09 April 2015

Endometriosis is defined as the finding of endometrial cells outside of the uterus. The commonest locations are the pelvic peritoneum, ovaries and rectovaginal space. In women between menarche and menopause, it is found with a background incidence of 6% to 10%. The incidence is 35%-50% in women with pelvic pain, subfertility or both.
Dr Nicolas Clark Fertility Specialist, Medfem Clinic

Classically, endometriosis has been considered an inflammatory condition with oestrogen dependence. No single theory exists as to the pathogenesis and a clear understanding of the cellular origin is still far off. Convincing support for multiple theories is abundant with the primary division being either uterine endometrial origin or other tissues giving rise to endometrial cells.

Retrograde menstruation remains the strongest theory of uterine endometrial cell origin. It is well documented to occur widely and a higher incidence of clinical disease is seen in outflow blockages that result in larger reflux. The questions are what keeps the cells alive and how does attachment and invasion occur? Under normal circumstances, immune clearance occurs, but in endometriosis, alterations to the apoptotic process are seen leading to extended cell survival.

Microarray comparisons of normal endometrial cells and endometriosis show differences in gene expression. An inherited component has been demonstrated but survival advantage is the key. Much has been written about nuclear factor-kappaB up regulation and its link to pro-inflammation and cell survival. Natural killer cell responses are altered through endometrial stromal cell release of intercellular adhesion molecule-1 (ICAM-1). This elevation to an immune-privileged status may predispose to disease. Abnormal macrophage behaviour is seen in endometriosis leading to reduced clearance. Women with autoimmune diseases have a higher incidence of endometriosis adding to the altered immune regulation evidence.

Epigenetic alterations resulting in abnormal endocrine behaviour of endometriotic tissue have been well demonstrated. Aromatase activity is increased, resulting in higher local concentrations of oestrogen. Progesterone responses are altered, resulting in abnormal proliferative to secretory phase endometrial transition.

Apart from retrograde menstruation explaining uterine cell origin a metastatic theory has been investigated with lymphatic spread being documented.

Coelomic metaplasia is the main theory of non-uterine cell origin. This is peritoneal cell transformation into endometrial cells. The concept of endocrine-disrupting chemicals and inducing agents as candidate promoters is key. Other sources of cells from bone marrow and embryonically derived Müllerian rests are both supported by some studies.

Clinically, endometriosis is an interesting condition, as in many cases it is asymptomatic. At the other extreme, it is responsible for chronic pelvic pain resulting in debilitation and suffering of great magnitude. Additionally, fertility problems may occur in symptomatic or, more commonly, the asymptomatic group. Diagnosis is classically made through laparoscopy as imaging is often unrevealing. A greater understanding of the operative findings exists now linked to the pathophysiological mechanisms at play.

Endometrial cell attachment mediated through elevated cytokines and the balance of matrix metalloproteinase (MMP)-3 with tissue inhibitors of metalloproteinases (TIMPs) leads to induction of the vascular supply. Nerve development possibly implicated in the pain is seen accompanying angiogenesis.As a result, red haemorrhagic vesicular-type lesions appear first and progress through ‘powder burn’ lesions then fibrotic and finally Allen- Masters peritoneal defects. Vascular endothelial growth factor (VEGF) levels are higher with increasing stages of endometriosis. Inflammation is part of the disease process mediated through prostaglandins and clinically manifests in the adhesive nature of the condition.

Endometriosis is staged by site between levels 1-4. Involvement of the ovaries is considered a stage 3 and bowel or beyond a stage 4. Clinically, there is poor inter-observer consistency in the recognition and classification of findings, as subtle distortions of anatomy can be easily missed, signifying a more advanced disease than superficially apparent.

The management of endometriosis is dependent on the presentation but falls into two categories namely medical or pharmaceutical management and surgical. Surgical ablation or resection, effectively debulking, remains the gold standard for advanced symptomatic disease. Advances in medical imaging and the use of multi-slice CT scanning is now considered vital in the preoperative assessment and planning stages. Surgery for advanced disease requires appropriate levels of skill to achieve meaningful results. It is a specific disease entity in itself. Mild-to-moderate disease easily treated by endoscopic ablation or resection has been shown to improve fertility outcomes both with natural conception and in ART. Inadequate treatment of advanced disease is unlikely to confer any benefit. Ovarian care is of paramount importance, since the follicular reserve can be adversely affected by destruction of ovarian tissue, which, in itself reduces, fertility potential.

Many drugs have been used for the management of endometriosis. Simple intermittent NSAID use might be adequate for some. Progestagens and gonadotrophin-releasing hormone (GnRH) analogues remain the mainstay of targeted drugs to counter the oestrogen aspect of endometriosis. Side effects might influence the duration of treatment, especially with GnRH analogues. The levonorgestrel intrauterine device has become popular as a progestagen source. Statins, metformin, VEGF inhibitors, valproic acid and aromatase inhibitors, among others, have been looked at favourably, but data is limited.

Endometriosis represents a complex condition with variable presentation if it presents at all. Effective management choices are based on the specific symptoms. Lifestyle is thought to be important, as ‘stress’ effects on the immune system and inflammatory pathways promote epigenetic changes that may cause a disease state, so a holistic approach is important. While surgery remains the cornerstone in definitive treatment, the pharmaceutical approach is paved with potentially more to offer in the future as we gain a clearer understanding of all that is at play in this chronic and often misdiagnosed condition.

The Endometriosis Society of South Africa (Endometriosis-SA) is a national organisation that is committed to providing support and information for anyone affected by endometriosis. For more information, go to: www.endpain.co.za


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