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Differential diagnosis of active and inactive endometriosis
Abstract
Endometriosis and infertility are frequently associated. There is controversy in the literature about the causal correlation. There is no doubt, that progressed disease causes infertility by mechanical disturbances of the reproductive organs. Mild and moderate endometriosis however is discussed to cause functional infertility by changes of the peritoneal fluid, by endocrine and immunological dysfunction. Ovulation, ovum transport, fertilisation and implantation has been shown to be negatively influenced in patients with endometriosis. Some randomised prospective clinical studies however have demonstrated, that pregnancy rates after medical or surgical treatment of endometriosis are not improved compared with no treatment of the disease. The morphological data of this study may explain these conflicting data of the past: inactive, not proliferative endometriosis is not a cause of infertility, but in contrast active proliferating disease reduces fertility and needs sufficient treatment.
Endometriosis has a wide range of symptoms and no pathognomonic signs. Therefore differential diagnosis is difficult and delay of the correct diagnosis is common. In addition, there is no correlation between severity of symptoms and stage of the disease. In clinical routine, improvement can be achieved only, when endometriosis is considered as differential diagnosis in all cases of lower abdominal pain - cyclical, recurrent, chronic pain. If endometriosis is proven by laparoscopy and biopsy, surgery or medical treatment is not the consequence in all cases. Only when proliferative activity, infiltration of pelvic organs and correlated pain symptoms of the involved organs are present, endometriosis can be considered as a disease, which must be treated - otherwise it is inactive and an accidental finding. Relief of symptoms can be achieved by analgesics or progestins continuously, using low dose treatment schedules. Regression of the implants and endometriotic cysts can be achieved by potent ovarian suppression using GnRH-analogous especially. Because only permanent absence of estrogens can lead to recurrence free results, endometriosis can not be healed by medication alone. Endoscopic surgery with removal of the disease and conservation of the pelvic organs is the central treatment principle. In case of difficulties to remove subperitoneal foci by surgery alone, or in case of persistent microscopic disease of the peritoneum, individual treatment strategies have to be developed using both surgical and medical therapy. The principles for infertile and pain patients are demonstrated.
The diagnostic laparoscopy is the gold standard today to stage pelvic endometriosis and to prove it by biopsy and histology. Other diseases of the pelvic organs can be seen or excluded by differential diagnosis. Laparoscopic treatment of peritoneal implants is the treatment of choice, which is proven for pain and infertility with prospective randomised studies.
In the last few years, considerable progress has been made understanding endometriosis and developing diagnostic procedures and therapeutic options. Sophisticated endoscopic instruments allow laparoscopic surgery even in progressed stages and deep infiltrating endometriosis of the bowel and bladder. The introduction of GnRH analogues with add-back medication and the development of new progestins have widened the range of options for effective medical therapy. Nevertheless new prospective studies have demonstrated in the last decade that the success is temporary and the recurrence rates are high even when the surgery was adequate. Often medical treatment is effective during the time of application only. This means that customised long-term therapy concepts based on guidelines developed by medical societies play a central role in the alleviation of pain, the reduction of recurrence rates, the avoidance of repeat operations and the improvement of the patients' quality of life.
During the last years understanding endometriosis and the diagnostic procedures and therapeutic options have improved considerably. Sophisticated endoscopic instruments allow laparoscopic surgery even in progressed stages and deep infiltrating endometriosis of the bowel and bladder. The introduction of GnRH-Analogues with add-back medication and the development of new progestins have increased the spectrum of possibilities for effective medical therapy. Nevertheless new prospective studies have demonstrated, that the success is limited und recurrence rates are high although the surgery has done sufficiently. Very often medical treatment is effective during the time of application only. To define an optimal therapeutic approach national and international guidelines are developed. For the individual patient a concept of long term treatment is essential, to reduce recurrence rate, avoid repeated operations and improved quality of life.
In the last two decades, a color based concept of disease activity in peritoneal endometriosis has been in use in the clinical context, with red lesions being considered active and black or white lesions being interpreted as less active or dormant.
Our aim was to analyze 4 main color categories of peritoneal endometriosis (black, white, red and brown) in one single patient group using histomorphological and immunohistochemical methods.
65 endometriosis lesions (30 black, 17 white, 11 brown, 7 red) were resected from 47 premenopausal, nulliparous women which had not received exogenous hormones for at least six months prior to the operation. Specimen workup, histomorphological analysis and immunohistochemical analysis were performed in a standardized manner.
The color categories showed a broad overlap in proliferative activity and hormone receptor expression. Differences were found in lesion morphology. Adjacent stromal reaction in particular showed a marked increase from red through brown and black to white lesions. Differences were also seen in gland pattern and gland content.
Lesion colors in peritoneal endometriosis seem to be determined by gland content and a varying adjacent stromal reaction and more likely reflect an aging process than different levels of disease activity.
Today GnRH-Analogues are the most effective substances for the regression of endometriosis and endometriosis related complaints. In combination with add-back medication the treatment is effective with only few tolerable side effects. The different types of GnRH-Analogues are equally effective, but depot preparation have the best compliance. The tailored application of GnRH-Analogues preoperatively, postoperatively or instead of surgery is dependent on the individual situation of the patient and dependent on the proliferative activity, localisation, type and stage of the disease.
The use of cetrorelix within ovarian-stimulation protocols demonstrates several advantages compared with gonadotropin-releasing hormone (GnRH) agonist-containing protocols, which include, for example, significantly less time for analogue treatment and a reduction in the amount of gonadotropins needed. Furthermore, fewer side effects can be expected. There is no difference regarding endometrium quality and hormone profiles, and the results of assisted reproduction cycles are comparable. Cetrorelix also seems to be useful in the treatment of endometriosis which, in most cases, is an estrogen-dependent disease. Furthermore, fewer side effects occur with this agent (e.g., postmenopausal symptoms) and no estradiol add-back is needed. In the future, new nonpeptic GnRH antagonists are expected to be available for oral administration. Although they are still under investigation, these agents have the potential to improve patients' comfort and compliance.
Owing to the lack of an ideal treatment for endometriosis when fertility must be preserved, there are differences of opinion between those in favour of a mainly surgical approach to therapy, those favouring expectant management of the disease's less severe forms and those who prefer an active medical approach. Such controversy has made endometriosis a constantly reviewed subject. According to the figures published in the medical literature regarding different treatment strategies for improving fertility in endometriosis cases, none of them shows any clear advantage over the next. Apparently, in minimal endometriosis, the expectation and correction of associated factors should produce identical results to any other therapy. Severe endometriosis should be treated surgically, since no response can be expected from medical therapy. Discussion on the best way to proceed arises in moderate endometriosis. The selection of the clinical treatment should be individualised with regard to the patient's condition: age, length of infertility, degree of severity of the condition, the patient's wishes and the surgical risks involved.