Transcript CASE STUDY

Current Approaches to Hormone
Therapy: Dialogues With Experts
1
Introduction
Andrew M. Kaunitz, MD
Professor and Assistant Chairman
Obstetrics and Gynecology Department
University of Florida Health Science Center
Director, Menopause and Gynecology Services
Medicus Women’s Diagnosis Center
Jacksonville, Florida
2
Faculty Disclosures
Dr. Kaunitz discloses the following:
 Clinical Trials (Funding to University of Florida
Research Foundation) ……………. Barr Pharmaceuticals,
Inc, Berlex Inc, Johnson & Johnson, National Institutes of
Health
 Speaker and/or Consultant ………… American College of
Obstetricians and Gynecologists, Association of
Reproductive Health Professionals, Barr Pharmaceuticals,
Inc, Berlex Inc, Johnson & Johnson, North American
Menopause Society, Procter & Gamble
 Stockholder . . . . . . . . .Noven Pharmaceuticals Inc, Roche
Pharmaceuticals, sanofi-aventis
3
Menopause and Estrogen Therapy
 More women are entering menopause
– Baby boomers
– Increased life expectancy
 Women and their clinicians are conflicted
regarding treatment
 Treatment options exist for every woman
4
Postmenopausal HT Use
1995–2003: Pre-WHI Trial Results
 HT prescriptions peaked in 2001,
remaining stable until June 2002
 Approximately 50% of users had no
uterus (ET)
 Oral estrogen/progestin combinations
accounted for most new prescriptions
 Ob/gyns wrote >70% of HT prescriptions
HT = hormone therapy; WHI = Women’s Health Initiative.
Data from the National Prescription Audit Plus IMS Health. Cited in Hersh AL, et al. JAMA. 2004;291:47-53.
[Evidence Level A]
5
Trends in Postmenopausal HT
Use (2001–2003): Pre-WHI to
Post-WHI Trial Results
 Estimated number of women prescribed HT
– 2001: 15 million
2003: 10 million
 US physician visits (%) at which HT was
prescribed
– Oral HT
2001: 86%
2003: 74%
– Transdermal HT
2001: 9%
2003: 11%
Hersh AL, et al. JAMA. 2004;291:47–53. [Evidence Level A]
6
Trends in HT Use Post-WHI
 During the 6–8 mo following initial WHI findings, most
HT users tried to discontinue1
 More than half of women with vasomotor symptoms
randomized to CEE/MPA in WHI reported return of
symptoms after discontinuation2
 About one fourth of women who tried to stop reported
that they were unable to discontinue HT because of
recurrent vasomotor symptoms3
 Some estimate that about half of women who stopped
HT after WHI findings have since resumed use4
1. Ettinger B, et al. Obstet Gynecol. 2003;102:1225–1232 [Evidence Level B]; 2. Ockene JK, et al.
JAMA. 2005;294:183–193 [Evidence Level A]; 3. Grady D, et al. Obstet Gynecol. 2003;102:1233–1239
[Evidence Level B]; 4. MacLennan AH, et al. Climacteric. 2004;7:138–142. [Evidence Level B]
7
WHI: Hazard Ratios With E+P
Breast Cancer
CHD
Global Index
Stroke
VTE
Colon Cancer
Nominal 95% CI
Adjusted 95% CI
Hip Fracture
0.5
1.0
2.0
Hazard Ratio
5.0
CHD = coronary heart disease; VTE = venous thromboembolism
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;28:321-333. [Evidence Level A]
8
Number of Cases per Year in 10,000
Women
WHI: Annual Disease Rates:
Combination HT vs Placebo
60
Combination HT
Placebo
50
40
30
20
10
0
CHD
Stroke
Breast
Cancer
VTE
Adapted from WHI HRT Update, June 2002. [Evidence Level A]
Colorectal Hip
Cancer Fracture
Total
Death
9
WHI Estrogen-only HT Initial Findings:
Summary
 Estrogen-only component of study stopped early
after 6.8 y of follow-up: elevated stroke risk and
minimally elevated VTE risk considered
unacceptable in view of no cardioprotection
 No significant impact on risk of breast cancer or
CHD
 Significant reduction in hip fracture risk
 Death rates not different in HT and placebo groups
Anderson GL, et al; Women’s Health Initiative.Steering Committee. JAMA. 2004;291:1701–1712.
[Evidence Level A]
10
WHI Findings May Not Be Applicable
to…
 Nonoral HT formulations and non-CEE
formulations
 Lower-dose HT formulations
 Women <50 y, including those with induced
menopause
 Women who have been surgically castrated or
experience premature ovarian failure
 Use of oral and other hormonal contraception in
premenopausal women
11
CHD Events and Route of HT
“To the extent that an initial increase in CHD
events—particularly in women with advanced
atherosclerotic lesions—is caused by release
of prothrombotic and proinflammatory factors
from the liver in response to oral estrogens,
such problems should be lessened by use of
transdermal estrogens…”
Manson J, et al. Menopause. 2006;13:139-147. [Evidence Level C]
12
HT: Safer in Younger Menopausal
Women?
 Recent meta-analysis, as well as the Nurses'
Health Study update, suggest HT use by younger
menopausal women reduces CHD risk
 WHI analysis of E+P, CHD risk also suggested
cardioprotection in women most recently
menopausal
 These findings are reassuring regarding HT
cardiovascular safety in younger women
Salpeter SR, et al. J Gen Int Med. 2004;19:791-804 [Evidence Level A]; Grodstein F, Manson JE,
Stampfer MJ. J Women’s Health. 2006;15:35–44 [Evidence Level C]; Manson JE, et al. N Engl J Med.
2003;349:523-534. [Evidence Level A]
13
Management of
Vasomotor Symptoms: ACOG
 Estrogens are the most effective treatment
 Effective alternatives include SSRIs, gabapentin
 Black cohosh and phytoestrogen supplements
have no effect on vasomotor symptoms
 Use of HT in treating symptoms should involve
lowest effective dose and be reassessed annually
SSRI = selective serotonin re-uptake inhibitor
American College of Obstetricians and Gynecologists. Obstet Gynecol. 2004;104(suppl):1S–
131S. [Evidence Level C]
14
Informed Choice Regarding HT in
Symptomatic Menopausal Women
 Educate that HT represents most effective
treatment for symptoms
 Inform and document regarding cardiovascular
and breast cancer risks, and fracture/colon cancer
benefits
 Assess individual patient’s risks for heart disease
and breast cancer
 Support patient’s choice to use or not use HT
15
HT to Treat Symptoms: How Long
Should Patients Continue?
 Symptoms often resolve several years
postmenopause, but may persist for many
more years
 Symptoms often return after
discontinuation of HT
 Periodically offer patients opportunity to
taper off and discontinue HT, arranging for
follow-up should symptoms recur
Oldenhave A, et al. Am J Obstet Gynecol. 1993;168:772-780 [Evidence Level B]; Ockene JK, et al. JAMA.
2005; 294: 183–193. [Evidence Level A]
16
Advances in HT: An Individualized
Approach to Transdermal HT
Sarah L. Berga, MD
James Robert McCord Professor and Chair
Department of Gynecology and Obstetrics
Emory University School of Medicine
Atlanta, GA
17
Faculty Disclosure
Dr. Berga discloses the following:
 Speakers’ Bureau …………Berlex Inc
 Advisory Board ……………Berlex Inc,
Novogyne Pharmaceuticals, Solvay
Pharmaceuticals, Inc, Wyeth Pharmaceuticals
18
Nonoral Estrogen Options
 Transdermal
– Patches
– Gel
– Creams; pharmaceutical vs compounded
 Vaginal
– Rings; local vs systemic
– Tablets
– Creams
19
Transdermal Patch Drug Delivery

Avoids first-pass metabolism
by liver and enzymatic
degradation by
gastrointestinal tract1
–
Minimal hepatic protein
synthesis/conversion to
inactive metabolites

Avoids erratic peaks and
troughs in hormone blood
levels2-4

Differences in delivery do not
imply increased efficacy or
safety
1. Potts RO, et al. Obstet Gynecol. 2005;105:953–961 [Evidence Level C]; 2. Hossain M, et al. Maturitas.
2003;46:175–185 [Evidence Level B]; 3. Scott RT, et al. Obstet Gynecol. 1991;77:758–764 [Evidence Level B];
4. Harvey J, et al. Climacteric. 2005;8:185–192. [Evidence Level A]
20
Transdermal Delivery Maintains
Steady-State Estrogen Levels
Levels During the Third 84-h
Application of Reservoir™
1
and Matrix Patch™ Systems
Levels—Oral Estradiol
Reservoir Patch E2 50 mg/day
Matrix Patch E2 50 mg/day
= Micronized estradiol, 2.0 mg orally
200
90
off
60
30
0
on
0 5 15 25 35 45 55 65 75 85 95 105
Time (h)
E2 Serum Level (pg/mL)
E2 Serum Level (pg/mL)
150
120
2
150
100
50
0
0 11
12
13
Time (d)
1. Marty JP. Eur J Obstet Gynecol Reprod Biol. 1996;64(suppl 1):S29–S33 [Evidence Level
B]; 2. Scott RT Jr, et al. Obstet Gynecol. 1991;77:758–764. [Evidence Level B]
14
21
Reduction in Daily Number of Flushes
With Twice-Weekly Transdermal E
Patch
Mean (SD) Reduction From Baseline
Week 4*
Week 8*
Week 12*
0
-2
-4
4.9 (4.8)
n = 125
-6
5.8 (5.0)
n = 120
-8
-10
8.4 (5.7)
n = 130
9.4 (5.6)
n = 129
9.8 (5.9)
n = 126
-12
TD 0.0375 mg/d
6.6 (5.3)
n = 118
Placebo
*P <.05 between transdermal patch and placebo.
TD = transdermal estrogen patch.
Vivelle-Dot [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp. [Evidence Level A]
22
Change From Baseline (%)
Percentage Change in Lumbar
Spine BMD with Twice-Weekly
Transdermal ET
4
3
2
1
0
-1
-2
-3
-4
Week 26
Week 52
Week 78
Week 104
Treatment Duration
TE 0.1 mg/d
TE 0.025 mg/d
TE 0.05 mg/d
Placebo
BMD = bone mineral density; ET = estrogen therapy; TE = transdermal estrogen patch.
McKeever C, et al. Clin Ther. 2000;2:845–857. [Evidence Level A]
TE 0.0375 mg/d
23
Advances in Patch Technology
 Reservoir patch (1985)
– Drug solubilized in alcohol

Skin irritation; large, bulky size; adhesion problems
 “Drug-in-adhesive” Matrix patch (1995)
– Drug dissolved throughout adhesive layer
– Skin-permeation enhancers to promote skin absorption

Skin irritation, adhesion problems
 “Drug-in-adhesive-with-silicone” DOT Matrix patch (1998)
–
–
–
–
Drug solubilized in acrylic and silicone layers
Excellent adherence even when wet
Low incidence of skin irritation
Small size
DOT = delivery optimized thermodynamics.
24
Patch Size: Evolution
Estradiol 0.05 mg/d
NETA 0.14 mg/d
Estradiol 0.05
mg/d
Estradiol 0.05
mg/d
Vivelle-Dot™
(2.5 cm2)
DOT Matrix
Today
Drug-in-adhesive
Early 1990s
Estraderm
(20 cm2)
Reservoir
1985
NETA = norethindrone acetate.
25
Transdermal Technology Formulations:
Evolution of Technologies
Technology: Reservoir System
Estradiol
Thick backing layer and liquid
reservoir containing estradiol
Rate-controlling membrane
Adhesive
Technology: Matrix System
Thin backing layer
Estradiol-releasing layer with
adhesive (acrylic)
26
Transdermal Technology Formulations:
Evolution of Technologies (cont)
Technology: DOT Matrix System
Thin backing layer
Estradiol-releasing
layer with 2 adhesives
(acrylic and silicone)
Estradiol is concentrated into submicroscopic acrylic pockets, enhancing delivery efficiency
of estradiol and allowing the patch to be smaller. Silicone helps adhesion.
27
Clinically Relevant Biochemical
Effects: Transdermal vs Oral
Transdermal
ET
Oral
ET
Patient
Relevance
HDL-C
↑
↑↑
CHD
LDL-C
↓
↓
CHD
Triglycerides
↓
↑↑
CHD
C-reactive protein
↔
↑
CHD
Renin substrate
↔
↑
Hypertension
Insulin resistance
↔
↑
Diabetes
CYP450 enzyme
↔
↑
Smokers
SHBG, TBG, CBG
↔
↑
Thyroid disease,
persistent
vasomotor symptoms
Estrone sulfate (SO4)
↔
↑
Estrogen monitoring
CBG = corticosteroid-binding globulin; CHD = coronaryheart disease; HDL-C = high-density lipoprotein cholesterol; LDL-C =
low-density lipoprotein cholesterol; TBG = thyroid-binding globulin; SHBG = sex-hormone–binding globulin.
Nachtigall LE. Am J Obstet Gynecol. 1995;173(3 pt 2):993–997 [Evidence Level C]; Campagnoli C. Gynecol Endocrinol.
1993;7:251–258 [Evidence Level B]; Godsland IF. Fertil Steril. 2001;75:898–915 [Evidence Level B]; Slater CC, et al.
Menopause. 2001;8:200-203. [Evidence Level B]
28
Association of Oral and Transdermal
ET With VTE
Odds Ratio of VTE
5
n = 32
4
3
2
n = 71
n = 22
n = 30
1
0
Never Used
Past Use
VTE = venous thromboembolism.
Scarabin PY, et al. Lancet. 2003;362:428–432. [Evidence Level B]
Current
Oral ET
Current
Transdermal
ET
29
Transdermal ET Improves Muscle
Hemodynamics
 Hypothesis: Can ET reverse impaired
sympatholysis in estrogen-deficient menopausal
women?
 Results: Transdermal ET improved muscle
oxygenation and decreased blood pressure
 Transdermal estrogen may attenuate vascular
resistance and blood pressure responses to
dynamic exercise in postmenopausal women by
reducing sympathetic vasoconstriction in active
muscles
Fadel PJ, et al. J Physiol. 2004;561:893-901. [Evidence Level B]
30
Case Study
31
Patient Profile
 52 y
 Last menstrual period (LMP): 6 mo ago
 Started weekly estrogen patch 10 wk prior
 Current complaints
– Bothersome vasomotor symptoms, occurring
5–6 d after ET patch application
– Insomnia, irritability
32
Personal History
 No significant medical history
 Current medications: transdermal
estradiol 0.05 mg weekly ET patch;
micronized progesterone 200 mg/d for
first 12 d of mo
 Notes 3–5 d of light bleeding on days
15–18 each mo
33
Family History
 Mother: deceased at age 75; lung cancer
 Father: aged 79; no significant medical
problems; controlled hypertension
34
Physical Examination/Findings
 Height: 5'2"; wt: 125 lb
 BP: 128/62 mm Hg
 General and gynecological exam: normal
35
Initial Discussion
 Patient is pleased with current HT approach,
except for recurrent vasomotor symptoms
5–6 d after patch application
 Patient is comfortable with light monthly
withdrawal bleed
 Patient claims that patch itches and gets
dirty-looking around the edges by d 5
– Sometimes the patch starts to falls off
HT = hormone therapy.
36
Laboratory Results and Diagnostics
 Pap smear: normal
 Mammogram: normal
 Vaginal pH: 6.0
 Total cholesterol, HDL-C, and LDL-C: normal
 Triglycerides: moderately elevated
 TSH: normal
 Fasting glucose: normal
 BMD: lumbar spine T-score, -1.6 SD; hip T-score, -1.2 SD
37
Question
 Based on this patient's history and
complaints, how would you proceed?
a. Switch to oral continuous combined HT
b. Increase dose of present transdermal ET patch
c. Switch to different progestin formulation
d. Switch to different patch system
38
Management Issues
 Patient’s complaints suggest patch
adherence problems
 Patient is comfortable with transdermal ET
 Understands transdermal route is
preferable in women with elevated
triglyceride levels
 A transdermal ET system with better
adherence might address her complaints
39
Clinical Profiles Vary by Transdermal
System
 Randomized controlled trial compared 2 onceweekly transdermal systems (generic vs branded
system)
 Site reactions and irritation were more common
with generic than branded system
 Odds of generic product lifting off or detaching
were ~7 times higher than with branded product
 Systems were not bioequivalent based on
estradiol, estrone, and estrone sulfate monitoring
Harrison LL, et al. J Clin Pharmacol. 2002;42:1134–1141. [Evidence Level B]
40
Transdermal ET: Clinical Strategies
 Consider changing to twice-weekly
0.05 mg Matrix patch
 If symptoms persist at 3-6 wk, check
serum estradiol level on d 2/3 of patch and
consider adjusting dose per results
41
Patient Counseling
 Counsel patient on appropriate sites for
application of patch
 Counsel patient on application process
– Site rotation
– Avoidance of creams/oils and irritated/lacerated
skin
– Patch schedule issues
42
Clinical Follow-Up and Management
 Patient returns in 4 wk on 0.05 mg
twice-weekly patch
– Vasomotor symptoms improved, virtually
eliminated
– Patient notes that twice-weekly patch remains
in place and does not become "dirty"
43
Key Points
 Different patches have different clinical
profiles
 An individualized approach tailored to
specific patient’s needs can result in
patient satisfaction with HT and clinician’s
care
44
Suggested Reading

Grodstein F, et al. Hormone therapy and coronary heart disease: the role of time
since menopause and age at hormone initiation. J Women's Health. 2006;15:35–44.

Guthrie JR, et al. Hot flushes during the menopause transition: a longitudinal study in
Australian-born women. Menopause. 2005;12:460–467.

Harman SM, et al. KEEPS: The Kronos Early Estrogen Prevention Study. Climacteric.
2005;8:3–12.

Harrison LL, et al. An evaluation of bioequivalence of two 7-day 17beta-estradiol
transdermal delivery systems by anatomical site. J Clin Pharmacol. 2002;42:1134–
1141.

Harvey J, et al. Hormone replacement therapy and breast density changes.
Climacteric. 2005;8:185–192.

Hossain M, et al. Dose proportionality study of four doses of an estradiol transdermal
system, Estradot. Maturitas. 2003;46:173–185.

Ibarra de Palacios P, et al. Comparative study to evaluate skin irritation and adhesion
of Estradot and Climara in healthy postmenopausal women. Climacteric.
2002;5:383–389.
45
Suggested Reading (cont)

MacLellan AH, et al. Hormone therapy use after the Women's Health
Initiative. Climacteric. 2004;7:139–142.

Marty J-P. Menorest: Technical development and pharmacokinetic profile.
Eur J Obstet Gynecol Reprod Biol. 1996;64(suppl 1):S29–S33.

McKeever C, et al. An estradiol matrix transdermal system for the
prevention of postmenopausal bone loss. Clin Ther. 2000;22:845–857.

Minkin MJ. Considerations in the choice of oral vs transdermal hormone
therapy. J Reprod Med. 2004;49:311–320.

Nassar AH, et al. Gynecologists' attitudes towards hormone therapy in the
post “Women's Health Initiative” study era. Maturitas. 2005;52:18–25.

Potts RO, et al. Transdermal drug delivery: Clinical considerations for the
obstetrician-gynecologist. Obstet Gynecol. 2005;105:953–961.

Salpeter S. Hormone therapy for younger postmenopausal women: how can
we make sense out of the evidence? Climacteric. 2005;8:307–310.
46