Discussing Hormone Replacement Therapy

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Dr. Mark Perloe: "I'm here with Dr. Genazzani and Dr. Carp. Can you tell us about your practice and where you're in practice?"

Professor Andrea Genazzani: "Yes, I am a Professor of Gynecology and Obstetrics in the University of Pisa in Italy."

Dr. Mark Perloe: "And Dr. Carp."

Dr. Howard Carp: "Yes, I'm senior lecturer in Obstetrics and Gynecology and Embryology and Teratology at the University of Tel Aviv in Israel."

Dr. Mark Perloe: "Thank you. Dr. Genazzani, you spoke earlier on menopause, and I hear that you have a conference coming up. Can you tell us a bit about the conference?"

Professor Andrea Genazzani: "Yes, we will organize for the 8th World Congress of Gynecological Endocrinology in Florence in December of 2000. This is a conference, which came after our previous venues in Buenos Aries, Barcelona, and others. We expect to have more than 2,000 people and all the areas of gynecological endocrinology will be analyzed starting from the embryonic function to the counsel of the other function to the placenta in pregnancy and then also we will move on to the effect of hormones on cancer tissues and how to manage the postmenopausal woman, how to take care of the pelvic floor disorders and as you can see a series of items will be covered."

Dr. Mark Perloe:: "Thank you."

Dr. Howard Carp: "Professor Genazzani, I was very interested to hear your lecture which you gave just a little while ago in the conference in which you were speaking about hormone replacement therapy after menopause. I think one of the things you mentioned was what are the indications. Is hormonal replacement therapy indicated for all patients, is it a preventative measure, is it just for some patients, and is it treatment for symptoms?"

Professor Andrea Genazzani: "I think that it's difficult to give a general answer. Certainly the hormone replacement therapy after menopause is treatment for symptoms but it's also very efficient therapy to prevent diseases later on then for it's positive effect on cardiovascular levels, for the prevention of osteoporosis, for the measure effect on the brain. I think it's conceivable for a woman without symptoms to start the therapy to prevent possible diseases later on. Mostly women are coming in from the symptoms, and their symptoms are not only the hot flashes or insomnia but are also other symptoms of the changes in the hormonal age that affect the female population. They don't accept having to watch their weight and the changes in the quality of their skin, and the quality of the mucosa. I think better attention from the general practitioner or the specialist should be on how the female body acts in regard to hormone deprivation right after menopause. This is considerable now, and I think a woman can start therapy and the therapy can be changed throughout the years because as long as she's under therapy, her body is changing so she will need different amounts of hormones at different times. There are also other therapies that can be done after the first year after menopause. They are considered to not only treat a woman for the preventative effect on the womb and on the cardiovascular but also to prevent some possible problems that she has by the fact that she has taken the estrogen therapy for ten years."

Dr. Mark Perloe: "We've had a lot of new estrogen replacement therapies and routes of administrations and protocols that have come in front of us. I think it's a bit confusing for physicians to understand both the safety and the efficacy of each of these various methods in relieving these symptoms. What are your comments on that?"

Professor Andrea Genazzani: "I agree completely with you but you know human beings are so different from one to another. So it's considerable, you don't have the same therapy for everybody. It would be impossible to treat all women with the same therapy. Some of them need other therapies, some need smaller doses, some higher doses, some may prefer the patches of administration or they prefer to have them by administration by any kind of gel or any other therapy. I think gynecologists now can provide general practitioners and the other specialists a variety of therapies because they are facing a variety of individuals. Not only do we now have hormonal replacement therapy with estrogen and progesterone but also it's conceivable now that after ten years of hormone replacement therapy, the woman can start with selective estrogen receptor modulators or other kinds of therapy when she's no longer symptomatic, and when she wants again to prevent the possible risk acquired and linked to the estrogen administration for a long time and also to prevent the bone deterioration and cardiovascular irregularities. I think we are facing forewarnings of the scientists to women to try not only to prolong their lives but to reduce the period of validity they have in the last five years of their life when the osteoporosis, the cardiovascular changes, and all the problems that a woman has, that can give absolute deterioration of the quality of life"

Dr. Howard Carp: "You mentioned in your lecture some of the problems a patient complains about, some patients might have bleeding during the time or after a course of hormonal replacement. Do you think women are getting enough supportive therapy when the side effects come up but they will still continue with treatment, particularly you mentioned the SERM, sometimes the symptoms such as hot flashes may come back. Is there still enough support in your opinion?"

Professor Andrea Genazzani: "I think we have to personalize the therapy. Concerning the bleeding, we have to change the therapy to correct the regular bleeding, such as menstrual bleeding, or in any case to correct the irregular bleeding. These are the things that women don't accept. Concerning the SERMs, for that reason I sustain that some are useful later on after menopause but not at the moment of the menopause because they activate in some subjects the hot flashes, and the hot flashes are symptoms. I think we have the experience from many studies that even though the woman start again, after a few months the hot flashes will disappear, The entity is absolutely not putting out some of the therapy for the patient, this was our experience. But certainly I believe that the woman has to ask the doctor when she's under therapy to personalize the therapy and she needs measure control."

Dr. Mark Perloe: "Many of the women that we see either have had thrombotic events in the past or as part of their screening for recurrent pregnancy loss or pregnancy complications. People have looked at various clotting factors such as Factor X Leiden and the like and have said that if these clotting factors are abnormal or there's been a past history, then estrogen is contraindicated. The only one hormone replacement that I'm aware of now that is not contraindicated is tibolone in that environment. Have you had experience with this or how do you redress the needs of that patient population?"

Professor Andrea Genazzani: "Yes, we also have an analogue of PSA tibolone for many years. First of all, the women who have real clotting problems, it's not so big and certainly estrogen that also serves to activate their clotting system. For that reason, they remain a risk factor, and tibolone doesn't seem to effect the clotting system in the same way even though tibolone also has estrogenic effects. I think it's very important that doctors make some kind of screening, mostly on an annual or periodic basis. We don't need to at each exam but certainly as a screening exam. But when on an screening basis you can be aware that it can be a possible risk, then I agree that you can measure those parameters which can indicate easy activation of the clotting system. In such a case, you have to try to correct it, and don't use therapies while there's an estrogenic effect on the vessels. Even with this genic effect on the vessels, they are very positive in another area because they are positive from the endothelial sense. They can give a better endothelial function, and they can show antiagonist sporadic effect on the arterial wall. Then I think you have to balance this impossible situation."

Dr. Mark Perloe: "I think in the states it will be hard to do those studies but I'd like to see in the low risk group maybe coming in with low estrogen and baby aspirin or some effective factor but I don't think those studies are going to happen in the states."

Dr. Howard Carp: "There's a chance only one of the major concerns of estrogen replacement therapy of course, is the effect on the breast and sometimes also on the endometrium where there also may be a constant genetic effect. What is current thinking on the effect of the breast?"

Professor Andrea Genazzani: "The effect on the breast, first of all, they have never shown from the estrogen any cardio-genetic effects on the breast. They have shown the promoting effect, this is what we believe more now, that we can activate the replication of the cells and then this can have some negative impact. But you know the figures are in 1,000 women followed for twenty years and who are not treated with estrogen - they have thirty-five with new breast cancer. If they are treated for five years, you move this forty-five to forty-seven, and for ten years you move this thirty-five to fifty-two. These are the figures, the figures also sustain that the mortality in these same groups are more or less the same, indicating that the quality of the tumors that they had, this seven in omission, are of a more curable kind. I think in another size and a series of studies that show that having a baby prior has shown that the positive effect of vascular levels are so deep, but if we make a mean of the pull and counts, the pull still remains more than the count. A record should be kept of any anomalies, it's very important for the woman to share any personal history regarding breast cancer in her family history to make an adequate screening protocol. I think at least now we can believe that our hormonal therapy can be given for ten years and probably can be a full load by certain therapy just to counteract the effect on the breast. This I think should be a good general strategy but as I was sustaining, this is on the breast. Concerning the endometrium, on the endometrium you know If we give a progesterone together with estrogen it has been shown that they have a reduction of naturally expected cancer or smaller - more or less 50%. It's the same from colon cancer, and speaking about cancers, I think that the dollars are in favor of the therapy. It may be adequate screening if we follow the woman, if we do mammograms as they have to be done, and then if you maintain a close connection between the patient and the doctor."

Dr. Mark Perloe: "Dr. Carp, I'm interested and have been following your work in the literature about evaluation of the immune system in patients with recurrent pregnancy losses. What is the status of immune testing now? How do you answer critics who say that there really isn't a place for this because if you do nothing, 65% of the people are going to do quite well if they've had three losses?"

Dr. Howard Carp: "I'm pleased that you mentioned that 65% of the people do well, because the opposite side of the equation is 35% do not do well. But there are people that actually seem to second that, now the first 35% will not do well, that means they will come back again with a fourth pregnancy loss, if you take as your basis three pregnancy losses. Those who come with four pregnancy loses, 60% do not do well. That means that you're talking about 20% or so of your patients who will come back after three pregnancy losses with a further two losses. I think that our responsibility as physicians is not to look at the 60% who do well but to look at the 35% who do not do well or the 20% who come back with the further two losses. That's why even though we treat patients with three or more pregnancy losses, we try to limit our research to patients with five or more losses because I think what tends to happen is that patients are told 60% do well, therefore, go away and become pregnant again. On that basis, when a patient comes to you with five or ten miscarriages, you may be denying her investigation and treatment on the basis that the patients with three loses do well. I really don't think that's fair to the patient."

Dr. Mark Perloe: "What happens to the patient who comes in with two losses and says, "I've heard about this immune stuff, I don't want to lose again."

Dr. Howard Carp: "You do have a very difficult clinical question because there are patients who will look up sites on the Internet such as this one and others, and they will come to you today and say, "I have heard about immunization, I have heard about immunoglobulin, I have heard about other methods of treatment. I want to be treated, I don't want another loss." I think with these patients you have to explain to them that the patient with two losses, 80% do well but we do not really have an accurate enough diagnostic test to see who is the patient who will do well and who will not do well. The patient has to realize that even if we investigate the pregnancy loss, and we find a cause of pregnancy loss, it will not necessarily be the cause of pregnancy loss, and that often treatment of the moment is empiric. Immunotherapy is empirical treatment, resection of the septum whether done hysteroscopically or in another way is empirical, and immunoglobulin is empirical. Recent work on reduction of LH levels has been empirical because patients with two pregnancy losses, for example, most pregnancy losses will be due to chromosomal arrangements in the fetus. I think it is still accurate, we can ask Professor Genazzani as well, what is current practice in Italy but I think it's still reasonable to say that in 90% of the world or 90% of the patients with pregnancy losses where there is two, three, five, or ten losses, that conceptus when it is lost is not karyotyped. We cannot even give the patient an accurate diagnosis against that basis. We are being asked to summarize treatment, to prove the treatment is effective, and that is almost impossible."

Dr. Mark Perloe: "So one of the things your suggesting when that second loss comes along is to try to get the chromosomes to a consultant who may see the patient after two or three losses for evaluation?"

Dr. Howard Carp: "I say that most definitely, yes, because if you find the patient who has lost an embryo which is chromosome 16 trisomy, x monosomy, you know that he's elected to be chanced chromosome agents. You can then say to the patient, "Your chance next time around is very, very good." You can even give them figures depending on whether this is two losses or three losses and discuss with them whether they want to spend the time for other investigations or not. If however, you find that a patient is losing normal embryos, then you have to investigate the other factors. Then I think there's a place with immune investigation and other investigations and probably treatment which is then much more directed at the cause of pregnancy loss rather than the empirical fetus."

Dr. Mark Perloe: "Do losses tend to cluster around the same indication so that if you have patients who've had three or four losses, and you know that one or two of them are chromosomal, is it in all likelihood that the others were chromosomal or that future loses will be chromosomal? If per chance you had someone with three losses, and you knew they were all chromosomal, would your evaluation be different?"

Dr. Howard Carp: "My evaluation would be different, my advice would be slightly different. It would depend on what sort of chromosome losses. The chance for an assembly arrangement such as chromosomal 16 trisomy, which is the most common, when we find in our series such as x monosomy, these do not have high recurrence risks and an open chance is very good. You do occasionally pick up a translocation, and when you pick up a translocation then there may be a chance of that coming from one of the parents. You can check the parents to see whether they have the same translocation, which they have passed on. In most cases there is a very high recurrence risk, and you can explain that recurrence risk to the patient. After that, you may decide to investigate patients of those. The patient who loses the chromosomally abnormal fetus may also have a septum present, similarly a patient with septum may also lose chromosomally abnormal embryos. One does not exclude the other and the fact that you have found one cause of loss does not mean that you have found the cause, this is problem that we're facing today. However, I do feel that much of the literature does depend on finding one cause of loss, they don't find other causes of losses. I think it also depends very much on the clinical presentation. If I give you an example, we had one patient who had two pregnancy losses at twelve weeks. She had septum within the uterus, she was advised of the contraindication, she lost the third pregnancy also at twelve weeks. We resected her septum, and she lost the third pregnancy at eight weeks. Now this obviously sounds like a failure with treatment. Now if I give you some more details about this patient and say that these three previous losses were losses of live embryos at twelve weeks there was a fetal heart present, the uterus started to contract, she started to bleed, and she aborted a live embryo. The fourth pregnancy loss was ablated over at eight weeks, now that sounds different because it doesn't sound quite so much as it is a failure of treatment. If I now present the patient with even more detail and say all pregnancy losses due to chromosome 16 trisomy, and that the fifth and sixth pregnancies were induced labor each time at forty-two weeks, you realize that the resection of the septum was not a failure of treatment. It was in fact, a successful treatment and unfortunately these things are not taken into account. As Professor Genazzani said about hormone replacement therapy, patients are individuals, and if we stay with this definition of assessing all patients with three or more losses, that's one homogeneous basket we're never going to make any sense on this subject."

Dr. Mark Perloe: "One invariance being evaluated is again the clotting factors that prothrombin gene mutations and Factor X Leiden in this area. Do you see patients in Italy being screened for clotting factors as part of that evaluation?"

Professor Andrea Genazzani: "Only if they have very special reasons to do this, and it's not yet in the general practice also in the measures that we have to start in some kind of screening problem but we also need to be concerned about pregnancy loss. This is one area where we're defectors. It has to be taken into consideration and we need to try to personalize all the screening project and the screening problem. So it's not only bad for the patient but also for the doctor who follows the patient when you have seen three to six losses. Then you have to exam the embryo and there may be some genetic defects in some and not in others and some others there might not be any presence of the embryo. At the end of the study, you cannot know what kind of therapy, if any therapy or what kind of approach you have to do. You only have to hope that God will help us and that she can have live children."

Dr. Howard Carp: "With thrombotic pregnancy loss, whether it's due to either antiphospholipid antibodies or simply by a cyst or due to genetic predispositions which is Factor X Leiden and prothrombin malformation and so on. I think that first of all, clinically we have to define a certain type of pregnancy loss. Now with antiphospholipid antibody syndrome, the preponderance of second and third trimester losses is much higher than it is in unselected patients in common pregnancy loss. Patients who receive it, the current pregnancy loss, 90% were in the first trimester and about 10% in the second and third trimesters. Patients with antiphospholipid syndrome, they're not 30-40% in the second and third trimesters so it may be that in traumatic pregnancy loss, we have a normal embryo or fetus but then due to the clotting, we get ischemia and the effects of retardation and fetal death. Now certainly if you look at Preston's paper summarizing the EPCOT study on thrombophilias, they did say that the chance of a stillbirth - and they define stillbirth as being a fetal loss of about twenty-eight weeks - is also much higher than the chance of what they call the scavenge, which in their definition is a loss below twenty-eight weeks. So I think there is a clinical picture starting to become clear, when this becomes clearer and more accepted, I think we'll have a much better indication as to who may need treatment for thrombotic pregnancy loss."

Dr. Mark Perloe: "Do you believe that placental evaluation is an important tool either in determining patients who may be at risk for an immune basis or a thrombotic basis for their loss?"

Professor Andrea Genazzani: "I can only say - what kind of placental evaluation? Maybe Dr. Carp can give us a better, more precise results on what kind of placenta screening and evaluation you would like to suggest to the standard patient."

Dr. Howard Carp: "First of all, if we're talking about first trimester losses - there is no placental evaluation. We're really in the hands of nature as to see what comes out after that but you do have to access maybe not the placental factors or the projected factors. Once we come to the second and third trimester, unfortunately antiphospholipid antibodies have not proven that good an indication of what goes on. So if you check 80% coagulum by clotting factors whether it's either the activated PTT or Russell's viper venom time, none of them has proven to be a good indication of what's going on in with the pregnancy. Anticardiolipin antibody is notorious for its intralaboratory/interlaboratory variation, you cannot trust antibody's levels. Therefore, you can only trust placental assessment, and it's usual to send for assessment, non-stressed cardiotopography, fetal growth on ultrasound, flow studies, and they'll give you an indication that the pregnancy is doing well or whether you may need to intervene and stand on a sentry basis."

Dr. Mark Perloe: "Dr. Genazzani, thank you."

Professor Andrea Genazzani: "I'm sorry, I thank you but I have to leave."

Dr. Mark Perloe: "Dr. Carp, thank you so much."

Dr. Howard Carp: "Thank you, Dr. Genazzani."