What is endometriosis?
Endometriosis is a medical condition where tissue similar to the lining of the uterus occurs outside the uterus where it can cause scarring and inflammation, leading to adhesion formation between the pelvic organs. If endometriosis grows on an ovary, it can develop into a cyst, called an endometrioma. Women typically present with either pain or infertility, sometimes both. There is no correlation between the amount of disease a woman has and the amount of pain she experiences; some women with early stage disease will have a lot of pain, some with more advanced disease will have little by way of pain symptoms. Endometriosis was first described in the latter part of the 19th century. Interest in this disease has grown, particularly since the widespread introduction of laparoscopy, in the late 1960’s early 1970’s.
What causes endometriosis?
Sampson’s theory of retrograde menstruation first described in 1927 still holds true today. The principle of this is that menstrual blood can flow backwards along the fallopian tubes at the time of a menstrual period, and with it carries viable endometrial cells from the lining of the uterus, which then implant and start to grow into lesions of endometriosis. However, although retrograde menstruation occurs in around 90% of women, only 10% will get endometriosis. This means that there must be additional risk factors. Recent research from the University of Toronto indicates that failure to clear Fibrin from the pelvic area predisposes to the development of endometriosis. Almost 100% of women with endometriosis have an increased level of Plasminogen Activator Inhibitor (PAI-1) and this inhibits Fibrin clearance (Bedaiwy, 2006). Another researcher has shown that endometriosis will grow very readily in Fibrin (Fasciani, 2003). Fibrin is in the non-cellular part of blood, and if it is not cleared forms clear jelly-like clots.
How does endometriosis present?
Around 70% of women with chronic pelvic pain will be found to have endometriosis. The typical pain symptoms are pain at the time of a menstrual period, pain during sexual intercourse, pain during bowel actions and also infertility. However, a minority of women with endometriosis will present with atypical pain symptoms and this may mean that they are investigated for another condition first, before being referred to a Gynaecologist. A great many medical conditions can present with pelvic pain symptoms, the most obvious being bowel and urinary complaints. During physical examination a doctor might be able to detect features which suggest or strongly suggest endometriosis. If this is the case the doctor may want to go on to arrange a number of tests as follows. Blood testing for Ca125 can be helpful; the Ca125 level can go up with endometriosis and also come down when the condition is treated. However, elevated levels of Ca125 are seen in a number of other conditions including pelvic infection and uterine fibroids. Transvaginal ultrasound is useful for looking for endometriotic cysts in the ovaries; these have a characteristic appearance on TV ultrasound. Occasionally, MRI scanning can be helpful to determine the extent of endometriotic disease present, particularly if this has proved to be difficult at the time of laparoscopy, or if the woman is not suitable to have a laparoscopy carried out.
How does endometriosis cause pain?
It has been known for many years that patients with endometriosis have an increased number of a type of cell called macrophages in the peritoneal fluid. These macrophages can produce chemicals which in turn will cause pain. Some endometriotic lesions (probably the minority) can bleed at the time of menstrual periods, causing pain. The current view is that the most likely explanation for pelvic pain is irritation or direct invasion of the pelvic floor nerves by infiltrating endometriotic implants.
Endometriosis can be a progressive disease and over time this will cause symptoms to get worse. However, some women will have static disease that does not progress, sometimes called smouldering endometriosis, and a minority will have endometriosis which will regress on its own without any treatment.
In the past, Gynaecologists have been reluctant to carry out laparoscopy on adolescents with pelvic pain, who might have endometriosis. The key features to suggest endometriosis in this age group, is pelvic pain which is unresponsive to the oral contraceptive pill, or which relapses after the oral contraceptive pill is discontinued. Recent research of the literature has shown that up to 70% of adolescents who fall into this category will have endometriosis (Laufer, 2003). This information needs to be shared with adolescents presenting with pelvic pain, and an informed decision made as to whether or not to proceed with laparoscopy.
Diagnostic and Operative Laparoscopy
The key technique for diagnosing and assessing the extent of endometriosis is to carry out a careful laparoscopic assessment. At the same time, laparoscopic surgery (keyhole surgery) can be undertaken to treat the disease and to divide any adhesions between the pelvic organs. The key techniques for treating the disease laparoscopically are either ablative (using techniques such as the laser and helium thermocoagulator), or excisional surgery where the areas of endometriosis are completely excised or cut out.
The medical research shows that between 50-90% endometriosis patients presenting with pelvic pain, will be improved with laparoscopic surgery for their endometriosis. However, endometriosis can be a recurrent disease and this can be observed in around 40% of patients. If endometriosis is present between the vagina and rectum (rectovaginal septum endometriosis), surgery is beneficial but needs to be weighed against the increased risks of operating in this area (the majority of patients with endometriosis do not have rectovaginal septum disease).
Medical Therapy
There are a number of different medical treatments to choose from and important considerations include the length of treatment proposed, the effectiveness of the particular medicine, side effects, whether or not the medicine completely suppresses menstruation and also cost. Overall, the use of medical treatment has declined as operative laparoscopy has increased. Although medical treatment can be effective, the benefit tends to be lost over time when treatment is stopped.
Non-steroidal anti-inflammatories, such as Nurofen, Brufen and Mefenamic Acid are helpful for pain relief, but some patients will get indigestion type side-effects. These drugs will not treat the disease directly. The combined oral contraceptive pill is useful for treating adolescents and for patients with early disease. The packs can be run together to reduce the number of menstrual days. Although the combined oral contraceptive pill is not a definitive treatment for endometriosis, it can be used as maintenance therapy following on from either medical or surgical treatment. Danazol and Gestrinone used to be the mainstay of treatment for endometriosis. They both work by opposing the action of oestrogen and there is clear evidence for their efficacy and regression of disease. However, both these drugs have a long list of side-effects to the extent that one in five patients or thereabouts, will be unable to complete the six months course of treatment. Progestogens such as Norethisterone can be used for treating endometriosis, but side effects, particularly menstrual irregularity can be troublesome. Used in low dosage form progestogens can be helpful for maintenance therapy.
Since the early 1990’s a new category of drug called gonadatrophin releasing hormone analogues (GnRHa) have become widely popular for treating endometriosis. The most commonly used examples are Zoladex and Prostap SR. These drugs are highly effective and cause the disease to regress. They work by switching off the pituitary gland, which is turn leads to switching off the ovaries, leading to a marked reduction is oestrogen production. This in turn produces side effects such as hot flushes and over time, there can also be a slight reduction in bone mineral density. For these reasons it is advisable to take add-back therapy, which can take the form of low-dosage hormone replacement therapy.
More recently, the levonorgestrel releasing intrauterine system (Mirena IUS) has been used for treating patients with endometriosis. It looks like a contraceptive coil and releases a tiny amount of progesterone to the uterus on a daily basis. Overall this treatment is effective in about a third of patients; it is particularly useful for patients with otherwise difficult to treat endometriosis.
Open Surgery for Endometriosis (laparotomy)
Laparotomy may be indicated for conservative surgery if laparoscopy is either contraindicated or if it is not possible to accomplish the operation laparoscopically.
Hysterectomy, with removal of the ovaries is occasionally indicated for patients with intractable symptoms where other treatments have failed. If hysterectomy is carried out it is usual to remove the ovaries; if the ovaries are retained there is a high chance that the patient will return with recurrent disease. Post-hysterectomy, hormone replacement therapy is recommended unless there are clear contraindications. I would advise continuing with hormone replacement therapy until at least the age of 50, at which point the decision to either continue or stop treatment should be reviewed.
Combined Medical and Surgical Treatment
Some Gynaecologists are keen to use medical treatment prior to surgery for endometriosis, the argument being that using medical treatment in this way can make the surgery both easier and safer. A different view is held by other Gynaecologists, in that they favour giving the medical treatment after surgery to help to prevent the disease returning also to treat any small areas of endometriosis which might not have been removed at the original operation. Both these approaches lack firm supportive evidence from the medical literature.
I have been using medical treatment prior to surgery for stage 3 and stage 4 endometriosis for some time and have found it to be beneficial. I believe it inactivates the disease and that this is turn makes the surgery both easier and safer, which is clearly advantageous for both the patient and me as a surgeon. My usual recommendation is a course of GnRHa injections for three months prior to surgery.
Endometriosis and Infertility
The mechanisms whereby endometriosis can cause infertility have been the subject of many research projects. Clearly, if a woman is having so much pain that intercourse is impossible, this is a clear explanation for why a pregnancy cannot occur. Also, if there are adhesions around the ovaries, even if an oocyte is released, it would become trapped in the adhesions and will not meet up with the sperm for fertilization. Occasionally the fallopian tubes can be blocked with endometriosis and this also is a very plausible explanation for failure to get pregnant. However, for the majority of women with endometriosis, none of the above factors apply and, in that situation it is felt that impaired endometrial receptivity is the cause. This has been suspected for many years but it was not until Lessey and co-workers published on this in 1994, that the full impact of endometriosis on endometrial receptivity was established. Since 1994 Lessey’s team have published a number of key research papers on this topic. They have shown that the endometrium or lining of the uterus does not interact with an embryo in the normal way and that the implantation mechanism is adversely affected. However, following on from treatment for endometriosis, endometrial receptivity is restored to normal. It has been suggested that the luteinized unruptured follicle syndrome is a cause for infertility in endometriosis patients. This means that although there may be good biochemical evidence for ovulation, the oocyte (egg) is not released from the ovary at the time of ovulation.
Overall, about 50% of endometriosis patients will have infertility and 50% of infertility patients will have endometriosis. Because endometriosis can be a painless condition, this begs the question as to whether or not all women presenting with infertility should be advised to undergo laparoscopy. Clearly the pros and cons need to be weighed up carefully and this is something I like to discuss on an individual basis.
With regards to early stage disease, minimal stage 1 and mild stage 2, treatment with operative laparoscopy has been shown to be effective. The key paper on this subject was published by a group of doctors from Canada in 1997 and this conclusively showed that it was beneficial to surgically treat women with small amounts of endometriosis who wanted to get pregnant. Although there are plenty of research papers in the medical literature about stage 3 moderate disease and stage 4 severe disease, the literature does not have what are known as randomized control studies to examine efficacy of treatment in these patient groups. However, the consensus view is that overall, about 50% patients will go on to have a successful pregnancy after treatment for stage 3 or stage 4 disease. It has been estimated that if a randomized control study was carried out, this would show a slightly lower benefit of perhaps somewhere between 30-40%.
An important sub-group of patients are those with rectovaginal septum endometriosis and it has clearly been shown that for these patients, treating their disease will not improve their chances for conception.
For patients who fail to conceive following treatment for stage 1 and stage 2 disease, intrauterine insemination combined with ovarian stimulation is recommended. The simplest approach is treatment with tablets called Clomiphene, plus intrauterine insemination, and here the pregnancy rates are about 14% for each cycle. f the ovaries are stimulated more directly with gonadatrophin injections, sometimes called parenteral induction of ovulation (PIO) and again combining this with intrauterine insemination, success rates are considerably more, around 23%. Clearly age has an impact, and success rates are much better in the under 38 age group. If a pregnancy is not established with these simpler treatments, or if there are additional factors affecting fertility such as poor sperm, IVF is a more attractive treatment. For patients with stage 3 or stage 4 disease, who have failed to conceive following surgery for their endometriosis, IVF is usually recommended as the next step. Overall, endometriosis patients do well with IVF treatment, with success rates of around 30%, sometimes more. However, there is a sub-group of patients who have poor success rates and these are women whose ovaries do not respond well to the drugs used for ovarian stimulation.
For couples who have been through IVF treatment where this has not worked and where the woman has never previously had a laparoscopy, it has now been clearly established by Littman and co-workers (2005), that carrying out a laparoscopy to look for endometriosis and to treat it at the same time, will have a significant impact in improving the chances for a subsequent successful pregnancy.
So far as medical treatment for endometriosis patients wishing to conceive, this has been used extensively in the past, but the current view is that prolonged courses of medical therapy on their own have little to offer in terms of benefit and may actually be counterproductive.
Future strategies for treating patients with endometriosis
Increasingly, doctors are trying to view the treatment of this disease from the woman’s perspective, which is usually centered on either relief of pain symptoms or the establishment of a successful ongoing pregnancy, or both. There is increasing awareness of endometriosis in the population at large and a genetic screening test for PAI-1 may prove to be a big step forward, particularly for women where there is a family history of endometriosis.
Clearly it is incumbent on all doctors carrying out laparoscopy, where the woman might have endometriosis, to possess the skills and training and to have the necessary equipment to continue there and then to treat the endometriosis at the same time.
With greater awareness about endometriosis, there is an increased drive to look for methods by which endometriosis could be prevented from happening in the first place, and also to reduce the risk of recurrence.
Meanwhile, the emphasis is on prompt diagnosis, effective treatment and establishing clear care pathways to optimize the results for all women who have endometriosis.