Postmenopausal HRT: Where Do We Stand in 2011?
By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff, Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
A quick search on pubmed finds 122 manuscripts published in the first half of 2011 that reference the Women's Health Initiative (WHI) study in the title, abstract, or as a keyword. Clearly, much continues to be learned about hormonal therapy, and this remains an important health decision for women. Therefore, I thought I would use this opportunity to provide a short review of key clinical points.
The principle risk of hormone replacement therapy (HRT) is thrombosis not breast cancer.1 Thrombosis is related to estrogen-induced changes in hepatic globulins. Throughout evolution, the selection pressure for mammals has favored a shift toward a pro-coagulant environment during pregnancy. The benefit of avoiding hemorrhage during vaginal delivery far outweighed the risk of venous thrombosis for our ancestors. Since the liver produces and regulates the proteins involved in the coagulation cascade, it became the arbitrator of the net estrogen balance in the body. During pregnancy, the liver recognizes the sustained rise in placental estrogens and this causes a shift to a slightly prothrombotic environment. Evolution did not prepare the liver to differentiate between high circulating levels of exogenous or endogenous estrogens. Work in the rodent suggests that the effect is mediated through the estrogen receptor alpha.2 Several important principles emerge from this knowledge:
- Once significant atherosclerotic changes are present, the risks of hormone therapy exceed potential benefits. Therefore, therapy must be started shortly after the onset of menopause.
- The effect of estrogen on coagulation is dose-dependent. This means that using the lowest dose of estrogen to achieve the therapeutic goal makes sense.
- Oral dosing of estrogens provides the biggest challenge to the liver as very high concentrations are presented to hepatic metabolism during first pass absorption.
- Progestogens affect estrogen effects in a complicated and tissue dependent fashion.
- Cardiovascular disease develops over time and is influenced by several important factors. Age, hypercholesterolemia, and obesity are important factors that influence the risk of thrombosis.
Let's illustrate these points with some of the key findings from the WHI and beyond. The WHI documented that combined estrogen/progesterone (E/P) therapy (Prempro®) increased the risk of cardiovascular complications like coronary heart disease (CHD), venous thrombosis (VTE), and stroke.3 Since these results conflicted with those from observational studies, subsequent analyses have revealed several key clinical points.
Timing of initiation of therapy matters. Most women evaluated in observational studies of CHD risk were younger than age 55 at the time HRT was initiated and within 2 to 3 years of menopause, while women in the WHI were almost a decade older. Mitch Harmon of the Kronos Longevity Research Institute has advanced this timing hypothesis, and provides a detailed review of the data in a recent publication in the American Journal of Medicine.4 Some of the best data refuting the main WHI findings come from the WHI itself. Follow-up reanalysis of the E/P treatment group documented a nonsignificant trend toward protection (hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.5-1.5) in women less than 10 years postmenopausal in contrast with the elevated risk (HR 1.71; 95% CI 1.1-2.5) observed in women starting therapy more than 20 years after menopause.5 Harmon's group has enrolled women in the Kronos Early Estrogen Prevention Study (KEEPS). Healthy women between the ages of 42 and 58 years of age at least 6 months and no more than 36 months postmenopausal were randomized to daily placebo, oral conjugated equine estrogen (CEE), or transdermal 17b-estradiol (E2) with placebo or pulsed progesterone for 12 days/month. The primary endpoint is to evaluate effects of hormone therapy on progression of atherosclerosis as defined by carotid intimamedia thickness and coronary arterial calcification. Enrollment was completed in 2008, and initial results from this study are expected by the end of this year.
Route of administration of estrogen matters. The WHI looked only at oral dosing of CEE. As mentioned above, oral estrogens exert a potent first pass effect on the liver that influences homeostasis of the coagulation system. Bypassing the liver with transdermal or vaginal administration of estrogen can avoid this first pass metabolism. Estradiol is rapidly isomerized to estrone and estriol, and circulates at physiologic levels. However, if a potent synthetic estrogen like ethinyl estradiol (EE) is administered transdermally the metabolites are highly active, and the liver continues to interpret the overall estrogen milieu as elevated (i.e., pregnant), shifting the balance toward coagulation. An important multicenter case-control study in France (ESTHER study) documented that oral estrogen increases the risk of VTE, but that transdermal estrogen does not.6
Dose and type of estrogen matters. Since WHI studied only one dose and type of oral estrogen (0.625 CEE) with or without oral medroxyprogesterone acetate, the study provides no information about dose effects. However, other epidemiologic studies and clinical investigations evaluating surrogate markers have demonstrated that increasing the dose of estrogen increases the risk of thrombosis in users of HRT and in users of combined hormonal contraception.7 This makes biologic sense as we expect to see a dose response. In the past, we adjusted dose based on symptoms. However, to reduce the potential for harm, it makes more sense to obtain blood levels. This leads us to type of estrogen. Unlike conjugated estrogens and EE, one can order a serum assay for E2 to ensure that a therapeutic range is maintained (40-100 pg/mL). The absence of hepatic activiation of prothrombotic globulins and ease of monitoring should make non-oral E2 the estrogen of choice.
Progestogens affect estrogen effects in a complicated and tissue dependent fashion. The results of the combined E/P and estrogen only WHI studies differ in several clinically important outcomes. First, there was no overall impact on coronary heart disease with estrogen only treatment. Of even greater interest was the trend toward a reduction in risk of invasive breast cancer in the estrogen-only arm. The decreased risk of invasive breast cancer persists in the most recent analysis (2011) of results from this study.8 The evidence suggesting that MPA may attenuate the favorable effects of oral estrogens on lipids emerged in the 1995 PEPI study.9 The ESTHER study found no significant association of VTE with micronized progesterone but an increased risk with norethindrone. A recently published experiment by Zerr-Fouineau and colleagues showed that MPA attenuates estradiol-induced inhibition of platelet aggregation by endothelial cells.10 Taken together, these data suggest that the safest choice for systemic progestogen therapy is oral micronized progesterone.
General health and duration of therapy matters. Observational studies suggest that longer duration of HRT use are associated with reduced risk of CHD and related mortality. The contradictory findings of WHI led many providers and professional organizations to recommend against the use of HRT except for short-term management of menopausal symptoms. A more selective approach makes better sense. The current literature strongly suggests that healthy menopausal women should initiate hormone therapy shortly after the onset of menopause (within 3-5 years). The Kronos study will provide important prospective information to learn whether this strategy reduces progression of atherosclerotic changes. Women with existing cardiovascular disease, such as hypertension or abnormal lipid profiles, represent a high-risk group for complications of hormonal therapy. A more detailed risk/benefit discussion is needed in this group. The central factor in all of these high-risk patients is pre-existing cardiovascular disease. Creating a prothrombotic environment with estrogen will increase the risk of an adverse event. Obesity represents a growing problem in all of our practices. The independent and additive effect with estrogen therapy of obesity on thrombosis risk is well documented. It is encouraging to note that transdermal estrogen did not elevate the risk of VTE in a case-control study of HRT in obese women by Canonico and colleagues.11 While the overall risk for VTE was increased in overweight (OR 2.5; 95% CI 1.7-3.7) and obese (OR 3.9; 95% CI 2.2-6.9) women, a significant increase was noted with oral (OR 4.5; 95% CI 2.6-7.7) but not transdermal (OR 1.1; 95% CI 0.7-1.7) estrogen therapy. Compared with non-users with normal weight, the combination of oral estrogen use increased the risk of VTE 10-fold for overweight and 20-fold for obese women. In contrast, transdermal users with increased BMI had similar risk as non-users with increased BMI. More information regarding the safety of transdermal estrogen in high-risk individuals is needed.
In my practice, I continue to recommend hormone replacement therapy to healthy menopausal women. I discuss symptoms, bone effects, cognitive effects, sexual function, and cardiovascular effects. Breast cancer is put into perspective (and another reason to avoid MPA?), and I recommend annual mammograms. I look at blood pressure, lipid profiles, glucose tolerance, family history, and BMI as predictors of cardiovascular risk. Women with well-controlled diabetes, hypertension, or hyperlipidemia may benefit from hormone therapy, but need a more detailed discussion of potential risks and benefits. I recommend transdermal estradiol, and try to target a blood level around 80 pg/mL. Oral micronized progesterone is recommended for women with a uterus, although I also discuss the off-label use of the LNG IUS for endometrial protection. More information is available every year. We can count on hundreds of new publications; some may even prove useful!
- Harman SM. Estrogen replacement in menopausal women: Recent and current prospective studies, the WHI and the KEEPS. Gend Med 2006;3:254-269.
- Cleuren AC, et al. 17alpha-Ethinylestradiol rapidly alters transcript levels of murine coagulation genes via estrogen receptor alpha. J Thromb Haemost 2010;8:1838-1846.
- Rossouw JE, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
- Harman SM, et al. Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med 2011;124:199-205.
- Manson JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007;356:2591-2602.
- Sandset PM, et al. Mechanisms of thrombosis related to hormone therapy. Thromb Res 2009;123(Suppl 2):S70-S73.
- Canonico M, et al. Hormone therapy and venous thromboembolism among postmenopausal women: Impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115:840-845.
- LaCroix AZ, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: A randomized controlled trial. JAMA2011;305:1305-1314.
- The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273:199-208.
- Zerr-Fouineau M, et al. Certain progestins prevent the enhancing effect of 17beta-estradiol on NO-mediated inhibition of platelet aggregation by endothelial cells. Arterioscler Thromb Vasc Biol 2009;29:586-593.
- Canonico M, et al. Obesity and risk of venous thromboembolism among postmenopausal women: Differential impact of hormone therapy by route of estrogen administration. The ESTHER Study. J Thromb Haemost 2006;4:1259-1265.