The Mystery Surrounding Endometriosis
Endometriosis is, likely, the most “mysterious” condition in gynecological practice:
- We do not understand what causes it.
- We, indeed, don’t even know whether it just represents a variant of normal or a “disease” because it is so frequent.
- Even with laparoscopy, the diagnosis is inaccurate because much of endometriosis is microscopic and not visible to the naked eye.
- The disease is being staged in severity from stages I-IV, but symptoms can be much more severe with stage I than stage IV disease.
We really have no treatment for the disease besides temporarily interrupting it either pharmacologically or via pregnancy, which is generally considered the most effective temporary clinical treatment of endometriosis. In summary, we basically don’t know anything of real importance with certainty about this condition.
It, therefore, should not surprise that many women with endometriosis go undiagnosed, receive no or inappropriate treatments and frequently end up with not only infertility but greatly decreased quality of life.
We, therefore, find it appropriate to offer in this issue of VOICE a concise summary of how CHR views some of the most contentious issues surrounding the condition of endometriosis. Investigators at CHR have a long-standing research interest in this condition. CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, was, indeed, likely the first to point out the very strong association of endometriosis with autoimmunity (Gleicher N et al., Is endometriosis an autoimmune disease? Obstet Gynecol 1987;70:115-22), thus pioneering the concept that women with endometriosis may be vulnerable to acquiring the condition because of a defect in their immune system.
That women with endometriosis, indeed, demonstrate immune system abnormalities has been widely accepted. Indeed, the high prevalence of autoimmune abnormalities in women with endometriosis is also widely believed to be a principal reason endometriosis is associated with increased miscarriage risk. Autoimmunity is, of course, considered the second most frequent cause of miscarriages after chromosomal abnormalities. However, are immune abnormalities causal to the occurrence of endometriosis, or appear as a consequence of endometriosis because the immune system responds to endometriosis? This question is, till today, still unresolved.
Such chicken or egg issues are not infrequent in clinical medicine and, like in endometriosis, are often difficult to resolve. We are still completely ignorant about what causes endometriosis.
What is endometriosis?
The endometrium, from which endometriosis derives its name, is the tissue layer that lines the endometrial cavity of the uterus. It is of crucial importance to reproductive success because it is the endometrium that allows the implanting embryo to make contact with the maternal vasculature and, thus, to receive the necessary nutrients for growth and development.
This endometrium is made up of highly specialized cells, which are responsive to the main female hormones, estradiol and progesterone. Under the influence of estradiol, the endometrium proliferates in the first half of the menstrual cycle (i.e., the proliferative phase) and becomes “hospitable” to a potentially implanting embryo in the second half under the influence of estradiol and progesterone (luteal phase). The endometrium, therefore, is a true endocrine organ, even though it is not widely recognized as such.
When a woman menstruates, she sheds the upper two-thirds of this highly specialized tissue, which over the length of the cycle has proliferated to considerable thickness, and the whole cycle starts anew.
Like many cells in our bodies, the cells that make up the endometrium are site-specific. This means that endometrial cells, both glandular and stromal components, are site-specific to the endometrium, and should not be present anywhere else in the body. When they are present outside of the uterus, the condition is called endometriosis.
How these cells make their appearance outside of the uterus is unclear: The most popular theory holds that some women menstruate retrograde through their fallopian tubes into the peritoneal cavity, and that some cells can implant and give rise to endometriosis. These implanting cells, therefore, are the same as endometrial cells and are subject to the same hormonal influences. Endometrial implants, like the endometrium, therefore proliferate and shed, and when they shed are perceived by the immune system as an “open wound.” The immune system attempts to repair those wounds, which leads to scarring. If scarring involves nerves, even small lesions can become very painful.
Since this theory of endometriosis was proposed, studies have demonstrated that basically most women menstruate retrograde into the cavity; yet, it is believed that only some women develop endometriosis. Why those endometrial transplants implant in these women and not in most others has remained an enigma. Some investigators have suggested that certain immune defects in women may predispose to implantation of endometrial cells, but no such immune defect has so far been described. It has also been suggested that, in principle, all women suffer from endometriosis because all women show at least minimal microscopic endometriosis (i.e. ectopic endometrial implants) if one looks hard enough. Some women, for whatever reasons, just have more disease. Once again, we hope that our description of current knowledge amply demonstrates how little is known about endometriosis.
Where is endometriosis?
Endometrial implants can be practically anywhere within the abdominal cavity, even the chest cavity. The most frequent locations are the so-called utero-sacral ligaments, which posteriorly hold the uterus in place. Because these ligaments are so frequently involved, a classical symptom of endometriosis is acute pain with deep penetration of the penis during intercourse when it hits against the ligaments. The ligaments’ tenderness is also a typical sign of endometriosis on pelvic examination or during vaginal ultrasounds.
The second most common location are ovaries and fallopian tubes. In ovaries the endometriosis can be superficial or deep. If it is deep, it takes the so-called endometriomas or “chocolate cysts” form, and it has been recently recognized that in the vicinity of those the ovaries speed up recruitment of follicles. This means that intra-ovarian endometriosis activates follicles at enhanced rate and, therefore, leads to speeded up loss of functional ovarian reserve, i.e., to premature ovarian aging (POA).
Not well recognized in the literature is the fact that the first and most frequently affected area of fallopian tubes are the fimbriae. Those are the very delicate mucosal folds of the distal end of the fallopian tubes, which have the function of “catching” the egg that is released from the close-by ovary during ovulation. Even very mild endometriosis can, and often will, lead to “clubbing” of those delicate structures, which then no longer allows them to guide eggs into the fallopian tubes, where they, close to the fimbriae, are meant to meet up with sperm and undergo fertilization. If eggs cannot enter the fallopian tubes, the woman becomes infertile. Even very mild endometriosis, therefore, can lead to infertility.
Fimbrial dysfunction due to endometriosis in our experience is one of the most frequently overlooked medical problem in female infertility, with affected women often being misdiagnosed with the so-called “unexplained infertility.” Readers of these pages will, of course, remember that CHR does not believe that this diagnosis really exists. It is usually inadequate testing and failure to dig deep enough diagnostically that leads to this “pseudo diagnosis.” A correct diagnosis can be made with relative ease if hysterosalpingography (HSG) films are properly read. Unfortunately, our radiology colleagues are usually only concerned with tubal patency: If contrast spills into the peritoneal cavity, in most cases, they consider the HSG to be normal, without further consideration of tubal flow patterns.
This is, however, too simplistic a view, and overlooks the fact that if the injection pressure is high enough, many, if not most, tubal obstructions will be overcome. Especially the early phimoses of the very delicate fimbrial tubal ends will not be able to resist such high pressures, and will allow contrast to escape into the peritoneal cavity. To visualize tubal phimoses, HSG films need to be interpreted with considerable care on a frame to frame basis—a reason why CHR physicians always assess HSG films themselves rather than rely on written reports from radiology colleagues.
Endometriosis implants, which can be anywhere within the peritoneal cavity and even on rare occasions in the chest cavity, can be superficial or deeply infiltrating. Deeply infiltrating implants can cause considerable damage on other organs. For example, ureters can be obstructed; endometriosis can penetrate bladder and bowels, and lead to blood in urine and/or stools; endometriosis can also invade the vagina and cause bleeding. Finally, if endometriosis reaches the chest cavity and invades the lungs, presenting symptoms can be hemoptysis (i.e., bleeding when coughing).
Wherever endometriotic implants occur, they lead to scar tissue formation. Very advanced stages of endometriosis (Stages II and IV), therefore, are characterized by severe pelvic adhesions, which not only immobilize the fallopian tubes, leading to infertility, but can cause significant pain, especially during ovulation and menstruation. During ovulation the pain stems from increases in ovarian size, which puts tension on scar tissue. During menses, endometrial implants “menstruate” as well.
Endometriosis does not require treatment if it does not negatively affect fertility and/or causes symptoms because, though at time invasive, it is a benign disease. This does not mean hat cancer cannot arise in endometriotic implants but the risk is extremely low.
Treating an endometriosis-associated pain condition can be very complex, and requires special expertise. As already mentioned, we have no good permanent treatment for the condition at our disposition. Moreover, whatever damage endometriosis already caused cannot be reversed by treatment. Available medical treatments allow only for interruption of the usual menstrual cycle. By stopping women from going through regular menstrual cycles, endometriotic implants are also stopped from doing so, and progress of the condition is interrupted. The disease process often, however, returns quickly once treatments are stopped.
Another limitation of currently available treatments is that they prevent pregnancy. Paradoxically, pregnancy is, however, likely the best possible treatment for endometriosis because, including lactation periods, pregnancy interrupts the menstrual cycle for over a year and, therefore, very reliably arrests the progression of endometriosis. Women in infertility treatment, therefore, cannot be treated for their endometriosis if they are attempting to conceive. How to address endometriosis in an infertility treatment paradigm is, therefore, till today quite controversial.
Since endometriosis is generally a progressive condition, proper time management is of importance. CHR, therefore, pursues a rather aggressive approach to endometriosis-associated infertility: we recommend early in vitro fertilization (IVF). How endometriosis affects IVF outcomes has remained highly disputed. While some studies suggested a negative effect on egg and embryo quality, others have shown no such differences. The likely explanation for the difference in findings lies in its wide range of presentations.
We already noted that recent data quite unequivocally demonstrated that presence of endometriosis within the ovary itself increases the speed of follicle activation and recruitment. Intra-ovarian endometriosis very obviously affects follicles and, therefore, oocytes. Superficial endometriosis on the ovaries, on the other hand, may show no such effects.
Treatments, therefore, have to be individualized. As in so many other areas of medicine, CHR strongly advocates such individualization of care. Every patient is different and is deserving of her individualized approach to treatment.
The place of surgery
As readers of these pages will be aware of, when it comes to surgery, CHR is clearly among the most conservative fertility centers. We are fully cognizant of the need for surgery to maximize pregnancy chances in some infertile women; we, however, also are fully aware that, at times, surgery cannot only be counterproductive but also reduce pregnancy chances.
When to recommend surgery to a patient with endometriosis is likely one of the most difficult decisions in reproductive medicine. We can probably best summarize CHR’s position on this subject as follows: CHR, in principle, does not consider surgery an appropriate treatment approach to female infertility in endometriosis. We, however, do consider surgery a potential treatment option if (i) endometriosis is associated with intractable pain; (ii) patients with endometriosis have failed a number of IVF cycles; and (iii) the surgery is done by a highly qualified surgeon, trained in the kind of conservative surgery infertile women need.
This is a part of the December 2015 issue of CHR VOICE.
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.
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