Customizing Hormone Replacement Therapy


From ACOG - Philadelphia, Pennsylvania - May, 1999


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Professor Rivard: "I'm Robert Rivard, Professor and Chair of the Department of Obstetrics and Gynecology at the University of Cincinnati College of Medicine. I'm here today with Dr. Bruce Ettinger, who is principle investigator - a senior investigator - at Kaiser Permanante in Oakland, California. We're here to talk about hormone replacement therapy and customizing therapy. Dr. Ettinger, you've had an interest in low dose estrogen therapy for many years."

Dr. Ettinger: "Absolutely, that's one of my favorite topics. We started in this field about fifteen years ago with some bone studies, and it's interesting to see how many others have come along in the last several years showing that low dose estrogen is adequate to prevent bone loss at the time of menopause and does a pretty good job of relieving menopausal symptoms."

Professor Rivard: "Now you're also a proponent of, if you will, cyclic therapy - but you have taken a look in the past and are giving a progesterone at less frequent intervals than once each month."

Dr. Ettinger: "Yes, but I like to call this long cycle therapy. We did a study and published that a few years ago in Obstetrics and Gynecology, looking at every three-month cycling using standard hormone replacement therapy and showed that that was safe - about a 1% hyperplasia rate at the end of one year and another 1% at the end of a second year. We're now about halfway through a very interesting study using both a low dose and a longer cycle that, I think, will be really revolutionary. What we've done is switched women from standard dose monthly cyclic HRT .625 with conjugated estrogens and cyclic monthly MPA to a low dose, half strength every six-month progesterone cycle. We're using an esterified estrogen Estratab .3 and we've actually gotten all the women into the study, 138 women, to switch from the standard dose monthly to the half strength every six-month - and you have some very interesting preliminary data. We really were interested in two aspects, one - would this be acceptable to women? Would there be a problem with symptoms when they made the switch, and would the bleeding pattern be acceptable? And we're very pleased to see that in both regards we're doing quite well. These 138 women had been on HRT for an average of nine years so they were pretty satisfied with their standard monthly HRT. Yet they were able to make the switch, and only 10% of them had any increase in vasomotor symptoms - so 90% of women had adequate control of hot flashes and night sweats, etc. and were happy to be on this. In fact, in addition to the good control of vasomotor symptoms, overall there was a reduction in both psychological and somatic symptom scores so women had less breast tenderness, less headache, less irritability, and less mood disturbance when they switched from standard dose to the low dose. From the point of view of bleeding, we looked at two things - one was the breakthrough bleeding that would occur during the six months of unopposed low dose estrogen, and we found just 9% of the women had any breakthrough bleeding. In fact, it was very close to the 6% breakthrough bleeding rate that these women had had previously on their monthly regiment. So breakthrough bleeding didn't appear to be a problem. What was a big surprise for us was that 60% of these women did not have significant withdrawal bleeding when they took their Medroxyprogesterone after six months. We gave them MPA 10 mg a day, for fourteen days - we wanted to be very conservative and give a very adequate amount of progesterone. Even after that much progesterone the bleeding, if there was any, was quite light so only 4% of the cohort had heavy periods compared to 28% that had reported heavy periods on their monthly standard dose of HRT. So 60% - no bleeding, very low incidence of heavy bleeding, relatively shorter cycles, and shorter duration of bleeding. So all of that, I think, says that this regiment is going to be very acceptable for women who want safety with this approach.

Professor Rivard: " What about the long term data for women who want safety with this approach?"

Dr. Ettinger: "Now that's a very important question. Our study is designed for one year, and we have done endometrial biopsies in all of these 138 women at baseline so we know that they do not have any endometrial hyperplasia to begin with. We will be repeating their biopsies as they close out their second cycle. Those first biopsies are going to be done in the next few weeks, and over the next six months we'll complete the study, so by early 2000 we should have all of the endometrial safety data. We're hoping that we can come up with the same low incidence of endometrial hyperplasia that we found in our previous study with every three-month cycling. We have good reason to believe that that will be the case. You know the esterified estrogen study that was published in the Archives of Internal Medicine - two year, unopposed, .3 mg had less than 2% hyperplasia rate, a rate that was actually similar to the placebo in that study. Of course .625 mg and higher doses have had higher rates but this was a remarkably low incidence of endometrial hyperplasia with .3 mg unopposed, and here we're giving very good opposition every six months. So we hope to get in that same range of about 1% or less hyperplasia."

Professor Rivard: "How about protection of bone and cardiovascular effects?"

Dr. Ettinger: "I think, of the best bone data that's out, in terms of the quality of the studies on esterified estrogens is the study that was published in the archives - Genant, was the first author in December 1997, had about one-hundred women in each arm of the study - one-hundred on placebo, one-hundred on .3 mg, one-hundred on .625 mg, and one-hundred on 1.25 mg. It was very convincing that the .3 mg was adequate to protect against bone loss over this two-year period. All of the women received calcium in that study, and I think that's an important element that total calcium intake of 1200 mg a day helps the estrogen to work better. I understand now that esterified estrogen testing approved the .3 mg dose by the FDA for prevention of osteoporosis. Of course, there are several other estrogens in the low dose category that are also being approved or considered for osteoporosis prevention. So I think it's just a matter of time until we are using half strength estrogens for prevention of osteoporosis in a much more wide spread fashion. Currently only 13% of women in northern California Kaiser are using half strength estrogen, it goes up to about 18-19% for women over age 65 but it's still a minority of women that are taking advantage of the benefits of low dose estrogen. I really think the benefits are the convenience, the lack of side effects, and probably in the long run - a safer regiment for women to be on. Now you did ask about cardiovascular disease, and that's a tough one because there aren't that many women who have been on .3 mg for a very long period of time. We don't have rock solid data on this, and we know that the half strength estrogen has a smaller effect on HDL than LDL cholesterol but the nurse's health study produced some very interesting data a few years ago in the New England Journal of Medicine. They showed that compared to women who weren't using hormone therapy at all, that those on .3 mg or the equivalent of a half strength estrogen, had about the same degree of cardio protection - around 45-46% reduction in MI rates as those on .625 mg and that women who use higher doses have less cardio protection. That's really interesting, and I think it makes us rethink about the mechanism - the way that estrogen is working to reduce heart disease may not be all that HDL-LDL dependant. There are a lot of other factors - the beta receptors that were now discovered in the endothelium that are very sensitive to small amounts of estrogen and other mechanisms whereby, a small amount of estrogen could protect against heart disease without having a big effect on HDL and LDL."

Professor Rivard: "So who is the ideal candidate for this kind of therapy to your way of thinking?"

Dr. Ettinger: "In my practice, I typically give standard dose estrogen to women who are very symptomatic at menopause, and who are having a lot of hot flashes and sweats. I will typically use a monthly cyclic regiment for them because the continuous combined is terrible for breakthrough bleeding and irregular bleeding at that time - right at the menopause transition. But if a woman is on HRT and she likes the way she feels, and she wants to continue it for the long term benefits, then I typically transition after a couple of years to a half strength estrogen. I think the choice right now is half strength estrogen with long cycle either the three-month cycle or if our six-month cycle works out or a low dose half strength with continuous combined. I know there are some studies ongoing looking at continuous combined half strength estrogen and the hope there is that we can get by with half as much progesterone. I think in a year or so we'll see those studies. So there are a lot of new options, and physicians are going to have to learn the new ways of using low dose estrogen."

Professor Rivard: "Bruce, I want to thank you for sharing your data with us. I'm sure we're all going to be looking forward to the completion of the study and the final presentation and publication of these results. Thank you again, Dr. Bruce Ettinger, from the Kaiser Clinic."

Dr. Ettinger: "Thanks so much."

Dr. Ettinger's Slide Presentation "Long-Cycle, Low-Dosage HRT Using Esterified Estrogens, (Estratab)" can be acessed here.



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