My take on HRT
Recently on the Today Show on NBC, Dr. Susan Love was interviewed as an expert on HRT for women. She has written a book, Dr. Susan Love’s Menopause and Hormone Book. In her interview she stated that it is essentially normal for women to quit producing hormones at menopause and they don’t need them replaced, or certainly for no more than three to five years. She said this is because that is normal and it is like the opposite of what happens as women go through puberty. I would like to offer my opinion of her statements with which I disagree.
First, it has not always been normal for women to stop producing hormones, it is only "normal" during the last century or so that women have been on this planet. Before that it was normal for women to die before hormone production stopped, indeed human life expectancy in the U.S. was only 47 years in 1900. Thus the natural system protected women for their expected life span, so why would there be a need to produce hormones longer than 50 years? Only through modern science overriding evolution is it now possible for women to live beyond the time when their bodies stop producing hormones. To believe Dr. Love's concepts, you have to believe that something that was virtually totally healthy at age 50 has now become unhealthy at age 51. I simply can't accept that. I do believe that science may not have figured out the correct form or way to replace the hormones that are no longer produced after menopause. But, if they do replace them with ones that mimic what women produced naturally as closely as possible, I have to believe they have improved that woman's health and increased her chances of a long life. Concomitantly, if they replace her natural hormones with the improper ones, they appear to be able to negatively impact her health and life expectancy.
Now that science has extended women’s life span, it is essential that women take advantage of that extended period. If they are unhealthier without hormones, then they risk not taking full advantage of what modern science can offer. Or, if they add hormones, but don’t increase their health, they take the same risk. The problem is there is no one single study to show women what to do, their only option right now is to piece together several interrelated studies and hope those results fit together to give a healthier and longer life. In my doing that, here is what I have come up with. I hope you come to the same conclusions. (A reminder of my disclaimer. I'm not a physician, and I'm not recommending you follow my advice nor am I even giving advice--I'm just reporting on my findings. I'm suggesting you educate yourself, speak to your physician, and between the two of you decide what is best for you.)
So, if it is not normal to quit producing hormones, why do women develop increased risk for breast cancer, blood clots, and heart disease when placed on HRT? From the studies done, which are by no means complete yet, that could possibly be due to: 1) The unnatural forms of HRT that are currently in use. That is, young healthy premenopausal women don’t make horse estrogen and they don’t make artificial progesterone. They don’t take their hormones in a pill and by mouth. 2) The level of the body’s estrogen has to be at least 80 picogram/ml or the beneficial effects of their natural estrogen production are not achieved. So, to give postmenopausal women unnatural forms of estrogen and progesterone, or to give them natural forms but in a suboptimal dose is not truly HRT. 3) Few if any HRT studies have followed women who started HRT right at menopause and continued it for several years. Instead, most studies have started HRT in women who are from 15 to 20 years after menopause. It is invalid logic to apply results from HRT studies on women started on therapy 20 years after menopause to women who would start it at menopause. Just as it is invalid to assume that results with CEE/MPA would apply to other forms of estrogen/progestin therapies. Yet this is exactly what is happening, and not just from the general practitioners, even the so called experts are drawing conclusions that aren’t logically possible from the studies that have been done. To help you interpret the conflicting information, I will repeat what I said in the HRT Web site that if you only have time to read one article it should be the one by de Lignieres B and MacGregor EA in Cephalagia 2000 Apr;20(3):164-9. You must get a copy of this article, read and understand it, and then take it to your care provider.
Based upon de Lignieres’ article and many subsequent articles that have verified the statements in it, women need transdermal 17 beta-estradiol in sufficient strength to produce 80 picogram/ml, and they need micronized progesterone for 10 or more days per month if they have their uterus. And, as noted in the de Lignieres article, there is some evidence that women need the progesterone in order to lower their risk of breast cancer whether they have a uterus or not. (Note, I suspect other progestins which are nonandrogenic will be found to be as safe and effective as micronized progesterone. But, these will be those progestins called gonanes. Examples include norgestimate and desogestrel, which I don’t believe are available in this country other than when combined with oral estradiol).
Pros and cons of transdermal HRT.
1. CAD risk increases only if estrogens are not replaced after surgical menopause. Neither CEE nor transdermal 17 beta-estradiol (TE2) impacted serum lipid profiles when given immediately after surgical menopause to premenopausal women. See Fertil Steril 1994 Feb;61(2):300-2, Erenus M and others. This is logical and to be expected since young premenopausal women have normal serum lipid profiles. It is only starting at about two years before menopause and continuing after menopause that serum lipid profiles become more atherogenic and place women at higher risk of coronary artery disease (CAD). See Maturitas 1990;12:321-331, Jensen J and others. If women take no form of HRT or do nothing else to reduce this increased risk of CAD caused by menopause, they are at higher risk than they were before menopause. A woman not taking HRT must understand this. This makes the monitoring of women's serum lipid profiles just prior to and after menopause very important. If that profile becomes significantly negative, the woman needs to discuss proper HRT with her physician since there appears to be only this one-time opportunity to retain the benefits of HRT: Right at menopause, not later. Think of this like using rust-preventing undercoating on your car. You can't apply this ten years after you buy the car and expect to prevent rust. It must be applied at or before you start driving the car. Similarly HRT can't be started 10 years after menopause and be expected to have cardiovascular benefits, the damage is irreversible at that time.
2. If women start nonoral 17 beta-estradiol the first year after menopause, carotid artery IMT does not thicken with age. This study by Tremollieres FA and others is in Atherosclerosis 2000 Nov;153(1):81-8. Women age 55 and older treated long term with nonoral 17 beta-estradiol had significantly lower total cholesterol levels than untreated women (P=0.005). Carotid artery IMT was significantly correlated to age in never users of HRT (P<0.0001), but not in women who were currently receiving HRT (r=0.2, ns). The authors conclude, "These findings suggest an apparent protective effect of long-term HRT on age-related thickening of the intima-media of the right common carotid artery." If the carotid artery intima-media thickens, this corresponds to increased risk of CAD. Note these women started HRT at or shortly after menopause and continued it long term, they did not start it twenty years after menopause. Women starting HRT that late in life should not expect similar results, nor any benefit for that matter.
3. TE2 is beneficial to the serum lipid profile and cardiac risk factors. This first study is by Bongard V and others reported in Maturitas 1998 Nov 16;30(#):265-72. Using TE2 on 693 postmenopausal women, the authors found significantly improved serum lipid profiles for everything tested other than HDL-cholesterol and apolipoprotein A1 (transports HDL-cholesterol). They concluded, "Transdermal ERT may confer a cardiovascular protection by lowering atherogenic lipoproteins. The next study is by Nieto JJ and others reported in Obstet Gynecol 2000 Jan;95(1):111-4. Oral HRT in general increases HDL-cholesterol, but also increases triglycerides, thus there may be no overall benefit. In this study, they showed that TE2 when combined with dydrogesterone was able to increase HDL-cholesterol without increasing triglycerides. This would appear to improve the serum lipid profile of TE2 compared to oral HRT. The next study by Wakatsuki A and others is in Circulation 2002 Oct 1;106(14):1771-6. It compared CEE and TE2 as to their effect on particle size and oxidative susceptibility of LDL-cholesterol particles. Their findings were very positive for TE2 and negative for CEE. Basically, TE2 decreases plasma triglyceride and produces larger LDL particles that are resistant to oxidation, this preserves the natural effect of estrogen, which is beneficial. CEE overides this beneficial effect. The next study is by Post MS and others in Thromb Haemost 2002 Oct;88(4):605-10. C-reactive protein (CRP) is a known risk factor for CAD. Women on CEE and other oral HRT may be at increased risk for CAD the first year of therapy, which could be due to increased levels of CRP. This study showed that TE2 didn't effect CRP levels during this 15-month trial. However, oral estradiol increased CRP by 75% compared to placebo. The next study is by Kvasnicka J Jr. and Zivny J reported in Ceska Bynekol 2001 May;66(3):161-5. This study looked at three risk factors for atherosclerosis: CRP, and two soluble adhesion molecules, sE-selectin and sICAM-1. After four months of TE2 HRT, all three risk factors were significantly lower than before therapy started. The last study compared oral CEE to TE2 as to their effect on CRP. It is by Decensi A and others and is in Circulation 2002 Sep 3;106(10):1224-8. This study found elevated CRP levels in postmenopausal women on oral CEE at both six and twelve months of therapy, 48% and 64%, respectively. Whereas CRP increased only 10% and 3% at six and twelve months, respectively for TE2 users. This could possibly explain the increased risk of CAD in women on CEE during their first year of therapy.
4. Progestins and breast cancer. This first study is by de Lignieres B in Climacteric 2002 Sep;5(3):229-35. Mitogenic activity is increased in breast tissue when CEE/MPA is used as HRT, but not when TE2 is used with micronized progesterone. This could explain the increased risk of breast cancer in studies that use only CEE/MPA for HRT. The second study is by Lundstrom E and others in Climacteric 2001 Mar;4(1):42-8. Postmenopausal women on CEE/MPA developed increased breast density 40% of the time whereas women on oral estrogen (estriol 2 mg/day), or TE2 developed increased breast density 6% and 2%, respectively. Increased breast density is considered a risk factor for breast cancer, especially before menopause. Whether it is after menopause is still in question. But this appears to be another plus for TE2.
5. TE2 and thromboembolisms. One of the findings of the WHI was increased risk of thromboembolism (blood clots which break loose and cause strokes, pulmonary embolism, etc.) with CEE/MPA usage. There are two important elements to blood clotting: The coagulation or formation of the clot and the breakdown or fibrinolysis. Several factors can be involved for both elements and can make the blood at increased or decreased risk of clotting, or can make a clot breakdown faster or slower. The first study on this part of HRT is by Scarabin PY and others in Aterioscler Thromb Vasc Biol 1997 Nov;17(11):3071-8. This study showed little effect on coagulation or fibrinolysis with TE2, whereas the oral route had significant effects on both coagulation and fibrinolysis factors. The next study is by Luyer MD and others in J Clin Endocrinol Metab 2001 Aug;86(8):3629-34. These researchers looked at the effects of unopposed CEE on markers of coagulation and inflammation finding clotting inhibitors were decreased in concentration. This could lower the threshold for a thombotic event.
Problems with CEE/MPA. This study is by Adams MR and others reported in Arterioscler Thromb Vasc Biol 1997 Jan;17(1):217-21. The study was done on surgically postmenopausal monkeys using CEE alone or CEE/MPA combined therapy. CEE alone reduced atherosclerotic plaques by 72% compared to controls. But, when MPA was added to CEE, there was no difference in plaques compared to controls--this in spite of the fact that plasma lipoprotein patterns were improved by the CEE/MPA therapy. In a similar study using implanted 17 beta-estradiol with or without cyclic progesterone on surgically menopausal monkeys, there was no difference in improvement of atherosclerotic plaques with or without progesterone. There was about a 50% improvement either way compared to non-treated controls, once again irrespective of the serum lipid profile results. See the article by Adams MR and others in Arteriosclerosis 1990 Nov-Dec;10(6):1051-7. Thus there is more involved than just looking at serum lipid profiles with HRT. As these studies show, various combinations of estrogen/progestin can have drastically different effects on CAD. These aren't theoretical improvements, they are shown at necropsy making them as objective as possible. These finding can be combined with those noted above that CEE increases CRP levels, produces larger LDL particles with increased risk for oxidation, that it increases triglyceride levels, and elevates hemostatic risk factors.
Bottom line. This brief summary appears to give the edge for safety and effectiveness to TE2, especially when compared to CEE/MPA. There are multiple estrogen patches available with or without a progestin component. Climara is a once-weekly patch which would need oral or micronized progesterone cream to avoid uterine complications as appropriate, and there is a generic form of this patch available. Prometrium is a recently FDA-approved capsule of micronized progesterone, one of the safest and most natural progestins available. The 200-mg daily dose taken at night to avoid drowsiness is recommended. If an oral estradiol is desired or needed, Ortho-Prefest(TM) appears to have one of the best risk/reward ratios. Particularly the norgestimate progestin used with it doesn't negatively impact the beneficial results of the oral estradiol on cardiac risk factors. See Am J Cardiol 2002 Jun 20;89(12 Suppl):47E-55E; discussion 54E-55E by Shulman LP.