WHAT TO DO ABOUT HORMONE REPLACEMENT THERAPY
In June 2002 the results of the WHI study on hormone replacement therapy (HRT) showed increased risks for heart disease, strokes, pulmonary embolisms, and breast cancer in women taking Prempro. See JAMA 2002 Jul 17;288(3):321-33, PMID: 12117397. Since then women have been trying to figure out if they should be taking HRT, and if so, which HRT. Since men are married to women, have them has friends, acquaintances, and family members, this is also an issue for us. My purpose in this paper is to provide men who visit the Men's Osteoporosis Support Group Web site with some scientific information they can provide to females who can then use that information to help them work with their care providers to get the best possible solution to their HRT situation. (Disclaimer: Nothing in the document should be interpreted as a recommendation for medical treatment. Everything mentioned here should be discussed with a person's care provider with decisions for medical therapy based upon those discussions). To see my personal observations on HRT, check this page.
Updates since original posting of this page
Update November 2004. 1. Orthoprefest no longer available. Orthoprefest, the combined oral therapy that was mentioned in this article, and recommended by many of the researchers, is no longer available. One of the patches with estradiol combined with micronized oral progesterone (Prometrium) may be the best available choice currently. 2. Low magnesium intake concerns. See PMID: 15466949 for a study which implicates low magnesium intake (or more correctly, high calcium/magnesium intake ratio) for the negative findings of the WHI study. This because women are told to take extra calcium to prevent bone loss, but not told to increase magnesium along with it. The authors implicate low magnesium intake in cardiovascular disease and embolisms that occurred more commonly with the women on HRT in the WHI study. Calcium/magnesium ratios were 2:1 in the early 1900s but as high as 6:1 by the end of the century. Women should probably strive to be closer to the 2:1 (and not higher than the 4:1) ratio for maximum cardiovascular benefits while on HRT. Women on HRT should discuss this with their care providers as this lower ratio can easily be accomplished with magnesium supplements.
Update May 2005. Critical review of WHI findings. For an excellent critical review of the WHI findings read The Women's Health Initiative Reports: Critical Review of the Findings, The Female Patient, Vol 20. October 2004, p. 35-41, Gambrell, RD. The author alludes to multiple flaws in the WHI study, while explaining that many clinicians misunderstood the methodology of the study, thus giving their patients faulty advice to discontinue hormone therapy. He explained that estrogen/progestogen therapy has at least nine benefits that women and their physicians need to consider. These include: Relief of vasomotor symptoms, prevention of urogenital atrophy, alleviation of psychogenic manifestations, improved quality of life, prevention of osteoporosis, prevention of cardiovascular disease, prevention of Alzheimer disease, reduction of macular degeneration, and reduction of cataracts. One other very important point made is that, not only is the type of progestogen important, but the dosing frequency is critical. The continuous progestogen therapies where estrogen and progestogen are combined throughout the entire month decrease the estrogen receptors on the arteries, minimizing the beneficial effects of estrogen.
Update August 2007. The HRT misuse and osteoporosis epidemic: a possible future scenario. See PMID: 17653953 for more details on this article in Climacteric 2007 Aug;10(4):273-5, Gambacciani M, Ciaponi M, Genazzani AR. The authors note that since the publication of the WHI, the number of HRT users in the USA dropped from 5.6 million in 2001 to 2.5 million in 2003. They also note that short-term exposure to HRT in the early postmenopausal years can confer long-term protection against fractures. A study by Bagger and others demonstrated that the effect of 2-3 years of HRT on bone mass persists for many years after stopping treatment and the relative risk of all osteoporotic fractures decreased by 52%. A 52% HRT-induced reduction in fracture risk after 10-15 years could have prevented 71,716 fractures/year with the number of women on HRT in 2001. However, considering the greatly reduced number of women on HRT in 2003, an excess of 43,008 fractures/year would occur. The authors note that if women continue to use HRT at the current reduced rate, other therapies will have to be implemented to prevent a future epidemic of osteoporotic fractures. Such alternative therapies could include raloxifene and bisphosphonates, or other approved osteoporosis medications. Editor's comments: These authors' findings suggest that women should at least transition in the early postmenopausal time period with HRT for up to three years to reduce the long-term chance of fracture nearly in half. Women should discuss these recommendations with their care providers.
Update September 2009. Review paper on the topic of bioidentical HRT. See PMID: 19179815 for more details on this article in Postgrad Med. 2009 Jan;121(1):73-85. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Holtorf K. As stated, the purpose of the article is, "This paper aimed to evaluate the evidence comparing bioidentical hormones, including progesterone, estradiol, and estriol, with the commonly used nonbioidentical versions of HRT for clinical efficacy, physiologic actions on breast tissue, and risks for breast cancer and cardiovascular disease." Editor's comments: The WHI study involved only the use of hormones that are not bioidentical and used them in forms, dosages, and regimens that are not natural for women, and for women who were, on average, several years postmenopausal. This excellent review explains the difference between the bioidentical and nonbioidentical forms with evidence as to why postmenopausal women would benefit from the bioidentical hormones, especially regarding breast cancer and cardiovascular disease risk reduction.
Update April 2010. Cancer J. 2009 Mar-Apr;15(2):93-104. Hormone replacement therapy: real concerns and false alarms. Bluming AZ, Tavris C. PMID: 19390302. This is a critical review of the WHI study of 2002 regarding hormone replacement therapy. It points out the weakness of the statistical results. This includes using relative risk as the means of evaluating the findings and of reporting them as "statistically significant," when they weren't in some cases. It also shows where, "the findings reported in press releases and interviews of the principal investigators were often distorted, oversimplified, or wrong." Here is an excellent online video explaining the problems with reporting statistical results using relative risk.
I suggest every woman going through menopause print this article and take it to her physician to read. Note, that as I also point out in the review here, the authors explain that many of the benefits of HRT occur from starting therapy early, either at or shortly after menopause. So you can't wait for ten years and then decide to start HRT. Based upon my experience with my wife as she has sought care from physicians knowledgeable about the HRT issue, you simply can't expect to find any practicing physician who has an understanding of the flaws in the WHI study, although I'm sure there are some out there. You'll have to show him/her this article, and perhaps others, to explain the problems with the WHI study.
The bottom line from this review is that the WHI study is flawed, the risks it suggested that HRT implied for women aren't really there, and that women should consider HRT for its many benefits when they are going through menopause for either short- or long-term help.
The book to read if heart disease is a concern to you
Update October 24, 2003. Since cardiovascular disease is a woman's greatest risk, I wanted to suggest a great book that I just read on this topic. It is The Heart Disease Breakthrough by Thomas Yannios, M.D. ISBN: 0471255335. In this book Dr. Yannios explains that just knowing your cholesterol and triglyceride levels is not enough. You, and especially your physician, also need to know about such things as LDL subclass A and B, apoprotein B, HDL subclass, apoprotein E isoform, Lp(a), homocysteine level, fibrinogen levels, LDL oxidation, IDL level, LPL activity and how all these interrelate to give each individual his or her cardiac risk status. Although this isn't light reading, it is very enlightening. If you'll follow the instructions in the book, you'll not only know your cardiac risk status, but you'll know how to keep that risk at the very lowest level possible. And, that will be based upon your own individual needs, not some formula that is supposed to work for everyone. It should make a woman's decision about what to do about hormones easier if she documents what happens to her important cardiac risk factors after menopause. If she takes HRT and those factors remain at low risk levels, that would reinforce her decision. If she goes off hormones and finds her risk factors increase, that might show the need to start HRT and reevaluate cardiac risk factors in a few months to see if there is an improvement. The important thing is that this is using objective scientific information to help makes decisions, not just emotions.
A Summary of Recommendations from Studies or Websites
1. The WHI study results apply only to one form and brand of HRT--Prempro. It is invalid to include all other forms of HRT with the study's findings. And, these women were older when starting HRT, meaning the study findings don't necessarily apply to younger postmenopausal women, especially those who start HRT right at menopause.
2. Other, especially natural forms of HRT that mimic the way a women's own estrogen and progesterone worked before menopause, appear to be safe, if individualized and monitored (initially after two months, and yearly thereafter) for each woman, and used in the proper dosage and form. Monitoring should include estradiol and serum lipid levels along with checks of other risk factors, as appropriate, such as C-reactive protein levels. Since cardiovascular disease is a woman's greatest risk of mortality or morbidity, it is important to maintain cardiac risk factors at the safest levels possible.
a. Women with an intact uterus in the U.S. should discuss with their care providers the use of transdermal 17 beta-estradiol and a natural form of progesterone in oral or transdermal dosing form or Ortho-Prefest(TM) as the oral form of combined estrogen/progestin HRT. Women without a uterus need only the 17 beta-estradiol for estrogen replacement. Although note that there is evidence that intermittent progesterone is still beneficial regarding reducing breast cancer risk, so discuss this with your care provider before taking unopposed estrogen in any form.
b. Women should start HRT as soon after menopause as possible once it is determined they need it. This reduces or eliminates the negative changes in serum lipid factors which in turn can lead to atherosclerosis. Early atherosclerosis can be more readily reversed or prevented for several reasons. And, this prevents the normal loss of bone mineral density (BMD) that occurs the first few years after menopause which can lead to osteoporosis and bone fractures.
3. HRT is taken by many women to prevent bone loss. Women should get about 1,500 mg/day of calcium and 800 I.U./day of vitamin D either through diet, sunshine, or supplements to assure an adequate supply of calcium for bone health. But it is important that they and their care providers understand that calcium, and to a lesser extent, vitamin D with or without calcium, are not adequate to prevent postmenopausal loss of bone mineral density nor to increase it if started long after menopause unless calcium and/or vitamin D deficiency has been clinically determined. Clinically proven nonhormonal alternatives to prevent or treat osteoporosis are discussed. Also, up to 40% of women taking long-term, continuous HRT can still have low bone mineral density, and 13% can have osteoporosis. Thus, HRT is not guaranteed protection against losing BMD. Even when on HRT, you must therefore work with your care provider to have periodic bone density testing, or test using biochemical markers of bone turnover, to see if you are losing BMD. If you are losing BMD while on HRT, other approved therapies can be added to HRT to prevent further loss of BMD, or to increase it.
4. A recent symposium on cardiovascular disease in postmenopausal women has been reported in The American Journal of Cardiology. I will summarize the very interesting and pertinent results of that to aid in women's decisions concerning starting or continuing HRT. It is recommended that all care providers who diagnose and treat women potentially needing HRT read this symposium. Additionally, women needing HRT may want to read it themselves, although some of it may be quite complex if they don't have a medical background.
5. Selective Estrogen Receptor Modulators (SERMs) are an alternative to HRT. I will summarize the pros and cons of their use.
6. Tibolone is a medication that (if and when approved by the FDA) could be an option to other types of HRT.
All HRT medications are not alike. It is important to put the HRT controversy into some understandable terms. The medical profession, the media, and virtually everyone uses the term "HRT" when discussing the results of the WHI study. It is very important to remember that this study actually involved the use of only CEE and MPA. Neither of these are natural hormones exactly mimicking either the structure or function of those that women produce before menopause. Thus, it is not logical to assume that "HRT causes such and such a problem" because the combination of CEE and MPA causes that problem, many experts' and the media's interpretation of the study results notwithstanding. Nor can you say that HRT won't work for individuals who start it immediately upon being postmenopausal because CEE/MPA wasn't beneficial for women who started it 13 to 15 years after menopause. Here is an analogy for car paint and undercoating that might make this more understandable. Assume you own a car in a New England coastal city. You drive it summer and winter for 15 years and notice it is rusting, so you paint it with indoor water-based latex paint and undercoat it. A few weeks later you notice there are holes in the car and the paint is peeling. Thus you write a national article and state that paint and undercoating don't work, so don't use them on your car. You would be laughed off the face of the earth for making such ridiculous deductions from obviously faulty materials and methods. People would say, "You didn't paint the car with the proper paint that is protective of the metal surface and you waited too long to undercoat it so the damage was already irreversible." The difference between the car paint and undercoating results and the WHI study aren't that far apart. The investigators are condemning all HRT based upon the findings with only one combination, CEE/MPA. This combination has been shown to be incapable of stopping coronary atherosclerosis in monkeys because MPA overrides the beneficial effects of estrogen, to increase blood clotting risks, and to negatively impact breast tissue so as to potentially increase the risk of breast cancer. This while other combinations of estrogen and progestin have not shown the same problems, and, in fact, had been shown to be positive in all those areas. Still the study implicated all HRT in their negative findings, not just the form of HRT that the study investigated. Truly fallacious deductive reasoning, easily spotted in the car example, but overlooked by the WHI investigators and many of those who have critiqued it.
An excellent summary article. If you only have time to read one article, this is the one I would suggest. It was published in 2000 by de Lignieres B and MacGregor EA in Cephalagia, so it came out before the WHI. But you will find that it predicted the results based upon many studies that showed in advance what the effect of CEE/MPA would be on serum lipids, breast cancer, and venous thrombosis, etc. See the abstract at PMID: 10997769 for details.
Medscape and Other Web Articles
Problem description with suggestions for treatment. One excellent article on HRT controversy is by Dr. Morris Notelovitz and is located at http://www.medscape.com/viewarticle/438356. NOTE: To read Medscape articles, you must register at www.medscape.com. There is no expense, but you must fill in some information before you can read articles. Here is my summary of the highlights of this article:
1. Tailor the therapy to each individual patient. When prescribed in that manner, HRT, if indicated, if individualized, and if monitored, is safe.
2. Risks of HRT: Cardiovascular events, stroke, and breast cancer.
3. Best therapies to reduce or eliminate risks: Use 17 beta-estradiol which is the same as the natural hormone being replaced, and in the lowest dose that will treat the reason the woman is on HRT.
4. The problem: ". . .physicians treat older women with established heart disease with estrogen." These older women should be treated with low-dose transdermal natural estrogen. Note, when British investigators used 17 beta-estradiol and norethindrone acetate, not Prempro, on older women with heart disease, they got no increased risk of heart attack compared to placebo.
5. Breast cancer risk: The best estrogen is a low-dose patch, but the important medication is the type of progestin and whether it is cyclic or continuous.
a. A breast cancer risk profile includes: Family history, increased breast density on mammogram before HRT (the most important factor), obesity, and mature-onset diabetes. High bone density is also an increased risk along with increased breast density.
b. The best progestin to use with an intact uterus and breast cancer risk is micronized progesterone-a natural progesterone-and in conjunction with low-dose transdermal (patch) estrogen.
6. It is critical to start women on HRT early in the postmenopausal cycle and on the lowest effective dose, and then to reevaluate results annually. At the annual evaluation, 17 beta-estradiol levels are tested from blood samples and modified, if needed. Heart problems are more common in older women who start HRT later in life, especially those not using ideal HRT.
Another excellent Medscape article can be found at http://www.medscape.com/viewarticle/438357. This article by Dr. Andrew M. Kaunitz has a wealth of prescribing information about HRT and related medications, and includes names of pertinent medications.
Online description of medications and dosages. For an excellent summary of estrogen, progesterone, alternative medications, etc., see http://www.midlife-passages.com/page43.html.
Calcium and/or vitamin D for postmenopausal bone loss
Calcium to prevent or treat osteoporosis. Since calcium is critical for bone development and health, there is the risk that health care providers will consider calcium supplements or dietary sources of calcium as adequate for prevention or treatment for osteoporosis. This is not the case, so women seeking answers to HRT questions should have research information to show their health care providers to substantiate this important point. The first and most important point is that when clinical research trials are done to test the effectiveness of a medication to treat or prevent osteoporosis, the test and control groups almost always are both taking calcium and/or vitamin D along with the test medication and the placebo (sugar pill). You can view study after study that will show the placebo group loses BMD while the test group gains it during the clinical trial test period, thus showing the inability of calcium to prevent bone loss in postmenopausal women. In early menopause, women lose from 2-5% of BMD per year until HRT or some other effective medication is taken to prevent this bone loss. It is vital for these women to understand that once the BMD is lost, even with medications, it is not always possible to regain all of it. Thus prevention of postmenopausal bone loss should be every woman's main goal. For example, I'm in touch with many men in the Men's Osteoporosis Support Group who have been on bisphosphonate therapy for their osteoporosis for up to six years. None has regained all BMD in both the hip and spine to my knowledge. Many of us are back to near normal BMD in the spine, but the hip is particularly hard to increase BMD in with today's medications (with the possible exception of Forteo, 1-34 human parathyroid.) There are also studies reported in PubMed to show the inability of calcium to prevent postmenopausal bone loss. See Clin Ther 1998 Sep-Oct;20(5):933-44, Evidence that increased calcium intake does not prevent early postmenopausal bone loss. Hosking DJ and others. PMID: 9829445. (You can click on this link or go to PubMed at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? and enter just the numeric portion of the PMID, then click on Go or hit the enter key. To then order the entire article, take the abstract to your local library and ask them to get a copy of the article from the National Library of Medicine, which they will do at no expense to you). This study looked at the 394 women in the placebo group of the Early Postmenopausal Interventional Cohort study which used Fosamax as the test medication. Women were stratified according to calcium intake and results showed approximately 2% loss in BMD no matter how much calcium they were taking during the study. The authors noted: "Despite wide variations in baseline calcium intake and changes in calcium intake, these measures were not significantly associated with changes in BMD or bone turnover." Additionally, they state: "We were unable to demonstrate that increases of this magnitude or much greater ( 1 g/d of calcium) were protective against declines in BMD at any site, even in women who had the lowest calcium intake at baseline. In addition to adequate calcium intake, more effective therapy appears to be required when the therapeutic goal is to increase or maintain BMD." Another study gives similar results. See BMJ 1988 Jul 2;297(6640):15-7, Dietary intake of calcium and postmenopausal bone loss. Stevenson JC and others, PMID: 3261612. This study looked at skeletal measurements and dietary intake of calcium in 59 healthy postmenopausal women, most within five years of menopause. The authors found no correlation between current intake of calcium and either total calcium in the body or the density of trabecular or cortical bone in the forearm or vertebral trabecular bone. The authors state: "The results of this study suggest that the bone density of women in the early menopause is not influenced by current dietary intake of calcium." Other controlled clinical trials found similar results, especially they showed no effect during the first three to five years after menopause. As an example, see: N Engl J Med 1990 Sep 27;323(13):878-83, A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. Dawson-Hughes B and others, PMID: 2203964. The authors report, "In women who had undergone menopause five or fewer years earlier, bone loss from the spine was rapid and was not affected by supplementation of calcium."
Vitamin D with or without calcium to prevent or treat osteoporosis. In a recent review article on this subject, the author concludes: "Results of large placebo controlled trials have shown that alendronate, raloxifene, risedronate, the 1-34 fragment of parathyroid hormone, and nasal calcitonin, greatly reduce the risk of vertebral fractures. Furthermore, a large reduction of non-vertebral fractures has been shown for alendronate, risedronate, and the 1-34 fragment of parathyroid hormone. Calcium and vitamin D supplementation is not sufficient to treat individuals with osteoporosis [my emphasis] but is useful, especially in elderly women in care homes." See: Lancet 2002 Jun 8;359(9322):2018-26, Treatment of postmenopausal osteoporosis. Delmas PD, PMID: 12076571. Applying some general logic, and the laws of cause and effect, should help explain the results studies have found with calcium and vitamin D. In elderly women in hospitals or extended care facilities, it is expected that they would be deficient in vitamin D, either from lack of sunlight or inadequate diet. Thus, supplementation of their diet with vitamin D would logically be expected to correct this deficiency and to improve any loss of BMD that occurred from the vitamin D deficiency. However, in postmenopausal women, the cause of their lost BMD is the decrease in hormone production. Thus, adding calcium and/or vitamin D is not treating the cause of the problem in women with normal serum calcium/vitamin D levels, and would not be expected to have a significant effect. This is what studies have found. In summary, postmenopausal women--especially younger women--must not expect calcium and/or vitamin D to reliably and effectively prevent or treat osteoporosis. They must look either to a proven hormonal or nonhormonal therapy for this help.
Estrogen to prevent osteoporosis and fractures
Although estrogen use is associated with increased BMD and decreased risk of osteoporosis in multiple clinical studies, it is not a virtual guarantee that a postmenopausal woman won't get osteoporosis or have a fracture. A recent study highlights this point by analyzing the data from the Study of Osteoporotic Fractures, a ten-year prospective cohort study of 8816 women 65 years or older that measured the number of fractures of the hip, wrist, vertebrae, and nonvertebral fractures. See Arch Intern Med 2002 Nov 11;162(20):2278-84, Osteoporosis and fractures in postmenopausal women using estrogen. Nelson HD and others, PMID: 12418942. The study found at baseline that 40% of continuous estrogen users were osteopenic and 13% were osteoporotic at the hip and spine. Women currently using estrogen lost less bone density than past users or those who never used estrogen, but all user groups on average lost bone from the hip and calcaneus. The ten-year adjusted probability of nonvertebral fractures was 19.6% for continuous estrogen users, similar to current partial users and lower than past users and those who never used estrogen (P<.05). The authors conclude: "Although estrogen use is associated with reduced prevalence of low bone density, less bone loss, and lower probabilities for fractures, osteoporosis and fractures are common in older women who used estrogen continuously since menopause. Estrogen users should be considered in strategies designed to detect, prevent, and treat osteoporosis." (Editor's comment: As if to show proof of the results of this study, two of my postmenopausal friends, one in her mid-fifties and one in her mid-sixties, have recently been diagnosed with osteoporosis. Both had been on HRT since menopause. Previously, it has been thought that estrogen was almost an iron-clad guarantee against osteoporosis. This study proves that concept is wrong. Postmenopausal women on HRT need to work with their care providers to assure they have periodic bone density testing to rule out excessive bone loss, and to catch it early, if possible, to prevent painful and debilitating fractures).
Cardiovascular disease in postmenopausal women
The symposium on cardiovascular disease in postmenopausal women. See Am J. Cardiol 2002 Jun 20;89(12 Suppl), A Symposium: Cardiovascular Disease in Postmenopausal Women, for an outstanding presentation of this subject. All health care providers involved with prescribing HRT should read this symposium. It also provides excellent information for the lay person interested in this subject, but it can be quite complex in certain areas. The supplement is broken down into several articles covering specific topics. I will simply refer to the author(s), page numbers, and PMID when summarizing the information presented below by topic.
Myths and realities of cardiovascular disease in women. See Lewis SJ, 5E-11E, PMID: 12084395. Cardiovascular disease is the greatest cause of morbidity and mortality in women, yet women think that cancer is their greatest risk. In fact, in a recent American Heart Association survey, 61% of respondents thought cancer was their greatest health risk, and only 7% correctly identified heart disease. The reason for this is probably that physicians don't commonly discuss heart disease with female patients (only 38% of the time). Women generally develop symptoms of cardiovascular disease (CVD) ten years later than men. Women's major modifiable risk factors for CVD are: dyslipidemia, diabetes, hypertension, cigarette smoking, obesity, sedentary lifestyle, and poor nutrition. Additional atherosclerosis-associated risk factors have also recently been identified: abnormal circulating levels of lipoprotein (a), homocysteine, C-reactive protein, serum amyloid A, intercellular adhesion molecule-1, and interleukin-6. Premenopausal production of estrogen helps maintain many of these risk markers within normal limits. Of significance is that within six months of menopause levels of total cholesterol, LDL-C,, and triglycerides increased significantly, while HDL-C decreased but at a slower rate than the other lipid markers. So, women have a much more atherosclerogenic lipid profile after menopause than before. (Editor's note: As will be seen, many of the studies on the effectiveness of HRT as concerns CVD have been on older women well past menopause. Realistically, HRT's benefits have to be minimized or totally gone if started late in life after the atherosclerotic lipid changes have affected the coronary and other vessels for years. As the article on atherosclerosis imaging methods listed below points out, the early atherosclerotic changes consist of more cellular fibrous tissue, whereas later this tissue consists more of dense fibrous tissue. These early changes are more capable of regression with proper therapy. Methylation of the estrogen receptor gene also occurs with age and increased atherosclerosis, making the blood vessels less responsive to estrogen's beneficial effects. This is another reason why HRT is not as effective in older women as concerns preventing CVD. Prevention of atherosclerosis by early HRT may prove to reduce this methylation thereby preventing or delaying CVD in women who started HRT early. This will have to be proven in future studies and is just conjecture now. So, there is great need for studies that follow women on HRT, particularly those taking natural hormones that don't negatively impact lipid and other cardiac risk factors, and those who have started it very soon after menopause to prevent the negative impact of increased cardiac lipid and other risk factors. Also of importance is that studies have shown that improvements in lifestyle or medications that improve cardiac risk factors are beneficial and significantly reduce the rate of coronary events. Thus it is impossible to overemphasize the importance of proper diet, exercise, nonsmoking, maintaining proper weight, etc., to prevent CVD whether a woman is on HRT or not).
Risk factors for coronary artery disease in women. See Knoff R, p. 28E to 35E (including discussion), PMID: 12084401. The author notes that women are generally protected from cardiovascular disease up until menopause, but with advancing age and menopause, this protection decreases. Particularly affected are low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. He points out that men and women differ in their response to these cardiovascular risk factors, with women in middle age particularly affected by lowered HDL-C and elevated triglycerides. He points out, "For women therefore (and increasingly so for men), it is believed that risk modification should focus on LDL-C first and then on triglycerides and HDL-C as well, using non-HDL-C goals as a guide. Therapy should aim to reduce the risk associated with multiple factors, both lipid and nonlipid." He also mentions that, "Almost all aspects of the lipid profile are improved by exogenous estrogen. Although progestins oppose the benefits of estrogen, this does not appear to be equally true for all HRT combinations."
Atherosclerosis imaging methods: Assessing cardiovascular disease and evaluating the role of estrogen in the prevention of atherosclerosis. See Hodis HN and Mack WJ, p. 19E-27E, PMID: 12084399. Atherosclerosis (fatty deposits in and fibrosis of the inner arteriole lining) can be slowed by various methods which reduce the risk of clinical coronary events. One way to tell if a therapy is beneficial is to use an imaging method to tell if atherosclerosis is increasing or decreasing over time. Multiple imaging techniques are available, with some being very expensive, time consuming, and invasive. However, B-mode ultrasonography of the intima-media wall thickness (IMT) of the carotid artery is noninvasive, while it correlates with atherosclerosis risk factors and clinical cardiovascular and cerebrovascular outcome. So, this is a relatively inexpensive, noninvasive, portable, and quick method to test whether HRT using various medications is effective in preventing or decreasing the progression of atherosclerosis in postmenopausal women. In the HERS and ERA studies (see below), there was no effect of CEE either alone, or with MPA compared to placebo on the progression of coronary artery disease. However, in the EPAT trial where oral 17 beta-estradiol was used unopposed (without progestin), there was a significant reduction in the progression of carotid IMT compared to women on placebo over two years. This is important for women from two angles: The 17 beta-estradiol can reduce the progression of cardiovascular disease and the B-mode ultrasonography can be used to help women determine their risk of cardiovascular disease--either before and/or after starting HRT. [Editor's comment: There is another important study for women to evaluate using IMT in 159 healthy postmenopausal women aged 45-65. See Atherosclerosis 2000 Nov;153(1):81-8. Effect of hormone replacement therapy on age-related increase in carotid artery intima-media thickness in postmenopausal women. Tremollieres FA and others, PMID 11058702. These women were grouped into four groups by age (<55 vs. > or=55 years) and use of HRT (current users of non-oral 17 beta-estradiol with a non-androgenic progestin and never users. All HRT users had started it within the first year of menopause. All women were free of cardiovascular disease (CVD) at the beginning of the study with no CVD risk factors. The authors found, "Carotid artery intima-media thickness was significantly correlated to age in never users (r=0.5, P<0.0001) but not in women who were currently receiving HRT (r=0.2, ns)." This apparent protective effect of both oral and non-oral 17 beta-estradiol on carotid IMT is quite important. It shows that these forms of HRT show long-term protection from CVD as evidenced by minimal thickening of the carotid IMT. This occurred in women without known CVD risk factors when HRT with oral 17 beta-estradiol (unopposed) was started at mean age of 61.1 years or when the progesterone-opposed non-oral HRT was started at or shortly after menopause. This is convincing objective evidence that transdermal or oral 17 beta-estradiol are effective at reducing carotid IMT thickness, a known CVD risk factor. Similar studies on older women with known CVD risk factors using CEE as the HRT found no effect on IMT thickness compared to placebo. The bottom line appears to be that starting 17 beta-estradiol HRT at or shortly after menopause and continuing it long term provides the greatest decrease in CVD risk as determined by carotid IMT thickness.]
Protective effects of estrogen on the cardiovascular system. See Mendelsohn ME, p. 12E-18E, PMID: 12084397. The author points out that there are two types of estrogen receptors in tissues throughout the body, particularly in the reproductive tract, the liver, bone, brain, and cardiovascular tissues. Using specially bred mice, studies have shown that estrogen prevents injury to the inside of blood vessels when a fine wire is fed into the carotid artery inducing internal vascular injury. Ovariectomized female mice given 17 beta-estradiol (natural estrogen) show no effect from the wire, whereas those mice given placebo have significant injury and damage to the artery wall. Other cardioprotective effects of estrogen include rapid arterial vasodilation (opening or widening). There are complex long-term effects that improve response to injury that are beneficial, too. Aside from the previous direct effects, there are indirect vascular effects on serum lipid concentrations, coagulation and fibrinolytic (clot breakdown) systems, antioxidant effects and the production of other vasoactive compounds. Orally, estrogen increases serum HDL-C levels, decreases LDL-C levels, and increases triglycerides. But, the coadministration of progestin with estrogen may alter the beneficial effects of estrogen on cardiovascular tissue and affect changes in HDL-C and LDL-C levels seen with estrogen treatment alone according to the dose and type of progestin used. Of importance to women wanting to avoid stroke and pulmonary embolisms is that continuous estrogen therapy reduces plasma concentrations of fibrinogen and the anticoagulants antithrombin and protein S. Thus high concentrations of plasma estrogens can increase the chance of a blood clot. Estrogen can also act as an antioxidant, reducing the oxidation of LDL-C. In summary, clinicians must understand that estrogen has multiple beneficial effects of the cardiovascular system, lipid profiles, etc. But, these benefits are modified by the progestin component of combined HRT therapies in women with a functional uterus. Manipulating both components of therapy to get the best results is critical
Hormone replacement and the prevention of cardiovascular disease. See Langer RD, p 36E to 46E, PMID: 12084403. The author points out that various studies have been conflicting as to the cardiovascular effects from HRT (Note: This study came out prior to the WHI study mentioned above). Since cardiovascular disease is the number one cause of mortality in women, this is an important issue. This risk for cardiovascular disease increases at the time of menopause and then sharply in older age. Additionally, studies have shown no significantly decreased risk for stroke with use of HRT, although most found no increased risk either. The author notes that a Swedish study looked at myocardial infarction and stroke during the 1980s for women taking either 17 beta-estradiol alone or opposed with levonorgestrel. The combined therapy produced the best results with lower risk for first myocardial infarction or first stroke compared to women not taking HRT and to women only taking estrogen replacement therapy (ERT). However, in the U.S., women were using a different estrogen and progestin than that used in the Swedish study. [Editor's comment: Probably expecting the same results, but using invalid reasoning and expectations]. The author mentions several studies on women at high risk for coronary artery disease (CAD), but most have limitations that cause reason to doubt the results. In general, however, they found estrogen replacement therapy (ERT) or HRT improved outcomes. There are two large prospective randomized trials of importance: the Estrogen Replacement and Atherosclerosis (ERA) trial and the Heart and Estrogen/progestin Replacement Study (HERS). The ERA trial looked at the effects of CEE or CEE plus MPA on progression of atherosclerosis and the HERS trial tested only the combination therapy for secondary prevention of heart disease in women. Additionally the WHI (mentioned previously) has shown some negative outcomes at the 2-year report period, but these were deemed not significant enough to be a safety hazard. The author notes that the HERS trial enrolled women with a mean age of 66.7 years and 18 years average time since menopause. So women looking for help with what to do who are just going through menopause will find little to guide them with this study. Although the HERS study found no significant effects of overall cardiovascular events, it did show a significantly higher triglyceride level (p <0.001 vs. placebo). In the ERA trial, women were also older (average age 65.8 years). Results did show improvements in lipid profiles but no effects on blood vessel diameter or development of cardiovascular events. There simply was no benefit to the CEE or CEE plus MPA used as HRT in this study on older women at risk for cardiovascular disease. In another study (The EPAT Study) using 17 beta-estradiol (E2) in the 1 mg daily dose vs. placebo, in women with LDL-C 130 mg/dl or less and without coronary artery disease, artery wall thickness was reduced by ERT. The author discusses the various progestins that are available and concludes: "These finding suggest that some of the commonly used progestins (eg, MPA and levonorgestrel) may limit the potential cardiovascular benefits of estrogens when administered in combination therapy."
Effects of progestins in different hormone replacement therapy formulations on estrogen-induced lipid changes in postmenopausal women. See Shulman LP, p. 47E to 55E, PMID: 12084405. There are an increasing number of steroid formulations for HRT with different routes of administration (oral and non-oral routes, including transdermal, gels, patches, or subcutaneous implants) and multiple types of estrogens and progestins, too. The author points out that, although CEE is used in the United States, plant-based 17 beta-estradiol has been widely used in Europe for years. All oral estrogens alter serum lipid profiles, but certain progestins can reverse these positive effects depending on the specific type and dose used. The author notes that the PEPI Trial compared the effects on heart disease risk factors of multiple combinations of HRT for three years. CEE was used as the estrogen and compared to CEE alone, or with MPA used for various time frames or continuously or micronized progesterone 200 mg/day for the first 12 days of the cycle. The author concludes: "Thus, the progestin MPA attenuated the beneficial effect of estrogen, whereas micronized progesterone almost completely preserved the full effect of unopposed estrogen on HDL-C. This finding indicated that not all progestins oppose the lipid-modifying effects of estrogen to the same degree. The route of administration of ERT is important. Studies have shown that oral doses, when compared to transdermal methods, increase HDL-C more, decrease LDL-C more, but with similar effects on total cholesterol. Whereas, transdermal methods decrease serum triglycerides while oral routes increase them. Also, various combinations of HRT have differing effects on lipids. The author mentions multiple studies and concludes: "The 17 beta-estradiol 1-mg and norgestimate 90 microgram (NGM) regimen preserved the cardioprotective effects of 17 beta-estradiol on both mean HDL-C and LDL-C levels, while minimizing the estrogen-induced increase in triglyceride levels. Regimens containing norethindrone acetate, however, were associated with a decrease in HDL-C levels from baseline. Regimens containing MPA were associated with a reduced increase in mean HDL-C levels compared with estrogen alone and did not attenuate the significant increases in mean triglyceride levels observed with estrogen alone. Another study using the E2/NGM regimen showed beneficial effects on women with unfavorable baseline lipid profiles. In a one-year study, >50% of women in the E2/NGM group returned to favorable range for each lipid parameter measured. For total cholesterol, significantly more women returned to normal with the combination E2/NGM than for unopposed E2 (56% vs. 38%), thus showing that NGM not only doesn't attenuate the positive effect of E2, it improves it. When comparing E2 combined with norethindrone acetate (NETA) and E2/NGM on women with unfavorable lipid profiles, the NETA therapy was found to markedly attenuate the positive benefit of E2 on HDL-C. Since women with lipid levels outside the healthy range are assumed to be at greater risk for cardiovascular disease, these findings appears to be of significance. The author concludes: "The 17 beta-estradiol 1-mg plus norgestimate 90 microgram intermittent regimen is currently the only HRT regimen that has a comprehensive beneficial impact on all 3 of these lipid fractions known to be established markers of cardiovascular disease. Importantly, beneficial lipid changes with this formulation were also found in postmenopausal women with baseline lipid levels outside the recommended range." (Editor's notes: This E2/NGM combination is available as Prefest(TM) in Europe, and Ortho-Prefest(TM) in the U.S. I suggest if a woman is taking any other formulation, that she and her care provider examine the effects of that HRT on her lipid profile and other CVD risk factors and compare them to published results with Prefest(TM). The goal is for HRT to improve cardiac risk factors--not to increase them. Prefast(TM) has done this in published studies. For additional information also see: Acta Obstet Gynecol Scand 2002 July; 81(7):654-660, Intermittent progestin administration as part of hormone replacement therapy: long-term comparison between estradiol 1 mg combined with intermittent norgestimate and estradiol 2 mg combined with constant norethisterone acetate. Ylikorkala O and others, PMID: 12190841. For a review of the effects of different HRT regimens on lipid and lipoprotein levels, see: Fertil Steril 2001 May;75(5):898-915, Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974-2000. Godsland IF, PMID: 11334901. This article reemphasizes that progestins tend not to affect the positive influence of estrogens on LDL and total cholesterol, but estrogen-induced increases in HDL cholesterol and triglycerides are opposed according to the type of progestin used. In the order of least to greatest effect, they are: dydrogesterone and medrogestone, progesterone, cyproterone acetate, medroxyprogesterone acetate, transdermal norethindrone acetate, norgestrel, and oral norethindrone acetate).
Summary. Cardiovascular disease is a woman's most significant risk of morbidity and mortality, so efforts to decrease risk should be well rewarded. Her natural hormones produced by her body until menopause appear to be nearly totally protective for cardiovascular disease. After that, both age and hormones become significant, with the exact proportion of each as a contributor to heart disease probably never to be known. Any positive changes to modifiable cardiac risk factors such as diet, exercise, not smoking, etc., are important to reduce cardiovascular disease. But, it appears that careful selection of the proper natural medications for HRT that reduce lipid risk factors may be something else that women can do. This HRT should be started as soon as possible after menopause and the results should be monitored to verify the HRT is beneficial--and changes made if it isn't. Shulman recommends E2/NGM as the best way to decrease cardiac lipid risk factors. Dr. Notelovitz recommends transdermal E2 and micronized progesterone in the lowest effective dose. As I suggest, there are published studies showing what Prefast(TM) can do to improve cardiac risk factors, so your current HRT results should be equal to or better than that, or you should probably consider switching. With these different recommendations women and their care providers need to learn as much as possible about HRT choices and how each might affect cardiac risk factors. Obviously lab work, carotid ultrasound, and other tests to determine pertinent lipid and other cardiac risk factors are important before embarking on HRT. Then continual evaluation of the effects of HRT on those risk factors will determine if changes in dosages or regimens are required to obtain safe levels, or if additional therapy such as statins might be needed.
Other studies involving natural HRT
1. Safety and effectiveness. Climacteric 2002 Mar;5(1):26-35, Endometrial safety and bleeding patterns during a 2-year study of 1 or 2 mg 17 beta-estradiol combined with sequential 5-20 mg dydrogesterone. Ferenczy A and others, PMID 11974556. Using multiple dosages of 17 beta-estradiol and dydrogesterone, and uterine biopsies to evaluate results on 137 women, this study found the higher dose of dydrogesterone was associated with a higher incidence of cyclic bleeds. The authors concluded: "Sequential combinations of 1 mg 17 beta-estradiol with 5 or 10 mg dydrogesterone and 2 mg 17 beta-estradiol with 10 or 20 mg dydrogesterone are associated with very good endometrial safety. The incidence of bleeding is lower with the 1-mg dose of 17 beta-estradiol." The next study looked at safety and vasomotor symptoms. See Menopause 2002 May-Jun;9(3):195-207, Safety and efficacy of continuous once-a-week 17 beta-estradiol/levonorgestrel transdermal system and its effects on vasomotor symptoms and endometrial safety in postmenopausal women: the results of two multicenter, double-blind, randomized, controlled trials. Shulman LP and others, PMID: 11973443. An interesting and convenient element of this study was the women used a once-weekly transdermal patch that contained both medications. Various dosages of this transdermal medication were compared to either oral placebo or daily transdermal therapy. The authors concluded: "All three doses of this once-a-week combined E2/LNG transdermal system rapidly and effectively control vasomotor symptoms in postmenopausal women while protecting against endometrial hyperplasia. Amelioration of vasomotor symptoms also is accompanied by improvements in aspects of subjective well-being. Once-a-week transdermal E2/LNG, therefore, offers an effective and convenient formulation, the dosing of which can be individualized according to the needs of the patient." The next study looked at long-term endometrial results. See BMJ 2002 Aug 3;325(7358):239, Effect on endometrium of long term treatment with continuous combined oestrogen-progestogen replacement therapy: follow up study. Wells M and others, PMID: 12153918. This study looked at intrauterine histology of 534 postmenopausal women taking 2 mg 17 beta-estradiol with 1 mg norethisterone acetate for up to five years and found no cases of endometrial hyperplasia or malignancy. The authors concluded: "These findings provide reassurance about the long term safety of this continuous combined regimen in terms of the endometrium."
2. Osteoporosis prevention/treatment with natural estrogen. The first study looked at both the prevention of lost BMD and the recovery of it after the placebo group switched to the therapeutic medication. See Am J Obstet Gynecol 2001 Jan;184(2):32-40, Three-year follow-up of the use of transdermal 17beta-estradiol matrix patches for the prevention of bone loss in early postmenopausal women. Delmas PD and others, PMID: 11174476. The women in the study received multiple dosages of transdermal 17 beta-estradiol (Menorest) for two years, and then an additional one year of an open-label extension of the study. The study found, "Gains in bone mass were maintained in patients who received 3 years of active treatment. In patients originally randomly assigned to receive placebo, initial losses in bone mass during the first 2 years were reversed and replaced with marked increases after the switch to active treatment." In patients receiving treatment after placebo, lumbar spine BMD increases ranged from 2.77% to 7.36% depending upon transdermal patch dosage. The authors conclude: "The Menorest formulation of transdermal 17 beta-estradiol maintained BMD gains in postmenopausal women and was well tolerated through a 3-year treatment period. It was also effective in reversing the initial bone loss associated with late commencement of therapy." This second study also looked at BMD of the hip finding positive results using continuous 17 beta-estradiol in 1- or 2-mg doses along with cyclic dydrogesterone. See Osteoporos Int 2001;12(4):251-8, The prevention of osteoporosis using sequential low-dose hormone replacement therapy with estradiol-17 beta and dydrogesterone. Lees B and Stevenson JC. PMID: 11420773. The study included 595 healthy postmenopausal women using a two-year multicenter double-masked prospective randomized, placebo-controlled study. Women taking either 1- or 2-mg 17 beta-estradiol dosages showed significant increase of BMD in the spine and femoral neck of the hip. The placebo group had decreases in BMD at both sites. The oldest women had the greatest treatment response.
4. Summary. These studies indicate that 17 beta-estradiol in combination with various natural progesterone formulations is effective, safe, and that it positively influences serum lipid profiles and BMD. The fact that results of varying dosages can be easily tested, that various formulations allow either oral or transdermal usage with multiple dosages, permits individualization of HRT. Women can receive dosages and medication forms that best suit their needs, presenting symptoms, cardiac risk factors, and bone health status.
SERMs for HRT
Raloxifene (Evista) is a selective estrogen receptor modulator designed to give the benefits of long-term estrogen replacement therapy without the risks. As such, it should be evaluated as a form of HRT in discussion with your care provider, and a decision to use it should be based upon your specific needs and symptoms. For a review of raloxifene, see Ann N Y Acad Sci 2001 Dec;949:295-393, Raloxifene: risks and benefits. Barrett-Connor E. PMID 11795366.
1. Osteoporosis prevention and treatment, including increased BMD and decreased fracture risk.
2. Breast cancer reduction by as much as 76% over a three-year study period; no effect on endometrial bleeding, hyperplasia or cancer;
3. Raloxifene improves several heart disease risk factors, including lowering LDL cholesterol and apolipoprotein B levels without affecting triglycerides, as well as lowering homocysteine and fibrinogen levels. A large study is currently ongoing to see if raloxifene gives an altered risk for heart disease among women taking it who are at high risk for cardiovascular disease.
1. Venous thromboembolic events, which includes a tripling of such events in one study. (NOTE: See Ann Intern Med 2000 May 2;132(9)689-96, Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Grady D and others, PMID 10787361. Although this study was not with raloxifene, they did find increased thromboembolic events with the use of CEE/MPA in older women taking them. But, they found a 50% reduction in those women taking aspirin or statins. Whether the aspirin or statins would have the same effect when used with raloxifene is uncertain, but might be something to consider.)
2. Hot flashes were greater in young postmenopausal women taking raloxifene compared to placebo (24.6% vs. 18.3%). In older women the same was true, but by a smaller margin, with 9.7% vs. 6.4% the end result. Hot flashes tended to be mild in both studies and caused discontinuation less than 2% of the time. But, women with severe vasomotor symptoms were excluded from the studies.
3. A miscellaneous adverse event that might be significant was leg cramps were more common in the raloxifene group (7 % vs. 3.7%).
4. Although not included in this paper as a consideration, raloxifene has no effect on vaginal dryness which would be a benefit from estrogen HRT.
Summary. Raloxifene has benefits on several heart disease risk factors-sometimes more favorable than estrogen--but not always. Until the results of clinical trials shows a definite cardiovascular benefit from raloxifene, the jury is still out on this important issue. Given its definite benefit in breast cancer and fracture reduction, if it is found to be beneficial concerning heart disease, it will be a strong competitor with other forms of HRT. The risk of thromboembolic events with it have to be considered, too.
The recent literature has multiple references to Tibolone (Livial, Organon) as a form of HRT. From my readings it appears to be approved for use only in Europe and countries other than the U.S. and Canada at this time, but there are clinical trials that have been done in the U.S. This probably means that the manufacturer is currently seeking FDA approval of the medication. The articles and abstracts I've read are all positive, so I suggest women watch for media information on the approval of this medication since it should be given consideration in their decisions about HRT.
Review articles. For an overall picture of the benefits, effectiveness, and possible side effects of Tibolone, see Maturitas 1998 Nov 16;39(3):295-305, Tibolone: a review. Albertazzi P and others, PMID: 9881330. The author notes that tibolone appears to be as effective as other forms of HRT on climacteric symptoms. It causes no withdrawal bleeding, may help depression and increase libido more than other forms of HRT. It improves some lipid profile parameters including Lp(a) and triglyceride, but reduces HDL cholesterol. Tibolone has a positive benefit on peripheral blood vessel dilatation, as well as on markers of bone metabolism and bone mass, with effect on fracture risk still pending. For a more recent review, see J Clin Endocrinol Metab 2002 Jan;887(1):16-23, Tibolone for postmenopausal women: systematic review of randomized trials. Modelska K and Cummings S, PMID: 11788614. This review suggests that many of the studies on tibolone involve insufficient participants, or are otherwise lacking to enable drawing solid conclusion about its effectiveness yet. So, the benefits reported in them await confirmation in larger, well-done studies.
Tibolone compared to combined equine estrogen. See BJOG 2002 Aug;109(8):886-93, Effects of tibolone and continuous combined hormone replacement therapy on bleeding rates, quality of life and tolerability in postmenopausal women. Huber J and others, PMID: 12197367. The authors looked at 501 postmenopausal women under 65 years old taking either tibolone or conjugated equine estrogen (CEE) continuously for one year and in combination with medroxyprogesterone acetate 5 mg. They found that tibolone significantly lowered bleeding rate compared to CEE,. Both treatments improved quality of life, well being, reduced climacteric symptoms, and urogenital complaints. Additionally, tibolone significantly improved sexual drive, interest and/or performance compared with CEE at 12 months. There was also significantly reduced breast tenderness with tibilone.
Long term BMD results using tibolone. See Osteoporos Int 2001;12(6)478-83, Effects of 8 years of treatment with tibolone 2.5 mg daily on postmenopausal bone loss. Rymer J and others, PMID: 11446564. This study used 59 women (postmenopausal for 6-36 months) who had taken tibolone for 8 years and compared them with 51 controls. Using dual-energy X-ray absorptiometry they found increased BMD compared to baseline was 4.1% in the spine and 4.6% in the femoral neck. Over the same period bone density in the control group decreased in the spine by 7.5% and in the femur by 6.7%. An interesting finding was that adherence to the tibolone medication regimen was high when compared to other HRT therapies with 58% of women continuing to take tibolone for 8 years. Although this improved BMD would be expected to decrease fractures, that was not tested in this study and remains an issue with tibolone.
Cardiovascular effects of tibolone. There are too many studies to reference them all in this area. In general, the ones I've read indicate positive benefits for lipid profiles other than an decrease in HDL cholesterol. Here is one study that compared CEE to tibolone and compared cardiovascular risk factors. See Atherosclerosis 2002 Jan;160(1):185-93, A comparison of the effects of two continuous HRT regimens on cardiovascular risk factors. Barnes, JF and others, PMID: 11755937. This study found that, "Between treatment effects were significantly different on triglycerides, HDL cholesterol, LDL oxidation, and LDLI+II:LDLIII ratio. The reduction in LDL induced by the continuous combined therapy is likely to be beneficial, despite the apparent shift towards the LDLIII subfraction. Changes in oxidisability and subfraction profile of LDL indicate that tibolone may have a more favorable effect on cardiovascular risk than previously suggested." So, in general, the cardiovascular effects of Tibolone appear to be beneficial, but controlled clinical trials comparing cardiovascular events are warranted before making a final decision as to the cardiovascular safety of tibolone.
Non-hormonal osteoporosis prevention/treatment
There are multiple FDA-approved medications to deal with the implications of postmenopausal bone loss. These include the bisphosphonates, such as alendronate (Fosamax) and risedronate (Actonel), human parathyroid hormone (Forteo), and Calcitonin (Calcimar). For women who have no vasomotor or other symptoms after menopause, one of these approved medications may be the route to prevent normal rapid postmenopausal bone loss. This preventive role has heretofore mainly been given to HRT, whose use is now in question. So, it is important for women and their care providers to realize that alendronate has been shown effective at preventing postmenopausal bone loss. See Ann Intern Med 1998 Feb 15;128(4):313-4, Alendronate prevents postmenopausal bone loss in women without osteoporosis. A double-blind, randomized, controlled trial. Alendronate Osteoporosis Prevention Study Group. McClung M and others, PMID: 9471927. In 447 women 6 to 36 months after menopause, women received either placebo, 1, 5, 10 mg/d, or 20 mg/d of oral alendronate for 2 years followed by placebo during the third year. Bone density measurements showed all alendronate dosages above 5 mg/d increased BMD from 1-4% while the placebo group lost from 2-4% of BMD during the study. The authors concluded: "In early postmenopausal women, alendronate given for 3 years at dosages of 5 mg/d or greater prevented the loss of BMD at the spine and hip and in the total body. Alendronate seems to be a safe and effective nonhormonal option for prevention of postmenopausal bone loss." (NOTE: All women in this study took a 500 mg calcium tablet daily or had a minimum of 1 gm calcium via their diet daily. Once gain, this shows that calcium doesn't prevent postmenopausal bone loss).
From the information presented, it appears that women must work with their care providers to determine their need for HRT on an individual basis, deciding for or against HRT based upon symptoms, age, risk factors, etc. If HRT is warranted, the safest and most effective therapy available should be used, with annual determination of effectiveness, followed by adjustments, as needed. Just taking additional dietary or supplemental calcium will not prevent or treat postmenopausal decreases of BMD. And, even though postmenopausal women are on HRT, their BMD must still be monitored since osteopenia and osteoporosis can occur while taking HRT. If HRT is not warranted or wanted, one of the approved nonhormonal therapies for prevention/treatment of osteoporosis may be indicated. If and when tibolone is approved by the FDA, it must be given consideration for women evaluating HRT options.
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