Diagnosis and management of endometriosis

Endometriosis is one of the most common benign gynaecological diseases affecting 6%–15% of women of the reproductive age[,] and is defined as the presence of endometrial tissue outside the uterine cavity. The disease is chronic oestrogen dependent with the tissue reacting in the same way as the endometrium during the menstrual cycle. The endometrial glands are typically located in the pelvis, including ovaries, pelvic peritoneum, uterosacral ligaments, fallopian tubes and broad ligaments, but implants may also occur in the urinary bladder, bowel, diaphragm or pleural cavity. The first description of this condition was made in 1860 by the German pathologist Carl von Rokitansky, who found endometrial glands in the myometrium and ovaries.[] The precise aetiology and pathogenesis remain unsolved. One of the oldest and widely accepted hypotheses is the implantation theory established by Sampson.[] Sampson assumed that endometriosis originates from endometrial cells that implant on peritoneal surfaces following retrograde menstruation. However, given that retrograde menstruation occurs in most women, it is unclear why only some women develop endometriosis.[,] The ectopic endometrial tissue causes local inflammatory response reactions, stimulation of nerve fibres and adhesions.[] This again has been linked to pelvic pain and dysfunction of the reproductive organ. However, the severity of endometriosis does not correlate with the intensity of symptoms.[] Typical symptoms include dysmenorrhoea, dyspareunia, dysuria, dyschezia and/or infertility. The clinical presentation can range from asymptomatic patients to severe impairment with a significant negative impact on the quality of life.[] In particular, pain and infertility issues, as well as comorbid depressive and anxiety disorders, affect health-related quality of life, imposing a substantial health-care burden. In fact, studies have demonstrated that endometriosis has a high socioeconomic impact on health-care expenditures.[] The wide variation of complaints might contribute to the considerable diagnostic delay of endometriosis. The average interval between the onset of symptoms and the final diagnosis of the disease has been reported to take up to 10 years.[] The delay of diagnosis clearly aggravates the burden to the health-care system. There are different subtypes of endometriosis: superficial peritoneal implants, endometriotic ovarian cysts (endometriomas), deep infiltrating endometriosis (DIE) and adenomyosis. DIE is recognised to be the most aggressive and severe manifestation of endometriosis and is defined as infiltration of the peritoneum deeper than 5 mm. It most commonly affects the uterosacral ligaments, bladder, rectovaginal septum, rectum and rectosigmoid colon.[] DIAGNOSIS For diagnosing endometriosis, the patient's gynaecological history, physical examination, transvaginal sonography (TVS) and/or pelvic magnetic resonance imaging (MRI) are used. However, histological confirmation remains to be the gold standard of diagnosing endometriosis.[] Laboratory tests are limited, as CA-125 is neither sensitive nor specific in diagnosing endometriosis.[] The discovery and validation of new non-invasive diagnostic biomarkers are the focus of current research,[,] however, to date, there are no reliable biomarkers available.[] The evaluation starts with assessing the patient's history on the typical complaints of dysmenorrhoea. The basic diagnostic approach equally includes a vaginal examination with separated specula to detect possible vaginal infiltration of the posterior fornix and a bimanual palpation detecting fixation of the uterus, tenderness of the uterosacral ligaments and/or of the uterus. This is followed by imaging evaluation. Given that TVS is readily available, it is the primary diagnostic tool in the hands of gynaecologists. Endometriomas or even lesions in the rectal or the bladder wall can be detected accurately by this means.[] A negative uterine sliding sign in TVS reflects uterorectal adhesions, predicting the presence of DIE involving the rectum.[] Adequate education and training for accurate diagnosis of DIE with TVS are mandatory.[,] In case of severe endometriosis, imaging should be completed by sonography of the kidneys to exclude ureteral obstruction. MRI of the pelvis is usually performed as second-line imaging, for pre-operative evaluation of severe DIE. When tailored for the evaluation for endometriosis, MRI is highly accurate in particular for the diagnosis of endometriomas and DIE lesions.[] Furthermore, a colonoscopy or cystoscopy can be done if DIE of the colon or the bladder, respectively, is suspected. However, diagnostic accuracy for DIE of the rectum or the bladder is higher with TVS as the disease is progressing from outside to inside the organ. An exact pre-operative evaluation of the severity of the disease is crucial for the pre-operative counselling and inter-disciplinary planning of the surgery. CLASSIFICATION During laparoscopic exploration, endometriosis is surgically staged according to the revised American Society for Reproductive Medicine scoring system (rASRM): Stage I – isolated implants without adhesions, Stage II – superficial implants on the peritoneum and ovaries, Stage III – multiple superficial or deep invasive implants, adhesions may be evident; and Stage IV – multiple superficial and/or deep invasive implants, including ovarian endometriomas and dense adhesions.[] As DIE is not exactly described by the rASRM scoring system, the ENZIAN score should be used in these advanced cases [Figure 1].[] MANAGEMENT AND THERAPY As patients often have a long history of suffering, they feel relieved to discover that there is a reason confirming why they are in pain and are unable to conceive. Endometriosis might require a life-long management plan with pain relief being the primary aim. The treatment includes conservative approaches and surgical interventions. Diet Patients may positively influence their endometriosis symptoms by changing their diet. A recent systematic review summarised the current evidence and reported on the positive effects after intake of additional fatty acids, antioxidants, vitamins and minerals.[] In particular, the use of curcumin may help in the dietary prevention and management of endometriosis by downregulating inflammation and oxidative stress.[] Medical treatment In women with pelvic pain, first-line therapy is non-steroidal anti-inflammatory drugs.[] Further options are contraceptive and hormonal agents,[] as well as gonadotropin-releasing hormone agonists (GnRHa).[] Concerning progestins, there are several routes of administration. Levonorgestrel-releasing intra-uterine devices represent an effective and well-accepted treatment option for women who do not wish to conceive.[] A continuous administration of these hormonal agents results in a hyperprogestogenic (oral contraceptives and progestins) or hypoestrogenic state (GnRHa) that suppresses endometrial cell proliferation and causes atrophy of the ectopic endometrium.[] Repeated surgical procedures should be avoided in endometriosis patients, however in the following situations, surgery should be considered: if the medication does not lead to sufficient pain relief; if a histological diagnosis of endometriosis is required; if the bowel or urinary tract is obstructed; and to exclude malignancy in an adnexal mass. Surgery The surgical strategy includes a nerve-sparing removal of all visually suspected and palpable endometriotic lesions and to perform lysis of pelvic adhesions, at the same time preserving fertility or optimising conditions for future conception. Up to date, surgery is performed through laparoscopy which allows both, a diagnostic and therapeutic procedure. Resection can be done with unipolar or bipolar cautery, laser ablation and excision techniques.[] Ovarian endometriomas are surgically removed or may be observed with serial imaging in a recurrent situation. An accurate and gentle technique of cystectomy is crucial to maintain the ovarian follicular reserve.[] These conservative, fertility-preserving surgeries achieve a significant pain relief in approximately 75%.[] However, the rate of recurrence and re-operation is reported to be 40% to 55% at 7 or 10 years of follow-up.[,] Therefore, women with therapy-refractory pain may be offered definitive surgery with hysterectomy. Endometriosis and fertility In case of endometriosis-related, impaired fertility, there are a several possibilities to help a woman to conceive: surgery, intra-uterine insemination or assisted reproductive technology (ART). Infertility treatment is dependent on the surgical staging of endometriosis as well as on the patient's age and preferences. For infertile women with symptoms suggestive to endometriosis and without previous surgical treatment, primary operative laparoscopy is recommended which has shown to significantly increase pregnancy rates.[] The main fertility benefit is achieved shortly after the primary operative procedure. For women with endometriosis who have no symptoms apart from infertility, surgical treatment to improve fertility is not indicated. Moreover, although repeated surgery may reduce pain, it is proven to not improve fertility/studies report lower pregnancy rates after second-line surgery.[] For women with mild endometriosis (Stage I/II) and age under 35, the initial treatment includes expectant management or ovulation induction with intra-uterine insemination.[] Women with advanced endometriosis (Stage III/IV) and/or age over 35 are advised to proceed directly with ART.[] Contrary to previous findings, a recent Cochrane Review reports that GnRHa pre-treatment before ART does not appear to be helpful.[] If women with endometriosis have succeeded in conceiving, endometriosis symptoms seem to improve during pregnancy. However, study results are controversial and the effects of pregnancy on endometriosis are based on studies with limited quality. Currently, there is no evidence that pregnancy can be expected to reduce the size and number of endometriotic lesions.[] Moreover, there is increasing evidence that endometriosis may be associated with adverse pregnancy outcomes. In a meta-analysis of 33 studies, the risk of pre-term birth, caesarean delivery, low birth weight and placenta praevia was increased among women with endometriosis.[] Although benign, endometriosis remains a debilitating disease with a high prevalence associated with high economic costs resulting in an important public health issue. None of the treatment options currently available are able to permanently eradicate the disease. New therapeutics as well as biomarkers which allow an early diagnosis are warranted and should further be the subject matter of future research. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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