Heather Appelbaum, MD
Early diagnosis and optimal timing of intervention: How to approach endometriosis in adolescents
Advancing the Science and Surgery of Endometriosis
Monday and Tuesday, April 18-19, 2016
The Union Club, New York
Thank you. We have now heard a lot about the basic sciences of endometriosis. I find the basic research fascinating and interesting so that we can understand the origins of the disease and hopefully have a better handle on how to treat. But I am going to talk a little bit about the clinical aspects of endometriosis, particularly in children and adolescents.
I am the Chief of the Department of Pediatric and Adolescent Gynecology for the Northwell Health System and I work for a pediatric gynecologist associate, somebody mentioned that I worked for Long Island Jewish I am not actually part of the faculty anymore. I do represent the health system in terms of pediatric and adolescent gynecology and see quite a bit of endometriosis in the adolescent population. I do not have any financial disclosures but if anyone wants to approach me afterwards and offer me something I will not resist.
Endometriosis in adolescents: A couple of things that I think are important for us to know just starting out when we review the literature is information about adolescents is that 66 percent of adults with endometriosis report that the first onset of pain occurred before the age of 20. Twenty-five to 47 percent of adolescents with chronic pelvic pain have endometriosis proven by laparoscopy. Again, when we look at girls who have chronic pelvic pain and have been treated with medical management in terms of hormonal therapy, when we do laparoscopy on those patients approximately 70 percent of them will actually have confirmed endometriosis and approximately one third of them will have moderate or severe disease.
In the 1990s Mary Lou Ballweg and her group queried the Endometriosis Association database and what they found was that on average women saw five doctors before they finally received the diagnosis of endometriosis. When they looked at girls under the age of 15 they on average saw 4.6 doctors, whereas adults saw 2.6 doctors. The delay in diagnosis was approximately 4.7 years. I would say that we can do better than that. We can do significantly better than that.
Really, if endometriosis is on our radar screen, and I know I am preaching to the choir, but if it is on our radar screen then we are more apt to make the diagnosis. The adolescent who spends once a month visiting the nurse or doctor’s office in the school or who is visiting the emergency room once a month with symptoms of pain and fatigue and having irregular bleeding, nausea, vomiting and headaches she is most likely not a typical patient with dysmenorrhea, normal period related symptoms. If it is cyclic it is happening over and over again. If she is having mid-cycle pain or it is somewhat unpredictable, and these girls are really debilitated by the symptoms that they are having, we have now outstretched outside the realm of normal and this requires special attention.
How do we make the diagnosis of endometriosis in adolescents? Well, I think different than the adult population or at least the sexually active population. I do not really recommend doing pelvic examinations because it is not really informative. The majority of the time these girls do not have deep infiltrative disease or rectovaginal nodularity or disease that you are going to detect on pelvic examination. So pelvic examination is not really necessary and generally is not all that informative. Ultrasound may be informative. We are going to learn in a few minutes that endometriomas definitely occur in the adolescent population and those can be detected by a transabdominal or transvaginal pelvic ultrasound depending on the patient population that you are dealing with.
But as you know, laparoscopy is the gold standard for diagnosis of endometriosis. I would advocate that in adolescents, more so than in the adult population, the disease is subtle and hydroflotation is a really useful tool in order to diagnose subtle endometriosis, subtle neo-vascularization and subtle lesions. Using saline can be very informative as opposed to just making a pneumoperitoneum where the vessels may be compressed or the disease may be a little bit more obscured and difficult to see.
Adolescents have the same lesions as adults. They have the power to burn. They have the brown lesions. But more often in adolescents we see the atypical red and clear lesions or in adolescents with mullerian duct anomalies or obstructive anomalies we see endometriosis as well.
In a review of the literature, this is a systematic review of the literature, we can see that the distribution of endometriosis in teenagers according to disease stage shows that there is a prevalence of stage one and stage two disease in the adolescent population. But that is not to say that adolescents do not experience advanced disease and in fact approximately a third of the time they do have advanced stage disease of stage three or stage four. The majority of the time though, what is interesting to note, is that disease is related to endometriomas and not deep infiltrative disease or nodular disease in the rectovaginal space.
Now that we have made a diagnosis, what do we do? Obviously we made a surgical diagnosis. But ACOG in their committee opinion recommends that not only is surgical intervention necessary to make the diagnosis but also for treatment purposes but following that combined with medical therapy is the appropriate approach. When we do a laparoscopy I would impress, and again, I know I am preaching to the choir here, but I would impress upon you and to discuss with your colleagues that a diagnostic laparoscopy should not just be a diagnostic laparoscopy unless you are diagnosing the lack of disease. It should be a diagnostic and therapeutic laparoscopy where I personally prefer to do a peritoneal resection for these patients because obviously we are looking at the ureter passing right through and we are in the ovarian fossa right by the uterosacral ligaments. There are vital structures so if we do burning we may injure the vital structures that are down below. In addition, if we burn we may not realize how deep we need to burn so I prefer peritoneal resection but I think either one would work just fine.
Once we have made our surgical diagnosis and intervene from a therapeutic perspective with surgery we have some options for medical management. We can treat with continuous OCPs or progesterones. We can use progesterone only implants like nexplanon or IUD. If that does not work we can use GnRH agonists to extend the period of post-operative pain.
Mike Lawford’s group at Boston’s Children has probably one of the biggest cohorts of adolescents with endometriosis. They did a retrospective review of 194 patients that they treated with oral progesterones. What they found, as you know, oral progesterones work very nicely to cause decidualization atrophy of endometriosis without causing loss to bone or without stimulating endometrial cells. They found that there were really no deleterious effects on the bone or lipid metabolism and that it can be used pretty successfully to reduce pain scores and also irregular bleeding associated with endometriosis. That can be used in combination with surgery or pre-surgery. But if that does not work or combined therapy does not work then we are left with using GnRH agonists. As you know using GnRH agonists can make a person feel really lousy. There are a significant amount of side-effects.
The same group looked at a cohort of patients out of their database and registry where they used GnRH agonists and then used add-back therapy and looked at the quality of life measures. They looked at the physical and mental health survey by looking at the short form 36-v2 survey and quality of life and they compared that to healthy age match controls but they also compared it to other women with chronic diseases like juvenile rheumatory arthritis or polycystic ovaries or girls with cystic fibrosis. They found that at baseline the girls with endometriosis had decreased quality of life when compared to age match controls and girls with other chronic diseases. When add-back therapy was given that actually significantly improved. They also used the Beck Depression Inventory and they found, as you would imagine, there was a mild impairment in depression scores when compared to normal age match controls. When they gave add-back therapy interestingly it was unchanged and that did not make a significant benefit.
They also looked at the menopause rating scale and what they found was that the baseline that these patients were normal but when they were treated with GnRH agonists there was also no change. I found that fairly interesting and I am not sure what the confounding factor is there because anecdotally, certainly, in my patients that are treated with GnRH agonists we do not give add-back therapy. They are experiencing hot flashes, insomnia and they do not feel very good, some joint tenderness and things like that. But with add-back they saw these patients reached baseline.
Later they further queried their database and they looked at specifically which addback therapy was provided and so when GnRH agonists were given to girls with either norethindone acetate and conjugated equine estrogens or norethindone plus placebo what they found was compared to baseline when looking at the quality of life surveys from the physical standpoint treatment with norethindrone acetate plus conjugate equine estrogens approached baseline in terms of physical health. It actually went above and beyond baseline in terms of mental health and quality of life measures. Whereas treatment with GnRH agonist plus norethindrone in and of itself did not reach baseline in either category and therefore may be sub-optimal in terms of quality of life for these patients when treated with combination therapy with GnRH agonists and just norethindrone alone.
Obviously when we are looking at the adolescent population we would be remiss if we did not discuss bone health because adolescence represents a time period where there is attainment of peak bone mass. If we are giving a GnRH agonist we may have an effect on overall accrual of bone mass and overall accrual of maximum axial growth of the bones. The same cohort of patients was looked at in terms of bone mass, bone density and bone accrual as well as lean mass. What they found I think probably is fairly intuitive in that when the patients were treated with GnRH agonists alone they had a loss of bone mass over the course of a 12-month period. But when treated with norethindrone acetate alone or norethindrone acetate plus the estrogens they found that the combined therapy was superior to norethindrone acetate alone. Again, we are reaching the conclusion that if we are going to give GnRH agonists to our patients that maybe just progesterone only is not the optimal way to treat those patients and the combined therapy is appropriate. I just want to make a note for you that when we talk about combined therapy we are not talking about oral contraceptive pills because if we use oral contraceptive pills we may be negating the effect of the GnRH agonist. What we are talking about is progesterone and norethindrone acetate plus the conjugated equine estrogens at a dosage of .625mg.
There are a bunch of areas of future investigation because I tell you that there is a lot of supposition in the adolescent population and there is a lot of extrapolation from the adult literature that we do to treat our adolescent patients. But I think it is really incumbent upon us to further look at this subside of patient population because their needs are different, they are still in a growing phase and I think that it is incumbent upon us to look at what are some of the risk factors for adolescent endometriosis. We talked a little bit about micro-genes and micro-MRNAs and I think we also need to look at some of the immune dysregulation in adolescence and maybe some of the effects of in-utero exposures or neonatal uterine bleeding is a hot topic right now and some of the early childhood exposures like endocrine disrupters. How that affects puberty and how it then affects the presence of endometriosis and the expression and the time frame which endometriosis is expressed. We also need to look at the long term follow up studies on disease progression, fertility and quality of life and pain with respect to medical management and surgical management. The data is rally lacking on the adolescent population.
It would also be important to look at the role of neuromodulators and treating chronic pelvic pain. It is certainly not going to treat the origin of endometriosis and may not really affect fertility but may significantly improve quality of life for adolescents who suffer from endometriosis and the long term effects of having chronic pelvic pain and possibly pelvic floor dysfunction. We should also look at the role of levonorgestrel implants including nexplanon and Mirena IUD in adolescents because we have extrapolated that the usage of those modalities from the adult population. We need to look at the short term and long term impact of behaviour modification, diet changes, lifestyle modifications and certainly complementary and alternative medicines and therapies.
Just to conclude a few points that I want you to take as the take home from what I had to say today is that endometriosis is definitely prevalent in the adolescent population. Early intervention may prevent further progression of disease, infertility and pain although we need many more long term studies to confirm that. GnRH agonists with add-back therapy is well tolerated in adolescents and certainly improves quality of life and further investigation is warranted to explore the role of multimodal therapy, including physical therapy, anti-inflammatory medications, gene therapy and hormonal therapy in adolescents with endometriosis.
Before I conclude I just want to thank you for inviting me. I do not have a lot of experience with your Foundation but I see on the roster all the fantastic topics that are going to be discussed today and that were discussed yesterday and covered tomorrow. It is a very, very comprehensive organization and I was able to arrive early enough this morning to read through some of the material and learn a little bit about the EMPOWR organization, which is something that really can be very beneficial for the adolescent population. Great work that you are all doing and thank you for allowing me to contribute a little bit this morning.