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1
Current Approaches to Hormone Therapy: Dialogues With Experts
2
Introduction
Andrew M. Kaunitz, MDProfessor and Assistant Chairman
Obstetrics and Gynecology DepartmentUniversity of Florida Health Science Center
Director, Menopause and Gynecology ServicesMedicus Women’s Diagnosis Center
Jacksonville, Florida
3
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
4
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
5
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
Data from the National Prescription Audit Plus IMS Health. Cited in Hersh AL, et al. JAMA. 2004;291:47-53. [Evidence Level A]
HT = hormone therapy; WHI = Women’s Health Initiative.
6
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 HT2001: 86% 2003: 74%
– Transdermal HT2001: 9% 2003: 11%
Hersh AL, et al. JAMA. 2004;291:47–53. [Evidence Level A]
7
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]
8
WHI: Hazard Ratios With E+P
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;28:321-333. [Evidence Level A]
Breast Cancer
CHD
Global Index
Stroke
VTE
Colon Cancer
Hip Fracture
Hazard Ratio0.5 1.0 5.02.0
Nominal 95% CIAdjusted 95% CI
CHD = coronary heart disease; VTE = venous thromboembolism
9
WHI: Annual Disease Rates: Combination HT vs Placebo
0
10
20
30
40
50
60
Nu
mb
er o
f C
ases
per
Yea
r in
10,
000
Wo
men
Combination HT Placebo
Adapted from WHI HRT Update, June 2002. [Evidence Level A]
Colorectal Cancer
CHD Stroke Breast Cancer
Total Death
Hip Fracture
VTE
10
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]
11
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
12
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]
13
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]
14
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
American College of Obstetricians and Gynecologists. Obstet Gynecol. 2004;104(suppl):1S–131S. [Evidence Level C]
SSRI = selective serotonin re-uptake inhibitor
15
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
16
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]
17
Advances in HT: An Individualized Approach to Transdermal HT
Sarah L. Berga, MDJames Robert McCord Professor and ChairDepartment of Gynecology and Obstetrics
Emory University School of MedicineAtlanta, GA
18
Faculty Disclosure
Dr. Berga discloses the following:
Speakers’ Bureau …………Berlex Inc
Advisory Board ……………Berlex Inc, Novogyne Pharmaceuticals, Solvay Pharmaceuticals, Inc, Wyeth Pharmaceuticals
19
Nonoral Estrogen Options
Transdermal
– Patches
– Gel
– Creams; pharmaceutical vs compounded
Vaginal
– Rings; local vs systemic
– Tablets
– Creams
20
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]
21
Transdermal Delivery Maintains Steady-State Estrogen Levels
0 5 15 25 35 45 55 65 75 85 95 105
150
120
90
60
30
0
Reservoir Patch E2 50 g/dayMatrix Patch E2 50 g/day
on
off
Time (h)
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]
Levels—Oral Estradiol2
Levels During the Third 84-h Application of Reservoir™ and Matrix Patch™ Systems
1
E2 S
eru
m L
evel
(p
g/m
L)
E2 S
eru
m L
evel
(p
g/m
L)
200
150
100
50
011 12 13 14
= Micronized estradiol, 2.0 mg orally
Time (d)
0
22
Reduction in Daily Number of Flushes With Twice-Weekly Transdermal E Patch
TD 0.0375 mg/d Placebo
8.4 (5.7)n = 130 9.4 (5.6)
n = 1299.8 (5.9)n = 126
4.9 (4.8)n = 125 5.8 (5.0)
n = 120 6.6 (5.3)n = 118
-12
-10
-8
-6
-4
-2
0
Week 4* Week 8* Week 12*
Mea
n (
SD
) R
edu
ctio
n F
rom
Bas
elin
e
*P <.05 between transdermal patch and placebo. TD = transdermal estrogen patch.Vivelle-Dot [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp. [Evidence Level A]
23
Percentage Change in Lumbar Spine BMD with Twice-Weekly Transdermal ET
-4
-2
0
2
4
Week 26 Week 52 Week 78 Week 104
Treatment Duration
Ch
ang
e F
rom
Bas
elin
e (%
)
TE 0.1 mg/d TE 0.05 mg/d TE 0.0375 mg/d
TE 0.025 mg/d Placebo
-3
-1
1
3
McKeever C, et al. Clin Ther. 2000;2:845–857. [Evidence Level A]BMD = bone mineral density; ET = estrogen therapy; TE = transdermal estrogen patch.
24
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.
25
Estradiol 0.05 mg/dNETA 0.14 mg/d
Estradiol 0.05 mg/dEstradiol 0.05 mg/d
Reservoir1985
Drug-in-adhesiveEarly 1990s
DOT Matrix Today
Patch Size: Evolution
Vivelle-Dot™ (2.5 cm2)
Estraderm (20 cm2)
NETA = norethindrone acetate.
26
Transdermal Technology Formulations:Evolution of Technologies
Technology: Reservoir System
Technology: Matrix System
Rate-controlling membrane
Estradiol-releasing layer with adhesive (acrylic)
Adhesive
Thick backing layer and liquid reservoir containing estradiol
Thin backing layer
Estradiol
27
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.
Technology: DOT Matrix System
Transdermal Technology Formulations:Evolution of Technologies (cont)
28
Clinically Relevant Biochemical Effects: Transdermal vs Oral
Transdermal Oral Patient ET ET 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 monitoringCBG = 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]
29
Association of Oral and Transdermal ET With VTE
Never Used Past Use Current CurrentOral ET Transdermal
ET
0
1
2
3
4
5
Od
ds
Rat
io o
f V
TE
Scarabin PY, et al. Lancet. 2003;362:428–432. [Evidence Level B]
n = 71n = 22
n = 32
n = 30
VTE = venous thromboembolism.
30
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]
31
Case Study
32
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
33
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
34
Family History
Mother: deceased at age 75; lung cancer
Father: aged 79; no significant medical problems; controlled hypertension
35
Physical Examination/Findings
Height: 5'2"; wt: 125 lb
BP: 128/62 mm Hg
General and gynecological exam: normal
36
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.
37
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
38
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
39
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
40
Clinical Profiles Vary by Transdermal System
Randomized controlled trial compared 2 once-weekly 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]
41
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
42
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
43
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"
44
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
45
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.
46
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.