John Buster, MD
Nanette Santoro, MD
Endocrinology and management of hormone therapy in older women

John Buster, MD
Good morning everybody. My name is John Buster and I’m from Brown University in Providence Rhode Island and my collaborator on the podium is Nan Santoro, Albert Einstein in Bronx, New York.

Welcome to Menopause morning of Menopause day. The first seminar that we’ll have for you today is on Endocrinology and Management of Hormone Therapy in Older Women. And it is divided into two parts.

The first part will deal with the chaos and decline of menopausal events in life and Nan Santoro will be talking to you in detail about some of the hormonology that take place as we go through the pre-menopause and menopause.

Nan has been involved in this area of research for many, many years and when you hear the presentation I’m sure you will be impressed that this is one of the most informed scheduled topic that you have seen.

My part will be on how to calm the chaos and decline of pre-menopause and menopause and we’ll be focusing on some of the new rules and new tools that have become available to treat this condition that are involved even very, very recently. Just to begin with a couple of comments about the chaos and decline, the most significant symptoms are twofold. One, the vasomotor symptoms which afflict many millions of women in this country with insomnia and fatigue and memory lapses and depression, all part of that picture that Nan will be talking with you about. And the second aspect of it relates to decreased sexual desire. We’ll be discussing both of those and then point out how it is that both these conditions are made worse by other co-existing situational and psychiatric issues. Without further adieu let’s have Nan now begin her presentation on the hormonal changes of the menopausal transition making sense of the chaos. Nan, the podium is yours.

Nanette Santoro, MD
I want to thank the Society for actually having a menopause day. I think this is a wonderful development for the ASRM. What I want to talk to you about today are some of the data that we have from a variety of population-based studies that look at menstrual cycles, hormones and then try to link them to symptoms.

So when do we see hormones changing with menopause? In the earlier part of the transition, estrogen is erratic and sometimes even elevated. So it is not low. As women get into the postmenopause and the later stages of the menopause transition, estradiols are constitutively low. During the transition progesterone declines slightly with ovulatory cycles and anovulatory cycles also increase in their prevalence and that may be another thing that contributes to the background hormone milieu that may or may not be driving symptoms. Clearly a minority of women has symptoms but for those of us who treat the women they’re the ones that we see in the office.

After menopause, the signature event is that there is no more progesterone for about a year. There’s a little bit of estrogen. And we look at gonadotropins and other protein hormones from the ovary FSH is intermittently elevated and then progressively goes up and stays up. It’s very tricky to pick it up in the earlier parts of the transition, which is why it can be frustrating to measure it. LH rises in the late part of the transition. And what’s now been characterized as the earliest event heralding menopause transition, is a decrease in Inhibin B. So before we see any drop in estrogen, which we used to think is the traditional sort of negative feedback inhibitor of FSH, Inhibin B is going down and that’s why we see these early and intimate rises in FSH. AMH is the new kid on the block, also called anti-mullerian hormone or MIS. And that decreases progressively throughout reproductive life. There’s a number of abstracts at the meeting that are now characterizing this in different patient populations. It’s unfortunately difficult to measure very close to menopause because of assay sensitivity issues but it may become a useful adjunct to look at ovarian reserve or even time to menopause. After menopause it’s a steady state. So as women go from this transition state to the steady state FSH is up. It only starts to decrease somewhere around the eighth decade of life. LH is up. There is some evidence that the pulsatile release of LH and FSH is more chaotic with age, which may be a feature of how aging neurons are working. But for practical purposes they’re up. Inhibin and AMH, the ovarian products, are down and undetectable and estradiol is low.

Now when we look at testosterone it’s a little more controversial. The biggest decrease in testosterone really is happening in a woman’s thirties. So it’s already decreased by the onset of the menopause transition. And this is important to keep in mind when we think about things like testosterone to improve libido in women. We are probably doing a pharmacologic intervention because the physiologic change has already happened. There is a mid-cycle rise of testosterone and androstenedione that seems to extinguish in about the fourth decade of life as well. And whether or not the postmenopausal ovary makes androgens remains a bit of a controversial point. One very well done, small study showed that there are no androgens or androgen producing enzymes in the ovary after menopause. But when you look at women who have had their ovaries removed, it looks like testosterone levels are lower. So there may be something different about those women who have had their ovaries removed that gives them lower levels or removing the ovary has removed a source of testosterone.

So what I want to bring you through are the stages of reproductive aging. These were conceptualized at a workshop that was done in 2001 and they are badly in need of a little updating. But I think the important points to see on this slide are right here, the final menstrual period, which is only defined after a year has gone by and a woman has had amenorrhea. And the transition stages of the menopause – so there’s an early and late transition stage. And the onset of the transition is marked by a woman noticing a change in her menstrual cyclicity, they either become more irregular by about seven days--and that really applies to the very compulsive group of women who actually keep track of their cycle length--or they skip a cycle, which is the much more common experience that a woman will have. So they’ve been previously regular and then they skip. Note that prior to that elevations in FSH are seen. They’re intermittent but they are used a lot in fertility practice to predict ovarian reserve. But you may or may not capture it. At this point, it tends to be more likely that FSH is going to be up so it’s more consistently elevated just a little bit and then as women move into the late transition they begin to show some of the more classic signs of low estradiol levels. So they tend to get more symptomatic with things that we associate with low estrogen. Hot flashes increase in prevalence, vaginal dryness begins to increase. There are some of those symptoms here but they tend to get worse. And the other thing that we now know from the SWAN study is that this interval of amenorrhea, 60 days or more, begins to show in a woman’s bone density. So that is the point at which bone density begins to decline. It’s really that late transition into the postmenopause.

The Inhibin Hypothesis is also important to explain. It’s been around since the seventies and has been circumstantially proven by a number of other studies including Henry Burger’s excellent study, the Melbourne Women’s Health Project, but when a woman is young she has lots of follicles and those small follicles are the ones that make the inhibin. And inhibin B is produced in huge quantities. As a woman ages, her inhibin decreases along with her ovarian follicle reserve and the cohort size, because inhibin is really measuring growing follicles in that cohort that shrinks. So as inhibin goes down, there are still a decent number of eggs left in the ovary but inhibin restraint of FSH goes down and FSH goes up.

You can see that quite nicely on this graph, which is taken from Burger and Dennerstein looking at the Melbourne Women’s Health Study. Women were observed from ages 45 to through their menopausal transition and estradiol is shown here, FSH, inhibin B and inhibin A, which is more a corpus luteum product, these samples were all measured in the early follicular phase. So inhibin A is not too useful. But time zero is menopause and right around menopause you see this nifty looking crossover of estradiol and FSH but note that in that year prior that’s when estradiol takes its biggest drop. So a year prior to a woman’s final menstrual period is when she’s having the drop. After that things are a little bit erratic. FSH also has its biggest rise the year after menopause and you can also see the circumstantial evidence that links inhibin B to the earliest change that we see in the transition. So here’s inhibin B starting to drop and FSH begins to escape. So the sequence of events is the loss of inhibin B, a small rise in FSH and then you’ve got the big drop in both estradiol and inhibin B, prolonged menstrual cycles and then this big rise in FSH that accompanies the postmenopause.

There are three population-based studies that have been very informative. SWAN is the US-based, multi-ethnic study that has examined hormones in women who are now going into their eleventh year of followup. So most of them have gone through menopause. We try to link hormones to symptoms and have found that FSH but not necessarily estradiol links to symptoms. Cycle changes also relate to symptoms and ovulatory cycles relate to some symptoms and I’m going to go through these in a little more detail. Hormone exposure does the same thing. In the Melbourne Midlife Health Project they focused a lot on inhibin as being one of the drivers of the transition. So that linked to some symptomatology but they did more of their studies linking the timing of menopause to symptoms. And then there is the Penn Ovarian Aging Study and I was happy to see Mary Sammel (Co-Investigator of the Penn Ovarian Aging Study) at the back of the room at the beginning of the morning. This is Ellen Freeman’s study, and she and Mary Sammel, who have a couple of presentations at this meeting, have done some very interesting analyses of the serial hormone data that they collect every six months in women. They have been among the first to show that the variability in hormones is something that predicts symptoms better than absolute levels. And to give you an idea of how difficult that is to do, you must assess the same woman longitudinally for a long period of time and then calculate the within woman variability in hormones. So I’m going to show you a little bit of that data.

Now we have seen in SWAN some differences in menstrual cycles themselves and symptomatology. We’ve characterized entire menstrual cycles because we have a dedicated group of women and investigators who are willing to do this and women collect a daily urine sample for an entire menstrual cycle. And we’ve characterized these daily patterns in both ovulatory cycles and in anovulatory cycles. This just gives you an idea of what the anovulatory cycles look like. We characterized our anovulatory cycles into two types. Ones that ended in a bleeding episode and ones that did not. So the anovulatory cycles without bleeding are shown in sort of the aqua blue and the ones that ended in bleeding are shown in yellow. And you can see that these types of cycles tend to tell us a little bit about where a woman is along that continuum of declining ovarian function. When a woman goes from these anovulatory bleeding cycles to a non-bleeding cycle her FSH is much higher. If she’s anovulatory but she has a bleed her LH is lower, her LH is higher if she does not bleed. Progesterone is very low in both of these cycles. This is progesterone metabolites in the urine because they’re anovulatory by definition. And there’s a huge difference in estrogen. So the anovulatory cycles that end in bleeding and the ones that don’t end in bleeding are characterized by a very big difference in estrogen production. So this may not be earth shattering to you because we’ve known that if you make estrogen you’re going to bleed but there is quite a bit of a difference here and it does appear that women that progress from this type of cycle (anovulatory with bleeding) to this type of cycle (anovualtory without bleeding) have actually undergone more of a milestone in their menopause transition. These cycles (anovulatory with bleeding) just appear and they’re more common but women sort of toggle back and forth between these anovulatory bleeding cycles and ovulatory cycles.

And to give you an idea of how common the anovulatory cycles are, let’s look at age alone in the earlier parts of SWAN when all of the women in SWAN were cycling fairly regularly. They had at least one period in the last three months. Based on age alone, a woman who was 50 is only about 50% likely to be having an ovulatory cycle. So even if the cycles are regular one shouldn’t always only assume that they’re ovulatory.

What we’ve also noted when we’ve looked at entire menstrual cycles (and these are just looking at the ovulatory cycles, cause they’re much easier to measure hormones in because we can separate them into a follicular and a luteal phase), as women get older their FSH gets higher and with time on study from the beginning, baseline and the followup one and two because we only have three years of these data analyzed at this point, FSH goes up, LH goes up with age, not necessarily with time on study and progesterone in both cases goes down. So in an ovulatory cycle women make a little less progesterone every year and the older they are the worse they are at making progesterone as well. And estrogen in the early part of SWAN, remember these women are in the early transition, it actually looked like it was going up a bit, not significantly so, but with time on study it looks like it goes down. But the important ones to take home from here are this increase in FSH and the decrease in progesterone.

We also know that the length of menstrual cycles changes and there seems to be an early transition shortening. Rebecca Ferrell just re-analyzed the Treloar database a couple of years ago and this is her newer analysis and that’s the traditional Treloar version. Cycles get a little bit shorter and cycle length is under 20 days in some samples of women about four years prior to the menstrual period and that corresponds in a population average to about the onset of the transition when a woman will first experience some irregularities. So the median age at which that happens is about 47, menopause happens about four years later, the final menstrual period. So, in summary, cycles progressively lengthen but they get a little shorter before they lengthen.

This is a very busy slide but I want to just call your attention to what was a very nice paper by Brad Von Voorhis using the SWAN data to try to analyze bleeding patterns. Because one of our main hypotheses was that hormones were going to be predictive of bleeding patterns and it died hard, we looked at a lot of the data, and it does not seem to be the case. So I have to drag you through this because there was an awful lot of work involved and then give you the punch line. But as cycles were very short or long, less than 21 days or longer than 36 days, they were very likely to be anovulatory. If a cycle falls within that sort of magic cycle length, in mid-reproductive age women, it’s 25 to 35 days, in older reproductive age women it’s 21 to 35 days, so it’s a little shorter and you’re allowed to have a shorter cycle. Very few of those were anovulatory. So women with that normal cycle interval are more likely to be ovulatory. The number of days of flow was mostly likely to be 4 to 7 days if they had an ovulatory cycle and if the flow was very short or very long, more than 8 days, it was more likely to be anovulatory and the heavy flow days were most likely to exist, a little more likely in ovulatory cycles but very few heavy flow days in those anovulatory cycles. So as women progressed from ovulatory to anovulatory cycles their menstrual periods overall get lighter. They may get longer for a period of time when they don’t ovulate but they tend to get lighter. So the faucet is sort of being turned off in terms of menstrual bleeding and that really led us to consider that women who have a lot of bleeding problems probably should be worked up most aggressively for anatomical problems and we should not be worrying so much about hormones being a big player here.

So as menstrual cycles are getting turned off, estrogen is going down, who are the people who get the most severe hormonal withdrawal? We have data from a number of different studies that have given us some clues as to who the target groups are, as to who gets in the most trouble. Women who have had pre-menopausal oophorectomies now in a number of studies seem to have more severe symptoms and may be at risk for some longer-term complications. Women with premature ovarian failure also appear to have worse symptoms. Overweight and obese women have a moderately increased risk of more symptoms. Women with poor physical functioning, depression and an early onset of the transition. So early onset transition seemed to be more annoying to women. And in some populations we’ve noted that if women have HIV infection or are exposed to HIV or substance use they also have worse symptoms.

There are clear linkages of estrogen withdrawal to hot flashes, vaginal dryness, sleep disturbances and now depressed mood in a number of studies and that risk seems to increase even through the early postmenopause now we’ve seen in SWAN.

Symptom severity has been linked to inhibin because it’s one of the harbingers of the early transition as well as its standard deviation so that point I was bringing up before about the variability of hormones within a woman help to predict her symptomatology. FSH and its standard deviation also are linked to symptom severity but only the standard deviation of estradiol was linked, not the absolute levels.

So that kind of leads to what I call the roller coaster hypothesis. The more erratic the roller coaster, the worse the transition symptoms. So the higher highs and the lower lows in estrogen and possibly even progesterone may be predictive of the woman who is going to have a more symptomatic menopause. So it then follows that interventions that smooth out the ride and I’m going to leave those to Dr. Buster to talk about, will make the transition less symptomatic. And indeed we’ve seen in recent years evidence of things like extended cycle, combination oral contraceptives or steady state hormone therapy being the most beneficial in terms of symptomatology.

It’s also important to remember that the responses to hormones change pre and post menopause. So when we intervene, the woman that we’re treating is changing over time and we’ve got to keep that in mind. So what we have noted in SWAN, which was really like many long-held beliefs, we always though obese women would have less hot flashes and that has been shown in the postmenopause. But in the perimenopause the opposite is true. And it may be that these women have either more erratic hormones or that their adipose tissue is more likely to be a better insulator and they don’t dissipate heat as well so that they’re more prone to hot flashes. But postmenopausally there’s a protective factor associated with obesity. And then we think it’s doing what we always believed it did, which is it supplies a little more estrogen.

Similarly, premenopausally, it appears that when one gives DHEA and other weak adrenal androgens they don’t contribute materially to the hormonal milieu but when the ovary drops out postmenopausally, these hormones may function not just as androgen precursors but I would argue also as estrogen precursors and that may be one of the ways that they exert effects.

As woman progressed in the Penn Ovarian Aging Study and we’ve seen something similar in SWAN and in the Melbourne Study, mean testosterone levels actually increased. Free testosterone in SWAN and in the Melbourne Study increased. So there isn’t a dramatic drop in androgen or testosterone at least associated with the menopause transition. And in the late transition to postmenopause estradiol was already low, it doesn’t get that much lower.

In the Penn Ovarian Aging Study some of the things we saw that have been duplicated in other studies as well are that headaches and particularly migraines go down so there’s some benefits to menopause. Irritability, mood swings and anxiety go down. Concentration doesn’t change much and the women who have more symptoms, and this is across many studies, are the ones with more depressive symptoms and what the Penn group has shown is that prevalent pre-menstrual syndrome at baseline also is predictive.

So to summarize, the menopausal transition is associated with irregularly irregular hormone patterns. And it’s important to appreciate that the amount of irregularity may be, while it’s very frustrating to characterize and summarize, that may be what we need to pay attention to. Each transition has its own pace and the pace alone may relate to symptoms. So a faster, later one may be better than an early-prolonged one. Hot flashes last on the mean eight years for women. That’s a long time to go without treatment if they’re really nasty. And a proportion continue to have them well into their sixties and beyond. So we do need to pay a lot of attention to symptoms, especially with global warming being what it is, and make sure that we’re on top of the latest data.

Hormones tell us part of the story, absolute levels, but again I want to bring home the message that the variability of hormones is important and remember that hormone levels alone don’t explain all of the vulnerability. There are a lot of other psychosocial factors that relate to symptoms susceptibility.

And with that I thank you for your attention and we’ll move to Dr. Buster.

John Buster, MD
Thank you, Nan. We’re going to be talking now about some of the new methodology available, new rules, new tools on calming the chaos, on smoothing out the ride, on slowing down global warming. Nan, I think that’s a great idea. That’s a nice contribution to make to society.

New rules, new tools. Women’s Health Initiative changed a lot about how we look at hormones. No one has disputed that the combinations of estrogens and other substances may in fact help a great deal to suppress hot flashes but the rules that have evolved, evolved from the charge received from the Women’s Health Initiative to treat with the lowest dose possible with a goal to imitate endogenous secretion of hormones. And those rules now apply to both estrogens, which are involved with treatment of vasomotor symptoms and are achieved in part through that deliver transdermally. And also testosterone, which is effective in treating hypoactive sexual desire disorder and also can be delivered transdermally.

Let me now extend the argument in the details. First of all hot flashes, I recall from my days in medical school as a fellow before most of you were born that in fact some people thought hot flashes were imaginary. Women carried fans to the opera and they were thought to be crazy. They were given phenobarbital and drugs of that sort to suppress them. This work of Sam Yen and Howard Judd, going back to the 1980s made this a very real event of pathophysiology. They measured the fingertip temperature in these women demonstrating very clearly during the perception of a hot flash that their temperature goes up as their body undergoes a thermoregulatory crisis of sorts with an increase in pulse rate, blood pressure stays about the same but heart rate does increase and a very, very uncomfortable experience.

What makes this more significant is the impact on sleep patterns and this is data also from 1980s and 1990s, showing how it is that during night, these are time of sleep hours, and this depth of REM sleep here, showing how the hot flashes are correlated with loss of deep REM sleep. Loss of memory, lethargic feeling and tiredness in morning are very common complaints that come from hot flashes. This is a huge psychosocial quality of life issue because it impacts women in positions of great responsibility, the workplace as well as moms trying to take care of families. It’s not a trivial matter.

So WHI changed the rules. It showed that estrogens don’t prevent cardiovascular disease. There is an issue of breast cancer, a very small increase. The rules in terms of treating vasomotor symptoms for our discussion for now is to give the lowest dose possible.

Oral estrogens are highly effective for vasomotor symptoms but the limitations are that when you deliver estrogen through the liver the actions through metabolites and the approximation of physiology is just an approximation. The doses you have to take are substantially higher of endogenous production and there’s an issue of first-pass effect, which for certain situations has been linked to the adverse reactions that are associated with oral estrogens.

The new tools are the very systems developed over the last 20 years that deliver chemically identical estradiol, the same hormone made by the pre-menopausal ovary through the skin, patches, gels and more recently there’s a spray on that is available as well. Let’s talk about those in a bit more detail.

So the new rules are the lowest dose possible and in a way attempt to imitate endogenous secretion of estradiol. That secretion in a pre-menopausal woman during menstrual flow is something like 50 to 60 micrograms per day, something along those lines, to try to approximate the early follicular phase production of estradiol. And the way to do it is to deliver the molecule directly into the peripheral microcirculation directly just like an ovary does it. That’s the idea behind this.

This illustrates the differences between the metabolic effects of oral delivery versus transdermal. When you take the drugs orally you have to take a large dose of steroid and present that steroid load to delivery every day. It affects liver, protein and lipid synthesis and has effects that in some cases are considered undesirable to get to the cells of the target tissue. When you deliver the hormone transdermally it goes directly into the microcirculation and directly to the cells of the target tissue with no first-pass metabolism, more stable levels and lower doses.

There are three systems out there that we’re familiar with that do this. The first are the patches and they’re available now clinically that deliver as low as .014 micrograms per day or milligrams per day, up to about 0.1 or a hundred micrograms per day. So those are around the envelope of normal production. There’s now estradiol spray that delivers in one two or three sprays from .019 to .040 mg. So it’s just a little shy of that. And then there’re now estradiol topical gels and emulsions that deliver a range of 0.012 up to 0.05 per day. So these are approximations of endogenous estradiol production you would see in a pre-menopausal woman.

This is the transdermal patch for estradiol. Estradiol is dissolved in alcohol and delivered directly into the microcirculation as we discussed before.

This is a slide showing the blood levels of estradiol with a 100-mg patch versus a 50 here and you can see the levels are in the middle range of pre-menopausal physiology and maybe a little bit higher right here with a larger dose.

And here is a gel that’s been available recently.

And here its applied, the patient puts it on her fingers and puts it on her legs and you see this illustration here.

And here, again, is the dose proportionality effect in which the largest dose produces levels just under about 40 and the lowest doses in the 20 to 15 rate as you see right here. And these do suppress hot flashes. They are effective but the doses are low and the blood levels are low.

Here’s an estradiol spray. This spray is applied to the arm once per day.

The rational behind the spray is that estradiol is dissolved ethanol, that’s the solution that it’s in, and it is mixed with a binding agent called octisalate, which is used to penetrate with sun skin lotions and released very slowly over the period of about a day so the level is very, very stable.

The blood levels are between about 15 to 30, 35, 40 pg/ml. So these are very low values. So the question is do these hormones in these low levels actually suppress hot flashes?

And the answer is yes they do. Here are the levels of various preparations out there. This is a gel right here. Here’s another gel here. Here are some patches and a spray. These are mean values all very low levels. And they do suppress hot flashes.

This happens to be from a seven-day patch. This work was done many years ago. But it shows very clearly, here’s placebo at the top. Here is a low-dose patch. Here is an oral preparation. And here is a higher dose patch showing over a period of one to three weeks suppression of hot flashes. So even in these low dose ranges these things really work quite well and they’re comparable to the oral preparations that have been available for many, many years.

So in summary, delivery of chemically identical estradiol through the skin is highly effective. The effects are delivered by direct delivery into the microcirculation. The doses approximate follicular phase estradiol secretion in pre-menopausal women during menses for the lowest part of the cycle and there’s no first-pass effect.

Well the first-pass effect issue has been a hypothetical thing for many, many years. We’ve known by looking various epic phenomenon that they don’t affect lipids, they don’t affect inflammatory factors and they don’t affect clotting factors. Furthermore, they produce estradiol ratio that really resemble pre-menopausal serum and there is little effect on coagulation factors. But it wasn’t really to about a year and a half ago we had good data on whether or not there’s an effect on deep vein thrombosis and thromboembolic effects of these preparations.

The key study in this regard is called the ESTHER Study. It’s a retrospective case controlled analysis very similar to the designs that were used 30 years ago with birth control pills showing a relationship between deep vein thrombosis and thromboembolic events and estrogen like hormones. The ESTHER Study compared transdermal estrogens against non-users and oral estrogens against non-users. The relative risk with adjusted odds ratio for venous thromboembolism for oral estrogens was about what we’d been seeing before around 4.2, against transdermals, which was less than 1, against non-users, which was 1.0 by definition. Very powerful evidence that that may actually have a payoff

Of more concern though are patients who are high risk for deep vein thrombosis, those who have the prothrombic mutations. In that regard with no mutation the orals run 4.1, the transdermals 1.2, 1.0 for the nothing but the orals run 25.5 relative risk against 4.4 and 4.1 for nothing versus oral. It’s about four or five times higher for those who are at high risk for deep vein thrombolic events.

Similar to this is the impact of obesity. Again, showing in the ESTHER trials that with the obese patients over 30, here we’re running high-risk people again on nothing, on orals, on transdermals is 20.6 versus the transdermals of 5.4 versus 4.0 for nothing at all. So even in people who are increased risk for obesity it appears that the difference still exists and the transdermals are a little different from nothing at all.

So in summary, these transdermal systems are effective in managing vasomotor symptoms. There appears to be minimal, maybe not really any, venous embolism risk. There are newer now and more friendly transdermal treatments and the doses are lower with no hepatic side effects and no affect on inflammatory proteins with little coagulation factor effect as well.

But there are still problems. Here are the principle transdermal systems out there. The patches some people think they’re ugly, I don’t but some of them do. They come off. They come off in the shower, there’s sun exposure issues and for some people they’re irritating. The newer ones have gotten much better with that; it’s not such a problem now. The spray is an applicator you’ve got to put on your arms it’s kind of bulky, it’s hard to carry on a plane, I guess. They do run dry. It’s hard to count the number of sprays, you’ve got to count 50 times to be able to keep track of it. The gels and emulsions are messy, require a large area, you’ve got to wait for them to dry. They get on your best friends, I guess. And there’s variability in dose with those that’s an issue. So everybody has got problems? Nothing is perfect is it? But this is where it stands right now in terms of those imperfections.

I’d now like to move to a different issue just to close on this. The principle of transdermal delivery also is applicable to testosterone, which is being used now to treat hypoactive sexual desire disorder. Patches for testosterone are not available in the United States of America. They are available in Europe and there’s a great deal of data on them. I’ll show you just a little bit of that. And there are gels that you can custom formulate for your patients if you’d like to use these things.

First of all, a little bit about new rules. The idea with the transdermal patches and with the gels, if you can, again is to deliver the active steroid directly into the microcirculation to avoid the first-pass effect. Again when you deliver through the skin, most of the bad things go away and the good things, many of them, stay. And the idea in a woman is to dose to approximate pre-menopausal production rate in a premenopausal woman during follicular phase, it’s about 300 micrograms per day. At mid cycle in a healthy, pre-menopausal woman it goes way, way up, maybe two or three fold, at mid cycle because of the tie-in with sexual desire in healthy pre-menopausal women. After menopause, as Nan told you, that effect goes away. So to approximate something like 2 to 4 micrograms of testosterone makes a lot of sense.

Sexual desire is an important quality of life issue. These molecules, these steroids affect sexual desire, which is part of the normal female sexual response. Sexual desire is thoughts and fantasies about sexual matters. Sexual thoughts and fantasies are fun. We all love having them and it’s an important quality of life. And when women lose their androgen production they commonly lose that aspect. It’s readily measured by psychometric testing and in that regard instruments have been derived that do very well to measure response to various hormones. Sexual arousal refers to the biophysical events of sexual arousal and orgasm is the third component. And if I have to tell you what that is you won’t get the answer.

When you take ovaries out of pre-menopausal women, blood levels and testosterone drop very precipitously, both actually in pre and postmenopausal women. And so one very common scenario is that a woman undergoes a hysterectomy at 51 years of age, ovaries are taken out, and sexual desire is driven by a new relationship, which she doesn’t feel because her ovaries have been taken away. Those kinds of women who have the infrastructure and the psychological architecture to respond to sexual matters are the ones best treated with these preparations.

There are several trials out there really well done. Prospective randomized, prospective trials showing that when you replace testosterone through the skin that in many patients you get sexual desire back again. These are two of them. One of them was a paper I was involved with, one with Dr. Simon published back three years ago. And then last week in the New England Journal of Medicine a paper from Australia shows much the same thing and there are really others that show that testosterone in these amounts is actually quite effective in bringing it back.

When you look at blood levels of testosterone delivered through a patch, the levels go, here are postmenopausal women with very low levels and these are the levels you see just a little bit above physiology delivered by these patches. So they work very well for that purpose.

And here is increase in desire, the two trials I mentioned, both of them demonstrated that sexual desire increases in randomized, prospective, properly blinded clinical trials.

Adverse events – not a lot. Some women do get hirsutism and acne but most of the things that occur in those dose ranges with transdermal testosterone are very, very low

So what you can’t get in this country the FDA for a reason that I’ll talk in a second here, has decided that we can’t use testosterone patches in the United States of America. It does work. They don’t realize and they’re only in a few cases some hirsutism but very minimal so why can’t you get it?

The FDA feels there’s not sufficient short-term data to do it even though there are 20 randomized trials out there. That’s where we stand today.

And so back in 2004 about three months after Vioxx, the FDA Advisory Committee said no to that testosterone patch.

It is available in Europe at the present time if you want to go there to get it or another option is to make your own. And that can be done by making a formulating pharmacy prepare it for you or you can use the materials available for men for the same purpose. The goals are dosing the physiologic and the simplest and safest therapies and I thank you for your attention, we are ready for questions. Thanks very much.