A Conversation About Hormone Therapy: Disclosures 2016 Is ...

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A Conversation About Hormone Therapy: Is There an Appropriate Dose, Route, and Duration of Use?

A Conversation About Hormone Therapy: Is There an Appropriate Dose, Route, and Duration of Use?

@JamesASimonMDJames A Simon, MD, PC

James A. Simon, MD, CCD, NCMP, IF, FACOGClinical Professor

Department of Ob/GynGeorge Washington University

Washington, DC

Medical DirectorWomen’s Health & Research Consultants®

Washington, DCwww.JamesASimonMD.com

Session 4—Special Areas of ConcernThe Impact of Route of Administration (Oral, Transdermal, Vaginal)

and Lower Delivered Doses on Risk-Benefit

Disclosures 2016• Dr. James A. Simon has served (within the last year) or is currently serving as:

• Owner/Board of Directors: James A. Simon, MD, PC

• Advisory Board/Consultant: A consultant to or on the advisory boards of: AbbVie, Inc. (North Chicago, IL), AMAG Pharmaceuticals, Inc. (Waltham, MA), Amgen Inc. (Thousand Oaks, CA), Apotex, Inc. (Toronto, Canada), Ascend Therapeutics (Herndon, VA), JDS Therapeutics, LLC (Purchase, NY), Merck & Co., Inc. (Whitehouse Station, NJ), Noven Pharmaceuticals, Inc. (New York, NY), Novo Nordisk (Bagsvrerd, Denmark), Nuelle, Inc. (Mountain View, CA), Perrigo Company, PLC (Dublin, Ireland), Radius Health, Inc. (Waltham, MA), Regeneron Pharmaceuticals, Inc. (Tarrytown, NY), Roivant Sciences, Inc. (New York, NY), Sanofi S.A. (Paris, France), Sermonix Pharmaceuticals, Inc. (Columbus, OH), Shionogi Inc. (Florham Park, NJ), Sprout Pharmaceuticals (Raleigh, NC), Symbiotec Pharmalab (Indore, India), TherapeuticsMD (Boca Raton, FL).

• Speaker: On the speaker’s bureaus of: Amgen Inc. (Thousand Oaks, CA), Eisai, Inc. (Woodcliff Lake, NJ), Merck (Whitehouse Station, NJ), Noven Pharmaceuticals, Inc. (New York, NY), Novo Nordisk (Bagsvrerd, Denmark), Shionogi Inc. (Florham Park, NJ).

• Grants/Research: Receiving grant/research support from: AbbVie, Inc. (North Chicago, IL), Actavis, PLC. (Dublin, Ireland), Agile Therapeutics (Princeton, NJ), Bayer Healthcare LLC., (Tarrytown, NY), New England Research Institute, Inc. (Watertown, MA), NovoNordisk (Bagsvrerd, Denmark), Palatin Technologies (Cranbury, NJ), Symbio Research, Inc. (Port Jefferson, NY), TherapeuticsMD (Boca Raton, FL).

• Patent and Trademark Holder: U.S. Patent: 4,816,257, March 28, 1989: "Method for Producing an In Vivo Environment Suitable for Human Embryo Transplant.", U.S. Trademark: Reg. No. 3,446,895, Registered June 10, 2008: “You talk…I’ll Listen. We’ll Plan Together”., U.S. Trademark: Reg. No. 3,676,269, Registered September 1, 2009: U.S. Trademark: Reg. No. 3,760,080, Registered March 16, 2010: “Women’s Health & Research Consultants & Design”, U.S. Trademark Serial No.:86-714,153. “DR. SIMON SAYS” Registered February 2, 2016.

• Stock Shareholder and/or other Financial Support: Dr. Simon is a stockholder (direct purchase) in Sermonix Pharmaceuticals (Columbus, OH).

• Dr. Simon served as chief medical officer (CMO) of Sprout Pharmaceuticals until April 2013.

Estradiol (Estrogens)

C18H24O2

Molar weight: 272.38 g/mol

(17β)-estra-1,3,5(10)-triene-3,17-diol

Metabolism of Oral Estradiol 17β

Lobo RA, Cassidenti DL. J Reprod Med 1992;37:77-84.

Oral E2 needs to be in a micronized or conjugated form in order to be efficiently absorbed by the gastric mucosa

It is mostly conjugated as E2 valerate, sulfate or acetate

Greatest metabolism during first liver passage (~ 30% spanchnic extraction)

Absolute bioavailability ~ 5-10%

Slide courtesy of RA Lobo with modification

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Some Special Characteristics of Oral and Transdermal Estrogen


Oral: conjugation or micronization to increase bioavailability; “shellacing” (Premarin) which affects pharmacodynamics

Transdermal:

–Patch: alcohol vs matrix – variable absorption, but less variability within a subject

–Gels: dermal reservoir, variable absorption but less within subject variability, transference a theoretical possibility E2needs to be in a micronized or conjugated form in order to be efficiently absorbed by the gastric mucosa


Oral Estradiol and Estrone: E1 Predominates Levels Achieved

Anderson ABM. Br Med J 1978;1:140.Slide courtesy of RA Lobo with modification

Accumulated Levels of E1s (pool) with Oral, but not Transdermal E2

Slater CC. Menopause 2001;8:200-3.Slide courtesy of RA Lobo with modification

Alcohol Increases E2 Levels with The Patch

Ginsberg ES. JSGI 1995;2:26-9.

Percent changes in serum E2 concentrations (mean ± SEM) before and after ethanol (solid circles) and carbohydrate-drink (open circles) ingestion. Estradiol patches remained in place throughout the study.*E2 significantly highter adter ethanol vs ethanol-drink ingestion, P = 0.038.ƚE2 significantly higher after ethanol-drink ingestion vs baseline, P ≤ 0.01.ǂ Change in E2 after carbohydrate-drink ingestion not significant.


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Excursion of E2 and E1 with Transdermal or Percutaneous E2 vs Oral

Scott RT. Obstet Gynecol 1991;77:758-64.

E2 E1


First Pass Hepatic Effects of Estrogens Taken by Mouth

Intestine

Liver

Oral Estrogen

EstradiolPatch

SystemicCirculation

Skin

Ovary

Decreased anti-clotting factorsIncreased clotting factors

Increased C-reactive proteinAltered Estrogens

Increased HDL Cholesterol


First Pass Effects (Stimulatory) Effects of Oral Estrogen


Effects on globulins (SHBG, CBG, etc.), coagulation parameters (antithrombin-III), inflamatory markers (CRP, etc.), lipids (HDL-C).

Effects determined by dose and potency of estrogen and its bioavailability.

Effects on lipids and inflammatory markers and insulin sensitivity to be reviewed.


Oral versus Transdermal Estrogen on Lipids (Multitude of Studies)

LDL-C, Lp(a), decrease similarly with both routes (unaffected by usual doses of added progesterone/progestogen).

Triglycerides increase with oral, (attenuated somewhat with progesterone/progestogen addition); no change or some decrease with transdermals.

HDL-C increase with orals (attenuated somewhat with progestogen addition); no change or very small increase with transdermals.


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Effects of Estrogen (Oral or Transdermal) on Inflammatory Markers

Estrogen generally decreases inflammation markers (CV protection) – dependent on potency and dose of estrogen.

ICAM-1, VCAM-1, MCP-1, E-selectin

Exception: An increase occurs with oral dosing in CRP and MMP-9 (as well as others); not observied with transdermal administration.

Decensi 2002, Sumino 2005, Lewandowski 2006, Salpeter 2006


Differences in Oral and Transdermal Estrogen on MMPs and Tissue Inhibitors in Normal Postmenopausal Women

Lewandowski KC, et al. J Clin Endocrinol Metab 2006;91:3123-30.Slide courtesy of RA Lobo with modification

HT and Plaque Rupture Susceptible Substrate

Incitant

PlaqueRupture

+

Early

Complicated Plaque

MMPHT +

MMPHT

ReactionCatalyst Substrate

Slide courtesy of H. Hodis with modification

Route of Administration:Coagulation and DVT

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Excess incidence of potentially fatal events attributable to oral ERT

(women aged 50-60 years)

Olie V. Current Opinion in Hematology 2010, 17: 457–463Data from both Women’s Health Initiative clinical trials.

NS = not significant

*vs placebo; †vs baseline; ‡between treatment groups after adjusting for baseline

Post M et al. Am J Obstet Gyncol. 2003;189:1221-1227 Rabbani L et al. J Am Coll Cardiol. 2002;40:1991-1999

Zegura B et al. Athero. 2003;168:123-129 Vehkavaara S et al. Thromb Haemost. 2001;85:619-625

O (E2, 1 mg)T (E2, 50 g)

O (E2, 2 mg)T (E2, 50 g)

O (CE, .625 mg)T (E2, 0.1 mg)

O (E2, 2 mg)T (E2, 50 g)

–7.7 (p < 0.05)*NS

–27.9 (p = 0.002)†

–11.6 (p = 0.007)†

NSNS

NSNS

-5.5 (p < 0.05)*NS

——

——

24.9 (p < 0.05)‡

NS

NSNS

NSNS

——

16.9 (p < 0.05)‡

NS

–6.8 (p < 0.05)* NS

NSNS

——

——

——

——

22.7 (p = 0.03)†

NS

NSNS

Fibrinogen Factor VII F1&2 TAT VWF% change from baseline

Coagulation Markers

Vehkavaara

Post

Zegura

Rabbani

Trial Active Tx

TAT = thrombin-antithrombinVWF = Von Willebrand factor antigen

Oral But Not Transdermal ET Impairs the Balance Between Procoagulant Factors

NS = not significant.vs placebo; †vs baseline; ‡between treatment groups after adjusting for baseline.

Post M et al. Am J Obstet Gyncol. 2003;189:1221-1227 Rabbani L et al. J Am Coll Cardiol. 2002;40:1991-1999

Zegura B et al. Athero. 2003;168:123-129 Vehkavaara S et al. Thromb Haemost. 2001;85:619-625

–8.9 (p < 0.05)*NS

–24.3 (p = 0.001)†

–25 (p = 0.05)†

–17.8 (p = 0.004)†

NS

–18.3 (p < 0.001)‡

NS

–29.2 (p < 0.001)*–7.3 (p < 0.05)†

NSNS

NSNS

-25 (p < 0.05)‡

NS

——

–62.8 (p < 0.05)†

NS

——

–66.7 (p < 0.01)‡

NS

NSNS

——

NS NS

NS NS

NSNS

96 (p < 0.01)‡

NS

t-PA PAI-1 Antigen PAI-1 Activity PAP D-dimer

% change from baseline

Fibrinolysis Markers

O (E2, 1 mg)T (E2, 50 mg)

O (E2, 2 mg)T (E2, 50 mg)

O (CE, .625 mg)T (E2, 0.1 mg)

O (E2, 2 mg)T (E2, 50 mg)

Active Tx

Vehkavaara

Post

Zegura

Rabbani

Trial

t-PA tissue-type plasminogen activatorPAI plasma plasminogen activator inhibitor

Oral But Not Transdermal ET Impairs the Balance Between Anticoagulation Factors

Scarabin et al. Lancet. 2003;362:428-432.

ESTHER: EStrogen and THromboEmbolism Risk

ESTHER Study: VTE Risk Factors

Multicenter, hospital-based, case-controlled

Postmenopausal women (45-70 y) with a first documented episode of idiopathic VTE

VTE (n = 155) Pulmonary embolisms (n = 92)

DVT (n = 63)

Controls (n = 381)

Assessed effect of oral vs TD route on thrombotic risk

Oral and TD groups included patients using ET and EPT Both groups primarily treated with EPT

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VTE Risk: Oral vs TD (ESTHER Revisited)

10.9

(0.4-2.1)

4.2

(1.5-11.6)

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Nonusers Transdermal

estrogens

Oral

estrogens

Adj

uste

d O

dds

ratio

(95

% C

I)

4.2 (1.5-11.6)3945Oral estrogens

0.9 (0.4-2.1)18067Transdermal

estrogens

1384146Nonusers

Adjusted odds ratio

95% CI

Controls

(n = 603)

Cases

(n = 259)Administration

route

• TD estrogens not associated with an increased risk of VTE

• Significant increase of VTE with oral estrogens

Canonico et al. Circulation. 2007;115;840-845.

*Adjusted for obesity status, family history of VTE, history of varicose veins, education, age at menopause, hysterectomy, and cigarette smoking.

Mutation Risk Factor

Dotted horizontal line indicates the OR of VTE associated with oral estrogen use in the whole population(OR, 4.3; 95% CI, 2.6–7.2). Factor V Leiden or prothrombin G20210A mutation

No mutationOne of prothrombotic

mutation*

Straczek et al. Circulation. 2005;112:3495–3550.

25.5

4.4

4.14.1

1.21.00.0

10.0

20.0

30.0

40.0

50.0

Nonuser Transdermal estrogen use

Oral estrogen use

Nonuser Transdermal estrogen use

Oral estrogen use

Adj

uste

d od

ds r

atio

95%

CI

100.0

90.0

Dotted horizontal line indicates the OR of VTE associated with oral estrogen use in the whole population (OR, 4.5; 95% CI: 2.6–7.7)

1.0 1.2

5.9

2.7 2.9

10.2

4.0

5.4

20.6

0.0

10.0

20.0

30.0

40.0

50.0

Nonuse Transdermalestrogen use

Oral Estrogen

use

Nonuse Transdermal

estrogen use

Oral estrogen

use

Nonuse Transdermalestrogen

use

Oral estrogen

use

Canonico et al. J Thromb Haemost. 2006;4:1259-1265

Obesity Risk Factor

BMI < 25 25 ≤ BMI < 30 BMI ≥ 30

100.0

90.0

Adj

uste

d od

ds r

atio

95%

CI

Differences in Body Composition with Oral and Transdermal Estrogen

With oral, decrease in IGF-1, increase in GH, decrease in lipid oxidation: increase in fat mass and decrease in lean mass

No appreciable change with transdermal – trend to increase lean mass.1-3

Untreated PM women gain abdominal fat with time, paralleled by increases in leptin; no changes observed with transdermal E2.4

1. O’Sullivan AJ. J Clin Invest 1998;102:1035-40. 2. Ho KK. Ann Endocrinol 2003;64:170-7. 3. dos Reis CM. Maturitas 2003;46:59-68. 4. di Carlo C. Menopause 2004;4:466-73.Slide courtesy of RA Lobo with modification

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What is the Effect of Hormones on Insulin Resistance/Sensitivity In Postmenopausal Women?

Data are mixed – influenced by status of women, type of regimen and length of treatment

In general estrogen increases with insulin sensitivity, but is very dependent on dose and type of patient treated.

Higher doses of estrogen decrease insulin sensitivity.

Higher doses (or continuous) progestogens decrese insulin sensitivity.

1. Lindheim and Lobo Fertil Steril 1993 & 1994, J Soc Gynecol Invest 1994.Slide courtesy of RA Lobo with modification

Oral versus Transdermal Estrogen on Insulin Sensitivity

Overall HT increases sensitivity and decreases insulin resistance (IR)

Attenuated by added progestogens (dose and type dependent)

Effect of transdermal E2 is slightly less than with standard doses of oral estrogen; with larger doses of oral estrogen sensitivity decrease (more IR): bimodal effect


Transdermal estrogen and change in bodyweight or BMI

• “One crossover study noted greater fat gain with oral vs. transdermal estrogen, results that are supportedby clinical data.”

Santen RJ. Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement. JCEM.2010:95,S1:S1-S66

Gallbladder Disease• Use of transdermal estrogens are associated with a substantially lower risk of gallbladder disease than

use of oral estrogens in a Prospective cohort study (Million Women Study).

• Over a five year period one cholecystectomy could be avoided for every 140 postmenopausal women of transdermal therapy rather than oral

• 45,984 (64.8%) of the participants in E3N Cohort were exposed to menopausal hormone therapy

• 2819 cholecystectomies were recorded between 1992‐2008

• Menopausal hormone therapy was associated with an increased risk of cholecystectomy (HR=1.10, 95% CI 1.01‐1.20) compared with non‐users

• The association was restricted to unopposed oral estrogen therapy (adjusted HR 1.38, 95% CI 1.14‐1.67)

• Risk was significantly higher with oral estrogens than with transdermal estrogens (p = 0.03)

• Risk was significantly higher with oral unopposed estrogens than with oral estrogens combined with a progestagen (p = 0.03)

• Over 5 years, about 1 cholecystectomy in excess would be expected in every 150 women using oral estrogen therapy without progestogens, compared with non‐users

Liu B et al. Br Med J 2008;337:a386. doi:10.1136/bmj.a386

Racine A, Bijon A, Fournier A, et al. CMAJ. 2013 Apr 16;185(7):555-61. doi: 10.1503/cmaj.121490.

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Colorectal Cancer Risk: Oral Estradiol vs. TD Estradiol

1. Writing group for WHI Investigators 2002. 2. Csizmadi I, et al. Br J Cancer 2004;90:76-81.3. Smith NL, et al. J Thromb Haemost. 2006;4:1701-6.

WHI suggested reduced risk of colorectal cancer, but data limited to oral CEE.1

Large population based case-control study suggests protective effects potentially greater for TD estradiol than oral estradiol.2

a Adjusted for age, race/ethnicity, cancer history, BMI, current statin use, estrogen daily dose, current progestin use, current smoking status, treated hypertension, treated diabetes mellitus, prevalent cardiovascular disease, and the number of GHC visits in the year before the index date.b Adjusted for age, race/ethnicity, BMI, current statin use, estrogen daily dose, current progestin use, current smoking status, treated hypertension, treated diabetes mellitus, prevalent cardiovascular disease, and the number of GHC visits in the year before the index date, as well as systolic blood pressure and total cholesterol level.

All WomenAmong women who had not had a

sigmoidoscopy 3-5 yr prior

Case (n=235)

Control (n=1071)

Age-Adjusted

OR95% CI Case

(n=216)Control (n=979)

Age-Adjusted

OR95% CI

OE Use Only 230 1013 1.000.15-0.94

212 925 1.000.12-0.90

TDE UseOnly 5 58 0.37 4 54 0.32

Limited by the small number of women with colorectal cancer who are exposed to TD estradiol, but if it is truly protective there will always be fewer exposed cases than control cases.

Are there differences in Oral or Transdermal Estrogen Treatment in Women with Metabolic Syndrome?

Inflammation and Coagulation Markers with Oral and Transdermal Estrogen in Metabolic Syndrome

Oral:

–CRP elevated but no significant increase

–MMP-9 increased

–TIMP decreased

–MMP-9/TIMP increased

–AT111 reduction

Transdermal: No significant changes

Chu & Lobo. 2007Slide courtesy of RA Lobo with modification

Route of Estrogen Administration:Sexual Function

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The Importance of Estrogen Therapy:Sexual Function

Healthy responsive genital tissues (eg, dryness,

dyspareunia, vascular dilation)

Impact on free and bioavailable testosterone (route

of administration)

Impact on bioavailable adrenal androgens

Percent Increase in SHBG at 4 Months

0

20

40

60

80

100

120

100%

CE (0.625 mg/d)

n = 37P < 0.001

% C

hang

e in

SH

BG

from

bas

elin

e

45%

12%

Oral micronized estradiol (1 mg/d) n = 25

P < 0.001

Transdermal estradiol (50 µg/d) n = 24

NS

Nachtigall et al. Menopause. 2000;7(4):243–250.

Changes in Binding Globulins With Oral Estrogen Replacement Therapy

Menopausal Conjugated estrogenstreatment (mg)

CB

G (

bind

ing

capa

city

)g

/100

mL

0

10

20

30 *

Menopausal Conjugated estrogenstreatment (mg)

Pre Post 0

0.15

0.30

0.62

5

1.25Pre Post 0

0.15

0.30

0.62

5

1.25

SH

BG

10

-8M

0

10

20

**

**

30

Adapted from Judd HL. Clin Obstet Gynecol. 1976;19:775-788.*P < 0.05 P < 0.001

Age- and BMI-Adjusted Variables by Current Exogenous Estrogen Use

in Postmenopausal Women

Rancho Bernardo 1972-1974, ages 50-79 years.Tazuke, et al. Medicine. 1992;71:44-51.

Estrogen use

Nonusers Current Users(n = 676) (n = 301)

Hormone (age, BMI-adjusted) Mean Mean P Value

Dehydroepiandrosterone sulfate (mol/L) 2.20 1.55 < 0.001

Androstenedione (nmol/L) 2.16 1.81 < 0.001

Testosterone (nmol/L) 0.86 0.83 0.91

Free testosterone (nmol/L) 0.40 0.30 < 0.001

Estradiol (pmol/L) 54 89 < 0.001

Sex hormone binding globulin (x10-5 M) 4.48 6.60 < 0.001

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Changes in Androgens and SHBG With Estrogen or Estrogen/Androgen Treatment

SHBG = sex hormone binding globulin; T/SHBG = testosterone/sex hormone binding globulin ratio;DHEAS = dehydroepiandrosterone sulfate.

All or represent statistically significant changes.

Simon et al. Menopause. 1999;6:138-146.

Estrogen Estrogen Estrogen/Androgen(0.625 mg) (1.25 mg) Half-strength Estrogen/Androgen

Testosterone (total)

SHBG

Bioavailable testosterone (T/SHBG ratio)

DHEAS

Androstenedione

KEEPS: Directions of Changes in CHD* Risk Factors

Factor O‐CEE T‐E2

Systolic BP Neutral Neutral

Diastolic BP Neutral Neutral

LDL Cholesterol Favorable Neutral

Triglycerides Adverse Neutral

HDL Cholesterol Favorable Neutral

Fasting Glucose Neutral Favorable

HOMA‐IR* Neutral Favorable

*CHD: Coronary Heart Disease; HOMA‐IR: homeostasis model assessment‐estimated insulin resistance

o‐CEE is Premarin 0.45mg/dt‐E2 is Climara 0.05 mcg/d

Simon JA, Laliberté F, Duh MS, Pilon D, Kahler KH, Nyirady J, Davis PJ, Lefebvre P.

Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy.

Menopause. 2016 Jun;23(6):600-10.

Page 40

Methods

Data Source: OptumHealth Reporting and Insights medical and pharmacy claims for more than 13 million privately-insured individuals from all census areas of the U.S. from January 2001 through September 2011

Study Population: Women ≥35 years of age newly initiated to either an ETS or oral ET agent and having ≥2 dispensings were selected

Exclusion criteria: prior VTE or CVD diagnosis OR receipt of any other estrogen containing hormone therapy agents during the 180-day baseline period

Study Design: a retrospective matched-cohort design was chosen to ensure that both groups were well balanced at baseline

Women using ETS were matched 1:1 with women using oral ET based on both exact matching factors (e.g., baseline menopausal and post-menopausal disorders) and the propensity scores

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Page 41

ResultsRisk of VTE and CVD complications

Overall, baseline characteristics and risk factors were well-balanced between cohorts

A total of 718 ETS users developed VTE or CVD complications compared to 828 women in the oral ET cohort (P=0.0040)

A total of 108 ETS users were hospitalized due to VTE or CVD complications compared to 177 women in the oral ET cohort (P<.0001)

Outcome

Frequency of EventIncidence Rate

(per 100 person-years)Univariate Analysis

ETS Oral ET ETS Oral ETUnadjusted IRR

(95% CI)P-value

All Events

VTE or CVD 718 828 7.15 8.28 0.86 (0.78 - 0.95) 0.0040

VTE 36 56 0.33 0.51 0.64 (0.42 - 0.97) 0.0375

CVD 696 794 6.91 7.91 0.87 (0.79 - 0.97) 0.0094

W/hospitalization

VTE or CVD 108 177 0.99 1.64 0.61 (0.48 - 0.77) <.0001

VTE 7 16 0.06 0.15 0.44 (0.18 - 1.06) 0.0675

CVD 104 167 0.95 1.54 0.62 (0.48 - 0.79) 0.0001

Page 42

Results Approach #2Incremental Healthcare Cost Associated with Oral ET

The adjusted all-cause healthcare cost difference was $56 per-patient per-month (PPPM) higher among oral ET users compared to transdermal users

$40

$23

$3

$7

$7

$0

$10

$20

$30

$40

$50

$60

Incr

emen

tal

Co

st P

PP

M A

sso

ciat

ed w

ith

Ora

l E

T i

n

US

$20

11

Hospitalizations

ER visits

Outpatient visits

Pharmacy

Adjusted incremental cost = $56 P-Value=0.0260

Adjusted incremental cost = $24 P-value=0.0240

All-Cause VTE / CVD-related

Conclusions Approach #1

• CVD and stroke risks-particularly in women in their 50s-would be mitigated or eliminated by switching from CEE to transdermal estradiol (at 50mcg/24h or lower).

• BrCA risk would have been reduced to the risk in HT non-users if women had used MP instead of MPA.

• Physicians seeking to reduce VTE risk (the greatest risk of HT for early menopausal women) even in women with obesity or prothrombic mutations should use transdermal ET rather than oral ET or CEE.

• Estimates from three case-control VTE studies suggest a reduced number of VTE cases with transdermal HT versus oral HT. The consistency of the three study results provides even greater support for this conclusion.

Simon JA, Laliberté F, Duh MS, Pilon D, Kahler KH, Nyirady J, Davis PJ, Lefebvre P. Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy. Menopause. 2016 Jun;23(6):600-10.

Conclusions (2)s Approach #2• Using a large matched-cohort study of over 15,000 women based on

real-world data over a ten year period suggests that women receiving transdermal estrogens have a significantly lower incidence of VTE or CVD events compared to oral ET users

• This study also suggested that women treated with transdermal estrogens incur significantly lower all-cause and VTE/CVD-related healthcare costs compared to oral ET users

Simon JA, Laliberté F, Duh MS, Pilon D, Kahler KH, Nyirady J, Davis PJ, Lefebvre P. Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy. Menopause. 2016 Jun;23(6):600-10.

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Progesterone (Progestogens)

C21H30O2Molar weight: 314.46 g/mol

pregn-4-ene-3,20-dione

Metabolism of Oral Micronized Progesterone

“Potential” Benefits of Oral Micronized Progesterone

E2: estradiol; mic P4: micronized progesterone; DHG: dydrogesterone; synt. Prog,: synthetic progestins (mainly nomegestrol acetate, promegestone, chlormadinone acetate, cyproterone acetate, medrogestone)

Relative Risks for Invasive Breast Cancer by Type of HT Progestogen (compared with HT never-users; E3N cohort study, n=80,377)

Fournier A et al. Breast Cancer Res Treat 2008; 107: 103-111.

00.20.40.60.8

11.21.41.61.8

2

E2 alone E2 + mic P4 E2 + DHG E2 + synth. Prog.

1.30

1.001.10

1.60

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Testosterone (Androgens)

C19H28O2Molar weight: 288.42 g/molΔ4-Androsten-17β-ol-3-one

Lipid Profiles Following 2 Years of Estrogen & Estrogen Plus Androgen Therapy in Postmenopausal Women

Adapted from Watts NB, et al. Comparison of oral estrogens and estrogens plus androgens on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol. 1995;85:529-537.

Per

cen

t ch

ang

e fr

om

bas

elin

e

0

5

10

15

20

25

-5

-10

-15

-20

-25

-30

-35

Estrogen

Estrogen plus androgen

HDL LDL Total cholesterol Triglycerides

*P <0.001*P <0.001

* Between group comparisons

Lipid Parameters Did Not Change with Transdermal T Administration

Cholesterol

0

50

100

150

200

250

Total HDL LDL TriglyceridesLip

id L

evel

(m

g/d

L)

Baseline 300 g150 gPlacebo

Shifren, et al. JCEM

Oral vs Trandermal Testosterone

1. Braunstein GD, et al. Arch Intern Med 2005;165:1582-9. 2. Bagatell CJ & Bremner WJ. N Engl J Med 1996;334:707-14.3. Basaria S & Dobs AS. J Clin Endocrinol Metab 2006;91:4743-52.

Primary difference between oral and transdermal testosterone is that transdermal avoids first-pass metabolism

Oral testosterone negative effect on lipoprotein profile1, but this is outweighed by hepatotoxic adverse effects:

– Hepatocellular adenoma

– Cholestatic jaundice

– Hemorrhagic liver cysts

Adverse events observed in males (female to male transsexuals) especially those with previous hepatic dysfuction, not women.2

Transdermal testosterone has no related hepatotoxicity and therefore would be the safer option.3

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14

What if the WHI Had Used Transdermal Estradiol And Oral Progesterone Instead?1

After the primary results of the WHI were published in

20022 (HT), 20043 (ET), many “what‐if”‐type questions were posed. Here we ask:

– 1) What if different estrogens and progestogens had been used?

(estradiol and progesterone)

– 2) What if a different route of ET administration had been used? (transdermal vs. oral)

If so, perhaps some or all of the adverse outcomes associated with CEE alone, or CEE with MPA, would have been avoided.

1) Simon JA. What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? Menopause. 2014 Jul;21(7):769‐83. 2) Rossouw JE, et al. JAMA 2002;288:321‐333. (3) Anderson GL, et al. JAMA 2004;291:1701‐1712. 4) Canonico M, et al. Stroke. 2016;47:1734–41.

Ischemic Stroke (IS) Risk by Estrogen & Progestogen Administration

1. Canonico M, et al. Stroke. 2016;47:1734–41.

Large Nested Case-Controlled Study of women who experienced IS was conducted to determine the risk of estrogens and progestogen type and dosage on IS.1

Oral estrogens significantly increase IS risk in a dose dependent relationship while transdermal estrogens displayed no association. Cardiovascular risks were not affected by administration.

Concomitant progestogens important determinate in IS outcome:– Progesterone showed no adverse effects on the transdermal reduction in IS– Pregnane derivatives, and nortestosterone derivatives showing no significant increase in IS risk– Norpregnane derivatives increased IS risk.

Odds ratios of IS according to estrogen dose by route of administration. Dotted lines represent overall OR for current users of oral (A) and transdermal (B) estrogens compared with nonusers.

P for homogeneity between oral estrogen use and transdermal estrogen use is significant (p<0.01).P for homogeneity between pharmacological classes of progestogens is significant (p=0.03).*Adjusted for antidiabetic medication, antihypertensive medication, antidyslipidemia medication, and long-term chronic diseaseȽ85% of the subjects used nomegestrol acetate

Just Imagine!

Estradiol (estrogen) Conclusions

Unique differences exist in E2 pharmacodynamics between oral and transdermal therapy.

Differences exist in lipids, insulin resistance parameters, and inflammatory and coagulation markers.

Data to date show lower CV effects with transdermal; including thrombosis, stroke (ischemic) and MI.

In metabolic syndrome (MBS), and other high risk women transdermal therapy may be favored, based on surrogate marker data.

The choice of therapy otherwise, remains an individual decision.

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Breast cancerCardiovascular disease (including

thrombosis and stroke)

Potential benefits > Potential risks

Woman with low CHD risk(eg, no CHD risk factors;

no risk determinants of themetabolic syndrome;

low CRP

All others(eg, established CHD, diabetes,

metabolic syndrome, obesity, atherogenic dyslipidemia, high CRP,

thrombophilia, history of DVT, low sexual desire or sexual dysfunction )

Selection guided by patient’s preferences Consider transdermal formulations

Menopausal symptomsOsteoporosis

Selecting HT Based on Risks/Benefitsin Symptomatic Individual Postmenopausal Women:

Impact of Route of Administration

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