Hormone Replacement Therapy bites the dust, again

Subject: Recent data reaffirm early reports that HRT does not decrease risk of cardiovascular disease but does increase risk of other diseases including breast cancer. The new data is consistent with earlier predictions and reaffirms our opinion that using natural hormones is preferable over synthetic hormones.

We have had numerous calls and questions over the last few weeks since the Women's Health Initiative (WHI) announced that they were discontinuing their study using combination hormone replacement therapy (HRT). The media and the medical community have acted surprised by this turn of events. The editor of the Journal of the American Medical Association, herself a user of HRT, described herself as, "Flabbergasted." in an interview on All Things Considered.

I have promised that I would write a letter explaining this calamitous change of events. The truth is little is new. The information hasn't changed significantly. The only thing different is the news media noticed this time. In canceling the study WHI had to send out letters to the 16, 608 women participating in the study telling them why. Women using HRT are more likely to get strokes, heart attacks, blood clots and breast cancer than women who are not. Though this information goes against the many promotional advertising claims used to sell these products over the years, it is consistent with earlier research.

Let me start at the beginning and try to put some prospective on these issues. Actually let me do a little cut and paste. The following is a newsletter we sent out in March of 2,000:

'HRT: No protection against heart attacks'

Over the last twenty or so years when a woman has debated with her doctor about whether she should use hormone replacement therapy (HRT), the arguments have been fairly standard.
On the negative side using HRT may increase the risk of eventually developing breast cancer. It is pretty well accepted that there is about an 8-10% increase in risk for every year on HRT.
On the plus side HRT helps maintain bone density and delay osteoporosis. This has not been doubted. But even for women not at risk for osteoporosis, HRT has been heavily promoted for cardiovascular protection. Early epidemiological studies on HRT suggested that it had a profound effect on cardiovascular disease, reducing heart attacks by half or more. Though these studies were frequently criticized for methodology, the patients were not randomized and estrogen users were healthier to begin with and continued to take better care of themselves, the numbers were compelling and many women were put on HRT as a cardiac protective. Over the last few years, the idea that HRT prevented heart attacks has gone up in smoke. In 1998 JAMA published data from the HERS Project, a thoroughly done randomized study of HRT that shook up the research community. This study was designed to be the final proof that would silence all doubters. 'HERS is the largest trial of any intervention to reduce the risk of recurrent CHD events in women with heart disease and is the first controlled trial to seek evidence of the efficacy and safety of postmenopausal hormone therapy to prevent recurrent CHD events.'[1] The results were not what was expected: HRT did nothing to protect women: 'Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes.............The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD.'[2] The tide of opinion among researchers has changed: 'Clearly, the use of HRT for secondary prevention of heart disease is more complex than was initially believed...............Until further data are available, clinicians should not use estrogen plus medroxyprogesterone for the sole purpose of secondary prevention of CHD.'[3] Hormone Replacement Therapy has its pros and cons. Preventing heart disease is no longer a reason to use this therapy.

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When I sent out this story the news wasn't a surprise. The studies I quoted are four years old now. Looking trough my files I find an earlier article we sent out titled, 'Another story the newspapers missed: Premarin bites the dust.' A 1995 JAMA article predicted premarin's ineffectiveness against heart disease by watching cholesterol profiles of users. Estrogen alone improved the HDL/cholesterol ratio. Adding natural progesterone produced a very slight decrease in overall improvement. But adding artificial progestins (as used in the current WHI study) completely negated any positive effect seen.[4] That was seven years ago.

So where do we stand with hormone replacement therapy?
Hormone replacement therapy raises the risk of breast cancer, roughly about 10% for each year using the medication. It also raises risk for some other cancers including ovarian cancer. Using estrogen without opposition of a progestin or progesterone, quickly increases the risk for uterine cancer to unacceptable levels. It is unethical for a doctor to prescribe estrogen without an opposing progestin to a woman with a uterus. HRT increase the risk of blood clots and stroke. Estrogen alone may be protective against heart disease but the protection is negated by adding synthetic progestin (Prempro) to the degree that HRT users are more likely to have heart attacks than non users. There is evidence that natural progesterone does not have the same negative effects as the synthetic progestins and might still allow the cardioprotection from estrogen to continue.

Let's look at the synthetic progestin which is used in HRT studies. It is a chemical called medroxyprogesterone acetate, marketed under the trade name Prempro. Though frequently called progesterone by the media, it is not progesterone. Technically it is a progestin, one of a number of chemicals which effect the body in a manner similar to progesterone.
Similar but not identical. It is not made in the human body and is a metabolic endpoint: the body cannot convert it to other usable hormones or chemicals as it does with progesterone. Prempro is frequently blamed for many adverse side effects in users. The Physician's Desk Reference (PDR) list of possible adverse side effects associated is so long that I'm not going to copy it here. It ranges from birth defects to strokes and then some. It has long been known that many of the progestins diminish the presumed beneficial effects of estrogen.[5] It looks like Prempro needs to be added to the list of progestins that cause problems.
Real progesterone, the hormone that is secreted by the corpus luteum formed in the ovary after a mature egg has ruptured through the membrane and begins its descent of the Fallopian Tubes, is very different from the synthetic progestins used in these heart disease studies. It produces a wide range of beneficial effects in the body. It is not a metabolic dead end. Enzymes in the body convert it into a range of other useful hormones. While Prempro is dangerous during pregnancy, inducing birth defects, progesterone is used to treat infertility and prevent miscarriages. The only side effect I know of in pregnant women is that their offspring have higher IQs. The PDR does not list side effects for progesterone. Whole books have been written praising the benefits of using progesterone. So why are synthetic progestins used? There are two reasons.
When HRT was developed no one knew how to get progesterone into the body by oral administration. The hormone was destroyed before it reached the circulatory system. Short of injecting it by hypodermic, there was no known way to administer it. Since then, several ways have been developed to administer progesterone. The simplest is to incorporate it into a skin cream. The hormone is absorbed slowly through the skin and into the blood system. Bypassing digestion and the liver first pass effect, small doses of progesterone have relatively significant effects on the body. The second method is to microencapsulate the progesterone in tiny pellets which when administered orally are absorbed without being degraded.
The second reason why synthetic progestins are used rather than natural progesterone is that they are profitable. Progesterone is a natural substance manufactured in the bodies of half of the world's population. A company cannot patent it. If a company cannot own progesterone as their trademarked product, why promote it? Another company could market the same product and steal your profits. Instead the money is in developing synthetic progestins which are patentable.

Lack of patentability unfortunately has had another effect. No company has funded the long term studies, such as the WHI study, on the use of progesterone and heart disease. All the smaller studies which compare it to the synthetic progestins suggest it will be protective, but these lack the size and scope to be as conclusive as one would like. Yet the idea that progesterone is safer and possibly beneficial makes simple sense.
The WHI study gave women Premarin, an equine estrogen. That is an estrogen made by female horses which is extracted from their urine. The WHI study used Prempro a synthetic chemical that no living organism can produce. This combination of HRT though it works, produces side effects. Are we surprised?

We have put women on various programs of HRT for years. Rather than using the heavily marketed patentable drugs we use what are best described as 'natural hormones.' This is a confusing term. They are not natural: we do not isolate them from horse urine or placentas. They are manufactured from plant extracts, mostly soy bean and Mexican wild yam. They are enzymatically converted into estrogens and progesterone that look identical to the ones made in the human body. A better term which has gaining acceptance is to call them 'bioidentical hormones.' We use low doses of hormones identical to what the body produces. This seems to make more sense than high doses of Premarin and Prempro. With estrogens we utilize the varied different estrogens made in the body and dose them in the same proportion that they are naturally found.

What about estrogen and breast cancer? We have no evidence that natural estrogens will raise the risk for breast cancer the way Premarin does.
At the same time we have no evidence that it will not. Again nobody is funding the large scale trials needed to determine this. There are good theories why natural hormones should be safer, but as yet unproven. The more estrogen a woman is exposed to in her lifetime the greater the odds of developing breast cancer. Even the natural hormones need to be used with caution.

Recent research is laying the framework for a number of new perspectives on estrogen and breast cancer. New theories are suggesting that instead of estrogen being the bad guy which causes breast cancer, some of the breakdown products of estrogen are the culprits. Estrogen is broken down in the body into other related chemical compounds. Certain ones of these estrogen breakdown products are now being spoken of as the bad guys in breast cancer development. Others are being described as good guys in cancer prevention. This is one of the most exciting developments in cancer research and gives us new opportunities for cancer prevention. Expect to see me writing about this at length in the near future.

In the meantime if you have any questions about HRT, please feel free to contact us.

references:
1. Grady D, Applegate W, Bush T, Furberg C, Riggs B, Hulley SB .Heart and Estrogen/progestin Replacement Study (HERS): design, methods, and baseline characteristics. Control Clin Trials 1998 Aug;19(4):314-35
2. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998 Aug 19;280(7):605-13
3. Wells G, Herrington DM. The Heart and Estrogen/Progestin Replacement Study: what have we learned and what questions remain? Drugs Aging 1999 Dec;15(6):419-22
4. The Writing Group for the PEPI trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995:273:199-208.
5. Ottoson UB, Johansson BG, von Schoultz. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestins and natural progesterone. Am J Obstet Gynecol 1985;151:746-750.