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.

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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]

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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]

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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

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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

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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]

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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

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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]

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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]

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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

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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

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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]

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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

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Faculty Disclosure

Dr. Berga discloses the following:

Speakers’ Bureau …………Berlex Inc

Advisory Board ……………Berlex Inc, Novogyne Pharmaceuticals, Solvay Pharmaceuticals, Inc, Wyeth Pharmaceuticals

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Nonoral Estrogen Options

Transdermal

– Patches

– Gel

– Creams; pharmaceutical vs compounded

Vaginal

– Rings; local vs systemic

– Tablets

– Creams

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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]

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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

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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]

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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.

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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.

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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.

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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

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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)

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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]

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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.

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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]

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Case Study

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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

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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

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Family History

Mother: deceased at age 75; lung cancer

Father: aged 79; no significant medical problems; controlled hypertension

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Physical Examination/Findings

Height: 5'2"; wt: 125 lb

BP: 128/62 mm Hg

General and gynecological exam: normal

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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.

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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

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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

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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

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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]

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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

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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"

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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

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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.

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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.