james h. liu, m.d. arthur h. bill professor dept of ...challenges: recurrence of endometriosis with...

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Estrogen Therapy After Postmenopausal Hysterectomy: Issues, Challenges, Risks/Benefits

Case Medical CenterCase School of Medicine Case Research Institute University Hospitals UH Medical Group

University Hospitals at Case Medical Center is the primary affiliate of Case Western Reserve University School of Medicine.

James H. Liu, M.D.Arthur H. Bill ProfessorChair of Reproductive BiologyDept of Obstetrics and Gynecology

Disclosure

• Advisory Boards– Pfizer– Actavis– Charter Venture– Sermonix– Nuelle

• Clinical Trials– AbbVie– NIH– Actavis– Palatin– Pharmacos

Epidemiology

“Truth is ascertained only when sufficient numbers of appropriate studies are conducted and no one study or one study design has a monopoly on the truth.”

Trudy Bush Int. J. Fert. 2001:46:56

Definitions

• Hormone Therapy (HT)– Use of an estrogen and progestin taken cyclically or in a combined

E + P mode taken on a daily basis.

• Estrogen Therapy (ET)– Use of an estrogen-only preparation daily

• Estrogen-Progestin Therapy (EPT)– Use of estrogen and progestin therapy (cyclic and continuous

combined)

– For the Women’s Health Initiative, E+ P was used on a daily basis

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2002

WHI (E)Arm ended

2004

Treat Menopausal Symptoms

Lowest dose, shortest period of time to meet

treatment goals

Today

FDA Treatment Recommendations

Is What We Know About Hormone Therapy a Delusion? HT Then and Now

WHI (E+P) Arm halted

Broadening therapy options

Key Findings of WHI-E Trial From 2004

So What Does this Elephant Look Like Now?

• Small decrease in breast cancer risk

• No change in cardiovascular risk

• Known DVT risk

• Increase risk of stroke

• Increase in urinary incontinence

• Reduce fractures10/6/09 University Hospitals Case Medical Center / Case Western Reserve University School of Medicine 6

Issues: Causes of Death Among U.S. Women

Heart Disease(45%)

Other (25%)

COPD (4%)

Pneumonia (4%)

Ovarian Cancer (<2%)Breast Cancer (4%)

Lung Cancer (5%)Other Cancer (11%)

Issues: Extended WHI Trial Results and Now the Post Treatment Follow-up

• Not publicized

• Lack of interest by clinicians as “old news”

• Too new to percolate into practice guidelines and recommendations

11/14/06 University Hospitals Case Medical Center / Case Western Reserve University School of Medicine 8

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Date of download: 9/22/2015Copyright © 2015 American Medical

Association. All rights reserved.

From: Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy: A Randomized Controlled TrialJAMA. 2011;305(13):1305-1314. doi:10.1001/jama.2011.382

Vertical dotted lines represent quintiles of duration of intended intervention and follow-up in the study population (elapsed time from randomization until the end of the intervention on February 29, 2004). CEE indicates conjugated equine estrogens.aIncludes events from randomization to August 14, 2009.bIncludes events from March 1, 2004, to August 14, 2009.

Figure Legend:



From: Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy: A Randomized Controlled TrialJAMA. 2011;305(13):1305-1314. doi:10.1001/jama.2011.382

Vertical dotted lines represent quintiles of duration of intended intervention and follow-up in the study population (elapsed time from randomization until the end of the intervention on February 29, 2004). CEE indicates conjugated equine estrogens.aIncludes events from randomization to August 14, 2009.bIncludes events from March 1, 2004, to August 14, 2009.

Figure Legend:



From: Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy: A Randomized Controlled Trial

JAMA. 2011;305(13):1305-1314. doi:10.1001/jama.2011.382

Annualized incidence rates were estimated for the overall follow-up period by dividing the number of events by the corresponding person-time for participants in each age stratum. The black squares indicate the HRs for the overall follow-up period. For comparison, the HRs for the intervention phase are shown as blue bars. CEE indicates conjugated equine estrogen; CHD, coronary heart disease; CI, confidence interval; MI, myocardial infarction.

Figure Legend:

The “Timing Hypothesis” for Cardiovascular Risk and Hormone Therapy: A Window of Opportunity (50-59yrs) Estrogen-Alone

• CEE versus placebo had significant reductions in CHD (HR 0.59; 0.38-0.9)

• CEE versus placebo had significant reductions in MI (HR 0.54; 0.34-0.86)

• CEE versus placebo had significant reductions in overall mortality (HR 0.73; 0.53-1.00)


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Challenges: Fear of Breast Cancer

• The fear of breast cancer is unlike any other health condition.

• Breast cancer is common, yet death from breast cancer is 4% among all other causes.

• Public is ill informed regarding breast cancer risks.


Issues: WHI CEE alone-Breast Cancer Risk


Lancet Oncol 2012; 13:476-86

Issues: WHI CEE alone-Breast Cancer Deaths


Lancet Oncol 2012; 13:476-86

Challenges: Why Would Estrogen Inhibit Breast Cancer in This Age Group?

• Decrease in breast ca in CEE group runs counter to perceived notion of role of E in breast carcinogenesis.

• Did you know that high dose estrogen (DES) was used to treat metastatic breast ca in the 1940-60’s?

• Concept of estrogen-induced apoptosis.


aCancer Prev Res 2011: 4(5): 633-7

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Challenges: Counseling Breast Cancer Risk and Hormone Therapy: Overall Perspective

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Climacteric 2012;15:241-249

RelativeRisk

Increase Breast Density High Serum E2 Obesity E+P E alone

Challenges: Recurrence of Endometriosis with Estrogen Therapy

• Over 100,000 hysterectomies are performed for endometriosis.

• Use of hormone therapy is associated with recurrence of pelvic pain in 3.5% of cases.

• Malignant transformation of residual endometriosis foci into endometriod cancer is rare.


Facts Views Vis ObGyn 2014; 6(4):219-227

Issues: Estrogen Dosing Options

• Local Vaginal Estrogen– Vagifem

– Premarin cream

– Estrace cream

– Estring

• High Systemic Dose E– 50 μg per day E2 Transdermal

– 0.625 mg CEE, E1 SO4, esterified E

• Low Systemic Dose E– 14 μg, 25 µg, 37.5 µg per day E2 Transdermal

– 1.0 mg oral E2

– 0.3 mg, 0.45 mg CEE, E1 SO4, esterified E

ET and VTE* in French Menopausal Women

Canonico M, et al. Circulation. 2007;115:840–845.

ESTHER Study: 1999–2005

Case n = 259 Control n = 603

OR 95% CI

None 1

Oral ET 4.2 1.5–11.6

Transdermal ET 0.9 0.4–2.1

VTE = venous thrombophilias.

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Mean concentrations of E1 and E2 in plasma of postmenopausal women following administration of E2 by the transdermal and oral route

Adapted from Etaigle JW, Schenkel L. Estrogens and Progestogens. Churchill Livingston, London; 1998.

Take Home Away Points

• For CHD (1o endpoint), the HR was NULL in CEE vs Placebo during and post-interval– HR for the 50-59yo group favored CEE

• For Breast CA (1o endpoint), the CEE risk was LOWER during the treatment and post-interval

• Stroke risk is higher with CEE but the risks dissipated during the post-interval for CEE

• Rates of total mortality and the global index of chronic diseases were the same in both groups overall.


Issues: NAMS Position Statement on Hormone Therapy in Older Women


The decision to continue or discontinue HT shouldbe made jointly by the woman and her healthcare provider that the woman has been advised of the increase in risks associated with continuing HT beyond age 60 and has clinical supervision, extending HT use with the lowest effective dose is acceptable under some circumstances, such as for the woman who has persistent bothersome menopausal symptoms and for whom her clinician has determined that the benefits of menopause symptomrelief outweigh the risks. Use of HT should be individualized and not discontinued solely based on a woman age.

The decision to continue or discontinue HT shouldbe made jointly by the woman and her healthcare provider

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