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The topic of hormone replacement therapy (HRT) continues to emerge as a central theme that we, as clinicians to female patients, address every day. We recognize that the public is much more aware of and interested in HRT now than was the case a decade ago.
Kaunitz: The topic of hormone replacement therapy (HRT) continues to emerge as a central theme that we, as clinicians to female patients, address every day. We recognize that the public is much more aware of and interested in HRT now than was the case a decade ago. But we also see a big discrepancy between the number of prescriptions we might write as we initiate appropriate candidates on HRT and the number of women who actually adhere to our therapeutic advice 6 months later. Dr Hillard, what are your thoughts on ways to improve HRT compliance and continuation?
Hillard: When I'm seeing a menopausal or perimenopausal patient, I ask her what she has read and heard about HRT. That tells me whether she's read a lot and feels that it's a reasonable idea to take HRT, or whether she's read a lot--and some of the sources are questionable, as far as I'm concerned--and has misinformation about it.
Williams: I take that a step further. I ask them, 'What's the worst thing you've heard about taking hormones?' I think that zeros in on the level of concern.
Burkman: I would second that--it's a matter of asking patients about their concerns. I think HRT probably has more issues--particularly when you relate it to some of the neoplasia. Unless you understand where the patient is coming from, the first episode of spotting may be interpreted as a major neoplastic concern. In your initial counseling session, you are going to have to guide the patient to overcome this particular barrier. About 50% of women who start HRT quit as early as the first year, and that is not usually just because of problems with the progestin or another hormone.1,2 It's often related to their understanding of the risks and benefits of the medication.
Carson: I consider patients who are menopausal and have hot flashes lucky because that usually brings them to their doctor. And I always think their hot flash is what leads to a news flash. It gives us an opportunity to educate them. It always worries me that once those hot flashes go away, they feel better--but they don't really realize why, and how important it is for them to stay on HRT for reasons that they can't feel (e.g., protection against osteoporosis and heart disease [see Editor's Note]). In that first meeting with patients, besides helping them with what they really came for (relief of their hot flashes), I also try to educate them about why they need to continue HRT.
Hillard: The number of women who never get their prescriptions filled is also high, and it's something that I acknowledge and discuss up front. I say to the woman, 'You have to understand and participate in this decision. And unless you feel that this has benefits for you, then you vote by not taking your medication.' Then she understands how much control she has.
Kaunitz: I think each of you is acknowledging the importance of patient education: It will lead to increased comfort level, compliance, and adherence with HRT use. Moving on, what are the panelists' routines: When would you see a new HRT patient for a recheck? For an annual exam?
Hillard: I'll plan to see her after a reasonable trial period--usually 2 to 3 months--and address how she is doing.
Kaunitz: When we talk about HRT, we're not only talking about treating symptoms, as Dr Carson mentioned, for those women with hot flashes (or 'power surges,' as some of my patients now call them). We're really talking about what may be a potential lifelong commitment. Helping women understand this commitment may run the course of not only one visit, but perhaps last throughout all of their monitoring visits.
Burkman: It's important to see these women early, catch them when they have side effects--especially those who were asymptomatic prior to therapy but experience side effects with HRT, because they are prime candidates for discontinuation. We need to reassure them and reinforce the benefits of therapy. If you don't schedule a follow-up visit for 6 to 12 months, you may never get the patient back, and you've lost that opportunity for therapy. Ask why the patient didn't get the initial prescription filled and discuss any problems she has. Most important, physicians need to dispel the myths about HRT.
Kaunitz: As for pre-HRT issues, when is endometrial assessment appropriate prior to initiating HRT in a woman with an intact uterus?
Carson: I don't routinely perform endometrial assessment prior to starting HRT. I need an indication to do an endometrial biopsy at that point, just like I need an indication at any other time in a woman's life. If she's having irregular periods or prolonged times without a menstrual period and I'm worried about endometrial hyperplasia, then I will do an endometrial biopsy.
Kaunitz: I perform an office endometrial sampling or biopsy procedure--selectively--in women who are at higher risk for endometrial neoplasia. We're starting to see more large HRT trials--both industry and federally funded--where the baseline incidence of endometrial neoplasia (including adenocarcinoma and hyperplasia) is extremely low in asymptomatic women who have not had abnormal bleeding, who have not been on unopposed estrogen. In many populations, it may be below 1%.3 Perhaps a woman has been cared for by a physician who has prescribed estrogen without progestins, or is at risk (including morbid obesity or hepatic disease) for endometrial neoplasia. Such patients warrant endometrial screening before starting HRT. So we agree that routine pre-HRT endometrial screening is not necessary and that selective screening is appropriate. Let's now turn to one of the biggest challenges that we and our menopausal patients face--prevention of osteoporotic fractures. Dr Williams, when do you order bone density testing?
Williams: Women understand that osteoporosis is a problem. Still, some women will say to me, 'Prove to me that I need to take estrogen.' Others voice their preference not to take estrogen. I think bone density assessments may be appropriate at the initiation of estrogen therapy.
Carson: The same consideration applies to menopausal women with contraindications to HRT.
Kaunitz: I think we've all seen examples where a DEXA (dual energy x-ray absorptiometry) showing low bone density at the hip or spine can be a powerful motivator to the otherwise reluctant patient to initiate HRT.
Burkman: I think physicians should monitor the patients with medical conditions that set them up for osteopenia because estrogen may not be enough. It's a small percentage of patients, but I think if patients are already at risk for osteopenia because of Cushing's or primary hyperparathyroidism, it's worth monitoring them.
Kaunitz: What about more common risk factors for osteopenia that we see every day in our office practice?
Hillard: Thiazide diuretics, for one. Long-term smoking is also a common and high-grade risk factor.
Carson: More and more women are now taking thyroid supplementation, and excess thyroid hormone is another risk factor.
Burkman: Sometimes we forget to notice, but as these women age, they actually decrease in height. I think that's a strong indication for a bone density test.
Kaunitz: A lot of patients who are referred to me to initiate HRT or for amenorrhea evaluations have had a follicle-stimulating hormone (FSH) drawn by their primary care physician. When do you order an FSH in this setting?
Williams: I think that among clinicians, there is the belief that you must order an FSH to evaluate whether a woman is menopausal. I don't find it necessary to order an FSH or an estradiol level except in unusual situations.
Carson: I order FSH levels when a patient is on low-dose oral contraceptives (OCs) during the perimenopause: She's 50 years old, still sexually active, and worried about getting pregnant if she stops the OCs. In those cases, I get it on day 6 or 7 of the hormone-free days. If it is over 30 mlU/mL, then I switch to HRT; if it's under 30, I continue her on the OC. The reason for that is because HRT has a lower risk profile than do OCs, and she is much safer taking the lower dose of estrogen.
Williams: My only concern is that we've probably all seen women whose FSH was 32 one month and 18 the next, so even that one reading may not tell us everything.
Kaunitz: That's an important caveat: In perimenopausal women, the gonadotropin one month may not predict next month's level. With the small but growing number of OC patients in their late 40s in my practice, if they do well on OCs, I continue them into their early 50s and then assess their contraceptive needs and how they feel. Then I individually switch them to HRT in their early- or even mid-50s, depending on their symptoms and contraceptive needs. The patients for whom I most commonly order gonadotropins--and I feel in this setting you really only need an FSH, which will go up more dramatically than luteinizing hormone at the time of menopause or ovarian failure--are women whose menstrual history is not a guide to their menopausal status. These are women without a uterus. We're seeing increasing data that the ovarian failure occurs earlier in these patients than in gynecologically intact women.4,5 For this reason, I've become more proactive in screening FSH in hysterectomized patients in their 40s as well as late 30s. Likewise, I've become more proactive about empirically supplementing these women with estrogen replacement therapy. Finally, I'm finding a number of women who are heavy smokers suffering from earlier menopause or ovarian failure. In my general GYN practice, the most common cause of menopause prior to age 48 is heavy smoking.
Williams: Is there general acceptance that heavy smoking increases estrogen catabolism?
Kaunitz: Endogenous estrogen levels6 and bone density7 are both lower in women who smoke heavily. It's also been well documented that the age of actual menopause is lower in women who smoke heavily.8
Williams: I believe all heavy smokers should be considered relatively hypoestrogenic.
Kaunitz: Let's get into the nuts and bolts of therapeutic options available to our menopausal patients. In the last 5 years, we've seen an explosive growth of new products, various formulations, and routes of administration of estrogens and progestins. Can I ask for your input on cyclical versus continuous HRT?
Williams: The initial approach would be different with women in their late 40s or early 50s who come to us having irregular periods and hot flashes, than with those who are truly postmenopausal. I am concerned that irregular bleeding is going to drive women away from taking HRT. I think there are tremendous advantages of continuous combination HRT in women whom you do not expect to bleed. But, I think the women who we do expect to bleed--those who are perimenopausal--do better on a cyclic regimen.
Burkman: The biggest problem I see with continuous therapy is with the early menopausal woman. I don't get the results that you see in many of the studies--that is, amenorrhea after several months' use.
Kaunitz: Your rate of amenorrhea is lower than what you see in the studies?
Burkman: Right. If you had a 58-year-old woman who has been menopausal for several years who wants to go on HRT, I think the continuous regimen seems to work reasonably well. Again, you really have to warn her of some erratic bleeding and get her back early for another visit to see if she tolerates the bleeding. But in someone who is just menopausal, with a recent onset of hot flashes and amenorrhea, I think the cyclical approach works better.
Hillard: I see patients who have been prescribed the fixed combination without much discussion. These women are perimenopausal, are prescribed Premproª, and aren't told a thing about what to expect in terms of bleeding. To me, that's a setup for failure.
Carson: A very interesting retrospective study comparing records of postmenopausal women on both continuous and sequential HRT showed that in the first year of therapy, about 34% of those on cyclic HRT had unexpected bleeding compared to about 37% of those on continuous HRT.9 But after taking the drugs for 2 years, the rates of unexpected bleeding were equal. In general, 1 in 3 HRT patients had unexpected bleeding. Overall, 1 in 3 women on combined and 1 in 6 on cyclic HRT had unexplained bleeding in the first year. Also, first-time users were more likely to discontinue, no matter what regimen they started, than those who stopped once before and then initiated therapy once again.
Kaunitz: It's also important for women to recognize that when they choose--and we should present this as a choice--between a continuous and a cyclical combination HRT regimen, it is not an irrevocable decision. It's important from the outset to let your HRT candidates know there is plenty of room to titrate, to adjust, and to switch approaches. In fact, it's normal and very easy to do that, and there are very few downsides to such changing. I ask my patient, 'You're likely to start bleeding with either the cyclical or continuous approach. Do you feel more comfortable with cyclical, predictable menses similar to what you may have experienced in your reproductive years, or would you feel more comfortable with perhaps lighter bleeding or spotting that's totally unpredictable?'
Hillard: There are certain women who I tend to start on continuous, even if they're close to menopause: those who have migraine headaches, particularly menstrual migraines. I want them on a regimen where their hormonal status will be more constant. They may, however, be a more difficult group to agree to take it, because perhaps they've heard that their headaches are going to go away with menopause. It's a longer discussion with that group, talking about risks versus benefits. But I do say, 'For you, I am recommending more strongly the combined continuous regimen.'
Kaunitz: In which patients would you choose a transdermal approach?
Burkman: Patients who have had nausea while taking oral estrogens--perhaps OCs--may do better on the transdermal HRT.
Williams: There is a small group of women with familial hypertriglyceridemia with a fasting triglyceride level of 300 or 500 mg/dL or greater who are at risk for massive increases in triglycerides if they take oral estrogens--putting them at risk for pancreatitis. There is some evidence they can avoid this complication if they are given estrogen transdermally.10
Burkman: There are also patients who have had past deep-vein thrombosis (DVT). I will present to them that the latest research in the British literature points to a potential risk for DVT and pulmonary embolus with the oral medications.11-14 Perhaps the transdermal might reduce that risk.
Kaunitz: Two other groups of candidates are women with chronic liver disease or those with biliary tract disease who have not yet been treated with a cholecystectomy.
Carson: Even transdermal estrogen can have many of these complications, though, if the dose is high enough. So once you start putting on more than one patch or even using the larger patch, you're getting close to some of these risks as well. And for anyone still using parenteral estrogen, it has many of these risks, especially those of DVT, even though it has the same route as the transdermal.
Kaunitz: Because IM estrogen represents such a high-dose approach?
Carson: That's correct. Again, most of the side effects are dose-related, rather than first-pass effect. Remember, after the first pass, it all goes to the liver. So it's really only the first pass that you're avoiding. Now that's definitely a higher dose to the liver in that first pass, but once that 5-minute circulation time passed, it's back to the liver. So we have to be very careful about doses when we're comparing estrogens.
Kaunitz: Let's now address issues related to calcium intake and the prevention of osteoporotic fractures. What are your observations and practical recommendations regarding calcium and its role in menopausal health?
Hillard: I'm concerned that many women have not been told or read anything about the need for sufficient calcium. I get questions from patients very concerned about taking the right kind of calcium: calcium lactate, calcium carbonate, calcium gluconate, or whatever. I tell them I'm more concerned that they find something they can tolerate, and take enough of it consistently, than I am with the differences in metabolism and absorption between the different types of calcium.
Burkman: I agree. But I think you also have to make the case that most women need supplementation. And you have to deal with some of the misconceptions--for instance, that skim milk doesn't have enough calcium, and so forth.
Carson: I also talk about what foods are high in calcium, such as calcium-enriched orange juice, and either skim or whole milk. All have the same amount of calcium. It's important for women to know that they can get almost all calcium as they need from foods and can cut down the constipation-producing supplement.
Kaunitz: I'm told that calcium citrate is associated with fewer GI symptoms such as eructation or flatulence than calcium carbonate.
Hillard: I tell patients to buy the small bottle initially--not a bottle of 500--and give it a try since there are individual variations.
Kaunitz: I encourage my patients to buy their calcium supplements from their pharmacists because I think they can get the best quality at lower prices there. Another myth I hear is that women get sufficient calcium from their multivitamin--when in fact, the amount of calcium in a multivitamin may represent just a small fraction of their daily requirement. At what age should a woman start taking calcium supplementation?
Hillard: Age 14--and I'm not kidding.
Kaunitz: Your answer, Dr Hillard, is ironic because the age at which our patients become interested in calcium supplementation tends to be mid-40s and beyond. But the age at which calcium supplementation might have the biggest impact on a woman's lifespan, in terms of reducing fractures, is before she reaches peak bone mass--meaning her teen-age years.
Carson: In menopausal women, calcium supplementation without estrogen does not maintain or increase bone mass.
Kaunitz: Let's focus on the woman with identified osteoporosis. She may be in her 60s or 70s or 80s and have had a clinical fracture. Perhaps more and more common might be the woman who recently had a bone density assessment and was found to be osteopenic or osteoporotic and comes for counseling and therapy. What are relevant approaches here?
Burkman: First make sure that this patient gets a DEXA, or whatever you're going to use for your density screening. If you can't convince her to take HRT, then you need to go to one of the other alternatives, because this is a patient who actually has symptoms. It's a different story when your patient is developing fractures, as opposed to someone who is 50 and has a potential for developing the disorder. Now you're treating an illness, as opposed to preventing one. So you have to be more aggressive about therapy.
Kaunitz: What are the practical considerations in initiating or adjusting therapy for a woman with documented osteoporosis?
Carson: It's important to remember some of the things that might be aggravating her condition. For instance, if she's on thyroid medicine, make sure the dose is not too high.
Kaunitz: Practically, how would you screen a patient on thyroid replacement to make sure her dose isn't too high?
Carson: Her levels of thyroid-stimulating hormone (TSH), thyroxine, and T3 and T4 should be measured. The T3 and the T4 should be within the normal ranges, and a sensitive TSH should also be within the normal range. If the TSH level is below the lower limit of normal, her thyroid medicine should be decreased. She should be on calcium and be encouraged to exercise. And if she's on a corticosteroid, it should be discontinued if possible. Sometimes, of course, it's not possible to discontinue some of the drugs that she's taking. If she's on less than 0.625 mg of conjugated estrogen, you can consider incrementally increasing the dose. If she's taking transdermal estrogen, she should be on at least the 0.1-mg dose. About 20% of patients who are on 0.3 mg or equivalent of conjugated estrogen will not be protected against osteoporosis and will benefit by an increase in their dose. After checking these issues, the bisphosphonates should be considered.
Burkman: What you just mentioned is important. If she is already on HRT and has suffered a fracture, I think it's a signal that you're probably going to have to go to the next line of therapy. But again, we are now treating a clearly pathologic condition; it's no longer prevention of fracture. She will have worse problems if you're not careful.
Kaunitz: In which patients should we be prescribing bisphosphonates, and what are practical guidelines for doing so?
Burkman: Patients with diagnosed osteoporosis, particularly those who have been on HRT. However, alendronate is not an easy medication to take.
Hillard: The requirements of taking it on an empty stomach, having to sit upright, and not even being able to have your cup of coffee first thing in the morning make it very difficult for some patients to take.
Kaunitz: In the menopausal woman taking HRT who is identified as having substantial osteopenia or overt osteoporosis--if you decide to begin alendronate or a bisphosphonate, would you continue her HRT?
Kaunitz: The dose of alendronate approved for treatment of osteoporosis is 10 mg daily, whereas the dose for prevention of osteoporosis in the osteopenic woman would be 5 mg daily. In practice, if a 10-mg tablet is available, it's okay to break it in two. But I think all of us agree that, just as long-term HRT has its own challenges, alendronate does too--in terms of our patients' morning lifestyles and of taking it without GI toxicity.
What about some of the newer agents on the market? In terms of osteoporosis, we've heard that the second-generation SERM (selective estrogen receptor modulator) raloxifene can improve bone density. Have any of the panelists prescribed raloxifene? If so, in which patients and how?
Williams: Let me say something first, without answering your question: I think it's important to bury the term designer estrogen. Selective estrogen receptor modulators are not estrogen; they're not meant to be. They have estrogen-like effects with some receptors, but not with others. I think the same thing is true with phytoestrogens, which, of course, are not estrogen either.
Carson: I would prescribe raloxifene for the woman who is afraid to take estrogen. Raloxifene doesn't prevent hot flashes, and so it worries me about whether it has any effect on treating Alzheimer's disease. It has a beneficial effect in lipids, but in primates and mice it doesn't have any beneficial effect on the blood vessels around the heart. So I don't know whether we'll see the same cardiovascular protection that we see with estrogen. It seems to protect the bones, although not as well as estrogen.15
Hillard: That's a point patients don't really understand. In their mind, they think this is so much better than estrogen in terms of the effect on the breast. But they do not understand that it's not as good for bone as estrogen.
Burkman: The recommended daily dose of raloxifene (60 mg) appears similar to 0.3-mg conjugated estrogen in terms of bone impact. So it's less effective. But it is an alternative for the breast cancer patient.
Williams: That's the point: It's really meant for the woman who can't take estrogen because of some neoplastic process. It will also help in women who won't take estrogen. It's certainly very important that these women understand that it is not going to alleviate the hot flashes or correct the problem of atrophic vaginitis.
Carson: I think it's also important for them to understand that the early data are very promising, but we don't yet know whether it will really protect the breast against subsequent cancer.
Kaunitz: Likewise, because it is such a recent drug, we only know that raloxifene has a beneficial impact on laboratory assessment of bone density, but we don't have fracture data to date. We know that estrogen and bisphosphonates prevent fractures. Now let's discuss how you would manage a menopausal woman on conventional doses of HRT who's complaining of persistent hot flashes, or vasomotor symptoms.
Carson: Hot flashes are the only symptom that I actually will 'chase' with increasing estrogen doses. When I get to a dose that I think is fairly high, then I may do serum estrogen measurements to make sure that her blood levels of estrogen aren't too high to put her at risk for venous thrombosis. If I am getting to very high doses, then I add an androgen.
Burkman: There are probably a few of those patients who don't absorb estrogen well orally, so you may try the transdermal route. And occasionally you're going to have to evaluate patients for thyroid problems because sometimes the hot flashes aren't menopausal hot flashes.
Kaunitz: Women who smoke heavily experience persistent vasomotor symptoms despite conventional HRT doses. I find that as I add doses of estrogen to these women who are already at higher risk for cardiovascular disease, my own apprehension increases at the same time. In these patients, I add progestins.
Menopausal patients have a broad array of oral, transdermal, and other estrogens available to them, and yet there are very few ways to provide progestin therapy. However, most complaints in patients taking HRT relate not to the estrogen but to the progestin. What are some of the apparent progestin-related side effects you see in your patients? How should we approach those?
Hillard: The most common one I see is mood changes, and I think that's the one that is most problematic for most women. It's a difficult thing to measure.
Burkman: I agree. It's much more common than suggested. The reason that I find most women are intolerant of HRT has nothing to do with the estrogen; it has much more to do with the progestin.
Kaunitz: I think there are subgroups of women, hysterectomized women, where on an individualized basis it may be appropriate to use progestins with estrogen. This would include the heavy smoker I just mentioned. Also, there's the woman who had a total hysterectomy with bilateral salpingo-ophorectomy for severe endometriosis, where residual endometriotic implants were left behind, placing her at increased risk for reactivation of residual endometriosis implants or even endometrioid adenocarcinoma.
Dr Carson, what are alternate approaches to progestin therapy in women intolerant of medroxypro-gesterone acetate (MPA)?
Carson: If a woman is on cyclic therapy, going to a continuous dose of a lower progestin sometimes helps--say 2.5 mg a day--switching the progestin to a daily dose of 100 mg of oral micronized progesterone instead of Provera¨.
Kaunitz: And I think that's a particularly timely observation, in that this approach was validated by the NIH-sponsored PEPI trial.16 And a standardized, micronized 100-mg progesterone (Prometrium¨) has recently become available.
Carson: Or switching to norethindrone, another progestin, which is available in a progesterone-only birth control pill. However, this dose is rather low and usually you do have to switch to a continuous regimen, giving the progestin-only pill with daily estrogens.
Kaunitz: So that would be norethindrone 0.35 mg (Micronor¨) daily.
Carson: And also occasionally, if the patient still can't tolerate that, then the next choice is going to megestrol (Megace¨) at a dose of 20 or 40 mg daily in the cyclic regimen.
Hillard: I also mention the progesterone IUD (intrauterine device) as another option.
Burkman: There is the option of giving pro-gestin less frequently. I think you would try some of these other options if you can, but it may be that every 2 or 3 months you withdraw them as opposed to every month.
Williams: There are still some women out there who just will not take any of these progestins. Will you prescribe unopposed estrogen for those women who not take progestin?
Burkman: I think you can, but roughly 15% to 20% of women taking unopposed estrogen will develop hyperplasia.17 But I think in those patients, you have to come up with a regimen of regular endometrial biopsies. But what is that regimen? I think as a minimum it's annually.
Kaunitz: Also, unscheduled bleeding is very common with unopposed estrogen. I recommend that whenever you use less than conventional progestin opposition to estrogen in menopausal women, you need to perform more frequent endometrial surveillance.
Burkman: I think you should also clearly document in the patient's chart that you're doing this and that you've explained these risks to her. There is some liability risk going against the general prescribing practices. But I think that it's appropriate as long as it's clear the patient understands, and it's well documented on the chart.
Kaunitz: Is there ever a role for hysterectomy in women benefiting from their estrogen replacement therapy, who are intolerant of pro-gestins despite the individualization approaches we've just reviewed?
Burkman: Or for endometrial ablation? There very well may be a role, particularly with some of the new tools.
Kaunitz: Ablation would minimize progestin-induced endometrial bleeding in women taking combined HRT. But it would not eliminate the need for progestins, because of the potential risk of endometrial neoplasia--albeit undefined but real--in women on unopposed estrogen post-ablation.
Carson: I think as a generalization, this is not an indication for hysterectomy.
Kaunitz: What about providing routine doses of HRT to menopausal patients with fibroids?
Hillard: I'm unaware of any evidence that fibroids will increase in size with our conventional doses. There are isolated reports of fibroids increasing in response to estrogen. One study found an increase with transdermal ethinyl estradiol 50 mcg plus 5 mg MPA but not with conjugated estrogen 0.625 mg and 2.5 mg MPA.18 An Austrian study suggested an increase but used a formulation of HRT not available in this country.19 Overall, there are few reports, suggesting that this is not a clinically significant problem.
Kaunitz: Having said this, we recognize that among the subgroup of HRT users with persistent bleeding abnormalities, some of those women will ultimately be found to have submucous or other fibroids, or endometrial polyps. All right. Let's revisit the DVT issue.
Williams: Years ago, I think we were all convinced we were overstating the role of HRT in DVT. Then the three Lancet articles, all in same edition in 1996, came to the conclusion that there was some risk.20-22 But if you analyze the three articles, there are lots of biases, lots of questions, lots of concerns, and so I don't think that there's great evidence--even today--that standard doses of estrogen replacement therapy or HRT increases the risk of DVT in normal women.
Burkman: I would take a different tack and say it would make sense that there would be some increase. Assuming the studies are valid, the absolute risk that you're talking about, however, would be about 30 events per 100,000 women-years. So the reality is that the risk would still be there. But from the practical standpoint, except for patients who might be found to have some unusual problems that would put them at increased risk, I don't think it's a concern--other than that you pay attention to leg symptoms, which I think is prudent anyway.
Kaunitz: In the woman with the previous history of documented DVT, what's your approach to HRT?
Hillard: This would be the patient that I would consider getting a screen for the inherited thrombophilias protein S, protein C, antithrombin III deficiencies, and factor Leiden mutation.
Kaunitz: Another subgroup of HRT candidates are surgically castrated women complaining of decreased libido.
Burkman: Should you add androgen to the regimen? Unfortunately, the data are not tremendous because the focus again was on parenteral administration of androgen. Although there is a suggestion that the oral-administrated androgens may help this group of women, I think that we have to say that the evidence-based research isn't there. But I think if you're going to find an indication for adding the androgen, this would be probably a group of women that I would consider.
Kaunitz: One small placebo-controlled study found that 5 mg of oral methyltestosterone daily will positively impact libido.23 But even this dose represents a dose two to four times greater than US physicians would conventionally prescribe.24
Hillard: In terms of the doses of androgens now available, there is some thought that they are perhaps too high in terms of effect on lipids.
Kaunitz: Right. I think that the physician who does prescribe combination estrogen-androgen formulations needs to be aware of the downside of prescribing androgens. And one that Dr Hillard just mentioned is lipoprotein--changes where androgens very predictably will decrease high-density lipoprotein levels. I perform lipid subfractions prior to initiating combination estrogen-androgen HRT. There are skin (acne) and hair (hirsutism) side effects, as well, that are quite common at the doses available to us. With prolonged use of higher dose androgens, we'll also see clitoromegaly.
Burkman: On the cardiovascular side, though, there's some animal evidence that suggests there may be some favorable direct effects with androgens when used in combination with HRT.25 The problem, of course, is that it's fine to look at animals, but we don't have direct clinical data with humans.
Kaunitz: Nonetheless, I think we can agree that concerns about sexuality, including libido, are real, common, legitimate concerns.
Hillard: I think there's a lot to be learned. I would completely agree that these are real and legitimate concerns. I think we're hearing them more now because we're dealing with patients who are willing to verbalize them. In the past, patients have not been.
Kaunitz: The last topic also relates to sexuality: addressing menopausal women already on conventional doses of HRT where vaginal atrophy continues to be a problem. I've often said to both professional and lay groups that if men lost a good proportion of their external genitalia, they would have done something years ago about menopause. And yet, we continue to see--particularly in our untreated menopausal women--that vaginal atrophy is common and sometimes can be severe, even notwithstanding the use of conventional HRT doses. How do we address this?
Burkman: Sometimes the systemic estrogen may not be enough to deal particularly with some of the vaginal atrophic changes. I think adding vaginal estrogen sometimes makes a big difference. You have to monitor these patients. If over time you're not paying attention and you're seeing loss of rugae and thinning of the epithelium, yet you're continuing to give 0.625 mg, that means you're not paying attention during your exam. If you do see the changes, the time to initiate therapy is early rather than late.
Kaunitz: Would you increase systemic estrogen in that patient or give it locally?
Burkman: I'd give it locally. Years ago, I'd have said, 'Oh, you know, it all gets to the same place.' But I think there's some evidence now, probably mostly anecdotal, that says direct delivery to the vagina does make a difference.
Williams: In fact, I believe that is the role for vaginal estrogen.
Kaunitz: In other words, conventional doses of HRT are addressing her hot flashes, hopefully there is a favorable impact on bone metabolism, and yet symptomatic vaginal atrophy progresses.
Williams: Because we don't really know how much or how little is metabolized. I think it's very difficult to use the vaginal route as a primary method of estrogen replacement.
Kaunitz: A new therapeutic for vaginal atrophy is available on the market--the 3-month estrogen-releasing silastic ring (Estring¨). What has been your clinical experience with this?
Burkman: I think this is an option to consider. The suspicion is it would work somewhat similar to the creams, but I think it's too early in its evolution to see whether you get the same effect.
Hillard: I do have some concern about the person who is quite atrophic and puts in a ring, that the vagina may erode or bleed.
Kaunitz: Almost all of my limited experience with Estring has been in breast cancer patients--many of whom suffer from debilitating vaginal atrophy but who may not be appropriate candidates for systemic estrogen replacement therapy. An approach to estogenizing the vaginal mucosa in these women, without providing systemic doses of estrogen, is very appealing. And in consultation not only with the woman but also with her oncologist, I am increasingly making Estring available to breast cancer survivors. I can tell you that this challenging subgroup of menopausal patients is delighted that this option is now available.
I'd like to thank all of the panelists for a very practical overview of approaches and insights that will allow us to better tailor hormonal replacement to individual patients. Thanks again for your excellent comments and enthusiasm.
1. Hammond CB. Women's concerns with hormone replacement therapy--compliance issues. Fertil Steril. 1994;62: 157S-160S.
2. Vestergaard P, Hermann AP, Gram J, et al. Improving compliance with hormonal replacement therapy in primary osteoporosis prevention. Maturitas. 1997;28: 137-145.
3. Archer DF, McIntyre-Seltman K, Wliborn Jr, WW, et al. Endometrial morphology in asymptomatic postmenopausal women. Am J Obstet Gynecol. 1991; 165(2):317-322.
4. Siddle N, Serrel P, Whitehead M. The effect of hysterectomy on the age at ovarian failure: identification of a subgroup of women with premature loss of ovarian function and literature review. Fertil Steril. 1987;47:94-100.
5. Watson NR, Studd, JWW, Garnett T, et al. Bone loss after hysterectomy with ovarian conservation. Obstet Gynecol. 1995; 86:72-77.
6. Jensen J, Christiansen C, Rodbro P. Cigarette smoking, serum estrogens, and bone loss during hormone replacement therapy early after menopause. N Engl J Med. 1985;313:973-975.
7. Daniell HW. Osteoporosis of the slender smoker: vertebral compression fractures and loss of metacarpal cortex in relation to postmenopausal cigarette smoking and lack of obesity. Arch Intern Med. 1976; 136:298-304.
8. McKinlay SM, Bifano NL, McKinlay JB. Smoking and age at menopause in women. Ann Intern Med. 1985;103: 350-356.
9. Ettinger B, et al. Unexpected vaginal bleeding and associated gynecologic care in postmenopausal women using hormone replacement therapy: comparison of cyclic versus continuous combined schedules. Fertil Steril. 1998;69:865.
10. Glueck CJ, Lang J, Hamer T, Tracy T. Severe hypertrigylceridemia and pancreatitis when estrogen replacement therapy is given to hypertriglyceridemic women. J Lab Clin Med. 1994;123:18-19.
11. Daly E VMP, Hawkins MM, Carson JL, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996;348:977-980.
12. Grodstein F, Stampfer MJ, Goldhaber SZ, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet. 1996;348:983-987.
13. Jick H, Derby LE, Myers MW, et al. Risk of hospital admission for ideopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet. 1996; 348:981-983.
14. Varas-Lorenzo C, Garcia-Rodriquez LA, Cattaruzzi C, et al. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study of southern Europe. Am J Epidemiol. 1998;147:387-390.
15. Heaney RP, Draper MW. Raloxifene and estrogen: comparative bone-remodeling kinetics. J Clin Endocrinol Metab. 1997;82:3425-3429.
16. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA. 1996;275:370-375.
17. Woodruff JD, Pickar JH, Group at MS. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogen alone. Am J Obstet Gynecol. 1994;170: 1213-1223.
18. Sener AB, Seckin NC, Ozmen S, et al. The effects of hormone replacement therapy on uterine fibroids in postmenopausal women. Fertil Steril. 1996;65(2):354-357.
19. Frigo P, Eppel W, Asseryanis E, Sator M, et al. The effects of hormone substitution in depot form on the uterus in a group of 50 perimenopausal women--a vaginosonographic study. Maturitas. 1995;21 (3):221-225.
20. Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996;348:977-980.
21. Jick H, Derby LE, Myers MW, et al. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet. 1996;348:981-983.
22. Grodstein F, Stampfer MJ, Goldhaber SZ, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet. 1996;348:983-987.
23. Myers I, Dixen J, Morrissette D, et al. Effects of estrogen, androgen, and pro-gestin on sexual psychophysiology and behavior in postmenopausal women: a 10-week double-blind study. J Clin Endocrinol Metab. 1990;70:1124.
24. Kaunitz, A. The role of androgens in menopausal hormonal replacement. Endocrinol Metab Clin North Am. 1997; 26:391-397.
25. Rosenberg MJ, King TD, Timmons MC. Estrogen-androgen for hormone replacement. a review. J Reprod Med. 1997;42:394-404.
Andrew M. Kaunitz, MD, is Professor and Assistant Chair of the Department of Obstetrics and Gynecology at the University of Florida Health Sciences Center, Jacksonville, FL. He is a member of the editorial advisory board of The Female PatientÂ¨.
Ronald T. Burkman, MD, is the Chairman of Obstetrics and Gynecology at the Baystate Medical Center in Springfield, MA. He is a member of the editorial advisory board of The Female PatientÂ¨.
Sandra Ann Carson, MD, is Associate Professor in the Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, at Baylor College of Medicine in Houston, TX.
Paula J. Hillard, MD, is Professor in the Department of Obstetrics and Gynecology, Associate Professor of Pediatrics, and Director of Women's Health, all at the University of Cincinnati School of Medicine in Cincinnati, OH.
J. Kell Williams, MD, is Associate Professor in the Department of Obstetrics and Gynecology, and Director of the Division of Gynecology at the University of South Florida College of Medicine in Tampa.
*This is one of four roundtable discussions conducted at the annual meeting of the American College of Obstetricians and Gynecologists. Look for these topics in upcoming issues of The Female PatientÂ¨: "Treating Depression in the OB/GYN Setting," "Advances in Screening for Infections During Pregnancy," and "Ectopic Pregnancies: The Latest in Treatments."
Originally published in The Female Patient -- November, 1998
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