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Editorial February 2008

Postmenopausal HT: Factoring our Knowledge of Clotting Risks with the Type of Estrogen and Progestogen We Are Using Today

Veronica Ravnikar, MD

As I strive to balance all of the reports still emerging from the Women’s Health Initiative (WHIa) regarding both clinical trials and observational studies and continuously reconsider the data, I am becoming more comfortable with treating women in their early menopausal years (ie, the first decade after menopause, ages 50 to 59). I have really never abandoned the view that hormone therapy (HT) is the best treatment option for selected younger menopausal patients who are symptomatic. My basis for treatment decisions is the severity of vasomotor and vaginal symptoms and the need to prevent osteoporosis—in other words, the FDA-approved guidelines.1

There are unmet needs today for patients requiring HT/ET therapy and physicians are seeking logical risk-benefit guidelines. In general, physicians are now deliberately giving such therapy to patients who ask for it; it is definitely an "if you don't ask, you don't receive" policy. There are no proactive discussions of the pros and cons of HT as occurred in the past. There are lists of recommendations to review, but many issues concerning risk-benefit analyses remain the subject of debate.2

Of particular interest to me is the discussion of venous thrombosis (VT)—eg, venous thromboembolism (VTE) and pulmonary embolism (PE). In a symptomatic patient who is a good candidate for HT/ET, the VT risk is one aspect of the risk-benefit ratio that must be considered as a potential negative outcome.

In my practice, candidates for HT/ET ask me whether I can at the very least screen them to assess their risk for clots before starting therapy. I can assure them that the absolute risk of VT is low, but the question always remains: who is at high risk? So why do we not screen for thrombophilias and clotting disorders in the symptomatic perimenopausal patient? Such screening would not eliminate all VTEs and strokes potentially associated with HT/ET, but these determinations could provide a more concrete risk analysis. In addition, what (if any) effect does the type and dosing of progestin have on VT risk, assuming that most of this risk is borne by the estrogen component of therapy?

The WHI found that:
• There is a 2-fold increase in VTE risk associated with HT/ET, particularly in the first or second year of treatment
• The VTE risk decreases with duration of HT/ET use
• The VTE risk is apparent even in younger women, but the absolute risk is low
• Risks associated with age, overweight/obesity, and the factor V Leiden mutation (6.7-fold risk increase) are augmented by HT, but there is no effect on other thrombophilia variants
• There is a 30% to 40% increase in stroke risk associated with HT/ET, although the absolute risk remains low
• Regarding the rates of these events in HT versus ET users, the rates of all events are slightly higher in the HT users, suggesting a progestin effect. For example, the absolute increase in stroke risk is 0.7 in ET users versus 1.2 in HT users (per 1000 women).3,4

With regard to thrombophilia screening, the ACOG Practice Bulletin on oral contraceptive use states: "Screening would identify approximately 5% of US oral contraceptive candidates as having a factor V Leiden mutation; however, most of these women will never experience venous thromboembolism… Given the rarity of fatal venous thromboembolism, one group of investigators concluded that screening more than 1 million combination oral contraceptive candidates for thrombophilia markers would…prevent two oral-contraceptive-associated deaths."5 As the factor V Leiden mutation is the only thrombophilia that confers risk in this setting, selectively testing for one genetic polymorphism may be cost effective. Also, the effects of aging, obesity, and decreased mobility are more than likely magnified in postmenopausal women, increasing the risk of clotting with HT/ET when the factor V Leiden mutation is present.

The Estrogen and Thromboembolism Risk (ESTHERb) Study group has found that:
• Oral, but not transdermal, estrogen is associated with an increase in VTE risk
• Transcutaneous estrogen does not confer additional risk in women with the factor V Leiden mutation, whereas oral therapy does (25-fold increase in risk)
• Progestins such as the norpregnane derivatives (eg, promegestone) are thrombogenic (4-fold increase in risk), whereas pregnane (eg, medroxyprogesterone) derivatives appear to be safe. Natural progesterone also appears to be safe. However, natural progesterone and progestins have not been studied in patients with the factor V Leiden mutation to test for differences in thrombogenicity in the same way that transcutaneous and oral estrogens have been studied.6-8

My conclusion from these recent reviews is to have a low threshold for ordering a test for the factor V Leiden mutation in women contemplating HT/ET. The results do not predict all aspects of stroke risk, but would give the patient some guidance as to the magnitude of her potential thrombotic risk. It would also clarify the most desirable form of HT/ET, favoring transcutaneous therapy. Certainly, immobility, obesity, and other comorbidities are risk factors that must be addressed with the patient as well.

I am in favor of using transcutaneous or oral estrogen at the lowest possible effective dose, with micronized progesterone given cyclically every 3 months. The Kronos Institute study—an ongoing, multicenter, 4-year project—is testing the benefit of administering oral or transcutaneous estrogen to recently menopausal women (aged 40 to 55 years) whose last menstrual period is 6 months to 3 years prior to study entry. Micronized progesterone is administered vaginally 10 days of each month. These results should help to guide us as to endometrial safety while also testing cardiovascular endpoints. In the meantime, we already know a good deal about thrombotic risks with HT, so why do we not include assessment for the factor V Leiden mutation routinely in all potential postmenopausal therapy candidates? I do not think it is necessary to wait for the Kronos results to validate safe, short-term treatment in symptomatic, recently menopausal women who desire treatment today.

aWomen's Health Initiative - Longitudinal, double blind investigational trial
bEstrogen and Thromboembolism Risk - Multicenter, retrospective case-control study

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Veronica Ravnikar, MD, Board Member

References

1. Grady D. Clinical practice. Management of menopausal symptoms. N Engl J Med. 2006;355(22):2338-2347.
2. Board of the International Menopause Society, Pines A, Sturdee DW, BirkhŠuser MH, et al. IMS Updated Recommend-ations on postmenopausal hormone therapy. Climacteric. 2007;10(3):181-194.
3. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the WomenÕs Health Initiative Randomized Controlled Trial. JAMA. 2004;291(14):1701-1712.
4. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292 (13): 1573-1580.
5. ACOG Committee on Practice Bulletins—Gynecology. ACOG practice bulletin. No. 73: use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol. 2006; 107(6):1453-1472.
6. Scarabin PY, Oger E, Plu-Bureau G; EStrogen and THromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003; 362(9382):428-432.
7. Straczek C, Oger E, Yon de Jonage-Canonico MB, et al. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation. 2005;112(22):3495-3500.
8. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115(7): 840-845.