Lunch & Learn with Padma Lakshmi
Nurses conference 2012 – Monique Regard, MD
Medical Treatment & Timing of Intervention
Hi, I am Dr. Monique Regard and I am a pediatric gynecologist who works with girls zero to 24. And because Dr. Seckin is not giving his first talk, and my talk was kind of built on his talk, I want to spend just about three minutes introducing the topic of endometriosis.
It is considered the uterine lining that grows for reasons that are unclear outside of the uterus. It grows usually along the pelvic wall in young patients. It can grow in the ovaries as an endometrioma, although it is much less common amongst young patients. The average woman has a seven year delay in diagnosis. Most girls, in a typical setting, will not find out they have endometriosis until their mid-20s, and they probably could have been diagnosed in their early teens or late teens. My youngest case is a 10 year old that I diagnosed this year after she had been out of school for six weeks. She had just a small vesicular area but horrible menstrual cramps in the first six months of her life. We took out that one resected lesion and she was pain free and back in school.
Dr. Seckin is going to talk more about what endometriosis is and why we think surgery is very important. I am going to go on to build on that talk with medical issues because we do think it is a combined medical-surgical treatment to get optimal results.
This is going to talk about the medical treatments and the timing of intervention for young patients and adolescents with endometriosis. I am going to talk a little bit about the off-label use of Lidoderm patches, norethindrone, which is known as the mini-pill, the tablets which are approved for endometriosis but not approved if you do not have surgical diagnosis, and the IUD, which is the new player on the field.
We are going to talk about medical therapies that we usually prescribe before surgery, how we make decisions about who goes to surgery and medical therapies that we generally choose after surgery.
This is a statement that I really love, “Endometriosis should be viewed as a chronic disease that requires life-long management plan with the goal of maximizing the use of medical treatments and avoiding repeat surgeries”. If you talk to experts in the field there are women who have had seven surgeries by the time they get to them, they never had the right surgery with the right person quick enough and it is really, really important that the person doing the surgery has a large volume of endometriosis in their practice, knows how to recognize early lesions and you have one good surgery and then you go on for medical management. Fifty percent of girls will come back with pain a year after their surgery. That is the statistic, even when they are done at Centers for Endometriosis, so we really feel medical therapy has to be a part of it, certainly for the young patient.
These are the general guidelines of the American College of OBGYB that you start with birth control pills, non-steriodals, and then go on to laparoscopy if you fail that for management. We are going to talk a little bit about the over-the-counter and prescription non-steriodals; how we decide to add hormone management and how we decide whether or not somebody goes for laparoscopy. These are your typical – over-the-counter are to your left, and in the middle are prescriptions non-steriodals. There have actually been a lot of studies done; there is no one non-steriodal that wins out over the others. There is no one that is superior but sometimes we will mix and match them. For the girls on over-the-counter I will say try Motrin. If you respond well that is great. If not, try Aleve, try that. Some girls respond better to one than the other but there is not a study that tells you one stands out. I have had kids be told that because of their stomach or because of Von Willebrand’s disease, which we are diagnosing more and more, they cannot take non-steriodals but you can take Celebrex. But you need to be careful because Celebrex does have a cardiac warning on it.
There is a wonderful study on omega-3 fish oils in girls with dysmenorrhea. These are not girls diagnosed with endometriosis but just girls with dysmenorrhea and they did have lower pain scores. It is because fish oils work on the prostaglandin cascade and his theory was developed bio-chemically first on the prostaglandin and the arachidonic acids. He went on and later proved it in the schools. A lot of my patients really feel an improvement when they add fish oils. I have had some luck with Lidoderm patches. I use them sometimes during the period and sometimes for girls with chronic pain. There were no studies that I could find on that.
Smoking was found to be associated with increased, prolonged dysmenorrhea – that is just one study. There was some study with obesity; there are some new feelings about inflammation and obesity spurring on endometriosis. In one study being overweight at age 10 correlated with a higher chance that you would have endometriosis later on.
You have used your non-steriodals, they are still in agony, they are saying – the typical story will be, “My pain is only down by 10 percent. You know I took the Motrin it’s just not doing much”. So then we want to go on and add hormonal management. Endometriosis is an estrogen dependent disease and your medical therapies for endometriosis are targeted at lowering the estrogen environment. This is going to be an issue because girls need estrogen to get their bone density. I am constantly playing against their bone density issues, they are in their peak of bone accrue years and their medical treatment for endometriosis and they are sort of running arrows in the opposite directions.
Back to the ACOG guidelines: “Begin with cyclic combination therapy and non-steriodals in any female patient with pain”.
So, what do we use for birth control? Well, birth control the mechanism of action is that it is a synthetic progestin, it produces an anti-estrogen effect and it inhibits endometriotic implants. We have the traditional combination pills, which you all know the different forms. And we have the newer forms coming out onto the market. The ring has a very low dose of estrogen so we like it in endometriosis but the patch has a very high dose of estrogen and so it is not really a particular pick for us in endometriosis. We always want a monophasic pill. There is no reason if you have endometriosis that you should change the doses every week. You really want that monophasic, and monophasic pills we can use continuously. A lot of these girls are on six weeks in a row or nine weeks in a row without taking a break. We can do that on a monophasic pill.
You want a progestin dominant pill because it handles the suppression of endometriosis best, a norgestrel or Levonorgestrel or norethindrone/ The newer generations, which everybody loves for acne, do not work so great for pain. There are a lot of girls who get put on a newer generation because they like their pimples to go away. But you can add back the ingredient in the newer ones, which is spironolactone, and give them the older generation, stronger progestin and given them Aldactone as an add back if they still want their pimple control.
Emerging studies are showing – these are small studies by Barbara Cromer – that low dose birth control, because everybody says, “Oh your going to put my daughter on a low dose, aren’t you?” No, I’m not”. Low dose birth control pills are sub-optimal for bone density acquisition. So the old “put my teenager on the lowest dose” is probably not panning out in science, although we do not have all the studies yet. I always aim for a 30 to 35 mcg pill if I can use it in a teenager based on the evolving concerns about bone density acquisition. But as you do a higher dose estrogen pill you are going to run against headaches, fluid retention, nausea, weight gain, hypertension and sometimes they feel more emotional. So that is always a juggle for me that I have to go with each individual patient.
A lot of times they will come to me and say, “I tried pills but I felt too nauseas. I had too many headaches. What do I do? I still have pelvic pain and I can’t take the pill”. Well, there are a lot of progestin only therapies out there that are very compatible for these patients. We have to use them if you have a known risk of a blood clot, if you have complex migraines or if you are just so nauseas or so headachy on any combination pill we are going to go onto progestin only therapy.
These are the ones that are available, FDA approved. You have got your mini-pill, which is often used in breast feeding. Norgestrel is Ovrette. It is actually kind of hard to get, so you may find that you cannot get it that much. And then you have your long-actings as listed. The long acting Implanon I have found girls do not always like because it gives you unpredictable bleeding and when they bleed they have pain. I do not find that particular therapy, while available, so helpful for somebody with chronic pelvic pain. Off-label, if they are not doing well on the mini-pill because there is spotting, I will take them to a plain tablet of Norethindrone 5 mg and cut it in half or quarter it because Norethindrone .35 is equivalent of a Norethindrone tablet quartered but I am giving three or four times the dose.
We have added hormonal management and they are still in pain. If the pain persists beyond three to six months the concern is they could have endometriosis. The recommendation is, at that point, to offer them, if they are under 18, the American College of OBGYN says you should offer them a diagnostic laparoscopy. Not GnRH agonist therapy because their bones are still developing and they do not want somebody ending up on Lupron with bone issues. If you are over 18 your bones are essentially formed in terms of density. There is some very nice data that you can give somebody Lupron and if they respond to treatment they do not necessarily have to go on to surgery. There is a whole other world beyond that. If you have deep lesions you probably should have had surgery. If you have minor superficial lesions you probably did not need surgery. But that is a whole hour topic.
The timing of laparoscopy – I want to take into consideration the family history. Endometriosis is enormously hereditary; 35 percent of women will pass it on to their daughters. If there is a family history that the mother had endometriosis, that is going to influence me. Often times they have had multiple ER visits and everybody has told them you are in pain and we do not know why. They are missing school. Early onset of their menstrual pain is a concern for endometriosis. So, if early on they have been in agony, and the caveat here, and Dr. Seckin was going to talk about this, if you have a girl who early on has terrible periods, focal to left side or right side and/or missing a kidney, the chances are very, very high that she has a mullerian anomaly. That is a rudimentary horn of a uterus that is not completely draining. Those need to be dealt with immediately. I had one 11 year old this year who had been suffering and transferred out of school. Horrible pain on the left side; I took one look at the ultrasound and she had a blocked uterus that was not draining. Girls are born with double uteruses and one is not draining and she could have had her surgery four months earlier had the person who saw the ultrasound not thought it was just a little ovarian cyst that was going to be normal.
I could tell from the history, I had not even seen the ultrasound that she probably had a mullerian anomaly. The girls that are missing a kidney often have a blocked vagina with the double system and that can be handled very easily. It just needs the quick, prompt diagnosis. Early menarchal dysmenorrhea, especially if it is one sided and especially if they are missing a kidney, should really flag out right away.
Focal tenderness, the little 10 year old had point tenderness on the left side. Dysmenorrhea that gets worse and worse and worse every year and then pain in between your periods; so pain in between those terrible periods. Those make us think this is a person we are going to find endometriosis in.
Now we have scoped them and we have found endometriosis. When we go to what are our medical goals of therapy we have got to take in how old is she, what is the severity of her symptoms, how long has she had them and what are the side effects that she is concerned about and I am concerned about, and what is the extent of the disease? I have a 17-year-old in my practice, she is stage four disease. I have another 16 year old stage four disease. You can have a lot of disease at a young age. We want to limit disease progression and there are some studies to say that therapy does limit disease progression. And, we want to control their pain.
These are the FDA approved treatments for endometriosis. Everything is FDA approved; it is not just necessarily for endometriosis. Lupron is your standard; Norethindrone has come on in the last few years as a solo agent. Danazol is an older agent we do not use as much.
So how does Lupron or GnRH work? It over stimulates the pituitary and leads to down regulation. It takes up to 21 days. If ten days after you gave her the shot she says she still in pain, it is going to take 21 days. There is a flare of estrogen in the first 21 days as it stimulates and then down regulates. You can have some bleeding and you can have some pain in those first 21 days of therapy. It is available by daily injection, by nasal spray, by i/m injection and now there is a sub dermal implant for one year that is generally used for kids with precocious puberty. It has not been studied in endometriosis.
The nasal spray is wonderful if you have a patient with migraines because they get that big “wompy” dose of Lupron shot and that can trigger a horrible migraine. You give them the nasal spray and you let them start out, and slowly kind of climb up that mountain and then convert them over because what migraines hate are the change in hormones. You can do well with your migraine patients on the nasal spray.
The daily complaints are hot flashes, headaches, vaginal dryness, and I would say my patients hate the anxiety. A lot of patients will not choose surgery because they do not want to have that feeling of anxiety. The long term problem is the decrease bone mineral density.
The new standard of care is that every girl on Lupron really should be on add back therapy. The one that has really evolved – there were several starting out – is Norethindrone 5 mg. It will stabilize the bone loss. As a paper by Katherine Gordon on this showed they have 50 girls on Lupron, Norethindrone will stabilize the bone loss and have them basically neutral. It will decrease the hot flashes. People usually start it right away with therapy.
I want to put in a little plug. There is now a lot of focus on Vitamin D and I think we really need to optimize Vitamin D therapy when we are giving girls things that can harm their bone density. There is now, if you are not aware, there is a 50,000 once a week for the child that just does not seem to take her daily medicine.
Norethindrone alone – sometimes I will use this pre-surgery but I use it sometimes also after surgery just to get somebody stabilized who cannot take regular pills. It comes in 5 to 10 mg tablets. The higher you go the more side effects. We try to get somebody to the lowest effective dose to handle their pain and their bleeding. But you do have to watch moodiness, weight gain and acne. Definitely, my concern about Norethindrone for long term use is the cholesterol profile and insulin resistance. My partner had a patient in the hospital and we had used very high doses. She was a ten year old Jehovah Witness having horrible bleeding who could not take regular pill, and we made her a diabetic in the process. So we took her up and over that line in terms of how much Norethindrone we used. We had to. The parents would not consent to blood and the girl had a hemoglobin of six and she was bleeding and it was our only choice. Sometimes you do what you have got to do but we definitely learned our lesson there.
Danazol actually works beautifully but the side effects for teenagers are really annoying and some things like potential voice deepening are no necessarily reversible. There is the thing on Danazol. It actually works really well if you have tried everything. I have used it in the past and loved it. My patients have liked it but it is just not used very much now.
These are medical treatments after the endometriosis is confirmed. They are non FDA approved. These are some of the newer things on the market. This is the Depo Provera that you know. There is a sub-q form out that is a 104 mg. It is more expensive and sometimes harder to get the insurance to pay for it. In addition, it turns out the bone studies were not any better. Everybody hoped that the bone studies would be better and “Yay” we would have a sub-q Provera injection, Medroxyprogesterone that would not affect bones. But it turned out the bone data was not any better. It is hard, other than less hormones, to get people to want to pay for it and insurance is not picking it up. You probably do have a little bit less weight gain. But we still have that FDA black box warning on Depo Provera that it may cause low bone density.
Aromatase inhibitors work with the idea that endometrial implants of endometriosis express an abnormal amount of aromatase. This is the Tamoxifin that women with breast cancer are on and it leads to a rise in local biosynthesis of estrogen. Aromatase inhibitors are felt to suppress local estrogen formation but they must be used with an OCP or GnRH because you will get follicular cyst development simultaneously. It cannot be used as a solo agent. But it can improve pain scores where traditional therapies have not produced optimal results. There are a few articles where they have added aromatase and gotten good results but we have long term bone loss as still of an issue.
This is the new kid on the block. This is the Levonorgestrel IUD. Its primary mechanism is thinning and stabilization of the endometrial tissues. It is approved for contraception and heavy menses by the FDA. It is not approved for these indications but people are using it all the time for this list of chronic pelvic pain; people are using it for endometriosis; we are using it in developmentally disabled girls for menstrual hygiene; we are using it for uterine hyperplasia or pre-cancer, and we are using it – there is a new case of a girl with uterine cancer, stage two who had her cancer reversed with the IUD and did not have to undergo a hysterectomy. It has wonderful, wonderful uses.
The first studies using endometriosis, treating it with the IUD, came out in Italy with Vercelli in 2003. He had a pilot study of 20 parous women and he was able to show that there was improvement in moderate to severe dysmenorrhea after surgery with Levonorgestrel IUD. He did a follow up study where half went in to IUD and half went in to the surgery alone. He showed a statistical improvement in those satisfied with their post-surgery pain reduction if they had the IUD inserted.
The next study came out with Dr. Petta and that was in 2005. He compared a group of women receiving the IUD to those receiving Lupron and those who had endometriosis and chronic pelvic pain. Pain scores went down in both groups but side effects were less in the group that had the IUD because you did not have the hot flashes and the anxiety and all the issues that come with Lupron. Patients with advanced disease treated either way reported a bigger reduction in their pain. IUD users did report more bleeding than Lupron users.
How does it work? Well, they did some biopsies on 11 women who underwent Lupron therapy and 11 women who underwent GnRH therapy. Self-proliferation is supposed to be one of the mechanisms of endometriosis and it went down. Expression of progesterone receptors went down in the IUD but not in the Lupron group. Expression of estrogen receptors went down in the IUD group but not in the ectopic group of Lupron. FAS is something that regulates – it is a marker for apoptosis which is the ability to sort of self-destruct an endometrial cell and so if FAS is up, then apoptosis, or destruction of the cells is up. That happened in the IUD group but not the endometriosis group.
What are the advantages to using IUDs in adolescents? Well, there is no user action required. There is no effect on bone density. This to us is our biggest issue; we are not going to be worried about bone density because your natural estrogens are still being produced while you are on the IUD. There is no effect on the lipid levels. Also, we think, no effect on pre-insulin issues that we have with Norethindrone. And, it is a five-year duration.
There is abnormal bleeding especially in the first four months and you really have to prep them that this first four months they have got to be ready for that. There is the pain of the insertion. The expulsion rate is slightly higher, really more for nulliparous uteruses than it is with teens per se, and teens are at a higher risk for contracting an STD. If you get an STD while you are on the IUD they will treat straight through. They will not pull the IUD right off the bat and I am going to show you a study of teenagers with the IUD.
This is a study of IUDs in young women. It is the largest study published today. It is 233 women. They were menarche to age 21, it was retrospective. Thirty percent had never had children, 50 percent were under age 18 and 95 percent had chosen Levonorgestrel. In this study two thirds were in a regular family planning clinic and one third were in a doctor’s office like mine that treats medical conditions of gynecology. Twenty-one percent of the girls asked to have their IUDs removed. The 18 and under were more likely to ask that their IUD be removed. I think they are the less patient crowd. Three point five percent was the expulsion rate, more common obviously if you had not had children. There was a 1.3 percent difficulty with insertion or unable to insert in the office. They did have 7 percent infections; those were typically girls who contracted an STD, only two cases of PID. Two percent of girls had significant pain upon insertion. Every mother always worries about perforation and in this study there were no perforations amongst all of these insertions.
Investigational therapies for endometriosis – they are looking currently at progesterone receptors, angiogenesis inhibitors, we think it is sort of an inflammatory angiogenesis disease so they are looking at inhibitors. They are looking at this matrix metalloprotease inhibitors, estrogen receptor beta-agonist and immune modulators. I think there is a lot of thinking that it is an immune disease. And at the NIH for pain there is a Botox injection trial undergoing. One of my patients is currently getting enrolled.
Conclusion: Hormone therapy is an essential component of long term management, pain control and prevention of disease. Adolescent women are undergoing major bone density acquisition that is dependent in large part on endogenous estrogen. Therapies to treat endometriosis can have a significant negative impact on bone density accrual. We have to factor in, with therapy choices, their age and the impact on their future bone density.
The Cochrane Review demonstrates that women were five times more likely to benefit from surgical management. Both I and Dr. Seckin definitely are big proponents of one good surgery. The risk of recurrent life long disease and pain, however, is high, especially in the adolescent group. Studies that combined surgical and medical treatment of endometriosis in adolescents may retard progression of the disease in this population.
Endometriosis should be viewed as a chronic disease that requires a combination of maximizing medical treatment and avoiding multiple surgeries. Each young woman has her own unique medical history, her own unique surgical findings, and her concerns. They all need to be considered to optimize her medical therapy.
Moderator: We will open up the floor for some questions if anybody has any. Any questions for Dr. Regard?
Padma Lakshmi: I have a question. Ever patient’s symptoms are different and when you have a young girl whose family may have some biased or stigmatic feelings about putting their child on birth control to begin with, how do you broach that subject? A lot of parents, I know it happened to me, worry that by giving… One of the reasons why young girls are not sexually active is that fear of getting pregnant as well as all the other things associated with becoming sexually active, but if there is a sense… Sometimes I know my mother experienced it where she thought, “Wow, I know I need to give her birth control because she has got these cramps but I don’t want that to give her a license of freedom that she may not have”.
Monique Regard, MD: When parents say, “I don’t want my child on pills” and that is very common in my office, I try to say, “What is your concern?” The fear that their child will have sex is definitely top three. Their fear that their child will get cancer is number two. And their fear that putting them on pills will harm their fertility is number three. I can tell you that with all mothers it is either A, B, C or all of the above.
Related to the question of will my daughter have sex I can usually read it on their face and I just say it out loud, “Are you concerned that my putting your daughter on birth control pills will make her have sex?” I just go out and say the elephant in the room. I do not tip toe around it and she says, “Yes”. I tell them six different studies have shown that if you take a group of 100 girls and put them on pills and a group of 100 girls not on pills, they initiate sex at the exact same rate. It does not make them have sex. They are either having sex and they are not on pills or they are on pills and they are having sex. My putting them on pills is going to make zero impact on whether or not they are having sex. I say, “Look, if your daughter is deeply religious my putting her on pills is not going to suddenly get rid of her entire value system and make her run out the door and want to have sex. Whatever values you gave her is what she is going to go out this door with”. So I really try to just say the elephant, say it out loud, and explain what the studies are and explain, really try to impart that the values you gave your daughter are not going to walk out of this room the minute I put her on pills. They are going to stay with her. That usually helps.
The cancer one I break it down. I say the risk of ovarian cancer goes down; the risk of uterine cancer goes down. The risk of cervical cancer does go up slightly when you have been on pills; therefore you should give her the Guardasil. The risk of breast cancer if she has never had a first degree relative with breast cancer is unknown. If her mother had breast cancer and she is under 18, and it was pre-menopausal breast cancer, there are some studies suggesting that we should wait until she is 18. That is what I do for cancer.
For fertility I say, “Until a new study came out this past month, which is going to be a long evolution, if you have been on the pill for under ten years at this point there is no concern for fertility”. There is a new study out about greater than ten years users and that is going to be controversial.
Does that answer the question? Okay.
Audience Member: I have young children and I would assume that some mothers and fathers would be concerned about putting them on medication so early. Do you ever get asked if there are alternative treatments?
Monique Regard, MD: I certainly…Amy and I were talking…I certainly offer non-steriodals, I certainly offer physical therapy and omega-3 fish oils. These are all people who are missing three days of school, they are miserable; they are up all night with their cramps. At that point they are ready for going on some kind of therapy or going directly to surgery. The reason I typically discourage surgery first is I say, “Look, if I look inside and your daughter has no endometriosis and she is missing three days of school every month – these are not people who are just taking Advil and feeling a little crummy – then she is still going to need to be on pills to control her cramps with a negative scope. If I scope her and she has endometriosis she is still going to need to be on pills to control the disease. I am not getting you out of pills by scoping her. But if she is on pills and she is feeling terrible then you need a scope because you probably have more significant disease”.
I think the girls with significant disease consistently flunk pills. I do not know if there are girls out there with terrible disease who are doing great on pills because I feel like the ones that are not doing well on pills I am scoping and I am getting their disease. But we are not scoping the kids that feel great.
Moderator: Thank you Dr. Regard.