Alan M. Altman, MD
Assistant Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School

Dr ALTMAN: About 20 years ago, Phil Sarrel first wrote this paper looking at low estrogen levels associated with the prevalence of sexual problems. Clearly, looking at below and above 50 picograms, there was a trend where the women with lower estrogen levels clearly had more of the problems of vaginal dryness, dyspareunia, and distress from these problems.

This was added to by the work of Gloria Bachmann a number of years later. Not only that estrogen had something to do with it, but the impact of this deficiency on all of these sexual problems listed here. The change in the anatomy itself, most importantly, the loss of elasticity, diminished lubrication, increase in pH, as well as thinning of the vaginal wall, with the loss of elasticity leading to dyspareunia, or pain with intercourse. But there were also other areas involved that were estrogen-related, such as a decrease in vaginal blood flow, which can impact the necessary arousal-related increase in blood flow, and reduced nerve transmission and discharge of nerve impulses, which can impact orgasm as well.

And let us not forget basic postmenopausal estrogen withdrawal, including mood changes, sleep disruption, night sweats, and so forth, which can have an overall impact on desire as well.

Does estrogen replacement, however, impact directly upon sexual desire? That's a question that we can’t answer well at the present time. We know that if hypoactive sexual desire disorder (HSDD) is due to vaginal pain, certainly one can treat the problem by replacing estrogen either systemically or vaginally, improving the elasticity of the vagina and hence altering the patient’s response: "Well, I didn't want to have sex because it hurt. Now it doesn't hurt, so now I want to have sex again."

You mustn't forget the concept of vaginal dyspareunia when a patient comes into your office looking for testosterone and has low sex drive, especially if she's peri- or postmenopausal, you've got to ask about the vaginal area first. "Do you have discomfort with sex?" She probably doesn't need any testosterone. We'll get to that a bit deeper in a moment.

What about progestogens? Now there is evidence that demonstrates that [with] synthetic progestins such as medroxyprogesterone acetate (MPA), in animal studies, an antagonistic effect of vaginal blood flow by MPA that we don't see with micronized progesterone.

Generally, genital atrophy can impact a large percentage of women as they become peri- and finally postmenopausal. In fact, every woman with estrogen deficiency for a long enough period of time will experience some degree of genital atrophy. A little bit different than the male rule with respect to erectile dysfunction and age, the 50, 60, 70 rule, where 50% of men over 50, 60% of over 60 and 70% over 70 have some degree of erectile dysfunction. This will be 100% of women with estrogen deficiency for a long enough period of time— some degree of genital atrophy.

And what you see in this list below is what we expect from these changes in genital atrophy. The loss of elasticity, as I just mentioned, can lead to vaginal dyspareunia.

We are all familiar with this slide of the pathophysiology of the estrogen deficiency, postmenopausal atrophic vagina on the left and the same patient using vaginal estrogen therapy for only one month with the increase in the epithelial layer. What is striking, however, is the epidemic of vaginal dyspareunia that has been visited upon peri- and postmenopausal women since the misrepresentation of the WHI data seven years ago, which frightened them away from use of estrogen. These patients fill our offices, and this has become a leading cause of HSDD.

Successful therapy for this problem does not depend only upon use of local vaginal or systemic estrogen. As Dr Kingsberg briefly mentioned, the use of progressive vaginal dilators, along with some sort of estrogen replacement, is vital for success. You saw her slide of those vaginal dilators and we must not forget to recommend their use. You don't rub vaginal estrogen cream around the introitus every night at bedtime and expect the vagina to magically open. You've got to mechanically dilate as well. Patients put in a dilator that just gives them some discomfort every day for 15 minutes, while reading the paper or otherwise relaxing at home, privately.

With daily use, she'll notice that she no longer feels discomfort. The next day she moves on to the slightly larger dilator and gradually works her way up. Don't forget the dilators. They're incredibly important. Google vaginal dilators and she will find sets of medical dilators that she can order.

This is to remind us that there can be a very distressing combination of vaginal atrophy and erectile dysfunction. This was best summed up by a patient’s response to the question with which I normally initiate this discussion. When I asked her, "Are you sexually active?" She said, "Well no. Actually my husband and I having sex is like trying to put a raw oyster into a slot machine."

Now think of that for a moment, because when you have that quasi-erectile dysfunction and you're trying to have that enter vaginal atrophy, you can kill the penile erection immediately. And that's why lubricants are so important as well, aside from fixing the problem as a whole.

So what do we remember about vaginal atrophy and hypoactive sexual desire disorder? Nobody wants to have sex when it hurts. This can lead to performance anxiety and avoidance of sexual activity completely. It is absolutely the first area to consider in postmenopausal women. Is it secondary to their being postmenopausal or is it possible that it's secondary because he had erectile dysfunction She didn't want to make him feel badly, so they really haven't had sex for six years and then he comes home with a little blue pill in his hand, hot to trot, ready to roll. “Gee, look what I found on the way home. I have my erection back”, But for her, the shop is closed. There is no desire because now she's got pain as a result of her avoidance and resultant lack of sexual activity, and we've got to work on that obviously as well.

Is the history related to discontinuation of estrogen or hormonal therapy? And just remember this when a patient comes in looking for testosterone, talk about this first.

Body image is involved as well with vaginal dyspareunia. It's part of her mental image of her body feeling old, so this all works into this. We see body image take its toll, not only in this area, but with the normal bodily changes that we see at midlife when it comes to both desire and sexual activity.

For those of you wondering, "How could he possibly be talking about estrogen when it's so bad for you?" This is from the WHI study’s oral conjugated equine estrogen-only arm. It is not an “estrogen-only” arm, it's an oral conjugated equine estrogen arm. For the women who started less than 60 years of age and within 10 years of their final menstrual period, look at the reductions in coronary heart disease, stroke, and an impressive 30% decrease in total mortality, of dying from any cause at all.

You don't believe that? This is the bar graph of it. There are age differences in WHI. If you take it before the damage has been done, that's where estrogen works. This, of course, is a conference in and of itself and time does not permit us to dwell on this important area.

This is not only the observational studies that predated the WHI, which showed a 50% decreased risk of coronary artery disease, not only the WHI in the appropriate age groups, but also since WHI the meta-analysis from Stanford. You see them in the middle here in that orange color. When you look at coronary heart disease—a statistically significant decrease—32% decrease in coronary heart disease, and you look at the 30 trials on total mortality. The women who started less than 60, a 40% decrease in the risk of dying from any cause at all. You can see much more of this in more detail elsewhere.

I do want to mention the difference between oral and nonoral estrogen use with our postmenopausal patients. When estrogen is taken orally, it moves from the GI tract to the portal system, and then directly to the liver before it goes out into the systemic circulation. We call this “first-pass effect”. Transdermally, it goes directly into the bloodstream, bypassing that first pass through the liver. When estrogen goes first-pass through the liver, it causes a number of adverse effects. The two main ones I'm going to mention this afternoon have to do with an increase in sex hormone binding globulin (SHBG) as well as an increase in the production of thrombogenic proteins. Hence you get more blood clots with oral. You get increase in SHBG with oral. You do not see those increases with nonoral estrogen, and there is a lot more literature to demonstrate this.

This is the increase in SHBG with the oral, and we don't see it with the transdermal. These are 3 of the slides from the ESTHER study. You see here the first paper that oral estrogen increases the relative risk by 400% of venous thromboembolic phenomenon while transdermal showed no difference from that seen in the non-users.

We saw this increase as well with increasing BMI. And most of all, these are women who have at least one prothrombotic mutation. You see the 2500% increase in the relative risk of venous thromboembolic phenomenon in the women who were on oral, and no difference between the non-users and the transdermal users. Be aware of that.

I just want to mention to you that nonoral estrogen is bioidentical estradiol. This is just to remind you that every time you use an FDA approved nonoral estrogen, whether it be a patch or gel or a vaginal ring, you are using bioidentical estradiol.

Transdermal, compounded natural progesterone creams do not absorb adequately through the skin to protect the endometrium. So when she's using compounded, transdermal, natural progesterone creams, it doesn't protect her endometrium, whereas if you use the natural progesterone, the micronized progesterone orally, it does protect the endometrium.

All right, we'll run through testosterone in about seven minutes. This is the natural age decrease that we see in blood testosterone levels. Testosterone doesn’t have a precipitous drop as estrogen does postmenopausally. It is a gradual age-related decline.

The postmenopausal ovary still produces 50% of that woman's testosterone. So if you are a gynecologist and you are doing a hysterectomy for fibroids and she's 47 years old, don't say she doesn't need her ovaries anymore. Be aware of that.

This is the way testosterone appears in plasma. One percent of it is free. Nineteen percent of it is albumen-bound, that means 20% is releasable— releasable and therefore potentially bioavailable. Eighty percent of it is bound to sex hormone binding globulin. What you can imagine here is if you triple the SHBG as oral estrogen such as conjugated equine estrogen does, you see what the impact on bioavailability of testosterone can be. You've got to be concerned about that.

That's because SHBG while it preferentially binds testosterone can also bind estrogen. You can put her into an estrogen or androgen deficiency or insufficiency situation by utilizing oral estrogen, kind of fighting what the oral estrogen is trying to do.

I have seen patients come in with relapse of estrogen withdrawal symptoms, hot flashes, night sweats, palpitations, headaches, because their SHBG is so high. Most clinicians around the country would simply increase their dose of oral estrogen, and they will improve. But, they will return months later with relapse. I have seen patients like this who were on CEE 1.25 mg twice a day, and still suffering with night sweats and hot flashes. The increase in CEE dosage kept making the situation worse. The better choice would have been nonoral estrogen.

Again, remember oral estrogen increases SHBG and will diminish bioavailability of testosterone as well. When I say that nonoral estrogen does not increase SHBG, I mean nonoral postmenopausal estrogen. We're not talking about nonoral contraceptives. Nonoral contraceptives need to give high levels of hormone in order to suppress ovarian function and provide contraception. These levels are high enough that they remain in the systemic circulation and hit the liver second and third pass. So when we're talking nonoral, we're not talking nonoral contraceptive.

This is what we have available for sexual dysfunction treatment. But none of it is FDA-approved. None of it. This is what we all use off-label. Other than the clitoral therapy device, which is FDA approved because it's a device. You can't ingest it. But anything that's ingestible, the FDA is lagging way behind on this, so all of this is off-label use.

We're going to skip through a number of these slides very quickly just to show you the growing body of data with respect to testosterone and low sex drive, both desire and sensation. This is the first one from Sarrel. You see the estrogen/androgen combination diminishing the distress and the sexual activities scores, or increasing here in blue the benefit that you get from using the combination.

All of these studies are from Goldstadt and from Sue Davis down under in Australia. This is transdermal testosterone enhancing well being in premenopausal women. This is improving sexual function. This is transdermal testosterone, premenopausal, actually peri-, looking at the increase in satisfying sexual events, positive there.

This is Jan Shiffern's article from New England Journal of Medicine almost 10 years ago looking at enhanced well being. We've built up this body of literature.

This is the study that was presented to the FDA amongst others, demonstrating an increase in satisfying sexual events and increase in desire with respect to testosterone use, again transdermal and a decrease in sexual distress.

Here is the main demonstration of increase in satisfying sexual events, but for those of you who are discriminating enough, look at this. You'll see it's only one event per month increase, which made the FDA look a little askance at this. If you look at the next slide, however, you see that vardenafil only had an increase in one-and-a-quarter sexual events per month. The FDA seemed to imply that was enough to show adequate benefit for the men but not enough for the women. You do the math. But they didn’t stop there. It seems that long-term data wasn’t necessary for the male data, but was necessary for the women using testosterone. Go figure.

However, Dr. Kingsberg, who you’ve just heard, re-evaluated that study and divided the study subjects into two groups; the “responders”, that is the women who reported overall benefit, and wanted to definitely continue the testosterone therapy, versus the “non-responders”, the women who reported no overall benefit and did not want to continue therapy. The “responders” showed an increase in satisfying sexual events an average of 4.5 episodes per month. So that's how we ferret out the benefit even better here.

So we're left with the following guidelines when it comes to testosterone. NAMS says there is consistent evidence that in postmenopausal women, either oral or nonoral testosterone results in a positive effect on sexual function, primarily increase in desire. The Endocrine Society, on the other hand, says although the evidence is there, because the indications are inadequate and the evidence of safety in long-term studies is lacking, they recommend against generalized use. Well, that's not recommending against specific use in each individual patient. This is more against generalized use.

Remember, when it comes to hypoactive sexual desire disorder and testosterone, most of the patients we all see in our offices do not need testosterone for their hypoactive sexual desire disorder. Either you need to take the time, or you need to find other clinicians who have the time to completely review this all with the patient, to “peel the onion” and discover all the factors potentially involved.

Look at vaginal atrophy; look at the couple as a unit; look at the psychosocial issues and at what other medications she is taking.

Also we're asked all the time, "What levels of testosterone do you get?" Well, we don't necessarily get any levels. Most importantly, we take a good history. Part of the reason for rarely getting levels is the fact that there is no diagnostic level with which we can make a diagnosis of androgen insufficiency. Even if there was, we're still working with male-based assays of testosterone and women live in the lower tenth percentile, so that's very difficult to use as a diagnostic tool with adequate sensitivity.

In closing, there remains a lingering question as to whether estrogen is necessary for testosterone to work. One study has finally come out from Australia and Sue Davis's group looking at this. The APHRODITE study demonstrated that postmenopausal women not on estrogen therapy seemed to have some positive response to testosterone therapy if they were selected properly with hypoactive sexual desire disorder.

The problem is when they gave the testosterone, they didn't have an arm of this study that also had aromatase inhibitor to prevent the testosterone to being aromatized to estradiol, which could have caused the benefit as well.

We don't have a good body of data to demonstrate that you've got to use estrogen before adding testosterone in postmenopausal women, but clinically, most of us recommend estrogen use first because that will often obviate the need for testosterone based on the beneficial effects of estrogen on genital blood.