Endometriosis

Published on 09/03/2015 by admin

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Chapter 4 Endometriosis

Gary Swift

Definition. Endometriosis is defined as the presence of endometrial-like tissue outside the uterus, which induces a chronic inflammatory reaction and is associated with pain, subfertility and impaired quality of life.

Cyclical bleeding into deposits causes inflammation, scarring and adhesions, leading to pain, anatomical distortion and pelvic organ dysfunction. Dysmenorrhoea, dyspareunia, non-cyclical pelvic pain, dysuria, dyschezia and infertility result from the disease, though it may be asymptomatic in a minority. Symptoms in women subsequently found to have endometriosis may commence soon after menarche, with the disease varying widely in severity, symptomatology, and clinical and social impact. The disease ranges from relatively trivial superficial deposits causing few symptoms to severe deep infiltrating endometriosis (DIE) affecting the muscularis of pelvic viscera and/or the rectovaginal septum with associated quality of life implications.

Prevalence. An estimated 10% of reproductive-age women, in all social and ethnic groups, have endometriosis; 30% of women presenting with infertility have endometriosis; 50%–60% of women presenting with pelvic pain have endometriosis.

Risk factors

• higher risk with early menarche, short cycles and heavy menstrual flow (>8 days relative risk (RR) 2.4)
• reduced incidence with smoking (reduced oestrogen) and exercise (increased sex hormone-binding globulin (SHBG) and reduced luteal oestrogen levels)
• relative risk greatly increased with first-degree relative afflicted
• dietary factors: reduced risk with high fruit (odds ratio (OR) 0.6) and vegetable (OR 0.3) intake and fish oil (animal studies); increased risk with high red meat consumption (OR 2.0).
• increased risk with higher levels of vitamin D
• inverse association between endometriosis and body mass index (BMI)
• possible increased risk with alcohol, caffeine, and polychlorinated biphenyls (PCB) and dioxin exposure

Aetiology

The exact aetiology is still not known. The most widely accepted theory is related to viable endometrial cells reaching the peritoneal cavity through retrograde menstruation along the fallopian tubes (Sampson 1927). At least 90% of women with patent fallopian tubes will have evidence of retrograde menstruation; yet, in the majority, the menstrual debris is rapidly and efficiently cleared, by macrophages and natural killer (NK) cells.

Alternative theories of ‘coelomic metaplasia’ and ‘embryonic cell rests’ are less favoured.

Increased susceptibility is possibly related to:

• increased exposure to menstrual debris
• abnormal eutopic endometrium
• altered peritoneal environment
• reduced immune surveillance
• increased angiogenic capacity

Genetics

Genes influence susceptibility to endometriosis.

• considered to be a complex heritable trait with many genes contributing to risk, with the contribution of any one individual gene likely to be small
• genomic linkages found on chromosomes 7, 10 and 20 so far
• relative increased risk with sibling affected: 2.34 to 15 times (higher risk in more severe forms of the disease)

Pathology

The lesions of endometriosis vary from superficial to deep and in appearance from clear to white to red to black in proportion to degree of inflammation, vascularity and haemosiderin deposition. Newly formed lesions tend to be clear to red, with older lesions more deeply pigmented, with variable proportions of pale scarring and fibrosis. With increasing fibrosis, lesions become nodular. Lesions in postmenopausal or hormonally suppressed women will tend to be paler.

The inflammation and fibrosis leads to adhesions and anatomical distortion. Shortening and thickening of uterosacral ligaments reduces uterine mobility and causes fixed retroversion. Shortening and thickening of ovarian ligaments displaces ovaries medially. Pouch of Douglas obliteration follows involvement of rectal serosa and sometimes muscularis.

Endometriomas or ‘chocolate cysts’ are specific lesions that form in the ovaries. They are thought not to be true cysts but invaginations of the ovarian cortex lined by typical endometriotic tissue. The thick altered blood content resembles melted chocolate. These lesions have high recurrence rates if not excised completely. Endometriosis deposits are histologically similar to eutopic endometrium, but not identical. Plaques contain oestrogen, progesterone and androgen receptors, and grow in the presence of oestrogen and atrophy with androgens.

Abnormal levels and function of growth factors, macrophages and proinflammatory cytokines have been observed in the peritoneal fluid and serum of women with endometriosis.

Pathogenesis

• Angiogenic processes are fundamental to the establishment of endometriosis.
• Polymorphisms in the vascular endothelial growth factor (VEGF) gene increase susceptibility to endometriosis in humans.
• There are current searches for endometriosis-specific angiogenic mechanisms.

Clinical presentation

Symptoms include:

• dysmenorrhoea
• deep dyspareunia
• chronic pelvic pain
• ovulation pain
• cyclical or perimenstrual bowel and/or bladder disturbance with or without abnormal bleeding (dysuria, dyschezia)
• infertility
• chronic fatigue
• asymptomatic in minority

Diagnosis

There is no reliable non-surgical diagnostic test for endometriosis. Endometriosis may be suspected clinically with appropriate symptoms and examination findings (nodularity in pouch of Douglas or uterosacral ligaments) or radiologic evidence of endometriomas. Unless endometriotic ‘blue dome cysts’ are visible in the posterior vaginal fornix, laparoscopy is required for diagnosis, with preferably histological confirmation, and is regarded as the ‘gold standard’.

Staging

• combination of clinical, radiological and surgical
• ideal system yet to be developed
• American Fertility Society (AFS) staging is complex and detailed, but is most used in research settings

Treatments

Medical treatment

• primary therapy, postoperative, preventative

Contraceptive

• hormonal medical therapies equally effective in symptom control, but vary in side effects and costs
• no evidence of improved fertility outcomes
• higher recurrence rates after medical treatment compared to surgical

Options

• progesterones: progesterone-only pill (POP), depot medroxyprogesterone acetate (DMPA), oral progestins, progesterone-containing intrauterine contraceptive devices (IUCDs)
• combined oral contraceptive pill
• danazol
• gestrinone
• gonadotrophin-releasing hormone (GnRH) agonists (goserelin, nafarelin, leuprolide)

Surgical treatment

Laparoscopy is the ‘gold standard’ for diagnosis and therapeutic intervention. If endometriosis is present at laparoscopy, it is recommended that it is surgically removed at the same time as diagnosis, as it is an effective treatment for endometriosis-associated subfertility and pain.

Alternative treatment

• acupuncture, Chinese medicine, naturopathy: potential positive effects on symptom control, but evidence based on randomised controlled trials is lacking

Prognosis

• natural history of early stage disease lacking
• tendency to progressive increase in number and size of deposits until excision, pregnancy, suppressive treatment or menopause

Special areas

Endometriosis in adolescence

Endometriosis can be responsible for admissions with pain in the 10–17-year-old age group. For adolescents with pelvic pain refractory to non-steroidal anti-inflammatory drugs (NSAIDs) and/or combined oral contraceptives (COCs), it is estimated 50% will have underlying endometriosis. First-line medical treatment is appropriate, followed by laparoscopy and surgical management if unsuccessful.

Endometriosis and fertility

Impact on fertility

• spontaneous and assisted conception reduced in proportion to stage of disease and anatomical distortion
• quality of oocytes, ovarian reserve and implantation success reduced
• pain and menstrual disturbance have a negative impact on coital frequency

Medical therapies contraceptive

Surgical management is proven to improve mild and moderate disease stages, with severe forms difficult to evaluate due to variables, but trends to improved fertility, natural and assisted, with optimal surgical management.

Impact on and role of assisted reproductive technology (ART)

Endometriomas are associated with reduced follicle numbers and ovarian responsiveness to gonadotrophin stimulation. Currently, there is debate on excision prior to in vitro fertilisation (IVF). Surgical excision is not proven to improve outcomes with IVF and may reduce ovarian reserve further. Generally, excision is recommended if >=4 cm, there is pain or access to follicles is affected.

Deep infiltrating endometriosis

• defined as deposits invading over 5 mm in depth
• severe form of endometriotic disease forming a subset with infiltrating deposits in bowel and/or bladder muscularis and rectovaginal septum
• management is complex with advanced surgical techniques required
• referral to centre with necessary expertise strongly recommended

Extrapelvic disease

This is rare, but it can affect any organ. Deposits have been documented in the umbilicus, lungs and central nervous system. It should be considered in any symptoms with a cyclical pattern, especially if it is associated with pain and/or bleeding.

Future issues

• Animal models show inhibition of endometriosis by substances that block angiogenesis (vascular endothelial growth factor (VEGF) antibodies, selective cyclo-oxygenase-2 (COX-2) inhibitors) (Hull et al 2003).
• Human Genome Project: genome-wide association studies are expected to provide greater insight into the genetic basis of endometriosis in the future.

Further reading and references

American Society of Reproductive Medicine (ASRM) Guidelines. Available at:www.asrm.org/

D’Hooghe T.M., Debrock S. Future directions in endometriosis research. Obstetrics and Gynecology Clinics of North America. 2003;30:221-244.

Eskenazi B., Warner M.L. Epidemiology of endometriosis. Obstetrics and Gynecology Clinics of North America. 1997;24:235-238.

European Society of Human Reproduction and Embryology (ESHRE) Guidelines. Available at: www.eshre.eu/

Garcia-Velasco J.A., Somigliana E. Management of endometriomas in women requiring IVF: to touch or not to touch. Human Reproduction. 2009;24:496-501.

Hull M.L., Charnock-Jones D.S., Chan C.L.K., et al. Antiangiogenic agents are effective inhibitors of endometriosis. Journal of Clinical Endocrinology and Metabolism. 2003;86:2889-2899.

Kennedy S. The genetics of endometriosis. Journal of Reproductive Medicine. 1998;43(Suppl 3):S263-S268.

Kennedy S., Bergqvist A., Chapron C., et alon behalf of the ESHRE Special Interest Group for Endometriosis and Endometrium Guideline Development Group. ESHRE Guideline for the diagnosis and treatment of endometriosis. Human Reproduction. 2005;20:2698-2704.

Parazzini F., Chiaffarino F., Surace M., et al. Selected food intake and risk of endometriosis. Human Reproduction. 2004;19:1755-1759.

Rogers M.S., D’Amato R.J. The effect of genetic diversity on angiogenesis. Experimental Cell Research. 2006;312:516-574.

Sampson J.A. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue to the peritoneal cavity. American Journal of Obstetrics and Gynecology. 1927;14:422-469.

Treloar S.A., Wicks J., Nyholt D.R., et al. Genome-wide linkage study in 1176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26. American Journal of Human Genetics. 2005;77(3):356-376.

Zondervan K.T., Treloar S.A., Lin J., et al. Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian autosomal inheritance on chromosome 7p13–15. Human Reproduction. 2007;22:717-728.

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