“Endometriosis: the Challenge of our time”
The topic was chosen by the scientific committee of the International Society for Gynaecologic Endoscopy to be the theme of their 8th Regional Meeting because many issues pertaining to this disease still beg to be resolved. To this day despite a plethora of scientific information and clinical observations its aetiology remains unresolved, its pathology disputed, and its treatment inadequate. This article will try to highlight some observations and trends that have developed over the recent past.EpidemiologyAlthough endometriosis is one of the most prevalent diseases in Gynaecology affecting about 15% of women of childbearing age, very little is known about its epidemiology. This is primarily because of the complex nature of the disease comprising both environmental and genetic influences affecting expression. In addition there is also a lack of consensus on a precise definition and pathophysiology. This statement is remarkable considering that a Medline search lists more then 10,000 articles.
Many aetiological factors for endometriosis have been proposed. Some like tampon㆐ use and stress have been found to be scientifically wanting.
In a recent² study when patients were investigated as a single cohort, a significant association was found between age and endometriosis. The results showed no significant association between the body mass index (BMI), smoking or alcohol intake and endometriosis. This study also confirmed previous evidence that indicated a higher rate of endometriosis among more educated women and those of high social class. The study did not confirm the notion that endometriosis associated with higher education is due to a delay in childbearing but suggests that the association between education and endometriosis reflects socio-economic issues such as access to medical care and the importance placed on seeking such care.
As far as reproductive factors are concerned the absence of gravidity was associated with significant increased odds of suffering from endometriosis, a finding consistent with other reports.
No significant relationship was found between endometriosis, spontaneous abortion and ectopic pregnancy. Many studies have suggested endometriosis to be associated with an increased exposure to menstruation thus supporting the retrograde menstruation theory of Sampson. However this remains a contentious issue with current epidemiological studies finding no significant association between length of menses, and age of menarche. As far as contraceptive use is concerned conflicting reports appear to be the order of the day. As a rule IUD exposure does not appear to have an association with endometriosis. Oral contraceptives (O.C.) do appear to have a protective effect on the development of endometriosis but these benefits quickly disappear after stoppage of oral contraception.
An interesting study² found a significant higher proportion of uterine leiomyomata among patients with endometriosis compared with controls. Uterine leiomyomata are the most common gynaecological tumors found in women and like endometriosis are hormone dependent. It seems that leiomyomata share several risk factors with endometriosis because when controlled for parity, length of menses, pelvic pain, previous o.c. exposure, smoking and B.M.I. the presence of uterine leiomyomata remains significantly greater in patients with endometriosis versus controls.Race as an aetiological factor in endometriosis has not been studied conclusively although the popular belief is that African females are affected to a lesser degree than White and Asian females. At the Cape Town conference a scientific team from Kenya will carry this debate forward. Observations at the Endometriosis Institute of Southern Africa, although not yet scientifically scrutinized certainly show a severe and debilitating infiltrative form of endometriosis in young African women, some of which are HIV positive. This association begs to be investigated because of the intertwined relationships between Endometriosis and the immune system.Biochemical and pathophysiological aspects of endometriosis.
Angiogenesis:Angiogenesis has been proposed as an important mechanism in the pathogenesis of endometriosis³. In fact investigators are going so far as to classify it with other angiogenic diseases like solid tumours, rheumatoid arthritis, psoriasis and diabetic retinopathy. The hypothesis is that the endometrium of women with endometriosis have an increased capacity to proliferate, implant and grow in the peritoneal cavity. Current data show that the endometrium of patients with endometriosis shows enhanced endothelial cell proliferation. In addition the cell adhesion molecule integrin alphavbeta 3 is expressed in more blood vessels in the endometrium of women with endometriosis when compared with normal women. Furthermore there seems to be an interplay between immunological factors and angiogenesis which is decisive in the pathogenesis of endometriosis. In women with endometriosis there appears to be an alteration in the function of peritoneal macrophages, natural killer cells and lymphocytes. Growth factors and inflammatory mediators in the peritoneal fluid produced mainly by peritoneal macrophages are altered in the endometriotic environment, indicating a role for these immune cells and mediators in the pathogenesis of endometriosis. Among the angiogenic factors, vascular-endothelial growth factor (VEGF) secreted from activated macrophages under the influence of ovarian steroids, interleukin-8, expressed in endometrial stromal cells and fibroblast growth factor (FGF) expressed in endometriotic tissue may contribute to the characteristic advancement of angiogenic lesions in endometriosis. These findings have opened a new direction in the medical management of endometriosis in that the successful pharmacological suppression or inhibition of angiogenesis may produce a breakthrough in the prevention and treatment of endometriosis.Endometriosis and Aromatase P450Estrogen is the most important known factor that stimulates the growth of endometriosis. Estrogen delivery to endometriotic implants is classically viewed to be solely through the circulating blood. Recently a positive feedback mechanism was discovered which favoured the continuous production of estrogen and prostaglandin in endometriotic stromal cells⁴.
The enzyme, aromatase P450 is aberrantly expressed in endometriotic stromal cells and catalyzes the conversion of C19 steroids to estrogens, which then stimulate cyclooxygenase-2 to increase the levels of prostaglandin and estrogen, which then again induces aromatase activity in the endometriotic stromal cells. It is by this positive feedback mechanism that high levels of estrogen are explained in endometriotic lesions. The increase of prostaglandin E, one of the best-known mediators of inflammation and pain, may explain some of the symptoms related to endometriosis.As previously mentioned endometriosis is an estrogen dependant disorder and this fact has been exploited to design medical cure for the disease. These include ovarian suppression by various pharmacological agents and hormones. The discovery of aromatase P450 in endometriotic tissue has opened the door for novel treatment strategies that include aromatase inhibitors and anti-estrogens. Cyclo-oxygenase-2 (cox-2) is also a promising new therapeutic target using cox-2 inhibitors. By targeting this positive feedback mechanism pilot trials have confirmed the analgesic effect when used for patients with endometriosis.
Medical treatment strategies
The ideal drug in the treatment of endometriosis should alleviate pain and cure sub-fertility without inhibition of ovulation or menstruation and without significant side effects or teratogenic side effects.Such a drug should allow conception during treatment and would fundamentally change the management of endometriosis from a surgical to a medical approach. This however is a very tall order and such a drug does not yet exist. As previously explained the focus of new research will be on the development of new hormonal and non-hormonal medical treatment models. These hormonal therapies will include aromatase inhibitors and estrogen and progesterone receptor modulators. On the non-hormonal side the new generation of anti-inflammatory drugs like tumor necrosis factor – alpha inhibitors, matrix metalloproteinase inhibitors and cyclo-oxygenase-2 inhibitors are being investigated and show promise.
Deep infiltrating pelvic endometriosis
This descriptive heading denotes endometriosis that is retroperitoneal, progressive in nature and affecting all organs present in the pelvis i.e. bowel, urinary tract and reproductive organs. Infiltration of pelvic spaces like the rectovaginal septum and extension to the neurovascular system and other extra peritoneal spaces of the pelvis must also be considered under this heading.Various theories trying to explain the pathophysiology of this disease have been proposed. These include a “congenital” origin of the disease that proposes that lesions form due to the aberrant laying down of Mullerian anlage at ectopic sites outside the uterus like in the rectovaginal septum. Some theories argue the “aquired” process first mooted by Sampson whereby regurgitated endometrial cells collect and implant in the most dependent portions of the peritoneal cavity and trigger an inflammatory process leading to adhesion of contiguous organs.
Regardless of the origin these lesions and especially the rectovaginal septum lesions greatly alter the quality of life of sufferers because of severe dysmenorrhoea and dyspareunia as well as posing particularly difficult surgical problems.
Treatment of infiltrating endometriotic lesion:
Medical therapy mostly in the form of hormonal medication does not cure endometriosis but may induce temporary quiescence of active lesions. In most cases of advanced disease surgery is the final solution. Drugs may be chosen as an alternative to surgery in the rare difficult cases in which the risk of morbidity and complications outweigh the benefits of a radical operation. Medical therapies should not be prescribed with the aim of increasing the chance of pregnancy because it has been definitively demonstrated that these drugs do not influence reproductive prognosis. For long-term pain relief anti inflammatory agents, danazol, GnRH analogs, progesterone and estrogen combinations as well as progestins have been used. Surgical StrategiesEndometriosis is an infiltrative non-malignant disease that affects young women with high expectations of conception and quality of life. Surgery for deep endometriosis may be technically demanding and often include procedures on the bowel, bladder and ureters. In these circumstances intraoperative and postoperative complications are perceived and tolerated with difficulty. The recurrence of incapacitating pain and persistent infertility after heroic surgery is very frustrating. Thorough preoperative investigations and careful, detailed counseling is imperative. A barium enema and I.V.P. should be done in all cases found to have rectovaginal nodules and dense infiltration of the uterosacral ligaments. Also the presence of rectal bleeding during menstruation and symptoms of irritable bowel syndrome during menses should alert the Gynaecologist to the possibility of deep muscular involvement of the bowel by endometriosis.Knowing the extent of the disease before the operation is vital to properly inform the patient about the type of surgery contemplated and its potential sequela. This will also help the patient to understand the clinical severity of the endometriosis and the proposed treatments.If the patient has completed her family and chronic disabling pain remains a problem definitive surgery like hysterectomy and exenteration of affected organs must be contemplated as it offers the best solution.
The first operation is crucial for the prognosis to be favourable. Traumatic or incomplete surgical procedures greatly reduce the fertility potential and increase the risk of disease recurrence and persistence. At 2nd and 3rd surgical attempts, one is often amazed at the extent of the remaining pathology and extensive iatrogenic damage.Often patients have only undergone “iceberg” surgery whereby the tips of lesions visible through the laparoscopy is treated and the bulk of the disease in the retroperitoneal spaces ignored. If adequate endoscopic experience is not available to deal with all forms of deep endometriosis, patients should be referred to specialized centres. This is essential because few Gynaecologists have the expertise to undertake the radical laparoscopic surgery required to dissect endometriotic tissue away from the great vessels, ureter, and to enter the rectovaginal septum and other retroperitoneal spaces. In addition the possibility of a rectal perforation or ureteric damage is sufficient to shy many surgeons away from this surgery.The decision to do radical surgery is often debatable and controversial. Deep endometriotic lesions should not always be treated just because they are there. Sometimes large infiltrating posterior vaginal fornix plaques are incidental findings and are completely asymptomatic. These lesions are not necessarily progressive and may be managed without surgery. Intestinal and ureteral disease which causes progressive stenosis put the function of these organs at risk and severe persistent symptoms constitute an absolute indication for surgery.
Endometriosis is the most common disease found in women being more prevalent then breast cancer, cervical cancer, sexually transmitted diseases and Diabetes. Extensive radical excisional surgery will cure 50% of patients and lead to good long-term symptom relief for up to 75% of patients if performed by appropriately trained surgeons. It is mandatory that a multidisciplinary approach be adopted to include Gynaecologists, surgeons and urologists for the management of this disease⁶.
Specialist training centres where women can receive advice and support to help them deal with this debilitating disease should be established. It is only in this environment that Endometriosis can get the multi disciplinary management that is essential for its eradication and treatment.The medical “magic bullet” is still wanting but the current literature has an optimistic ring as there seem to be new treatment models being extensively investigated promising a breakthrough in the near future.
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