Breast Cancer Risk categories: Objectives 1. Breast cancer risk 2. - - PDF document

9/13/2019 1

Hormone Management 101: Orals vs Transdermals

Denise Black, MD, FRCSC

Disclosures

• Consulting: Bayer, BioSyent, Duchesnay, Merck,

Pfizer, Teva

• Speaker: AbbVie, Allergan, Amgen, Bayer,

Merck, Pfizer, Searchlight

Objectives

• To review the published data and

recommendations exploring the differences between oral and transdermal estrogens in the following categories:

• 1. Breast cancer risk
• 2. CVD risk or benefit
• 3. Venous thromboembolic risk

Breast Cancer Risk

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Breast Cancer Risk: Orals vs Transdermals

• Recent data from a large meta analysis, in

women using estrogen only preparations, shows NO DIFFERENCE in breast cancer risk dependent

• n route of administration
• RR 1.33 (CI 1.27‐1.38) for oral preparations, RR

1.35 (CI 1.25‐2.46) for transdermals

• Limitations: data does not discriminate for

dosing

Cardiovascular Disease Risk

CVD Risk/Benefit: Orals vs Transdermals

• Issue of primary prevention of CVD

with MHT is difficult to “prove”:

• Large epidemiological studies will

likely never be undertaken again

• The MOA partly due to enzymatic

alterations (MMP), endothelial changes (PG, NO, ILGF) and these are difficult to elucidate and quantify

• The anatomic model (great for

imaging male model of CVD) of limited usefulness in young women

Endothelial cells Smooth-muscle cells Estrogen

Rapid Effects Without alteration of gene expression Long-Term Effects Related to alteration

• f gene expression

Adapted from Mendelsohn et al, N Engl J Med. 1993;340:1801‐ 1811

CVD Risk/Benefits: Orals vs Transdermals

• Many studies have suggested CVD

benefit with MHT: Nurse’s Health Study, WHI in women age 50‐59, WHI CAC sub‐ study, DOPS, ELITE, Finnish Database Study, PEPI

• All of these studies have used oral

estrogens

• KEEPS recent release: oral CEE slowed

epicardial fat deposition, while transdermal estradiol increased paracardial fat deposition and increased progression of coronary artery calcium deposits1

• 1. El Khoudary et al, J Am Heart Assoc. 2019;8:e012763

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CVD Risks‐‐Stroke: Orals vs Transdermals

• A Cochrane sub‐group analysis, looking at

data from the WHI and DOPs, and restricting analysis to women who initiated MHT less than 10 years from menopause did not demonstrate an increased risk of stroke: RR 1.37 (CI 0.88‐2.34)1

• The Renoux case‐controlled study

purporting less stroke with Td administration did not adequately compare bioequivalent estrogen doses: 50 ug Td was compared with up to 2 mg oral estradiol2

• Recent RCTs in women age 50‐59 using

lower dose orals did not demonstrate any increase in stroke risk

• 1. Boardman et al, The Cochrane Library 2015, Issue 3 2. Renoux et al, BMJ 2010;340:c2519

Venous Thromboembolic Risk

Venous Thromboembolic Risk: Orals vs Transdermals

• First was the ESTHER Study—a case

control study

• Numbers were small (total of 62

cases were MHT users)

• Average age was 62
• Not controlled for endometrial

protection agent

• Stratification of dosing incorrect

Hazard Ratios of Idiopathic VTE by Route

• f HT—E3N Trial

Treatment Cases n=549 Person‐Years 811,643 Hazard Ratios (95% Confidence Intervals) Age‐Adjusted Multivariable Adjusted* Never use 181 291,399 1 [reference] 1 [reference] Past use 66 100,943 1.0 (0.7‐1.3) 1.1 (0.8‐1.5) Current use of oral estrogens 81 93,211 1.5 (0.9‐2.3) 1.7 (1.1‐2.8) Current use of transdermal estrogens 174 268,481 1.1 (0.7‐1.6) 1.1 (0.8‐1.8) No progestogen use 26 46,163 ‐‐ ‐‐ Current use of micronized progesterone 47 87,959 0.9 (0.6‐1.4) 0.9 (0.6‐1.5) Current use of pregnane derivatives 91 125,804 1.3 (0.8‐1.9) 1.3 (0.9‐2.0) Current use of norpregnane derivatives 69 78,855 1.7 (1.1‐2.6) 1.8 (1.2‐2.7) Current use of nortestosterone derivatives 22 22,911 1.4 (0.8‐2.5) 1.4 (0.7‐2.4) Current use of other treatment 30 47,693 1.0 (0.7‐1.5) 1.1 (0.7‐1.8) Unknown 17 9,916 2.0 (0.5‐3.9) 2.0 (0.5‐3.9) *Adjusted for age, body‐mass index, parity, education level, and time‐period. P for homogeneity between current use of oral estrogens vs. current use of transdermal estrogens is significant (P = 0.01). P for homogeneity between progesterone subgroups is significant (P < 0.01). Canonico M, et al. Arterioscler Thromb Vasc Biol 2010;30(2):340‐5.

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Recent RCTs

• n VTE
• KEEPS (n=727 over 48 months): This is the
• nly RCT that pits an oral and a

transdermal head‐to‐head, using relatively bioequivalent doses of estrogen and the same endometrial protective agent (micronized progesterone). Results: One VTE in transdermal group, one in placebo group, none in oral

• ELITE (n=271 over 5+ years): no cases of

VTE seen. Low dose oral estradiol (1 mg) and micronized progesterone were used.

• KEEPS: Harman SM, Black DM et al, Ann Intern Med. 2014;161:249‐260
• ELITE: Hodis HN, Mack WJ et al, N Engl J Med 2016;374:1221‐1231

Recent RCTs

• n VTE
• SMART Trials (n=1585 over 24 months):

no increase in VTE risk seen with use of

• ral CE/BZA (0.45/20) compared to

placebo1

• REPLENISH (n=415 over 52 weeks): no

VTEs seen in 415 subjects in oral estradiol 1mg/MP 100 mg group, none in placebo2

VTE Risk: QResearch and CRPD Study

• Two nested case‐control studies involving over 450,000

women age 40‐79

• Stratified for age, co‐morbidities, dose and route of

administration of estrogen, as well as endometrial protective agent

• Results: VTE risk with oral estrogens was dependent

upon dose and endometrial protective agent: low dose

• ral estradiol, when combined with dydrogesterone, did

not result in increased VTE risk, irrespective of age group

• r BMI. Overall odds ratio was 1.12 (CI 0.90‐1.40)
• Tibolone showed no increased VTE risk
• Transdermal estrogens did not increase risk, independent
• f dose or endometrial protective agent

What do the guidelines say?

• Compared to standard dose oral HT, lower dose
• ral as well as lower dose transdermal therapy

has less effect on risk of stroke (RCT data lacking)

• Compared to standard dose oral HT,

transdermal HT as well as lower doses of oral

• r transdermal HT have less effect on VTE risk

(RCT data lacking)

• Micronized progesterone may be less

thrombogenic than progestins

• Older women, obese women, or those with

elevated TG or liver issues may consider lower doses of transdermal preparations

2017 Position Statement of the North American Menopause Society, Menopause Vol 24, No. 7, 2017

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Why is this important?

• This allows healthy, younger, low risk women the
• ption of the product that meets her specific

needs (individualization of therapy)

• Combined oral preparations with choice of

endometrial protective agent allows customization for convenience, side effect profile, potential other benefits such as neutral effect on breast density, breast cancer risk, and specific QOL parameters, including amenorrhea

• Women with additional risk (VTE, CVD) should
• pt for a transdermal estrogen preparation,

with micronized progesterone for endometrial protection

Thank you