Begin Presentation #1

Owing to her in-depth understanding and research experience on the subject of menopause, Dr. Chervenak won grants from ACOG/Solvay Pharmaceuticals to study the postmenopausal effects of conjugated equine estrogen and soy, and the effects of menopause on sleep quality. Her major research interests include maximizing health and quality of life in perimenopausal women, hormonal and ultrasonographic markers for endometrial receptivity, and the effects of environmental toxins on sperm morphology and oocyte fluid. Her numerous publications reflect her strong interest in this study of menopause issues. Dr. Chervenak...

So during the perimenopause we have high estrogen, low progesterone, occasionally, and ovulatory cycles with very high estrogen but no progesterone to protect the uterus-and this does put a woman at risk in the future, potentially, for endometrial cancer.

Now the perimenopause and estrogen levels. You may hear patients asking about estrogen levels and perimenopause. The perimenopause has very high highs and very low lows, where they go like a "roller coaster" up and down, so you really cannot predict what is going to happen next month.

Now this is in comparison to Guthrie, who has found 62 percent of postmenopausal women were having hot flushes, including 15 percent on standard hormone replacement therapy. That’s horrible. A patient is coming to us to alleviate her hot flushes and she still is having them. I propose that perhaps those patients on standard HRT are just not having customization of the dose. It’s really important for each woman to have it customized.

There have been multiple therapies suggested for the treatment of hot flushes, from cold bubble baths to ...

hanging out in your supermarket grocery section -

and for the carnivores you may even want to hang out in your meat locker. But the best therapy for amelioration and relief of hot flushes is estrogen replacement therapy.

This data is from the CHART study in yellow, actually. In the red, now, we see placebo and the ones underneath that - see the red? And then underneath that, we see a combination of norethindrone acetate and ethinyl estradiol, and those are any new product available to give to our patients. All three of the doses tested, including the one currently available, we do see relief of hot flushes.
So at all three doses we do see relief from hot flushes. So again, estrogen replacement therapy is the number one choice for relief of hot flushes.

Now the psychophysiologic symptoms are the problems, which you really can’t pin a cause to, but are real for the patients. She may be tired, have difficulty sleeping I propose from the hot flushes, which are awakening her - headaches, depression, muscular pain, and palpitations. Now these symptoms are real to the patient, however we don’t necessarily know what the etiology is. It’s possible it’s from the decreased estrogenic environment associated with menopause because they’re more common in the menopausal female. But it’s also possible that it can be from - as I propose, the sleep changes also - from the decreased estrogenic milieu. So while we don’t necessarily know what the cause is of the palpitations, etc., we do know, however, that we can make it better for many patients with hormonal replacement therapy and that will therefore increase their quality of life. If we’re going to be spending one third of our lives in the menopause, and men, you’re going to have to deal with us, you’ll really want to have our quality of life improved. Now we’re talking about quality-of-life issues - the long-term longevity.

The two major causes of morbidity and mortality in the older woman are heart disease and osteoporosis.

Starting at age 40 the leading cause for death in the United States for women is heart disease. After age 50, women have the same rate of heart disease as a 40-year-old man, and eventually the same or higher rates as men. After age 50, women do have higher rates of hypertension than men. So as the population is changing and the baby boomers come of age, we’re going to see more and more of these potential problems.

Now, with the menopause, women have changes in all of these parameters except for smoking, which do worsen with menopause.

So a woman has higher cholesterol and other lipid profile alterations, abnormal glucose tolerance, insulin resistance, hypertension, and obesity. All of these things get worse in a patient who is not on HRT.

Now the insulin resistance is an important issue - you know you hear all this stuff - the carbohydrate addicts diet and all that different issues. Well a lot of research is being done now and it does seem that insulin resistance and its association with diabetes, etc., does play a role in cardiovascular disease - not only for women. But there’s something called syndrome-X in men, which puts them at high risk for cardiovascular disease as well. Now after the menopause we have higher cholesterol, triglycerides, total/HDL cholesterol, insulin, and increased body weight. In all of these things may have clinical impact since they are predictive of cardiovascular disease.

Now hormone replacement therapy has been associated in some studies with a 50 percent decrease in the incidence of cardiovascular disease in women who were previously healthy. Except, of course, if their heart disease was secondary to smoking.

Now let’s talk about a different parameter here. In this cartoon the woman says, - Well at least mine is where I don’t have to look at it - in comparison her butt versus his belly.

When they are younger this may be the case, but as a woman ages there is a change from the gynoid or pear shape to the android or apple shape. And this increase in waist-to-hip ratio does put a woman at very bad risk for cardiovascular disease, and it’s also associated with an increase in intraperitoneal fat, which also creates cardiovascular risk.

Now what about hormone replacement therapy? Hormone replacement therapy with long-term use is going to be found in the blue as control - and the purple is with HRT - is going to create. And this is going to help to reduce your cardiovascular risk. We see with HRT a decrease in your total body fat mass, a decrease in your trunk fat mass, and eventually a decrease in your arm fat mass. Now we may see a slight increase in leg fat mass - well, cosmetically, someone with chubby thighs to begin with may not be too pleased with this - however my cardiovascular risk, which means my long-term life, will be improved with HRT.

Now independent of its effects on lipids, estrogen may have other cardioprotective effects. It’s thought, from different animal and other models, that estrogen helps to widen the blood vessel, increase the pulsatility of blood through this widened vessel, and since you have more blood going through this widened tube faster, you get decreased atheromatous plaque formation,

and it’s thought actually that these other effects independent from the effects of lipids, make up 75 percent of the pie. And 25 percent of the pie is thought to be from the lipid effects.

Now there’s a lot of concern about - is estrogen replacement therapy and hormone replacement therapy detrimental to the heart? It seems there is a huge study, are you familiar with the HERS study? It’s a huge study and everything - and you know - in the first year there may have been an increased risk. Although when you equate that to numbers and etc. it’s not huge. Long-term wise, estrogen hormone replacement therapy seems to be cardioprotective, but we’re not sure what’s really happening. In long-term wise it does seem that hormone replacement therapy is beneficial. And it seems that estrogen itself is cardioprotective. Let’s look at Bush’s study. He looked at estrogen in - what he did was he looked at heart disease mortality in patients who used estrogen compared to nonusers of estrogen. And he also compared those women, here in blue, who did not have cardiovascular disease at baseline, and we see in those women there’s a decrease in mortality. But even more impressive are those women who have heart disease to begin with. There’s an even greater decrease in mortality. So we can say right now we are not sure about the effects of estrogen on cardiovascular. It seems estrogen itself may be cardioprotective, but we need to know more in the future. There are some concerns though regarding the use of progestins. Does everybody - you are pharmacists, you probably know this better than me - what a progestin is compared to a progesterone. A progestin is a synthetic progesterone. It can be derived from, let’s say, you can derive it from progesterone and that would be, let’s say, your medroxyprogesterone acetate. Or you can have progestins derived from other sources, let’s say your C19 or your testosterone derivatives, and that would be your norethindrone acetate. You may be able to spit this out better than me, but it makes a difference. If we were talking progestins, not all progestins are alike.

Well if we look at the Nurses’ Health Study it seems that sequential regimens using medroxyprogesterone acetate seem to be cardioprotective, but when it is given continuously, as in the HERS study, it may not be cardioprotective. Now we see with the HERS study that it seems that year 1 is where the problem is, while overall HRT is cardioprotective. So as per ACOG, etc., and all of the big OB/GYNs we still consider that hormone replacement therapy, i.e., estrogen replacement therapy, is something to use for cardioprotection. So we do see clinical evidence existing for estrogen’s protective effects even in high-risk women.

How did we define a high-risk woman? A woman let’s say who has angioplasty or quadruple bypass surgery, if she’s on estrogen replacement therapy some studies have shown that she has increased patency of her vessels, but what seems to be the negative with this may be progestins. Progestins we know counteract the effects of estrogens, that’s how they work on the endometrium; that’s why we have to give progestins - to protect the uterus from endometrial cancer if we give estrogens. They decrease estrogen receptors, indirectly, and there are also direct effects. However, what are the clinical effects of adding progestin - and are all progestins alike?

Well, obviously we’re here tonight, so no, they’re not. We do have several progestins available, we all know that.

Let’s look at Adam’s study, which compared plaque area with conjugated equine estrogens and conjugated equine estrogens/medroxyprogesterone acetate compared to control. Atheromatous plaque area is decreased with conjugated equines. If we add medroxyprogesterone acetate, this decrease is not as great, and if we were to give medroxyprogesterone acetate alone, we don’t have that protective effect.

Now this is a comparison to Alex Anderson who looked at ethinyl estradiol and ethinyl estradiol with norethindrone acetate in a 1-mg and 3-mg dose, and we looked at the accumulation of cholesterol. Ethinyl estradiol causes a decrease in the accumulation of cholesterol, but when you combine norethindrone acetate with the ethinyl estradiol there is an even greater decrease in cholesterol plaque area. This is quite impressive. We need one final answer, and when it comes in the future, this, to me, as a gynecologist, is quite impressive and something to consider.

So in summary, we have a lot of evidence that estrogen is cardioprotective even in high-risk women. Progestins counteract the actions of estrogen. The HERS study combined with other studies in humans, monkeys, rabbits, you name it, suggests that MPA largely opposes the positive effects of progestins but not all progestins, blunt this positive effect to the same degree.

Now what is the other major cause of morbidity and mortality in the older woman? Osteoporosis. Osteoporosis is a hideous disease, which is preventable and treatable. On the left we see normal bone. See how it’s nice and thick, the trabecular, which are the first sites of bone loss - and you can depend on this to hold you up, right?

Now look at this, this is osteoporotic bone with a microfracture. In the first five to eight years after the onset of menopause, we have the greatest decrease in trabecular bone in the vertebra. So here’s normal bone, osteoporotic bone, osteoporotic bone with microfracture magnified. How does this compare? What does this mean?

Well in her 50s, a woman is going to lose the bone in her spine. When she gets to be in her 70s, 80s, and later, she’s going to lose it in her hip. Of course there are variations depending on the patients, but that is usually how it goes - the vertebra goes first and then other sites of bone. What does this mean clinically? Well I love this picture because I think it says so many things. This is a woman and her daughter. The woman is in her 70s and the daughter is in her 50s, and believe it or not when they were younger the mother was actually taller than her daughter. Remember when we were younger you used to think, wow, is Grandma shrinking? I don’t think I’m getting taller. In truth she may have been. The average white woman could shrink - who is not on HRT - could shrink 2½ inches because of this dorsal kyphosis, which creates the Dowager’s hump secondary to vertebral web fractures. Vertebra are like this, you have osteoporosis with trabecular bone loss, the vertebrae compress, could pinch on the nerves which are around the vertebrae, cause the sciatic pain, and also cause that Dowager's hump.

Now forget it being unsightly, what are some of the health care issues associated with this? Well, she has decrease in her intraabdominal and intrathoracic cavities, therefore her abdominal and her thoracic cavity structures like her heart, lungs, etc., can be compromised because of the decrease in the intrathoracic volume. So let’s say she has emphysema, she has heart disease, etc. This osteoporosis can actually make her worse with her other medical parameters. Now let’s look at another thing - she’s walking with a walker. We are going to be spending one third of our lives in the menopause. She is only in her 70s, which is actually quite young. That’s just huge. If we’re going to be living that long, we want to be as mobile, and as healthy - and you want us as mobile and healthy so you don’t have to wheel us - as possible. Now how can we summarize this? A 50-year-old white woman has a 15 percent lifetime probability of getting a hip fracture. Depending on the study, within the first year after a hip fracture, five to 20 percent of women will die because of the hip fracture, indirectly. Twenty-five percent of women will have to enter into a long-term health facility, and 25 to 50 percent of women will never regain full mobility. This is hideous. Healthcare costs are abysmal - I will leave that to my colleague here, but it’s horrible.

Osteoporosis is preventable and treatable. Some things we can fix, some things we can’t. We can tell them to cut out cigarette smoking, cut down on alcohol intake, because it’s directly toxic to the osteoblasts. A glass of wine is okay; let them have a glass of wine. Three to four glasses of wine, that’s when you’re talking about a risk. Of course it depends on how big their wineglass is. The other thing is estrogen deficiency. One of the biggest factors for what puts a woman at risk for osteoporosis is how much bone she has going into the menopause. So, it’s never too early to intervene to maximize what her bone is going to be like later. If we have a young patient for example, who has early menopause or surgical menopause from removal of the ovaries, or let’s say she has prolonged premenopausal amenorrhea, lack of menses because she’s an athlete, she may have an eating disorder, etc. She is at risk for osteoporosis, we can try to correct that.

We have lots of estrogens available which may be useful for helping with bone density, however it's important to remember that potency and dosages vary.

We do know that estrogen replacement's going to stabilize or prevent osteoporosis. With ERT we can see a 50 to 60 percent decrease in hip fractures. With ERT and calcium, an 80 percent decrease in vertebral web fractures, especially if we give the ERT for a long period, greater than five years - so compliance is important. Now interestingly, we say that ERT helps with bone, and in our textbook, in my textbooks, I see progestins have a beneficial effect on bones, but remember not all progestins are alike. Some progestins have better effects than others.

Let's look at ethinyl estradiol on vertebral bone. We see that after two years there's an increase in vertebral bone density with ethinyl estradiol. If we combine that with norethindrone acetate we see a huge increase not only from baseline but from that of ethinyl estradiol alone. So it seems that the addition of norethindrone acetate to the estrogen is having a synergistic or added effect on bone, but not every patient can take HRT, and not every patient should take HRT, and not every patient wants to take HRT.

There are other options available. We have the bisphosphonates such as alendronate, we have our SERMs such as raloxifene and we have our calcitonin. One thing though, while ERT has basically a three plus beneficial effect, these other agents may have a one plus beneficial effect. Another caution is the alendronate stays permanently in the bone. We don't have that 30-year assessment of it. The FDA passed it because we need good drugs for osteoporosis, and it is a good product; however, for example, let's think back to fluoride. Remember fluoride used to be given for bone and it did make thicker bone, however, that thicker bone was more susceptible to fractures because having more of something is not necessarily good. We just don't know with that long-term wise. So as a first line, I'm cautious with the alendronate in a younger menopausal patient in her 50s or 60s.

So in summary, osteoporosis is preventable and treatable. HRT, estrogen replacement, is first line therapy for osteoporosis, and as we customize our HRT regimens for the patient we have to decide how much of our choice is based with osteoporosis, etc. Not all progestins are alike, and some are better than others for that. For those who can't or won't take HRT but have a risk for osteoporosis, we do have other agents.

Now let's talk about something else a little bit lighter. What about skin? What happens to skin as we age? There is actually thinning of the epidermis and the dermis; there is decreased elasticity; decreased collagen content, etc. If we give HRT, i.e., ERT, we are going to have an increased plumping - the dermis is going to get thicker, okay, and it's going to have more water content. It's going to be associated with improvement of dry skin, skin wrinkling, and skin atrophy. Now what about this skin wrinkling? It is going to be associated with an improvement of fine wrinkling. The coarse wrinkling we cannot help. Not all patients though are going to have improvements to the same degree, so we shouldn't look to this as a miracle for a cosmetic, and then we'll find the patients may be very pleased.

Now this cartoon says my smile lines are cracking up - and that kind of alludes to what happens with skin as we age.

Now what about Alzheimer's Disease? Now forget the numbers, forget whatever, for any of us who have known anyone, a loved one or anyone who has Alzheimer's Disease. Even Reagan - forget what everyone's political agenda is and things. This is a horrible, horrible disease. If there is anything that we can do to minimize the incidence, try to prevent it in any way, I think it behooves us to try.

Some studies such as Paganini-Hill have suggested that estrogen at higher doses and for continued use will help to minimize the onset of Alzheimer's Disease. I know Thornycraft and others have also said that perhaps-and these are people from like my Bible, like you have your Bible-thinks that perhaps it's important to give the estrogen replacement therapy early on because if you can help to improve the dendritic, the neuronal connections early on, that's what you want to do. So to give ERT early on would be beneficial because later on some studies show it doesn't necessarily have much of an effect. So compliance is key, though.

What about colon cancer risk? Some retrospective epidemiologic studies suggest that it may be associated with a decrease in colon cancer risk, however, these are retrospective epidemiologic studies. They are very suggestive. The women's health initiative will give us that final answer in a few years.

What is the number one reason why women don't want to take HRT? Fear of breast cancer.

What are the facts? We don't know. Some studies say that estrogen hormone replacement therapy may be associated with an increased risk. Other studies say that there's not an increased risk, and other studies say that if you have breast cancer you actually may do better, but we don't have a final answer.

Why don't we have a final answer? The studies that we have are not significantly powered. We have a lot of different meta-analysis out there. A meta-analysis is like a soup. It's only as good as the ingredients put into it, and to be honest, for lack of a better term, some of the studies - suck. They're just not, they're really not a well-powered type of study. So you have these things, and you have people publishing things, which you just have to be careful of. You can look at everything just because it's published as such. But we do know that HRT has been used for a long time. If the change was huge we would know that.

There may be an increased risk but we have to look at things as a scale, the risks and benefits for each patient. To make informed decisions though regarding HRT, we really have to educate patients. And you play a very big role in this, because if a woman is going to use HRT, when "Gladys down the street's mother had breast cancer," you know, etc.-if we're going to have them stick with the regimens we have to educate them and know the possible risks, the possible benefits, and let them be involved with the choice. It seems that a combined estrogen progestin program continues to offer significant benefits for postmenopausal women definitely regarding bone, and possibly regarding heart.

What about endometrial cancer? Well, in the 1970s there was a huge incidence of endometrial cancer because the conjugated equine estrogens were given alone, so there is a huge incidence. Then, suddenly someone figured out it's probably because of the unopposed estrogen, and decided to give progestins. When medroxyprogestin acetate was added, there was a decrease in the endometrial cancer rates and HRT prescriptions started to be refilled again.

What are some of the potential risks and benefits? Venous thromboembolism. A patient may say to you, "Am I risk for getting a blood clot?" Well, we used to be able to say hormone replacement therapy is a much lower dose of estrogen than a birth control pill, for example, 5 micrograms of ethinyl estradiol would be equivalent to .625 of a conjugated equine estrogen, so a low dose OC would contain 20 micrograms, it would be like four times a .625 of a conjugated equine. So we used to say, "Don't worry, birth control has much more estrogen. You're not risk." Some studies do show that there's an increased risk of venous thromboembolic events, however if we look at the numbers, look at this, it says, well, if we give estrogen replacement therapy, we have increased relative risk from one which is the standard, to two or three. Doesn't that sound huge? It sounds huge, but you can't look numbers. Because how does that equate to patient numbers. A woman not on HRT has a 1 in 10,000 risk of getting a venous thrombolic event. If she is on HRT what this increase in relative risk is telling us, is that she increases her risk from 1 in 10,000 to two or three in 10,000. So while the numbers-and you may be talking about that we can get fooled by numbers, it doesn't really equate to patients, but it's something to consider. The number one reason why patients don't want to go on it is fear of breast cancer.

The number one reason why they go off of it is compliance. They don't want to bleed; patients do not want to bleed. We know that compliance is important because in order to get the long-term benefits they have to stick with it, and bleeding is the number one reason why they go off of it. And what's interesting is one large drug study showed that the number of patients who were filling their HRT regimen prescriptions after a year was only 50 percent, so compliance is abysmal.

Only 17 percent of menopausal women currently use estrogen; 55 percent of women had never used it; and 25 percent of women have used it in the past but then quit.

We have different ways to give it; you know I can play with how I give it. I can give it continuously, however, this will be associated for many patients, especially the younger patients that don't have a chance for the uterus to be equated, to be atrophic, they are going to have breakthrough bleeding. If you give it continuously, for many patients after a year's time, that bleeding will improve. However, they are not sticking with filling their prescriptions after a year, so we have to address that issue before a year. I could give it sequentially combined, however 80 to 90 percent of women on sequential combined regimens are going to have bleeding, although predictable. So at least they know that they are going to get it, but they're still going to get it. Let's face it, when you're menopausal, one of the perks is that you don't have to worry about getting a period anymore. So, that bleeding is a real issue. In women who are likely to discontinue HRT due to bleeding, we do have alternatives available today that are going to enable long-term use. Women are going to find every possible reason to go off of their regimen.

This cartoon says, "But officer, I couldn't possibly have been speeding. I've been out of my estrogen for a week." We have to educate them about what the estrogen really is what it's associated with.

Let's go back to bleeding. OK. This is a study that looks at accumulative amenorrhea in continuous combined regimens: conjugated equines and medroxyprogesterone acetate. And we see that after a year we have a 68 and 78 percent incidence of cumulative amenorrhea. That sounds great, however, only 50 percent of the patients are still filling their prescriptions. So let's look earlier. After six months we have a 32 to 40 percent incidence of the cumulative amenorrhea.

Let's compare this now with the norethindrone acetate ethinyl estradiol combination. At a year we have 82 percent cumulative amenorrhea, compared to that 68 and 78 percent. So it's better, but not as great a difference as I'm going to point out now. At six months with the norethindrone acetate combination with ethinyl estradiol, we see a 60 percent incidence of cumulative amenorrhea in comparison to the 32 to 40 percent. So we really want to address this problem early on. They are not filling their prescriptions after a year. So if we can increase and improve their bleeding profile early on, that is wonderful.

So in summary, unwanted vaginal bleeding with women with a uterus is the most important factor in nonadherence. I have to make sure that there's not a mechanical reason. Any woman who has postmenopausal bleeding has to be evaluated by someone who knows what they're doing. You can't just "pooh-pooh" a problem saying it's from a different hormone. She may have a polyp, etc. Predictable vaginal bleeding occurs in 80 to 90 percent of all women on sequential combined. Unpredictable vaginal bleeding is a significant problem for continuous combined regimens, especially in the younger menopausal patients. Although certain regimens appear to be definitely more quick at effectively producing amenorrhea, a continuous combined regimen that can create amenorrhea early on will help to improve compliance-and that we have with the norethindrone acetate EE combination. In women who are likely to discontinue HRT due to vaginal bleeding, consider that as an alternative.

We do have different ways that we can give estrogen. We can give it orally, we can give it transdermally, we can give it intravaginally, etc. There are certain patient populations who should get certain routes. For example, transdermal would be good if a patient, let's say, can't tolerate something GI, etc., but for the most part patient desire is really how they determine which form they are going to get.

It's important though to remember that estrogen preparations differ in dose and potency, etc. You know we have our conjugated equines at .625 - that would be equivalent to a micronized estradiol of 1 mg and ethinyl estradiol of five micrograms. These are just the equivalents-like I really expect people to remember this when you're sitting here at the Phoenician with wine.

So in summary we have a lot of evidence that suggests that hormone replacement for therapy is beneficial. If we were, you know, a utilitarian society, we would say greatest good for the greatest number. We may even say that in a utilitarian society they will include hormone replacement therapy, but we are not a utilitarian society. And our management of patients has to be customized, but hormone replacement therapy should be considered for all patients and then decide whether or not they're candidates and when they want to use it. So as a gynecologist who works with menopausal patients, I feel it's important to really maximize their health care and educate them so that we don't end up with ...

rebels with the "pause." And I thank you.

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