrease
from
Baseline
60
70
80
90
100
Estrogen
SSRI, SNRI,
Gabapentin
Clonidine
CAM
Vasomotor symptoms
Stopping Menopause Hormone Therapy
Factors Associated with Successful Discontinuation
of Hormone Therapy
Newton J Women’s Health 2014
• Survey of 1,358 women on HT at Group Health,
Washington State, Harvard Vanguard Medical Associates
in Massachusetts, 802 attempted discontinuation, mean
age 57 years, 91% white
• Factors associated with successful discontinuation:
•
•
•
•
Doctor’s advice OR 2.62
Lack of symptom improvement with HT OR 4.21
Vaginal bleeding OR 5.96
Learning to cope with symptoms OR 3.36
• Factors associated with unsuccessful discontinuation:
• Trouble sleeping OR 0.40
• Mood swings/depression OR 0.63
6 Weeks of Weekly Cognitive Behavioral Therapy Improves
Quality of Life for Women with Hot Flashes and Night Sweats
10
9
8
7
Hot
Flush
Rating
Scale
6
5
*
4
*
3
Usual Care
CBT
2
1
0
Baseline
9 weeks
26 weeks
*Statistically better mood, sleep, quality of life. No
significant difference in hot flash frequency
Mann Lancet Oncol 2012: 13:309
Dysparunia and Sexual
Dysfunction
Etiology and Treatment
Study of Women’s Health Across the Nation
90
80
70
60
50
40
30
20
10
0
% of Midlife women
Infrequent or no Content with
sexual desire
sexual
experiences
Basson NEJM 2006
Newly FDA Approved for Treatment of Vaginal Atrophy
• Ospemifene (Osphena ®)
• SERM approved in 2013 by the FDA for treatment of moderate to severe
dyspareunia
• Boxed warning: risk of endometrial cancer, stroke, DVT, contraindicated in
pregnancy, MI, known or suspected estrogen-dependent neoplasia, use of
estrogen, another SERM; fluconazole, ketoconazole coadministration may
increase risks
• 52 week study of endometrial safety showed RR 3 for endometrial
thickening and polyps and RR 6 for proliferative endometrium; ? need
for progestin if used longer term (not studied)
• Studies lacked power to adequately assess stroke and DVT, but
increased risk known for HT and other SERMS (only 409 women
studied for one year or more)
• Breast cancer, osteoporosis effects unknown
• Dose 60 mg daily with food, based on limited safety data, would possibly
consider in refractory cases, significant concerns for
longer term use in women with a uterus
FDA 2013
# per thousand women per year
Ospemifene FDA Warning Regarding Risk of Endometrial
Cancer:
Approval based on 12-15 months of follow up in 409 women
90
80
70
60
50
Ospemifene
Placebo
40
30
20
10
0
> 5 mm endometrial
thickness
FDA 2013
Proliferative
Endometrium
Uterine polyps
Treatment of Vaginal Atrophy
• Lubricants
• Eg, KY Jelly ®, Astroglide ®, etc, as needed or on a regular basis
• Replens ® on a regular basis
• Local hormone therapies- more effective/good safety data
• Estring ® insert one q 12 weeks
• Vagifem ® 10 ug nightly x 14 d then biw
• “Low dose” topical estrogen
• Cochrane review found ? more risk of endometrial hyperplasia,
Premarin ® vaginal cream .5 gm biw studied for one year
• Systemic dose therapies- use only if other treatments fail or if using systemic
dose estrogen for vasomotor symptoms
• Systemic dose estrogen delivered vaginally (cream or Femring ®), use
progestin if patient has a uterus
• Ospemiphene (SERM): If patient has a uterus, concern for endometrial
hyperplasia/cancer with longer use
• Other systemic dose hormones
Cochrane Database Syst Rev. 2006, 2010; FDA 2013