Jin Hee (Jeannie) Kim, MD
Update on medical treatment options
Patient Awareness Day
The Lifecycle of Endometriosis: From Diagnosis to Coping with Disease
Sunday April 17, 2016
Lenox Hill Hospital, Einhorn Auditorium
Good afternoon, as he is pulling up the slides I just wanted to express how grateful I am to be able to speak to you today and thank you to the Endometriosis Foundation and Dr. Seckin. I am actually a faculty member at Columbia University. I am in the division of gyn surgery. Just a disclosure that I receive research grants support from Abbvie.
Just a quick overview of this 15 minute lecture, still a lot of material to go through but briefly as mentioned before you know there are medical management options so we will specifically be looking today at endometriosis related pain medical options. That would include non-steroidals and hormonal therapies and then moving on to sort of more off-label use of other medical therapies that are available and what is potentially coming down the pipeline. We will review, to wrap up, how we make the medical treatment decision.
This is a busy slide but this is just sort of just to show the reason why people who have endometriosis is extremely complicated and there are immunologic reasons, inflammatory mechanisms that contribute to endometriosis and genetic and environmental factors play a role as well. We also know that it is the production of estradiol, which is a type of estrogen in the body that promotes and stimulates the endometriosis. Most of the medical therapies that are out there are targeting this particular estrogen to decrease it in the body. Again, this is a busy slide but briefly this is, we will be going back to this table just so that we organize it in different categories of medications that are available. We will be referring back to this.
First I will start with combined estrogen and progestin options. In terms of the birth control pill I think most people are very well aware of this medication. The way that it works is it induces atrophy of these endometriotic implants. I think I get a lot of questions about “oh it’s estrogen that you’re giving to your body, won’t you be stimulating the endometriosis?” but it is really the opposite in terms of the negative feedback that happens in the body. So by receiving this combined estrogen/progestin the actual estrogen level in the body is actually decreased. It also decreases prostaglandin production which is also a way that uterine contractions occur. It reduces the inflammatory status. It is important to note that it is not cytoreductive, which means that it does not destroy the cells of what is already pre-existing. It is also important to know that a lot of these symptoms can recur once the medication is discontinued, so long term therapy and we will discuss this should be considered the norm.
As we know the pros and cons about birth control pills. We know that it can improve cramps, decrease the flow, you know exactly when you are getting your period. Also it provides contraception and also other sort of dermatologic benefits potentially. But we also know that there are potential side effects of birth control pills, including breast tenderness, bloating and abnormal bleeding. Your body may take a little bit of time to get adjusted, also headaches, especially people with migraines and also some nausea. The important thing is also to know just the blood clot concern, especially if you are at higher risk, for example, if you are greater than age 35 and you are an active smoker.
Just to give an example of a study that showed some reduction in menstrual pain with birth control intake. This shows that after a course of three months certainly there was a decrease in pain. There is adequate evidence to prove that birth control pills actually decrease pain.
There was also a study of people who did not respond well to birth control pills. When we talk about taking it cyclically it means it is the traditional way of taking it, 21 days of the active pills with one week of the placebo. There was a study that looked at patients who actually just skipped the placebo we gave them Midol so be aware of that use. The whole goal is just to prevent getting a period. Again, there is evidence that potentially that this continuous use of birth control pills because you are not getting your period may benefit some women who do not respond to this once a month having a period kind of regimen.
But there are some side-effects to this as well, which is that it does increase your risk of breakthrough bleeding so if you are taking this hormone continuously the lining becomes so thinned out and so brittle that you may have some experience of abnormal bleeding. This can be very frustrating for many people because you do not expect to have your period when you are sitting on a beach in Jamaica but you may be experiencing some of these breakthrough bleeding issues and also pain issue.
So there is just a study that basically looked at a two year period and there were about 5.5 of episodes of breakthrough bleeding over the course of two years.
Moving onto other types of combined estrogen and progestin regimens, there is the NuvaRing, which as opposed to the pill that is taken daily, the NuvaRing is a similar regimen just a different route. It is vaginally administered so it is three weeks of the ring, it is given monthly, so three weeks on and one week off. And on that one week off that is when you would have your period. And then there is that patch which is a weekly administration and essentially it is usually given three weeks of the patch and then the last week no patch. That is when you would have your period. Again, with all these regimens you can take it continuously by not having an inactive period.
Moving on to more progestin only options and there are reasons why one might consider progestin only options. The other option we talked about was the combined estrogen and progestin. There are women who may have contraindications to estrogens, for example, active smoker, greater than age 35 in addition to a blood clot history, whether it is personal or in the family or people with migraines with aura there is a higher risk of stroke. You might want to avoid estrogen. There are different ways to give the progestin. There is the pill form, so there are different kinds, Norethindrone, you might have heard of Micronor which is FDA approved as a birth control medication. There are other technically non FDA approved contraceptive progestin only pills, for example Aygestin or Provera are some of the common names. Also, there is the Depo-Provera injection, which is given every three months. It is easier to use because you just get that and you do not have to think about taking a daily pill. There is Nexplanon which is a newer version of Implanon, which is a subdermal implant that goes under your skin. Again, that is good for three years. There is the Levonorgestrel IUD or commonly we know it as Mirena IUD which is good for five years, Skyla is the newer version for three years. Essentially these all contain a similar type of progestin. It is just administered in a different way with different time frames frequency of when to administer it. The whole goal is to prevent periods but it may also cause some spotting issues.
A little background study to suggest the efficacy of the Levonorgestrel IUD; essentially it is placed in the office, not necessarily with anesthesia, or you can have a local. Also, the advantages like we discussed is it is pretty low maintenance, minimal side-effects, lasts for five years and the lucky 20 percent actually stop having their period but there are side-effects such as irregular spotting that is unpredictable. There have been randomized controlled trials where this has been compared to what I will talk about next, which is the GnRH agonist or Lupron and all these head-to-head trials have shown no major difference in terms of pain outcomes.
Another study that looked at this IUD after surgery and it did significantly decrease the pain level compared to just surgery alone so it does go along with what Dr. Lewis was saying in the previous lecture about medical management potentially after surgery itself.
Moving on to GnRH agonists which is the third class of medications and commonly we talked about Lupron, Zoladex and there are other nasal forms, which is called Synarel. Essentially it is sort of touted as the endometriosis drug probably because it is very potent in its side effects as well. It does induce temporary menopause, for example, hot flashes, vaginal dryness and bone density loss are some of the common side effects. It can be given monthly as a monthly injection or as a three month injection. It is commonly given with addback therapy. That means an additional hormone just to decrease the risk of bone density loss and decreasing sort of the hot flash symptoms. Typically it is given for six months and up to the maximum is about 12 months with addback therapy.
Again, there have been studies, randomized controlled trials comparing Lupron versus birth control pills and really at six months and 12 months there is no major difference in terms of pain scores. Is it all worth the side effects? You know it is sort of questionable and it is something that you would want to talk to your provider about.
We will move onto the aromatase inhibitors. So what I have discussed so far are some of the very common, conventional medical therapies. Moving onto sort of more off label use for the treatment are aromatase inhibitors which are Letrozole or Anastrozole. A more common name that you might be familiar with is Femara. It is a pill form that is taken daily. There are limited studies to evaluate really long term use of this medication. There are some short term data. But it does induce similar sort of menopausal symptoms potentially. If it is taken without contraception and you do get pregnant it could potentially cause fetal abnormalities. The way that it works is the way that the other hormonal therapies is we talked about a decrease as the estrogen in your body that is produced by the ovaries but the Femara or Letrozole decreases conversion of fatty tissue making estrogen. Essentially it is sort of blocking the other ways that estrogen is made in your body not just from the ovary itself.
Just another study that compared the Lupron versus Lupron with Femara and essentially there was potentially a longer time to recurrence of pain and there were fewer recurrences of pain.
Moving on to Danazol which is, like Dr. Lewis said, has sort of fallen out of favor due to side effects. Essentially it does have, it is a pill form as well but it does have severe side effects of facial hair, body hair, acne, deep voice, weight gain and increased cholesterol so it has fallen out of favor.
But moving onto more what might be in the pipeline is a GnRH antagonist called Elagolix. Essentially it is an oral formulation. It is not on the market yet. There have been data, phase 2 data that suggested improved pain scores after eight weeks and currently, and you may have already been a patient in a study, there is ongoing phase three trials that are coming to an end. We will get the results of that as well but the preliminary report is that there is significant difference in terms of pain scores menstrual and non-menstrual pain after six months of applications. If everything goes forward the anticipated launch for the drug application will be 2017 and it might provide an alternative to Lupron, etc. as it is an oral form.
There are some studies about acupuncture, very limited, one randomized control trial is suggesting significant pain improvement with acupuncture versus Chinese herbal medicine. I think there were other talks today mentioning gene therapy. This is something that is done in cancer therapy where there is a transplantation of normal genes into cells where it is defective in order to correct actual genetic disorders. So it is actually very exciting and it is a relatively new trend in molecular medicine endometriosis. It is very early stage but hopefully down the line there will be treatment options available targeting the gene.
In terms of post-operative medical therapy several randomized trials have shown increases of duration of pain relief and delays of recurrence of disease. Generally again, medical therapy is recommended after surgery. However, there was a Cochrane study, a review which is a review of all the studies available out there and although there was a delay to the time to recurrence unfortunately there was no difference whether or not you actually have pain improvement. It is a little bit of a confusing issue but nonetheless I think medical providers would recommend medical therapy afterwards.
The limitations of medical therapy, I think we know that symptoms are likely to recur following surgical or medical treatment. While you are taking the hormonal pill or what-have-you I think it is important – you know you can feel the side effects and be bothered by it but having the tenacity just to continue on for relief of the pain symptoms. Obviously with all these hormonal therapies you cannot get pregnant. That is a consideration when you are opting for medical therapy. We talked about the various side effects from medical therapy that are common and often prohibitive.
I think the take home points are that a lot of these medications are fairly equal in head-to-head trials. On average, the majority of people report improvement in symptoms and I think you have to really individualize your treatment options based on your patient preference, side effect profiles, the frequency, the administration, what you are comfortable with, not comfortable with, potentially costs. The other thing is that when medical treatment fails you do have to make sure that you are treating the correct thing, whether it is endometriosis and we talked about other providers have talked about, other reasons for chronic pain. It is just important to recognize that.
Thank you so much.