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Jewish Home > Cholesterol and Metabolism Center > Research > Paradigms Lost, 2005-2006
Paradigm’s Lost, 2005-2006
Charles J. Glueck MD, Medical Director, Alliance Cholesterol Center,
Alliance Hospitals,
Cholesterol Center, ABC Building, 3200 Burnet Avenue, Cincinnati OH, 45229; phone 513-585-7800, fax 513-585-7950, email glueckch@healthall.com (12/13/05)
BENEFITS AND ADVERSE EVENTS OF PERI-POST MENOPAUSAL ESTROGEN (HORMONE REPLACEMENT THERAPY, AND ESTROGEN’S ADVERSE INTERACTION WITH INHERITED COAGULATION (CLOTTING) DISORDERS
HISTORICAL BACKGROUND, BENEFITS OF ESTROGEN (HORMONE REPLACEMENT THERAPY), AND ADVERSE EVENTS
1. Benefits:
Historically, it was a long-held belief in the medical community that peri-postmenopausal estrogen-hormone replacement therapy (HRT) not only relieved the vasomotor symptoms of menopause (hot flashes, night sweats, etc), protected against osteoporosis, protected against thinning out of the vaginal epithelium (vulvovaginal atrophy symptoms, and also helped protect women against heart disease, and stroke. It was also thought that HRT might help preserve cognitive function, and help relieve depression. However, FDA currently approved indications for HRT 1-4 include the following (Figure 1) :
- Relief of vasomotor symptoms. This benefit is conferred by estrogen, and there are no uniformly effective substitutes.
- Vulvovaginal atrophy symptoms. This benefit is conferred by estrogen, and there are no uniformly effective substitutes.
- Osteoporosis related fracture prevention. This benefit is conferred by estrogen, and there are effective substitutes including Fosamax, Actonel, and Evista.
2. Adverse Events:
In the past decade, several major controlled clinical trials have revealed that the demonstrated benefits of HRT are limited to the 3 above, and that HRT was significantly associated with many adverse events, 5-12 as follows (Figure 1):
As summarized in Figure 1, when estrogens are given to peri-post menopausal women, there are many adverse outcomes, to a large degree caused by the estrogen- induced increased tendency to form blood clots, particularly in women with common inherited or acquired clotting abnormalities (Figures 2,3). Cigarette smoking strongly amplifies the estrogen-induced clotting tendencies, and increases likelihood of estrogen-induced arterial clots, particularly in the heart or brain. When estrogens are given to women in the general population, they increase the likelihood of the following (Figure 1):
- Thrombotic stroke or transient ischemic attack (TIA), caused by an arterial blood clot.
- Retinal vein thrombosis or retinal artery thrombosis, caused by venous or arterial blood clots, sharply reducing vision, occasionally leading to blindness
- Pulmonary emboli, caused by venous blood clots usually arising from blood clots in the legs or abdomen and traveling to the lungs. These are very dangerous, up to 40% of patients with pulmonary emboli die as a result of the acute event.
- Breast Cancer. Estrogens increase the risk of developing breast cancer about 2.7% per year, cumulative, so that risk is increased ~15% after 5 years. L onger duration of use of either unopposed estrogen or estrogen-progestins increases the risk of invasive breast cancer regardless of formulation. However, the rate of increase in risk is greater for combination estrogen-progestin therapy. Continuous combined estrogen-progestins and sequential estrogen-progestins seem to have comparable breast cancer risk. Unresolved issues remain about the dose of estrogen and progestins in relationship to breast cancer risk, and about identification of women for whom short term estrogen-progestin use for relief of vasomotor symptoms may be safe and effective.
- Heart attack. Estrogens increase the risk of heart attack, not decrease it, as was originally felt.
- Elevation of triglycerides in the blood. Estrogen alone can do this, or the triglyceride lowering effect of the estrogen may be superimposed on an inherited tendency to high triglycerides
- Endometrial cancer. Particularly if given without concurrent progesterone, estrogens increase the risk of endometrial cancer.
- Superficial and deep vein thrombosis. A blood clot forms in the superficial or deep leg veins, promoted by the estrogen-induced increased tendency to clot. Often, the venous blood clots in the deep veins travel to the lungs, causing pulmonary emboli.
- Continuous HRT (Premarin-medroxyprogesterone) and continuous unopposed estrogen (Premarin) substantially increases the risk of dementia of any cause and promotes cognitive decline.
3. Patches, pills, and plant (phytoestrogens)
Overall, adverse events are similar for patches and for pills. Not enough is known about the plant estrogens (phytoestrogens) in regards to safety, but in general, if estrogens have produced an adverse event, phytoestrogens are also probably not safe.
Heritable and Acquired Clotting Factors, Adverse Events, and adverse interactions with HRT:
In general, when the increased risk of clotting conferred by estrogens (or pregnancy) is superimposed on heritable and acquired clotting factors, then the risk of blood clotting is strikingly increased, often by a factor of 10-20 times. Hence, it is very important to avoid giving estrogens-HRT to women with known clotting factors, and it is probably important to test for major inherited clotting factors before giving HRT.
Separate from estrogens, inherited or acquired clotting disorders (Figures 2, 3) commonly cause blood clots, particularly in women who are also taking estrogens. The three most common thrombophilic (loves to clot) gene mutations are the Factor V Leiden (occurring in ~6% of the population), the MTHFR (in ~11% of the population), and the Prothrombin (~5% of the population), Figure 2. These gene mutations are diagnosed by a PCR method using either white cells or a mouth swab to obtain DNA. Of these 3 mutations, the Factor V Leiden is probably the most important, accounting for about 50% of all clotting disorders. There are also many important clotting disorders in the liquid blood (serologic clotting disorders), some of which are hypofibrinolytic (reduces the body’s ability to dissolve blood clots), Figure 2. Of these serologic clotting disorders, the most common is Lp(a), but this has only a weak hypofibrinolytic effect. The most important serologic clotting factors are Factors VIII and XI (both inherited), homocysteine (inherited and acquired), and anticardiolipin antibody and lupus anticoagulant (usually acquired) (Figure 3).
Women with inherited or acquired clotting disorders may develop the following problems:
- Thrombotic stroke or transient ischemic attack (TIA), caused by an arterial blood clot.
- Retinal vein thrombosis or retinal artery thrombosis, caused by venous or arterial blood clots, sharply reducing vision, occasionally leading to blindness
- Pulmonary emboli, caused by venous blood clots usually arising from blood clots in the legs or abdomen and traveling to the lungs. These are very dangerous, up to 40% of patients with pulmonary emboli die as a result of the acute event.
- Superficial and deep vein thrombosis. A blood clot forms in the superficial or deep leg veins, promoted by the estrogen-induced increased tendency to clot. Often, the venous blood clots in the deep veins travel to the lungs, causing pulmonary emboli.
Inherited and acquired clotting disorders (Figures 2,3) commonly cause the following obstetrical problems:
- Sporadic miscarriage. The normal high estrogens of pregnancy increase the risk of clotting, and this increased risk is superimposed on inherited or acquired clotting disorders to cause clots in the spiral arteries of the uterus, causing placental insufficiency and fetal loss. Treatment in the subsequent pregnancy with the anticoagulant, Lovenox, reduces pregnancy loss to ~20%, as compared to ~80% loss without Lovenox.
- Recurrent miscarriage ( ³ 3 pregnancy losses <20 weeks gestation). The normal high estrogens of pregnancy increase the risk of clotting, and this increased risk is superimposed on inherited or acquired clotting disorders to cause clots in the spiral arteries of the uterus, causing placental insufficiency and fetal loss. Treatment in the subsequent pregnancy with the anticoagulant, Lovenox, reduces pregnancy loss to ~20%, as compared to ~80% loss without Lovenox.
THE WHI STUDY
Since the release of the data from the Women’s Health Initiative (WHI) study in 2002, much has been written on the safety and efficacy of estrogens and progestins, collectively known as hormone replacement therapy (HRT).
Unfortunately, before the WHI, the data describing the benefits and adverse effects of HRT was based on so-called “observational, epidemiological studies” which were the only ones available at the time. With an observational study, a researcher basically would look at either a previously collected set of data or a prospectively gathered data set and attempt to identify a variable that explains a difference between groups.
The WHI was radically different from these previous epidemiological studies, in that it was a “prospective controlled clinical trial”, where two or more groups of people are selected to receive or not receive an intervention – in WHI this was hormone therapy – and then are observed over time to try and show a difference. Though harder to do and usually more costly in time and resources, prospective controlled clinical trials like WHI are widely regarded as more reliable because any relationship between a variable and an outcome can be shown under more controlled conditions and hence with less chance for error. Because of this fundamental difference the data from WHI and subsequent studies has caused much change in the perception of HRT’s utility and the following attempts to sum up the important points that have been learned:
WHI AND CORONARY HEART DISEASE (CHD) (myocardial infarction, heart attack)
- 16,608 postmenopausal women, ages 50-79, conjugated ethinyl estradiol 0.625 mg plus MPA 2.5 mg (Premarin), or placebo were given.
- The Primary efficacy outcome was CHD events
- After a mean follow-up of 5.2 years the trial was terminated because risks exceeded benefits. The conclusions were:
- Estrogen-progestin treatment does not confer cardiac protection and may increase the risk of CHD, especially in the 1 st year after starting HRT. The treatment should not be prescribed for prevention of CHD. To reduce the development of CHD in women, treat high LDL cholesterol with statins, high triglyceride with fibric acids, and treat high blood pressure and diabetes aggressively.
- Primary Prevention – Analysis of the WHI data based on age subgroups showed an increase in CHD risk as time from menopause lengthened, most strikingly in women 20 or more years out from onset.
- Secondary Prevention ---Two earlier studies, the HERS and ERA trials showed no difference in cardiovascular mortality or amount of coronary atherosclerosis between patients taking HRT and placebo who already had a history of CHD. This data therefore refutes any benefit for secondary prevention.
WHI AND STROKE
- An excess of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of CHD, use of hormones, statins, or aspirin.
- The later WEST trial showed no increase in stroke but just as importantly no DECREASE in stroke incidence with use of E/P
WHI: BREAST CANCER AND MAMMOGRAPHY
- Relatively short term EP increases incident breast cancers, which are diagnosed at a more advanced age, compared to placebo.
- EP substantially increases the percentage of women with abnormal mammograms.
- EP may stimulate breast cancer growth and hinder breast cancer diagnosis.
WHI-GYNECOLOGIC CANCERS
- Continuous EP may increase the risk of ovarian cancer while producing endometrial cancer rates similar to placebo.
- Estrogen alone sharply increases the risk of endometrial cancer.
- The increased burden of endometrial biopsies required to assess vaginal bleeding further limits acceptability of EP regimens.
- Caution should be used when using continuous EP therapy
WHI- FRACTURE AND BONE MINERAL DENSITY
EP increases bone mineral density and reduces the risk of fracture, present in all subgroups of women examined. This was a positive outcome of WHI, and was expected. However, When considering the effects of HRT on other important disease outcomes in a global model, there was no net benefit, even in women considered to be a high risk for fracture.
WHI-QUALITY OF LIFE
- EP did not have a clinically meaningful effect on health-related quality of life.
- Among post-menopausal women, 65 or older, EP did not improve cognitive function when compared to placebo. There was a small increased risk of clinically meaningful cognitive decline in the EP group.
WHI AND DEMENTIA
- The WHIMS portion (WHI Memory Study) of WHI indicated a doubling in the risk of all-cause dementia in women over 64 with HRT. This was true for both HRT (estrogen plus progestin) or Premarin alone. Neither therapy had any benefit in arresting the cognitive decline of ageing.
- Other studies which are purely observational indicate that a decrease in risk may only be seen with early use of HRT and only after 10 yrs of continuous use. Those studies also indicate that the risk increases with new HRT initiation at a later age (est. 74+)
SUMMARY AND RECOMMENDATIONS
- NO—NEVER! In women with a known inherited or acquired coagulation disorder or a previous major blood clot, exogenous estrogens should never be given, and estrogen agonists (Evista, Tamoxifen, Arimidex) should be given cautiously, if at all.
- PROBABLY---NEVER! In women who smoke, risks of estrogen-mediated side effects are so high, that exogenous estrogens should never be given.
- TO PREVENT-TREAT OSTEOPOROSIS: Benefits as great as estrogen for bones are provided by Fosamax or Actonel, without the risk of major side effects (Figure 1).
- TO PREVENT HEART ATTACK AND STROKE: Treat elevations of LDL cholesterol with statins, elevations of triglycerides with fibric acids. Treat hypertension and diabetes. Do not use estrogens as an approach to prevent heart attack and stroke.
- TO REDUCE LIKELIHOOD OF BLOOD CLOTS IN WOMEN WHO ARE GOING TO RECEIVE ESTROGENS: If there is a family history of blood clots, or a history of sporadic or recurrent miscarriage, at a minimum measure the Factor V Leiden and Prothrombin gene mutations first, before giving estrogen.
- PATCH VS PILL VS VAGINAL CREAM: There are no major differences in the likelihood of blood clotting or major estrogen-related side effects related to the method of delivery (patch vs pill vs vaginal cream).
- THINK TWICE BEFORE STARTING PERI-POST MENOPAUSAL ESTROGEN: Unless the vasomotor symptoms of estrogen withdrawal (hot flashes, heavy sweats) are intolerable, and since these last on an average for only 12 months, either take estrogen for a limited period of time, but well less than 5 years, or not at all.
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