Transcript

Lee Tetreault:

Hello and welcome to frequently asked questions from the session 'Menopause Hormone Therapy: Where are we Now?' We are joined today by Dr. Martin Quan. First off, doctor, in low-dose vaginal ET use for atrophic vaginitis, are you still prescribing micronized progesterone in women with a uterus? 

Dr. Quan:  

It's really dependent on the dose of the estrogen product that you're using. If you're using what we would term 'low-dose vaginal estrogen therapy', which would be a vaginal estradiol tablet of 10 micrograms a day... Or 10 micrograms per tablet, or if you're using, let's say, conjugated equine estrogen and the dose was 0.3 milligram. If that's the dosing that you're using, the answer would be the... When you measure estradiol levels in the bloodstream, the estradiol levels are generally less than 20 picograms per ml, which is the level of estrogen that you actually see during the menopause. Therefore, in those patients, no, I don't think you need to be concerned regarding endometrial stimulation.

If you're using a higher than recommended dose, let's say you're using a 25 microgram tablet of the estrogen tablet, or let's say 0.625 milligram of conjugated equine estrogen as your dose. In that particular circumstance, you can't be quite as confident. And oftentimes, what we do is we do need to do some sort of surveillance of the endometrium, and what I often do is to administer a progestin challenge test. What that is, is I prescribe Provera, which is medroxyprogesterone acetate, at a dose of 10 milligrams a day for 10 days. If there is a withdrawal bleed as a result of that, then you know that the amount of vaginal estrogen is stimulating an endometrial lining, and yes, that patient is at higher risk for developing endometrial cancer, and there may very well be the need for a progestin.

If you do this, though, what I typically do is I'll do it at the end of, let's say, the first year of use, and then you can't stop there. In some patients, that stimulation isn't seen for a couple of years later, so you would need to repeat it. I would repeat it for another couple of years before I would feel confident that we're not stimulating the endometrial lining.

Lee Tetreault:

Can you speak to the safety of oral versus transdermal ERT? 

Dr. Quan:  

Okay. The issue with that primarily is the fact that when you give oral estrogen, there's what we call a first pass effect through the liver. As a result of that, there's an increased production of proteins by the liver, including coagulation factors, and that is really the genesis of the procoagulant effect that we see with estrogen therapy. If you give it transdermally, you do not get this procoagulant effect, because there is no first pass effect. As a result, the patient does not become as hypercoagulable, if you will, as they would when they take oral estrogen. Studies indicate that with the use of transdermal estrogen, the risk of deep venous thrombosis is less than with oral estrogen.

Lee Tetreault:

What are your thoughts regarding bioidentical hormones? 

Dr. Quan:  

Well, the short answer to that is that three preeminent organizations have come out against the use of bioidentical hormones. Specifically, those organizations are the North American Menopause Society, the Endocrine Society, and the American College of Obstetrics and Gynecology. Why do they not favor it? Well, there's a number of reasons. Many of these people that prescribe bioidentical hormones rely on salivary hormone concentrations. There's absolutely no evidence that salivary hormone concentrations have any value as a tool for assessing a patient's hormonal needs. In addition, salivary hormone concentrations are known to vary throughout the day, which casts even greater doubt on their validity as a guide for prescribing and monitoring hormone therapy.

In addition, there's an uncertainty regarding the formulation that the patient actually gets. There's no standardization, this is not regulated by the FDA. And studies indicate a great variability in the actual prescription or formulation that the patient actually gets when they fill their prescription. This has been looked at in studies in which they've taken the same prescription to a number of different pharmacies, and when you look at the actual content, there's great variability as to what the patient actually gets, despite the fact that they're getting the same prescription filled.

Finally, there's this lack of even rudimentary data pertaining to the benefit and risk of compounded bioidentical hormone formulations. I typically will tell the patient that when they use these bioidentical hormones, they're basically conducting an experimental study on the benefits, and just as importantly, the risks of that agent. An experiment in which the end is one, meaning, namely the patient. You're conducting an experiment on yourself.

Lee Tetreault:

Why is micronized progesterone becoming more popular? 

Dr. Quan:  

Well, the use of micronized progesterone, I think, is becoming more popular among clinicians when they prescribe menopause hormone therapy for a number of reasons. One, Prometrium, which is the brand name for micronized progesterone, interferes less with the beneficial impact of estrogen on the lipid profile compared to what's typically been prescribed in the past, which is medroxyprogesterone acetate. Second, studies indicate that micronized progesterone interferes less with the favorable basal dilatory action of estrogen on normal and diseased arteries when exposed to acetylcholine, and the thought is that this is mediated through a mechanism in which there is an increase in nitrous oxide.

Thirdly, medroxyprogesterone acetate or Provera, was the progestin agent that was used in WHI, the Women's Health Initiative. And oftentimes I think clinicians try to distance themselves away from the agent that was used in that trial in the hopes that the adverse effects that were seen in that trial may not apply to a different progestin agent. Lastly, there's a suggestion that maybe the higher breast cancer risk may be related to the progestin agent as well. The E3N trial was a study that was a French observational cohort study that was reported in 2008, and although they found a higher risk of breast cancer in women taking estrogen plus progestin, it was... In that particular study the progestin agent in which there was a higher risk was medroxyprogesterone acetate or Provera. Whereas, the women in that study who took estrogen plus progestin in which the progestin agent was micronized progesterone, there was no higher risk.

Lee Tetreault:

Can you discuss use of unopposed estrogen? 

Dr. Quan:  

The one thing we know absolutely about the use of unopposed estrogen is that there's a higher risk of endometrial cancer in those patients. As a result, generally, the use of unopposed estrogen is only for women that do not have a uterus. Having said that, there's a number of patients that have a hard time tolerating a progestin agent, and the approach to those patients is to try them on the different types of progestin agents that are available. If they're not able to tolerate that, there is a product out now that contains both estrogen plus what we call a SERM, a selective estrogen receptor modulator called bazedoxifene which instead of using a progestin to protect the endometrium, it uses the... The SERM is your agent that protects the endometrium from stimulation by the estrogen in the formulation.

In Europe, they've been using a Levonorgestrel-containing IUD. This would be an off-label use of that IUD, but it's another potential way of providing a progestin agent to a patient who's unable to tolerate it with the oral formulations.

Lee Tetreault:

And lastly, doctor, since unopposed estrogen seems to show a benefit on breast cancer and coronary heart disease, after looking at recent post-hoc analysis of WHI, what are your thoughts regarding long-term use? 

Dr. Quan:  

What the Women's Health Initiative indicated regarding the use of unopposed estrogen in women who had previously undergone a hysterectomy was a higher risk of deep venous thrombosis and pulmonary embolism as well as a small increased risk of stroke. The use of unopposed estrogen would not be completely a free lunch. Now, the WHI did demonstrate a lower risk of breast cancer mortality, and that was demonstrated in a post-hoc analysis of its findings that looked at these women 11 years later. But you need to be cautious about this, because that reduced mortality was not in a person who took the unopposed estrogen therapy for 18 years, meaning the seven years of WHI and the 11 years that followed it.

It was in women that took the estrogen therapy for seven years, and then, following that, those women... The great, great, great majority of those women discontinued estrogen. All you can really conclude from the standpoint of WHI is the fact that if you take unopposed estrogen for seven years, 11 years out, meaning 11 years after you stop estrogen therapy, you do not see an increased risk of breast cancer mortality, and instead you actually seem to see a reduction of mortality.

Lee Tetreault:

This is great information, doctor. Thank you so much for your time today.



 

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