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Quality of Life,
Menopausal Changes,
and Hormone Therapy
A CME Slide Library From the
Council on Hormone Education
Quality of Life, Menopausal Changes, and
Hormone Therapy
Section 1: Quality of Life Definition and Assessment
Section 2: Menopause-Related Changes
2a. Vasomotor Symptoms
2b. Sleep Quality
2c. Urogenital Changes
2d. Sexual Well-Being
2e. Skin Changes
2f. Bone
Section 3: Recent Evidence and Critical Review
of QOL in Menopause
Section 4: Summary and Conclusions
Quality of Life, Menopausal Changes, and
Hormone Therapy
Section 1:
Quality of Life Definition and
Assessment
Definition of QOL
 Global
sense of self-satisfaction
 Sense
of well-being
 Patient’s
perception of her interest in life
 Maintaining
satisfactory interpersonal
relationships
 Perception
of physical and psychological
wellness
 Satisfaction
with position in life in the
context of culture and value systems1
Utian WH, et al. Menopause. 2002;9:402-10.
1WHO Division of Mental Health. 1993.
Global and Health-Related QOL
 Global
QOL
– “Sense of well-being” that is impacted
by experience of symptoms but not
solely determined by symptoms
– Patient’s own subjective appraisal
of overall life satisfaction/sense of
well-being
 Health-related
QOL
– Patient’s perceptions of their physical,
cognitive, and mental health
Utian WH, et al. Menopause. 2002;9:402-10.
Menopause-Related QOL
 Validated
tools for assessment1
– Utian Menopause QOL Score2
– Menopause Rating Scale3
– Greene Climacteric Scale4
– Women’s Health Questionnaire5
– Menopausal Symptom List6
1Schneider
HPG. Best Pract Res Clin Obstet Gynaecol. 2002;16:395-409; 2Utian WH, et al. In: The Menopause at the
Millennium. 2000:141-4; 3Schneider HPG, et al. Climacteric. 2000;3:50-8; 4Greene JG. J Psychosom Res. 1976;20:42530; 5Hunter M. Psychol Health. 1992;7:45-54; 6Perz JM. Women Health. 1997;25:53-69.
Importance of QOL Measurement
Accurate Appraisal of QOL
 Critical
to enhancing treatment adherence
 Enhances
clinician interactions with patients
 Helps
assess and optimize treatment
effectiveness
 Improves
overall patient satisfaction
with treatment
Utian WH, et al. Menopause. 2002;9:402-10.
Utian Quality of Life (UQOL) Scale



Measures QOL during the
climacteric years
23-item questionnaire
4 domains
– Occupational QOL
– Health QOL
– Sexual QOL
– Emotional QOL
Utian WH, et al. Menopause. 2002;9:402-10.
Purpose of UQOL

Assess QOL

Gather data about the woman’s
perception of the overall quality
of her life

Follow progress in clinical practice

Evaluate drug responses in
clinical trials
Utian WH, et al. Menopause. 2002;9:402-10.
Greene Climacteric Scale
 21-item
symptom questionnaire
 Patients
assign score to each symptom
using 4-point scale
3
subscales
– Psychological (anxiety and depression)
– Somatic
– Vasomotor
Greene JG. J Psychosom Res. 1976;20:425-30.
Greene JG. Maturitas. 1998;29:25-31.
HT Use After the WHI

Telephone interviews with 670 of 1000 randomly
selected female HMO members aged 50 to 69
years (mean age, 58.9 ± 5.1 years) who had been
using HT for 1 year before July 2002

Reasons for starting HT
– Symptom relief (57%)
– Health promotion (23%)
– Hysterectomy (11%)

56% reported trying to stop HT between July 2002
and March 2003
Grady D, et al. Obstet Gynecol. 2003;102:1233-9.
HT Use After the WHI continued

Of the 377 women who had attempted stopping HT, 74%
were not using HT at time of interview (had been off HT a
median of 5.7 months)
– 26% had resumed HT

After stopping HT, 30% reported troublesome symptoms
– Flushes (88%)
– Excessive sweating (76%)
– Difficulty sleeping (54%)
– Fatigue (39%)
– Depression (38%)
– Vaginal dryness (38%)
Grady D, et al. Obstet Gynecol. 2003;102:1233-9.
Factors Associated With Restarting
HT After Attempt to Stop
Multivariate OR
(95% CI)
Troublesome symptoms after stopping HT
8.8 (4.9–16.0)
HT prescribed by non-gynecologist
2.2 (1.2–4.0)
Hysterectomy
1.9 (1.1–3.6)
Perceived high risk of hip or spine fracture
1.4 (1.1–1.8)
Grady D, et al. Obstet Gynecol. 2003;102:1233-9.
HT and Antidepressant Prescription
Patterns: A Reciprocal Relationship
Number of Prescriptions
60000
Period 1
Period 2
50000
40000
30000
20000
HT Prescriptions
10000
SA Prescriptions
0
SA = serotonergic antidepressants.
McIntyre RS, et al. CMAJ. 2005;172:57-9.
WHI Publication,
July 17, 2002
Duration of HT Use
FDA 20031

Recommends shortest duration and lowest dose
consistent with treatment goals
NAMS 20042

Recommends duration and dose consistent with
treatment goals

Extended use recommended under specific
circumstances provided patient is aware of risks/benefits
– Patient perceives benefit of symptom relief
outweighs risks
– Symptomatic women at high risk for fracture
– Viable option for prevention of osteoporosis
1FDA
News, 2003. Available at: http://www.fda.gov/bbs/topics/NEWS/2003/NEW00863.html. Accessed 3/2/04.
Menopause. 2004;11:589-600.
2NAMS.
Quality of Life, Menopausal Changes, and
Hormone Therapy
Section 2:
Menopause-Related Changes
Menopause-Related Changes
 Vasomotor
 Sleep
quality
 Sexual
well-being
 Urogenital
 Skin
symptoms
symptoms
changes
 Bone
loss
Quality of Life, Menopausal Changes, and
Hormone Therapy
Section 2a:
Vasomotor Symptoms
Hot Flushes May Continue
Years After Menopause
Ages 29 to 82 Years
50
Number of Subjects
45
Number of years women report having
hot flushes as estimated by a survey of 501
untreated women who experienced hot flushes
40
35
30
25
20
15
10
5
0
0
2
4
6
8
10
12
14
16
18
20
22
24
28
Years
Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years.
Kronenberg F. Ann NY Acad Sci. 1990;592:52-86. Used with permission.
30
36
41
SWAN Study: Reported Prevalence of Vasomotor
Symptoms in Perimenopausal Women
Women Reporting Hot
Flushes/Night Sweats (%)
Ages 40 to 55 Years
African American (n = 3650)
Hispanic (n = 1712)
Caucasian (n = 5746)
Chinese (n = 542)
Japanese (n = 707)
50
40
30
20
10
0
Race/Ethnicity
n = 12,357; SWAN = Study of Women’s Health Across the Nation.
Gold EB, et al. Am J Epidemiol. 2000;152:463-73.
Hot Flush Mechanisms

Hot flushes and shivering may result from small
fluctuations in core body temperature superimposed
on an extremely narrow thermoneutral zone*

Hot flushes occur when core body temperature rises
above the upper (sweating) threshold

Shivering occurs when core body temperature falls
from the elevated level to a level below the lower
threshold of the thermoneutral zone
*Zone in which neither sweating nor shivering occurs.
Freedman RR, Blacker CM. Fertil Steril. 2002;77:487-90.
Body Temperature and Time to Reach
Sweating Threshold in Symptomatic and
Asymptomatic Postmenopausal Women
Substance
Administered
Core body temperature (°C)
Skin temperature (°C)
Time to sweating threshold (min)
Symptomatic Asymptomatic
(n = 12)
(n = 7)
Placebo
37.1  0.07*
37.4  0.05†
Clonidine
37.3  0.09
37.2  0.03
Placebo
36.0  0.2
36.5  0.2
Clonidine
36.2  0.2
36.5  0.2
Placebo
84.7  9.1*
130.4  9.9
Clonidine
132.0  10.6*
149.4  10.2
*P < .05 vs asymptomatic women; †P < .05 vs clonidine.
Adapted from Freedman RR, Dinsay R. Fertil Steril. 2000;74:20-3.
Sweat Rates in Symptomatic and Asymptomatic
Postmenopausal Women During Body Heating*
Sweat Rate
(mg/cm2–minute)
0.16
Symptomatic (n = 12)
Asymptomatic (n = 7)
0.14
0.12
††
0.10
† †† †
††
†
0.08
0.06
0.04
0
1
2
3
4
5
6
7
8
9
10
Minutes After Sweating Threshold Reached
*Room temperature increased from 23°C to 26°C and subjects’ torsos were covered with 2 circulating water pads at 42°C.
†P < .05.
Freedman RR, Dinsay R. Fertil Steril. 2000;74:20-3.
Reduction in Mean Daily Number of
Hot Flushes with HT
Women’s HOPE Study (n = 241†)
Adjusted Mean Daily Number*
10
8
6
4
2
12
Adjusted Mean Daily Number*
Placebo
0.625
0.45
0.3
12
Placebo
0.625/2.5
0.45/2.5
0.45/1.5
0.3/1.5
10
8
6
4
2
0
0
1
2
3
4
5
6
7
Week
8
9 10 11 12
1
2
3
4
5
6
7
8
9 10 11 12
Week
*Adjusted for baseline.
Mean hot flushes at baseline = 12.3 (range 11.3–13.8); †Efficacy-evaluable population included women who recorded
taking study medication and had at least 7 moderate-to-severe flushes/week or at least 50 flushes per week at baseline.
Utian WH, et al. Fertil Steril. 2001;75:1065-79. Used with permission.
Effect of Synthetic Estrogens on Hot Flushes
0
CE 0.3 mg
CE 0.625 mg
CE 1.25 mg
Placebo
% Reduction in Number
of MSHF
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
0
4
8
Study Week
MSHF = moderate-to-severe hot flushes.
Utian WH, et al. Obstet Gynecol. 2004;103:245-53.
12
Position Statement on Treatment of
Vasomotor Symptoms
North American Menopause Society
 The
gold standard for moderate-to-severe
vasomotor symptoms remains HT
 For
mild vasomotor symptoms, lifestyle
changes alone or combined with a
nonprescription remedy can be considered
– However, due to inconclusive efficacy
data, this was not a consensus
recommendation
The North American Menopause Society. Menopause. 2004;11:11-33.
Quality of Life, Menopausal Changes, and
Hormone Therapy
Section 2b:
Sleep Quality
Unopposed Estrogen Improves Sleep




1Schiff
Decreases the frequency of
– Night sweats1-4
– Periods of wakefulness during
the night3,4
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
I, et al. Maturitas. 1980;2:179-83.
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.
2Scharf
Mean Number of Occurrences
Effect of Unopposed Estrogen on Sleep Quality
Ages 45 to 60 Years
14
Mean Number of Hot Flushes
per 24 Hours
Mean Number of Hot Flushes
With Awakenings per Night
12
10
8
6
4
2
*
*
0
-4
0
6
11
16
Treatment Days
21
26
*P < .01 compared with baseline.
n = 7; treatment was CEE 0.625 mg for 27 days.
Reprinted from Scharf MB, et al. Effects of estrogen replacement therapy on rates of cyclic alternating patterns
and hot-flush events during sleep in postmenopausal women: a pilot study. Clin Ther. 1997;19:304-11. ©1997,
with permission from Excerpta Medica, Inc.
Percentage of Women Using Alternative
Therapies to Improve Sleep
Any
Alternative
Therapy
Body Work
(Massage)
Soy
Products
Herbal or
Homeopathic
Stress
Management
Mild
20%
2%
9%
10%
9%
Moderate
27%
5%
9%
17%
11%
Severe
33%
7%
8%
21%
16%
Trouble
Sleeping
n = 886; age range 45–65 years; 19% of women surveyed were using HT and some form of alternative therapy.
Newton KM, et al. Obstet Gynecol. 2002;100:18-25.
Quality of Life, Menopausal Changes, and
Hormone Therapy
Section 2c:
Urogenital Changes
Physiology of Vulvovaginal
Changes: Structure and Histology
1Oriba

Loss of collagen and
adiposity in vulva1

Clitoral glans loses
protective covering2

Vaginal surface thinner,
less elastic; more friable2
HA, Maibach HI. Acta Derm Venereol. 1989;69:461-5.
GA, et al. In: Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. 2nd ed. 1999:195-201.
2Bachmann
Presenting Genital Symptoms and
Physical Signs of Vaginal Atrophy
Symptoms
Dryness
Itching
Burning
Dyspareunia
Burning leukorrhea
Vulvar pruritus
Feeling of pressure
Yellow malodorous discharge
Signs on Physical Exam
Pale, smooth, or shiny vaginal epithelium
Loss of elasticity or turgor of skin
Sparsity of pubic hair
Dryness of labia
Fusion of labia minora
Introital stenosis
Friable, unrugated epithelium
Pelvic organ prolapse
Rectocele
Vulvar dermatoses
Vulvar lesions
Vulvar patch erythema
Petechiae of epithelium
Adapted from Bachmann GA, Nevadunsky NS. Am Fam Physician. 2000;61:3090-6.
Vaginal Biopsies
Postmenopausal, Atrophic
Same Patient, Local E Alone (1 month)
Increase in Vaginal Dryness
With Menopause
47
50
40
Percent
32
30
25
21
20
10
3
4
0
PreEarly
Late
Postmenopause Perimenopause Perimenopause menopause
1 Year
(n = 172)
(n = 148)
(n = 106)
(n = 72)
Postmenopause
2 Years
(n = 54)
Dryness increased significantly in late perimenopause and postmenopause (P < .001).
Dennerstein L, et al. Obstet Gynecol. 2000;96:351-8.
Postmenopause
3 Years
(n = 31)
Prevalence of Superficial Dyspareunia and
Vulvovaginal Atrophy by Menopausal Age
60
Percent
50
Superficial Dyspareunia
Atrophy
40
30
20
10
0
Perimenopause
(n = 133)
0–1 Year
(n = 52)
2–3 Years
(n = 39)
Atrophy increased significantly with increase in menopausal age (P < .001).
Adapted from Versi E, et al. Int Urogynecol J. 2001;12:107-10. © 2001, Springer-Verlag.
4 Years
(n = 67)
10 g Estradiol Administered Vaginally
Treats Urogenital Symptoms
Symptom Score
10
Total Symptom Score
8
Urethral Symptom Score
Vaginal Symptom Score
6
4
2
*
*
0
0
2
4
6
Weeks
n = 7.
*P < .05 compared with baseline for total and urethral symptom scores.
Santen RJ, et al. Menopause. 2002;9:179-87. Used with permission.
8
10
12
Effect of CEE and CEE/MPA on
Vaginal Maturation*
Women’s HOPE Study
Change From Baseline
% Superfical Cells (median)
25
Cycle 6
Cycle 13
20
†
15
†
†
‡
‡
10
5
0
CEE
0.625 mg
0.45 mg
CEE/MPA
0.3 mg
0.625/
2.5 mg
0.45/
2.5 mg
0.45/
1.5 mg
Placebo
0.3/
1.5 mg
Treatment Groups
*P < .05 vs baseline and placebo for all active treatment groups; †P < .05 vs CEE 0.625; ‡P < .05 vs CEE 0.3/MPA 1.5.
Utian WH, et al. Fertil Steril. 2001;75:1065-79.
Vaginal Lubricants and Moisturizers

Multiple vaginal moisturizers
and lubricants are available
over the counter

Selection of product is based
on individual preference
HT and Urinary Incontinence:
Conflicting Findings
 Diagnose
cause of incontinence
– Atrophic urethritis
– Stress
– Urge
 Check for irritative and atrophic factors
 Measurements must include subjective &
objective modalities
 Vaginal estrogen superior to oral estrogen in
most cases
 Progesterone may decrease action of estrogen
HT and Self-Reported Urinary
Incontinence
Nurses’ Health Study (N = 39,436)
 Elevated risk of incontinence with HT vs
never-users
 Risk similar for E alone and E+P
HERS (N = 2,763)
 Incontinence improved by 26% with placebo
vs 21% with E+P
WHI (N = 27,347)
 E-alone and E+P increased risk among
asymptomatic women
Grodstein F, et al. Obstet Gynecol. 2004;103:254-60.
Grady D, et al. Obstet Gynecol. 2001;97:116-20.
Hendrix SL, et al. JAMA. 2005;293:935-48.
Efficacy of Low-dose Vaginal Estriol on
Urogenital Symptoms

88 women with stress incontinence were treated
with estriol (n = 44) or placebo (n = 44)
– Estriol ovule (1 mg) once daily for
2 weeks, then 2 mg once weekly for
a total of 6 months

Vaginal pH, colposcopy, vaginal and urethral
smears, and urodynamics were studied

68% subjective improvement in incontinence

Statistical improvement in MUP, MUCP, and PTR
MUP = maximum urethral pressure; MUCP = mean maximum urethral closure; PTR = abdominal pressure
transmission ratio.
Dessole S, et al. Menopause. 2004;11:49-56.
Efficacy of Low-dose Vaginal Estriol on
Urogenital Symptoms continued
Treatment Group (n = 44)
Control Group (n = 44)
Before
Treatment
After
Treatment
Before
Treatment
After
Treatment
PValue*
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
50.82  6.15
62.15  8.64 52.35  6.30 49.40  6.54
<.05
45.25  7.20
56.87  9.23 44.77  6.86 43.32  6.32
<.05
72.52  10.31 88.85  9.66 70.75  9.08 70.77  9.04
<.05
Variables
Clinical
MUP (cm H20)
MUCP (cm H20)
PTR (%)
*P-value is comparison between the 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.
Quality of Life, Menopausal Changes, and
Hormone Therapy
Section 2d:
Sexual Well-Being
Physician-Patient Communications Concerning
Sexual Problems May Not Be Optimal
If You Wanted to Talk to Your Doctor About a Sexual Problem,
How Concerned Would You Be About the Following?
There Would Be No Medical
Treatment for Your Problem
46
Your Doctor Would Dismiss
Your Concerns and Say
It Was All Just in Your Head
30
51
20
76
71
Very
Concerned
Somewhat
Concerned
Your Doctor Would Be
Uncomfortable Talking About
the Problem Because It Was
Sexual in Nature
46
0
20
23
40
60
68*
80
100
Percentage
*Numbers do not add up because of rounding; n = 500.
Bennett, Petts & Blumenthal. National Survey of American Adults 25 and Older. Washington, DC: March 1999.
Marwick C. JAMA. 1999:281:2173-4. Used with permission.
Validated Inventories for Assessing
Sexual Complaints
Sexual Function Index (FSFI)1
 Female
 Brief
Index of Sexual Function for Women
(BISF-W)2
 McCoy
Female Sexual Questionnaire3
 Derogatis
 Arizona
Sexual Function Inventory4
Sexual Experience Scale5
 Personal
Experience Questionnaire6
Bachmann GA, Leiblum SR. Menopause. 2004;11:120-30; 1Rosen R, et al. J Sex Marital Ther. 2000;26:191-208;
2Mazer NA, et al. Menopause. 2000;7:350-63; 3McCoy NL. Qual Life Res. 2000;9:739-45; 4Rosen RC. Curr Psychiatry
Rep. 2001;3:182-7; 5Freedman M, personal communication; 6Dennerstein L, et al. Maturitas. 1997;26:83-93.
Sexual Response Cycle: Models
+
Orgasm
Plateau
+
Emotional &
Physical
Satisfaction
Sexual
Excitement/
Tension
Emotional
Intimacy
Motivates the sexually
neutral woman
To find/ be
responsive to
Sexual
Stimuli
Arousal
Reduction
Desire
Time
Traditional Sexual Response Cycle
Kaplan HS. The New Sex Therapy Sexual Dysfunctions.
New York, NY: Brunner/Mazel; 1974.
Psychological
and biological
factors govern
“arousability”
Arousal &
Sexual
Desire
Sexual
Arousal
Alternative Model of
Sexual Response Cycle
Basson R. Obstet Gynecol. 2001;98:350-3. Reprinted with
permission from the American College of Obstetricians and
Gynecologists.
Sexual Response: Male vs Female
Female Sexual Complaints

20%1 to 43%2 of women report sexual
complaints

Multidimensional and multicausal
combining biological, psychological, and
interpersonal factors1,2

Physically and emotionally
distressing and socially disruptive1,2

Increases with age1
1Basson
R, et al. J Urol. 2000;163:888-93.
EO, et al. JAMA. 1999;281:537-44.
2Laumann
Increase in Sexual Inactivity With Age
Sexually Inactive in
Past Year (%)
45
40
Men (n = 1330)
35
Women (n = 1664)
30
25
20
15
10
5
0
18–24
25–29
30–34
35–39
40–44
45–49
50–54 55–-59
Age (years)
Data from the National Health and Social Life Survey.
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.
Female Sexual Dysfunction
Definition and Classification*




I: Sexual desire disorders
– Hypoactive sexual desire disorder
– Sexual aversion disorder
II: Sexual arousal disorders
– Genital arousal disorder
– Subjective arousal disorder
– Combined genital and subjective
– Persistent arousal disorder
III: Orgasmic disorder
IV: Sexual pain disorders
– Dyspareunia
– Vaginismus
*International Consensus Development Conference on Female Sexual Dysfunction.
Basson R, et al. J Urol. 2000;163;888-93; Basson R, et al. J Psychosom Obstet Gynecol. 2003;24:221-9; Leiblum SR,
Nathan SG. J Sex Marital Ther. 2001;27:365-80.
Prevalence of Male and Female
Sexual Complaints
National Health and Social Life Survey Ages 18 to 59 Years
Experience Pain During Sex
Women (n = 1664)
Sex Not Pleasurable
Men (n = 1330)
Unable to Achieve Orgasm
Lacked Interest in Sex
Anxiety About Performance
Climax Too Early
Men Unable to Keep an Erection
Women Have Trouble Lubricating
0
5
10
15
20
25
30
35
Percentage
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.
Contributions to Female Sexual
Complaints





Androgens
Estrogens
Medications
Illness
Fatigue
Biological/
hormonal


Stimulation
Partner
dysfunction
Lack of
appropriate
stimuli
Interpersonal


Relationship discord
Absence of emotional
intimacy

Past history of
disappointing sex
Expectation
of negative
outcome

Contextual


Lack of privacy
Safety
Emotional rapport
Intrapersonal
development
history


Trauma
(sexual, physical, medical)
Negative emotions
(anxiety, fear, shame, guilt)
Risk Factors for Sexual Dysfunction


Biological risk factors
– Gender/age
– Neuro/endocrine/vascular factors
– Depression
– General health
– Medication (eg, antidepressants)
Psychosocial risk factors
– Emotional or stress-related problems
– Physical/sexual abuse
– Relationship conflict
Leiblum SR. J Gend Specif Med. 1999;2:41-5.
Massachusetts Women’s Health Study
Women’s Sexual Complaints
Population Sample
Sexual Activity Outcomes
200 Women
Mean age, 54 years (range, 51–61 years)
Satisfaction with sexual relationship
23 (6–30)
35% pre-, 26% peri-, 39% postmenopausal
Sexual desire
10 (0–20)
Frequency sexual
intercourse day/year
58.2/365
Less arousal compared with 40s
39.0%
Difficulty reaching orgasm
(sometimes/usually/always)
37.2%
Pain during intercourse
22.5%
90% currently married
96% health status better or same as others
50% hot flushes and/or night sweats
22% currently smoking
20% regular exercise
27.9 kg/m2 mean BMI
24% partner limits sexual activity
13% depression
40% psychological symptoms
BMI = body mass index.
Avis NE, et al. Menopause. 2000;7:297-309.
Changes in Sexual Arousal
After Menopause*
Women (%)
100
80
60
45.1
50.2
40
20
4.7
0
Less
Same
More
Change in Arousal Compared With Premenopause
*As measured by the Sexual Activity Questionnaire. This scale has not been validated.
n = 79.
Avis NE, et al. Menopause. 2000;7:297-309. Used with permission.
Evaluation of Postmenopausal Patients
With Complaints of Sexual Dysfunction
Classes of Medications That May Interfere
With Sexual Function
 Antihypertensive
 Antidepressant
agents
medications (eg, SSRIs)
 Chemotherapeutic
agents
 Central
nervous system agents
 Agents
that affect hormones
Berman JR, Goldstein I. Urol Clin North Am. 2001;28:405-16.
Effect of Menopausal Transition on
Parameters of Sexual Functioning
Mean Change in SPEQ
(Sexual) Domains
Cross-sectional Data Reported From a Longitudinal, Population-based
Cohort of Australian Women, 45–55 Years of Age
0.4
*
0.27
*
0.15
0.2
0
-0.2
–0.17
*
–0.14
Sexual
Responsivity
Sexual
Frequency
*
-0.4
–0.20
*
Libido
Vaginal
Dyspareunia
n = 438; SPEQ = Shortened version of the Personal Experiences Questionnaire.
*P < .05 for postmenopausal compared with perimenopausal women.
Dennerstein L, et al. Fertil Steril. 2001;76:456-60.
Partner
Problems
Comparative Efficacy of Oral EE With or Without
MT in Postmenopausal Women With Hypoactive
Sexual Desire
 Double-blind,
 EE
randomized, 16-week study
+ MT vs EE alone
 218
women receiving HT, 20 centers
 Postmenopausal
 Adequate
 Onset
 No
6 months, age 40–65 years
desire before menopause
of low desire with menopause
mood disorder
EE = esterified estrogens; MT = methyltestosterone.
Lobo RA, et al. Fertil Steril. 2003;79:1341-52.
Comparative Efficacy of Oral EE With or Without
MT in Postmenopausal Women With Hypoactive
Sexual Desire continued
Mean Change in Sexual Desire Scores
1.0
Mean Change
EE/MT
0.8
EE
0.6
*
0.4
0.2
0.0
Baseline
*P < .02.
Lobo RA, et al. Fertil Steril. 2003;79:1341-52.
4
8
Study Week
12
16
Comparative Efficacy of Oral EE With or Without
MT in Postmenopausal Women With Hypoactive
Sexual Desire continued
Results
 Also
improved sexual interest and
responsiveness for EE + MT (3.29 ± 5.5) vs
EE (1.28 ± 4.65; P = .002)
 Significant
association between changes
in women’s sexual interest and bioavailable
testosterone
Lobo RA, et al. Fertil Steril. 2003;79:1341-52.
Effect of Testosterone on Low Libido

75 women who had undergone bilateral
salpingo-oophorectomy and hysterectomy
– All treated with CEE

Randomized to transdermal testosterone
150 mg/d or 300 mg/d, or placebo

Testosterone therapy increased scores for
frequency of sexual activity and pleasure-orgasm

Testosterone/CEE increased serum
concentrations of testosterone to normal range
Shifren JL, et al. N Engl J Med. 2000;343:682-8.
Increase in Desire at 24 Weeks With
300-mcg Testosterone Transdermal Patch
Mean Change From
Baseline (SEM)
14
12
10
P = .0006
8
6
4
2
0
% Increase
From Baseline
Placebo
TTP
29%
56%
TTP = testosterone transdermal patch.
Nachtigall L. Presented at NAMS 15th Annual Meeting; October 7, 2004; Washington, DC. Personal communication.
Nachtigall L, et al. Menopause. 2004;11:651. Abstract S-11.
Mean Change From Baseline (SEM)
Improvements in Other PFSF Domains With
300-mcg Testosterone Transdermal Patch
25
P < .0001
Placebo
P = .0003
TTP
20
P = .0001
P < .0001
15
P = .0006
P = .023
10
5
0
Arousal
Orgasm
Pleasure
Concerns
Responsiveness
Self-image
Nachtigall L. Presented at NAMS 15th Annual Meeting; October 7, 2004; Washington, DC. Personal communication.
Nachtigall L, et al. Menopause. 2004;11:651. Abstract S-11.
300-mcg Testosterone Transdermal Patch:
Similar Adverse Event Rate to Placebo
Patients (%)
Placebo (n = 279)
TTP (n = 283)
Patients with any AEs
79.6
77.7
Serious AEs
2.5
2.5
Withdrawals due to AEs
6.8
8.5
Application site reaction
39.1
31.1
Upper respiratory infection
9.3
9.9
Headache
7.5
9.9
Acne
6.1
6.0
Alopecia
3.2
3.2
Hirsutism
6.5
5.7
Voice deepening
2.9
2.5
Breast tenderness
2.5
2.5
Hot flushes
2.2
1.8
AEs of special interest
Nachtigall L. Presented at NAMS 15th Annual Meeting; October 7, 2004; Washington, DC. Personal communication.
Nachtigall L, et al. Menopause. 2004;11:651. Abstract S-11.
Possible Dose-Related Adverse Effects
With Testosterone Treatment
 Hirsutism
and acne
 Voice
changes
 Lipid
and cardiovascular changes
 Clitoromegaly
Sands R, Studd J. Am J Med. 1995;98(suppl 1A):76S-79S.
Princeton Consensus Statement on Female
Androgen Insufficiency

Female androgen insufficiency consists of a pattern
of clinical symptoms in the presence of
– Decreased bioavailable testosterone
– Normal estrogen status
– Clinical symptoms
 impaired sexual function
 mood alterations
 diminished energy and well-being
Bachmann G, et al. Fertil Steril. 2002;77:660-5.
Princeton Consensus Statement on Female
Androgen Insufficiency continued

Female androgen deficiency may occur from the
decline in androgen levels with age

Androgen insufficiency should only be diagnosed
in women who are adequately estrogenized because
of the strong association of estrogen levels and
sexual function

Large, randomized, controlled trials are needed to
determine normal levels of androgen in women of
different ages and reproductive states
Bachmann G, et al. Fertil Steril. 2002;77:660-5.
Treatment Options for Sexual
Dysfunction/Complaints

Sex therapy/couples’ therapy

Hormone therapy
– Topical estrogen
– Systemic estrogen
– Estrogen ± progestin
– Estrogen/androgen*
– Androgens*

Lubricants/moisturizers
*Not FDA approved for treatment of sexual complaints.
Postmenopausal Sexual Health:
Summary
Sexual dysfunction affects many
postmenopausal women
 Physicians and patients may be
reluctant to discuss sexual issues
 Genital atrophy is a major
consequence of estrogen deficiency
 HT is effective in preventing
and reversing genital atrophy and
associated dyspareunia

Quality of Life, Menopausal Changes, and
Hormone Therapy
Section 2e:
Skin Changes
QOL Impact of Skin Appearance

Preserving physical appearance confers
psychological benefits1
– Physically attractive older women have
better self-image than less attractive women2
– Physically attractive women rate themselves
more favorably with regard to mental,
physical, and social well-being2

Dermatologic conditions (eg, psoriasis) can
negatively affect QOL3
1Kligman
AM, Graham JA. In: Aging and the Skin. 1989:347-55.
JA, Kligman AM. Int J Cosm Surg. 1985;7:85-97.
3Finlay AY. Semin Cutan Med Surg. 1998;17:291-6.
2Graham
Appearance of Skin: A Major and
Costly Concern
Natural, healthy appearance coveted by most
women
 $36.6 billion in cosmetics and toiletries were
sold to consumers in 20001
 In 2001, rhytidectomies (“facelifts”) were the
most common cosmetic procedure in adults
51 years old2
 Total number of facelifts increased 74% from
1992 to 20013

1Sauer
M. In: Chemical Market Reporter. 2001;259:FR3.
Society of Plastic Surgeons, 2002. Available at: http://www.plasticsurgery.org/mediactr/agedist.pdf.
Accessed 6/19/02.
3American Society of Plastic Surgeons, 2002. Available at: http://www.plasticsurgery.org/mediactr/
2001expanded_stats/cosmetic_trends.pdf. Accessed 6/19/02.
2American
The Physical Impact of Intrinsic
Aging on Skin
1Young

Altered barrier function of skin1

Increased rate of skin disorders, such
as actinic keratoses and skin cancer2

Impaired wound healing

Deterioration in physical appearance

Decreased blood flow3-5
EM Jr, Newcomer VD. In: Geriatric Dermatology: Clinical Diagnosis and Practical Therapy. 1989;17-21;
S, Gilchrest BA. Arch Dermatol. 1987;123:1638-43; 3Gilchrest BA, Chiu N. In: The Merck Manual of
Geriatrics. Section 15. Dermatologic and Sensory Organ Disorders. Available at: http://www.merck.com/pubs/
mm_geriatrics/sec15/ch122.htm. Accessed 4/11/02; 4Haenggi W, et al. Maturitas. 1995;22:37-46; 5Petersen MJ. In: The
Biology of the Skin. 2001:209-18.
2Beauregard
Aging of the Skin
Results in
Dryness
Hair
Collagen Fibers
Skin Thickness
Glycosaminoglycans
Elasticity
Vascularity
Petersen MJ. Aging of the skin. In: The Biology of the Skin. 2001:209-18.
Young EM Jr, Newcomer VD. Anatomy of aging skin. In: Geriatric Dermatology: Clinical Diagnosis and Practical
Therapy. 1989:9-15.
Dryness and Atrophy
Photograph from Marks R, ed. Skin Disease in Old Age. 2nd ed. London: Martin Dunitz Ltd; 1999.
© 1999 www.taylorandfrancis.com. Used with permission.
Skin Is Estrogen Responsive

ERs have been identified in1
– Epidermal keratinocytes
– Dermal fibroblasts
– Blood vessels
– Hair follicles

1Brincat
2Nelson
Both aromatase and 17b-hydroxysteroid
dehydrogenase type I expressed in skin2
M. Maturitas. 2000;35:107-17.
LR, Bulun SE. J Am Acad Dermatol. 2001;45:S116-S124.
Skin Collagen and Estrogen Loss

Collagen loss is associated with
decreased estrogen
– 30% of skin collagen is lost in
the first 5 years after menopause1
– Average rate of loss = 2.1% per
postmenopausal year2*
*Women were monitored for up to 20 years postmenopause.
1Brincat M. Br J Obstet Gynaecol. 1985;92:256-9.
2Brincat M, et al. Obstet Gynecol. 1987;70:840-5.
Thigh Collagen Content (g/mm2)
Collagen Content and
Menopausal Age
280
HT (n = 52)
260
Placebo (n = 77)
240
220
200
180
160
140
120
100
0
2
4
6
8
10
12
14
16
Years Since Menopause
P < .001.
Reprinted from Brincat M, et al. Long-term effects of the menopause and sex hormones on skin thickness. Br J
Obstet Gynaecol. 1985;92:256-9. ©1985, with permission from Elsevier Science.
Mean Collagen Fibers (2)
E+P Increases the Skin Collagen Content of
Upper Arm of Postmenopausal Women
25500
25000
Placebo
E+P
*
24500
24000
23500
23000
22500
22000
21500
21000
Baseline
6 Months
E+P = valerate estradiol 2 mg/d for 21 d/mo combined with cyproterone acetate 1 mg/d for 10 d/mo.
*P < .05 versus baseline and placebo; bars represent standard deviations.
Sauerbronn AVD, et al. Int J Gynecol Obstet. 2000;68:35-41.
HT Maintains Skin Thickness
in Postmenopausal Women
Skin Thickness (mm)
1.00
*
0.95
0.90
0.85
0.80
0.75
Premenopausal
Postmenopausal
No HT
*P < .01 vs untreated postmenopausal group.
Chen L, et al. Skin Res Technol. 2001;7:95-7. Used with permission.
Postmenopausal
HT
Early Intervention With Estrogen
Prevents Collagen Loss
 Deficiencies
in skin collagen can be
corrected by estrogen treatment1,2
 Estrogens
are of prophylactic value when
initiated in the early postmenopausal years2
 An
increase in collagen with estrogen
depends on the collagen content at the
start of treatment1,3
1Brincat
M, et al. Br J Obstet Gynaecol. 1985;92:256-9.
M. Acta Obstet Gynecol Scand. 2000;79:244-9.
3Brincat M, et al. BMJ. 1983;287:1337-8.
2Brincat
Summary: Skin Changes
With Menopause
 Skin
is estrogen responsive
 Postmenopausal
skin
– Atrophy, dryness, and wrinkles
– Impaired wound healing
 Hormone
therapy
– Increases skin thickness
– Enhances wound repair
Quality of Life, Menopausal Changes, and
Hormone Therapy
Section 2f:
Osteoporosis and QOL
Osteoporosis and QOL
Osteoporosis-related events negatively impact
QOL through
– Incident vertebral fractures
– Pain
– Loss of mobility and independence
 QOL may impact development and outcome of
osteoporosis through
– Level of activity and exercise
– Adherence to therapy
– Healthy diet

Oleksik A, et al. J Bone Miner Res. 2000;15;1384-92.
Silverman SL, et al. Arthritis Rheum. 2001;44:2611-9.
Jacka FN, et al. Menopause. 2005;12:88-91.
Quality of Life, Menopausal Changes, and
Hormone Therapy
Section 3:
Recent Evidence and Critical
Review of QOL in Menopause
Global and Health-Related QOL
 Global
QOL
– “Sense of well-being” that is impacted
by experience of symptoms but not
solely determined by symptoms
– Patient’s own subjective appraisal
of overall life satisfaction/sense of
well-being
 Health-related
QOL
– Patient’s perceptions of their physical,
cognitive, and mental health
Utian WH, et al. Menopause. 2002;9:402-10.
Problems With QOL Construct

Minimal definitional agreement

Objective measurement difficult

Current publications have
oversimplified QOL as health status

Cultural differences are often
minimized or ignored
Utian WH, et al. Menopause. 2002;9:402-10.
HERS: QOL-Related Instruments

Physical function—Duke Activity Status
Index

Energy/fatigue—RAND scale

Mental health—RAND Mental Health
Inventory-5

Depressive symptoms—Burnam screening
scale
None of these inventories are validated to
measure global QOL
Hlatky MA, et al. JAMA. 2002;287:591-7.
HERS and QOL
 Reported
no benefits on QOL except for
flushes
 Study
considerations:
– No sexual function included
– No urogenital problems included
– No skin aspects studied
– Few vasomotor symptoms in older
age group (mean age, 68 years old)
 For
this age group, no true QOL issues
were measured
HERS = Heart and Estrogen/progestin Replacement Study.
HERS: E+P Improves QOL Measures
in Symptomatic Women
RAND
Mental Health
Inventory Score
Better
80
CEE/MPA
Depressive
Symptom Score
P = .04*
Placebo
75
70
65
0
Better
Mental Health
4
12
24
Depressive Symptoms
-4
36
P = .01*
-5
-6
0
4
12
24
36
Follow-up Months
n = 434 women at baseline reporting flushes “all of the time,” “a good bit,” “most of the time,” or “some of the time.”
*P-values indicate significant improvement compared with placebo over 3 years.
Hlatky MA, et al. JAMA. 2002;287:591-7. Used with permission.
Women’s Health Initiative (WHI):
QOL Evaluation
Study Design Randomized, double-blind,
placebo-controlled
Subjects 16,608 postmenopausal women
50 to 79 years old (mean age,
63.3 years)
Intervention CEE 0.625 mg + MPA 2.5 mg daily
(n = 8506) or placebo (n = 8102)
Follow-up Assessments* made at baseline,
1 year (all women), and 3 years
(subgroup of 1511 women)
*Assessments did not include any of the most commonly accepted, validated instruments for measuring
menopause-related QOL
Hays J, et al. N Engl J Med. 2003;348:1839-54.
WHI: Surrogate Measures NOT Validated for
Assessment of Menopause-Related QOL

Health and functional status—RAND-36

Depression—CES-D

Sleep quality—WHI Insomnia Rating Scale

Satisfaction with sexual functioning—
1 item with 4-point response scale

Cognitive functioning—mMMSE

Menopausal symptoms—5-item checklist
CES-D = Center for Epidemiological Studies-Depression; mMMSE = modified Mini-Mental State Examination.
Hays J, et al. N Engl J Med. 2003;348:1839-54.
WHI QOL: Baseline Characteristics
Characteristic
Moderate or severe vasomotor
symptoms (%)
Yes
No
Number of years since
menopause (%)
<5 years
5 to <10 years
10 to <15 years
15 years
Hays J, et al. N Engl J Med. 2003;348:1839-54.
CEE/MPA
(n = 8506)
Placebo
(n = 8102)
12.7
87.3
12.2
87.8
17.1
16.3
19.1
21.0
19.8
20.9
42.8
43.0
WHI QOL: Study Considerations

Unclear how “moderate” and “severe”
vasomotor symptoms were defined

Moderate or severe vasomotor symptoms were
reported by only 12% of participants

Vaginal symptoms were not evaluated

Scores were high at baseline, limiting potential
for therapy to increase them further

63% of the participants were ≥10 years
postmenopausal

No validated QOL tools used
Hays J, et al. N Engl J Med. 2003;348:1839-54.
WHI and HERS QOL:
Summary of Findings


WHI1 found
–
No significant clinical QOL benefit on any of the
outcomes, including general health, vitality, mental
health, or sexual satisfaction
–
A statistically—but not clinically—significant benefit in
sleep disturbance, physical functioning, and body pain
at 1 year
Findings were similar to HERS2
–
No improvement in QOL was seen with HT use in
older, asymptomatic, postmenopausal women utilizing
instruments that have not been validated for
menopause-related QOL*
*Duke Activity Status Index, RAND scale, Burnam screening scale.
1Hays J, et al. N Engl J Med. 2003;348:1839-54; 2Hlatky MA, et al. JAMA. 2002;287:591-7.
Conclusions

QOL is a multi-dimensional construct

QOL is more than presence/absence
of symptoms

QOL is useful as complement to
symptom inventory

UQOL and the Greene symptom profile
are sound instruments to follow patient
progress in clinical practice
Utian WH, et al. Menopause. 2002;9:402-10.
Quality of Life, Menopausal Changes, and
Hormone Therapy
Section 4:
Summary and Conclusions
HT and Menopausal Symptoms:
Benefit/Risk Assessment

Benefit is significant and consistent
– Vasomotor symptom relief
– Vulvovaginal atrophy
– Skin changes
– Indirect measures contributing
to improved QOL
– Decreased fractures
HT and Menopausal Symptoms:
Benefit/Risk Assessment continued
 Assessment
of risk in newly menopausal women
– Breast cancer—generally no increased relative
risk observed with short-term use
– CHD—absolute risk is generally low in newly
postmenopausal women, dependent on
background rate and risk factors1
– Must consider other potential risks (ie, DVT, PE,
stroke, gallbladder)
 For many newly menopausal women with moderate to
severe symptoms, benefits will outweigh risks
CHD = coronary heart disease; DVT = deep vein thrombosis; PE = pulmonary embolism.
1Hall MJ, Owing MF. Advance Data from Vital and Health Statistics 329. Hyattsville, MD; National Center for Health
Statistics. 2002:1-20.