Endometriosis – Pathogenesis, Diagnosis, and Therapeutic Options for Clinical and Ambulatory Care

and must always be performed as the basis for customised therapy strat- egies [33]. Here are some arguments in favour of the generous use of laparoscopy and biopsy to work up a suspicion of endo- metriosis: – There are no pathognomonic symp- toms of endometriosis. The symp- toms can be multi-faceted and either cyclical or acyclical! – The severity of the disease and the se- verity of the subjective symptoms are not correlated with each other. In- stead, the complaints vary with the lo- cation of the lesions. – Although a laparoscopy is invasive, failure to carry it out often leads to the wrong diagnosis and therefore the wrong treatment. Only in 35% of cases is cyclical and/or acyclical pelvic pain caused by endometriosis [34]. All attempts made so far to diagnose endometriosis in a less invasive way using biochemical parameters, tumour markers or auto-antibodies in peripheral plasma are not clinically helpful because they re- quire too much laboratory work [35] and are not sensitive and specific enough. Practical Recommendation In order to avoid overdiagnosis and re- duce the above-mentioned diagnostic delay, the following practical approach is recommended: In view of the fre- quency of dysmenorrhea especially among young women, it is not useful to subject every patient with dysmenorrhea and pelvic pain to invasive differential diagnostics. If the gynaecological ex- amination is normal, a combined oral contraceptive should be prescribed for 3–6 months as a symptomatic interven- tion (so-called COC test). If the symp- toms do not improve even after increas- ing the dosage or changing the proges- tin, a long-cycle application can be at- tempted based on the experience of the last few years [36]. If there is still no im- provement within 6–9 months, laparo- scopy must be performed for further diagnosis (Fig. 5). Figure 5. Practical approach to work up dysmenorrhea and cyclic abdominal pain. Endometriosis J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 107 In this way, unnecessary laparoscopy can be avoided and the diagnostic delay kept to a maximum of 1–2 years. Therapy-resistant or recurrent “inflam- matory adnexal diseases” and chronic pelvic pain must also be worked up laparoscopically since endometriosis is the underlying disease in a third of these cases [34] (Fig. 6). There is a large vari- ety of macroscopic manifestations, rang- ing from small lesions to cysts or even tumorous nodules (Fig. 7). Figure 7 is a macroscopic and Figure 8 a microscopic illustration of the clinical case of an “ap- pendicitis” with the differential diagno- sis “salpingitis” [37]. Adequate diagnostic pelviscopy requires the exact description of the location and severity of endometriosis; there are also calls for an assessment of the growth type and the degree of activity as well as for the histological examination of tissue samples [10]. In a typical case, the histo- logical diagnosis of endometriosis is based on evidence of ectopic endome- trial glands and stroma. The glands are mostly inactive or proliferative; in very rare cases, they are secretorily trans- formed or hyperplastic, but the histo- logical pattern does not necessarily cor- relate with the functional condition of the endometrium [38]. The endometrial stroma is similar to the normal stroma of the inactive or proliferative endo- metrium; occasionally, a smooth muscle metaplasia of the stroma is found. In many cases, the cytogenic stroma is only very narrow and exclusively found periglandularly. The term “atypical endometriosis” is used for cytologically atypical forms, but also for endometrial hyperplasia (simple or complex) in endometrial lesions [39]. Endometriosis may often be masked by peritoneal changes such as whitish thickening, colourless bubbles, flame- shaped changes, hypervascularisation, defects or fibrosis (Fig. 9a–f). If these atypical cases are not worked up histo- logically, the patient has been subjected to an invasive but inadequate diagnosis. Endoscopy is often inadequate in cases of deeply infiltrating, retroperitoneal endometriosis. Vaginal and rectal palpa- tion combined with vaginal sonography are the key examination methods in this case. However, for adequate interdisci- plinary surgical planning purposes, it is crucial to know the exact extent of the disease. For this reason, further exami- nations are helpful when the patient is affected by deeply infiltrating endo- metriosis (Tab. 2) even in cases where the exact extent of the disease can only be identified intraoperatively. “ Active – Inactive” – A Relevant Criterion? Electron microscopy of endometrial foci allows an assessment of the degree of proliferation, differentiation and hor- monal modulation. Since these sophisti- cated examination methods are too ex- pensive for clinical routine, simple mac- roscopic criteria such as growth type and implant colour have been included in the revised classification by the American Society of Reproductive Medicine (1997) [21]. The macroscopic appearance of the dis- ease depends not just on the growth type and the hormone dependency of the im- plant. Natural ageing and reactive in- flammatory processes also influence the progression and regression of these foci. For these reasons, the appearance at the time of the diagnostic pelviscopy is just Figure 6. Share of endometriosis as a cause of chronic abdominal pain. Mod. from [34]. Figure 7. Endoscopic appearance of endometriosis. (a): fresh peritoneal endometrial lesion on the pelvic perito- neum with distinctly visible vessels (Rimbach/Saarlouis); (b): Older, nodular peritoneal endometriosis in the area of the lig. sacrouterinum (Rimbach/Saarlouis); (c): Endometriosis in the area of the tube wall with peritubal adhesions (Rimbach/Saarlouis); (d): Conglomerate of appendix and tube in endometriosis: The infundibulum and the inflamed appendix stick together, mixed with vesicular, partially bloody endometriosis (Endo). a b c d 108 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) Endometriosis a snapshot of a complicated, multifacto- rial, dynamic process. Microscopically, the diversity of the im- plants is even greater than macroscopi- cally. The important factors are the vary- ing degrees of differentiation, variable hormone dependency (cyclicality, re- ceptor status), variable or absent prolif- erative activity (mitosis index, prolifera- tion marker), concomitant inflammation and degenerative processes [40]. Studies on steroid hormone receptors and proliferation markers [41] show that medicinal treatment is particularly effec- tive for fresh implants, while older foci must be removed surgically or may pos- sibly not require any therapy at all be- cause they are not actually the cause of the patient’s complaints. Findings from molecular biology [42] support the view that endometriosis and healthy endometrium are different kinds of tissue. Defective enzyme systems in the ectopic foci, e.g. 17 β-steroid dehy- drogenase type 2, lead to autonomous estrogen production and acyclical, con- tinuous proliferation. These findings also have practical con- sequence for medicinal therapy con- cepts. Low levels or the complete lack of progesterone receptors in implants and disruptions of the intracellular progest- erone metabolism (so-called progester- one block) explain the inadequate effect of a progestin therapy against endo- metriosis (Fig. 10). Activated enzyme systems which are blocked in the eutopic endometrium such as aromatase facili- tate local estrogen production, locally amplifying the proliferation of the ec- topic focus and also the inflammatory reaction via the effect on the prostaglan- din metabolism (Fig. 11). In view of contradictory data, it is not clear whether aromatase is activated in the endometrial lesion itself as first suggested by Noble et al. [43] or whether the endometrial le- sions show no aromatase activity them- selves but the cells of the affected organs express the enzyme [44]. The answer to this question has no clini- cal consequences, and the use of aro- matase inhibitors is at the experimental stage with some positive case reports but no valid and convincing studies. Figure 8. Microscopic image of endocrinically active endometriosis of the appendix (E = intramural endometrial focus; M = mucous membrane of the appendix). (a): highly differentiated, proliferative endometrial foci (HE stain, 200 ×); (b): highly positive estrogen receptors (ERp, brown stain, 200 l). Figure 9. Various types of peritoneal endometriosis. (a): vesicular form (V); (b): nodular (N) und plaque-type growth (Pl); (c): flat, fibrotic form (F); (d): clear vesicles, no bleeding (B); (e): blood-containing vesicles with flame-shaped inflammation (E); (f): brown, grey residual blood with delicate adhesions (A). c d e f a b Endometriosis J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 109 Once all the information mentioned above is available, based on the woman’s age, her family planning and her com- plaints, a symptomatic, a conservative, organ-sparing or an aggressive resective therapy or a combination of these mea- sures can be discussed and agreed upon with the patient.    Surgical T reatment Strate- gies Differential diagnosis require invasive laparoscopy, if possible with a biopsy. Consequently, surgical measures are at the centre of primary treatment. The ob- vious choice is that a surgical interven- tion should directly follow on from the diagnostic laparoscopy under the same anaesthesia (single-stage procedure); if there is a risk of extensive resection, a two-stage procedure can certainly be ac- cepted if it is preferred by the patient be- cause she wants to receive more differ- entiated advice. The ablative procedures include all surgical techniques removing pathological changes to the organs (endometrial lesion, endometrial cyst [Fig. 12 a–d], scars and adhesions) and preserving healthy organ parts (conser- vative ablative therapy) or removing the affected organs in toto (radical ablative therapy). Antiestrogenic or antiinflammatory sub- stances are suitable for a drug-based therapy. The former lead to a suppres- sion of the ovarian estrogen synthesis of varying duration and intensity. This can be achieved temporarily by various drugs (GnRH agonists, GnRH antago- nists, antigonadotropins, progestins, combined oral contraceptives) or perma- nently through surgical ovariectomy. Anti-inflammatory and analgetic pros- taglandin synthesis inhibitors have also proven effective. COX-2 inhibitors caus- ally interfere with the metabolism of the areas of endometriosis. Due to cardiac side-effects, these substances have been withdrawn from the market with some exceptions and not been approved for endometriosis therapy. The third treatment option consists of symptomatic measures which may range from complementary medicine to physi- cal applications and balneotherapeutic measures with a relaxing, cramp-releas- ing and perfusion-promoting effect. These options also include homeopathy, T able 2. Special Diagnostic Procedures for Deep Infiltrating Endometriosis Based on the Guidelines of the German Society for Gynecology and Obstetrics. From [29].

Diagnostic Finding Coloscopy Exclusion of primary bowel diseases*, stenosis, external pressure MRI Involvement of the bladder wall, stenosis of the ureter, uterine adenomyosis Rectal ultrasound Involvement of the intestinal wall, depth of invasion, extent of the tumor Colon barium enema Involvement of higher bowel sections, stenosis Renal ultrasound Ureteral congestion, hydronephrosis Intravenous pyelogram Ureteral involvement, stenosis of the ureter Cytoscopy Bladder failure * only useful for intestinal bleeding and/or women > 35 Figure 11. Vicious circle in the endometrial focus maintains the proliferation and inflammatory reaction: (1) local estrogen is produced by aromatase activation; (2) estrogens stimulate prostaglandin synthesis via the activation of the COX-2 enzyme; (3) Prostaglandin E-2 again stimulates aromatase. Whether the aromatase is activated in the endometrial lesion itself or in the surrounding tissue (fat, peritoneum) is controversial. Figure 10. Estrogen metabolism in endometrial lesions: Defective 17-beta-steroid-dehydrogenase type 2. This means that the bioactive estradiol cannot be converted into the less active estron. In the normal endometrium, progesterone activates this 17-beta-HSD Type 2 and has an antiproliferative effect; this mechanism is disrupted in endometrial lesions (so-called progesterone block). 110 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) Endometriosis TCM and other therapies which can be used successfully especially for chronic pain patients. Principles of Surgical T reatment Minimally invasive surgical techniques have become standard today. Various endoscopic techniques of destroying or removing endometrial lesions are used. Comparative studies have shown that these different techniques – mono- or bipolar coagulation, heat application, vaporisation or excision – are equivalent as long as the foci are completely re- moved. However, the cycle phase does have an influence on the relapse rate: When peritoneal endometriosis was endoscopically removed premenstrually, the relapse rate after 2 years was twice as high (15%) than when the intervention had been carried out postmenstrually. It is assumed that this is due to peritoneal defects caused by the operation which had not healed by the time of the subse- quent menstruation [45]. Therapy Goals: Pain Removal and/or Pregnancy The hardest facts on the therapeutic value of endoscopic intervention for pain patients – also for low-grade endo- metriosis – have been produced by the studies of Sutton et al. [46]. In a prospec- tive, double-blind (fake operation!) ap- proach, it was shown that the pain symp- toms had improved after 6 months in 63% of the patients in the therapy group while only 23% of the women in the pla- cebo operation group reported pain re- lief. However, this also means that one third of the women experienced no pain relief as a result of the operation and that adjuvant drug therapies are crucial to improve the results and reduced the re- lapse rates. The effectiveness of the surgical therapy for endometriosis can conveniently be compared looking at the subgroup of in- fertile patients since pregnancy is a more

treatment goal than pain relief. When used appropriately, the different laparoscopic resection and coagulation techniques lead to results which are comparable or even superior to those of microsurgical laparatomy [47]. How- ever, these older studies are open to criti- cism for lack of randomisation and retro- spective analysis. Only two studies have been carried out in a prospective and randomised way and yielded controver- sial results. According to a Canadian multicenter study [48], surgery for en- dometriosis improves the pregnancy rates significantly compared with purely diagnostic laparoscopy (31% vs 18%), but this was not confirmed by an Italian group [49] (20 vs 22%). More recent publications are no better in terms of methodology since it is difficult to estab- lish a control arm with placebo surgery both for infertile and pain patients. An- other problem is surgeon quality. It is an open question whether the published data, which originate from centres, can also be achieved in routine care. How- ever, the type of endoscopic removal does not seem to play a role [50]. More recent data suggest that secondary dam- age such as adhesions are more relevant than the area of endometriosis itself. Maruyama et al. [51] report on 41.8% pregnancies within 18 months of surgi- cal removal for endometriosis without adhesions and only 13.27% for endo- metriosis with adhesions on both adn- exa. Customised Surgical Concepts Based on the woman’s personal situation and her symptoms, customised treat- ment strategy must be developed which accounts for not only the acute pathol- ogy but also the chronicity of the disease and is specific for the different forms of endometriosis. Peritoneal endometriosis is a particular challenge for the surgeon since its appearance can vary; the sur- geon needs to know and recognise even atypical manifestations (see above). Fur- thermore, the diffuse spread of endome- trial lesions and their growth even under adhesions requires a subtle and patient approach. The risk of an incomplete op- eration is high; many recurrences are probably due to persistent active foci. In a case of suspected ovarian endo- metrosis, if there is an indication for sur- gery due to complaints and in order to investigate an unclear adnexal enlarge- ment, the need for a histological diagno- sis is controversial, since old hemor- rhagic corpus luteum cysts or follicular cysts have the macroscopic appearance of a typical “chocolat cyst” in a quarter of all cases. However, functional cysts require neither surgical nor drug therapy. The most efficient method is the com- plete excision of the endometrioma while sparing the healthy residual ovary. Surgical experience is crucial as, by con- trast with other benign ovarian cysts, it cannot be avoided that some healthy tis- sue is also removed and the follicular reserve reduced while resecting endo- metrial cysts. There have been reports about falling AMH levels, reduced fertil- ity – also in IVF programmes – and, in Figure 12. Endometrial cyst in the area of the ovary. (a): Left-sided endometrial cyst of the ovary with adhesions and concomitant reactive inflammation; (b): Ultrasound view of an endometrial cyst: homogeneous, low internal echo (bleeding) and thickened cyst wall; cap-shaped residual ovary on right picture margin (Elsässer, Heidelberg); (c): Extensive, endocrinically inactive endometrial cyst of the ovary with bleeding (HE, 25,5 ×); (d): Florid, endo- crinically active endometrial cyst of the ovary within the hyperplastic cyst wall (HE, 40 ×). a b c d Endometriosis J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 111 extreme cases, premature menopause. There are contradictory data about pre- operative treatment with GnRH ago- nists, whereas postoperative treatment reduces the risk of recurrence [52]. Deep infiltrating endometriosis (DIE) in- cludes forms of endometriosis which grow tumourously below the perito- neum. Endometriosis often affects the septum rectovaginale, the parametrium, para- rectal tissue, the rectum (Fig. 13, 14) and the sigma, but also higher intestinal sec- tions as well as the pelvic wall with con- secutive involvement of the ureter. Due to their high proportion of fibrous tissue and muscle cells, these nodular growths show a poor response to drugs. The im- plants stay vital and start to progress soon after the cessation of the medica- tion. For this reason, surgery is predomi- nant in the treatment of these manifesta- tions; permanent medication is an option only in exceptional cases. If there are no symptoms, intestinal endometriosis which can be easily controlled and does not result in stenosis can be treated ob- servantly; active therapy is only indi- cated in these cases if there are symp- toms or progression. The goal of therapy is the complete exci- sion of the endometrial foci and their secondary lesions while preserving or- gan function. In the case of small nod- ules, the defect on the bladder or the in- testine can be closed primarily; in exten- sive deep infiltrating cases, the affected intestinal segment must be resected and intestinal continuity restored by anasto- mosis. If the ureter is affected, this often means a psoas hitch reimplantation. Even in cases of advanced intestinal endometriosis, complete removal can be achieved by careful preparation in the muscularis without opening the lumen. A musculo-muscular and sero-muscular two-layer suture is possible so that a resection with anastomosis can often be avoided [53]. These operations are normally carried out by laparotomy; however, there are more and more reports about endoscopic techniques, showing that with adequate training and an interdisciplinary ap- proach, even partial intestinal resections and Stabler-type anastomoses can be performed endoscopically [54]. In terms of therapy success and quality of life, the Figure 13. Deeply infiltrating endometriosis: surgical site. (a): Fibrotic tumour infiltrating the rectum; (b): Resec- tion with good safety margin, saving the posterior wall of the rectum and the mesorectum. a b Figure 14. Deeply infiltrating endometriosis: macroscopic view of the resected part of the rectum (a) and micro- scopic image (b), showing that even in such an extensive case, the mucosa of the rectum can be intact and colo- scopy cannot be used to confirm the diagnosis. Figure 15. Adenomyosis uteri interna. (a): In the sonographic cross-section, the inhomogeneous appearance of the myometrium can be seen with a poorly delineated area of adenomyosis (unlike myomas); (b): Doppler sonography shows the increased perfusion in the area of adenomyosis (US images: Elsässer, Heidelberg); (c): The endometrial focus visible within the uterine muscles (HE, 12,5 ×); (d): With a higher magnification, the glands and the cytogenic stroma can be clearly discerned (HE, 40 ×) a b c d 112 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) Endometriosis route of access is irrelevant as long as the lesion has been removed adequately, as shown by a recent prospective random- ised study [55]. If the wall of the uterus is also involved, e.g. in cases of retrocervical endometrio- sis, or if there is concomitant uterine ad- enomyosis (Fig. 15), physicians should discuss with the patient whether to per- form a hysterectomy as the only way to remove the endometriosis completely so that the risk of recurrence would be greatly reduced. There is a controversy about whether preoperative drug treatment is useful in cases of intestinal and bladder involve- ment. The arguments in favour are that the surgical trauma is reduced and that shorter operating times, less blood loss, and pelviscopy rather than laparotomy are possible; the arguments against are that the preparation of the more fibrosed tissue is more difficult and there is a risk of missing small, regressive, non-pal- pable implants and of reduced circula- tion in the operating area, possibly lead- ing to healing disorders and insufficient anastomosis. Whether the success rates and relapse rates are improved by the preoperative use of e.g. GnRH agonists as a depot is unknown because of a lack of follow-up data. These carefully chosen customised treat- ment options avoid surgical overtherapy and are tuned to the type of endometrio- sis and progression risk. On the other hand, the surgeon is required to make a substantial diagnostic effort and be very knowledgeable about the different thera- peutic options: surgery, drugs and a combination of both. Based on current knowledge, this is the only way to re- move or alleviate the symptoms and se- quelae of this disease, which has a ten- dency to recur (Fig. 16). It should be noted that there is still a lack of compre- hensive controlled studies, and the long- term value of the exclusively surgical treatment of a pain patient is just as over- rated [56] as the improvement of fertility in a fertility patient [57].    Drug Therapy Basic research has shown in vitro and in vivo that various immunological, in- flammatory, paracrine and endocrine factors are relevant for the progression of endometriosis. Although some inter- esting therapeutic concepts can be de- rived from them (Fig. 17), they have so far only been tested experimentally in vitro or in animal studies. The existing drug treatments which are still used in practice rest on two pillars: (1.) Suppres- sion of ovarian function and (2.) reduc- tion of the reactive concomitant infec- tion. The clinically tested substances are, on one hand, steroid hormones inter- fering with the negative feedback of the hypothalamic-pituitary-ovarian axis but where these hormones or their metabo- lites do not develop any estrogenic prop- erties (progestins, selective progestin- receptor modulators) and, on the other, substances such as GnRH analogues (agonists and antagonists) which directly block the release of gonadotropin at the pituitary level. Pain through endometro- sis can be influenced by PG synthesis Figure 16. Combined treatment principle for endoscopically and histologically confirmed endometriosis, which needs to be adapted to the individual case. Figure 17. Concept for the pathogenesis of endometriosis and the corresponding therapeutic strategies, which are partly used in practice, partly experimental or hypothetical. From Petraglia, Pinzauti a. Trosti 2011, pers. communi- cation; by courtesy of the author. ER-βα: estrogen receptor- α; PR-A B: progesterone receptor A and B; NSAIDs: non-steroidal anti-inflammatory drugs; SPRM: selective progesterone receptor modulators. Endometriosis J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 113 inhibitors. Whether these merely sup- press the inflammatory reaction in the involved tissue or directly influence the endometrial lesions themselves is the subject of current research, since COX-2 expression was found in all three forms of endometriosis [58]. As endometrosis is a chronically recur- ring and systemic disease, neither a tem- porary drug-based nor a surgical therapy can protect the patient from recurrence unless castration or chronic medication lead to permanent estrogen withdrawal. This is a crucial fact when it comes to advising the patient and setting up a therapy plan. As a result, repeated inter- mittent or long-lasting continuous drug therapies are often required: The ques- tion is not just whether a substance is effective in terms of leading to endo- metriosis regression and pain relief but also how it is tolerated and whether the individual side-effects are acceptable. Progestin T reatment For decades, low-dosed progestins have been used successfully in clinically rou- tine – alone or in combination with low- dosed estrogens, even though the scien- tific data about specific mechanisms of action of progestins for endometriosis are still patchy. In contrast with their sta- tus in uterine endometrium, specific enzyme systems are blocked (e.g. 17 β- HSD Type 2) or activated (e.g. aroma- tase) in endometrial lesions, the proges- tin receptor concentrations are low and progestins reduce the synthesis of pro- gestin receptors so that long-term therapy further reduces the sensitivity of the im- plants to the therapeutic substance. This is described as a so-called progesterone block in ectopic foci (Fig. 10). Earlier animal experiments also suggest that there is no direct effect of progestins on the implant. In castrated animals with endometriosis, progestin alone did not lead to disease regression; there was a persistence of vital implants [59]. The choice of substance depends on sub- jective tolerance, while dosage is based on the biological effect on the endo- metrium (transformation dose). How- ever, since the continuous administra- tion of progestins leads to low estrogen levels, this frequently results in spotting or breakthrough bleeding, whereupon the dosage is often increased or estrogen is added. What is clear is that the endo- metriosis-related symptoms can be sup- pressed in up to 80% of the cases, but the recurrence rate after discontinuing the medication is high. Mechanism of Action of Progestins Physiologically, progestins oppose es- trogens. There is a large number of sub- stances which are eigher derivatives of progesterone (medroxyprogesterone acetate, dydrogesterone etc.) or or C-19- nortestosterone (norethisterone, lyn- estrenol, desogestrel etc.). They differ by their active profile and intensity of action on the metabolism of various or- gan systems. They all cause the secre- tory transformation of the estrogen-pre- treated endometrium, but their biologi- cal activity varies so that adequate trans- formation requires different amounts of active substance (Fig. 18). In addition to the progestinic effects, all synthetic progestins also have other ef- fects which can be explained by their structural similarity with other steroids; for example, progesterone derivatives have estrogenic effects and nortestoster- Figure 18. Biological activity of various progestins based on the transformation dose and the dosages used to treat endometriosis. Figure 19. Possible mechanisms of action of progestins for endometriosis. 114 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) Endometriosis one derivatives have androgenic effects. Progestins reduce the frequency and in- crease the amplitude of the GnRH pulse, thereby suppressing the release of gona- dotropin, which leads to an anovulatory situation with low peripheral estrogen and progestin levels. Their mechanism of action for endometriosis is complex. Apart from the negative feedback effect on the centrally controlled estrogen pro- duction of the ovaries, progestins are also assumed to lead to the suppression of the concomitant local intraperitoneal inflammation (Fig. 19) and of the result- ing pain. They reduce the increased number and activity of macrophages in the pouch of Douglas fluid [60]. Under the influence of estrogen, the in- crease of TNF-alpha in the pouch of Douglas fluid stimulates the nuclear fac- tor Kappa-β and increases various inter- leukins as inflammation mediators [61]. Progestins also interfere suppressively with this metabolic pathway. In addition, direct changes are assumed to occur in the endometrial implant similar to those leading to the secretory transformation and decidualisation of the endometrium. Morphological [37] and in-vitro studies [42] suggest that this assumption is in- correct. This would explain clinical find- ings showing that there was still micro- scopic evidence of vital endometrial lesions after 6 months of treatment with 5 mg/day of lynestrenol in all cases at the time of surgical removal [62]. The histo- logical changes under progestin therapy and the precise mechanism of action is still not clear after years of experience with this therapy.

of T reatment for Endo- metriosis Low-dose oral progestins (5–20 mg/day) have been described as effective for symptoms of endometriosis. The re- ported subjective success rates vary be- tween 60 and 94%. Due to short follow- up periods, there are not many meaning- ful data about the rate of recurrence; however, in the long term, they are above 50% [63]. As nearly all progestins used for endo- metriosis treatment have been withdrawn from the market in Germany (e.g. lyn- estrenol, medrogestone, norethisterone acetate) and the use of estrogen-proges- tin combinations (oral contraceptives) is in line with the guidelines but off-label, the newly approved dienogest in a dos- age of 2 mg/d has become particularly important. Under this treatment, the sub- jective symptoms of endometriosis im- prove significantly even though break- through bleeding is frequent [64]. The estrogen receptor concentrations in the uterine endometrium only return to the level of the normal secretion phase after three months of dienogest treat- ment, and delayed maturation as well as the appearance of a late proliferation phase were seen histologically. Exami- nations of endometrial lesions showed a very disparate rate of regression under progestin therapy, confirming that the reaction may vary greatly, apparently depending on the varying receptor ex- pression in ectopic foci. Prospective ran- domised studies with dienogest 2 mg/d compared with leuprorelin [65] showed the same effectiveness in treating the symptoms and a clear superiority com- pared to placebo (Fig. 20) [66]. Preg- nancy rates after treatment with medro- xyprogesterone acetate, lynestrenol, norethisterone acetate or dienogest vary between 5 and 90% on account of differ- ent selection criteria in the study groups and therefore do not allow a scientifi- cally proven statement. Other routes of application have also been tested successfully. Depot medro- xyprogesterone acetate (100–200 mg) effectively suppresses subjective endo- metriosis symptoms, but the suppressive effect may last for months or even years, so it is only recommended for older pa- tients who do not wish to have children [67]. The intravaginal continuous progestin- estrogen application in a three-weekly rhythm or the continuous application of the progestin over two years as a subcu- taneous implant are also theoretically suitable for symptomatic therapy and have been used successfully in some cases [68]. However, there is a lack of systematic prospective studies, and the direct effect on the endometrial lesions is unknown. Furthermore, progestins can be locally applied by an intrauterine sys- tem releasing 20 µg levonorgestrel daily. The suppression of the endometrium, the reduction of apoptotic processes as well as antiinflammatory effects have been shown [69]. Endometriosis-related complaints in cases of adenomyosis or rectovaginal endometriosis such as dysmenorrhea or dyspareunia are reduced. Apart from high local progestin concentrations in utero, the low systemic concentrations of levonorgestrel also seem to play a role. This is the explanation given for the positive effects on peritoneal forms of endometriosis [70], and the ovulation in- hibition in 85% of the users – at least in the first few months after the introduc- tion of the system – is also evidence of systemic effects. An advantage is that the system remains in place for 5 years, although the effect on endometriotic complaints seems to subside after 12–18 Figure 20. Effectiveness of 2 mg dienogest vs. placebo for dysmenorrhea and abdominal pain using the visual ana- logue scale (mm, mean scores). Mod. from [66] with permission from Elsevier publishers. Endometriosis J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 115 months. The disadvantage is that spot- ting and breakthrough bleeding still occurs in the first 6 months before the system reaches its full effects. In terms of clinical practice, it should be noted that all these useful applications are off- label applications in Germany. GnRH Analogue T reatment GnRH analogues are agonists and anta- gonists of the natural LH-RH. They act directly on the pituitary-hypothalamic system. While the antagonists are used in oncology and reproductive medicine, GnRH agonists have become widespread in endometriosis treatment despite their initial stimulation effect. Regression and atrophy of the endometrial lesions with- out relevant metabolic side-effects is achieved by reversible medicinal ova- rian suppression caused by desensitising the pituitary (Fig. 21). There is no differ- ence between the substances used in terms of the subjective and objective success rates [71]. Because of improved compliance and reliable suppression, de- pot preparations are preferred in prac- tice. The side-effects are mainly hypo- estrogenic and comparable with meno- pausal complaints. The treatment period is limited to 6 months despite good toler- ability because the hypoestrogenic situa- tion causes a reversible bone deminerali- sation by 4–6% on average with big variations, similar to the lactation pe- riod. In order to reduce demineralisation without minimising the therapeutic ef- fect, a so-called “add back” therapy [72] with low-dosed estrogens or progestins has been introduced. If the add-back dosage is too high or in the case of cycli- cal application, the therapeutic effect of the GnRH agonists is obviously reduced or suspended. Compared with progestins, GnRH ana- logues are more effective in achieving a regression of the endometrial implants as confirmed by prospective randomised studies [73]. They are at least as effective in reducing the symptoms, as corrobo- rated by a comprehensive Cochrane analysis [74]. It is important to note that the much-used inexpensive combined oral contraceptives are inferior to GnRH in terms of their effectiveness [75]. The different commercially available GnRH agonists are similarly effective in terms of pain reduction and endometriosis re- gression, as confirmed by a review by Shaw et al. [76]. However, after 6 months of therapy, 50% of the patients still have residual scarry lesions containing vital endometrial glands and stroma [37, 77]. This explains why endometriosis which persists after this potent treatment can become symptomatic again, and a recur- rence is merely a question of time. Antiinflammatory T reatment In order to prevent the development of a chronic pain syndrome, pain therapy concepts should be integrated directly into the treatment plan. The synthesis of COX-2 in normal endometrium, endo- metriosis and adenomyosis has been de- scribed [78], and women with endo- metriosis overexpress this enzyme. This explains its high concentrations in endo- metrial lesions and pouch of Douglas fluid [79]. Apart from proliferative and inflammatory effects, specific prosta- glandins cause vasoconstriction, is- chemia, cell necrosis, spasms and tissue pain. Non-steroidal antiinflammatory drugs (Aspirin ®, Ibuprofen ®, V oltaren®) inhibit the activity of cyclooxygenase non-specifically, thus reducing the syn- thesis of prostaglandin. This explains their varying clinical success in cases of endometriosis-related abdominal pain [80]. The specific COX-2 inhibitors de- veloped some years ago block the intra- cellular COX-2 activity and have fewer gastrointestinal side-effects. So far, they have not been approved for endometrio- sis, and their use should first be investi- gated in studies as no data are available about possible teratogenic effects [81]. Since all drugs except Etoricoxib (Arcoxia ®) have been taken from the market due to cardiac side-effects, prac- titioners will have to make do with non- selective preparations for the time being. If no adequate pain relief can be achieved by these substances in combination with combined oral contraceptives or pro- gestins, additional retarded opioids of WHO stages I and II must be used. The drug-based pain therapy should be ac- companied by pain coping seminars. Physical therapy like baths, local ther- mal treatment and relaxation exercises are useful complements. These methods should aim to prevent pain from becom- ing the focal point in the patient’s life.    Practical Recommenda- tions Pain Patients Although the surgical removal of endo- metriosis is the primary treatment, de- pending on stage, location and type of the disease, the rate of recurrence within 5 years after endoscopic surgery ranges between 25 and 70%. Surgeon quality and the timing of the intervention within the menstrual cycle contribute to this problem [45]. The adjuvant use of GnRH agonists reduces the rate of recur- rence and prolongs the recurrence-free interval significantly [82]. A treatment period of only 3 months can be equally effective in terms of pain re- Figure 21. Mechanisms of action of GnRH agonists: By desensitising the pituitary, a pseudomenopausal situation is created. 116 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) Endometriosis duction, but the recurrence-free interval is significantly longer if the suppression phase lasts 6 months. The clinical benefit of an additional drug therapy can be significant especially in patients with pain due to active perito- neal endometriosis. Although the use of oral contraceptives in the treatment of endometriotic complaints is widespread, a prospective randomised study [83] has shown that their postoperative use is not as effective as the adminstration of GnRH agonists. On the other hand, oral contraceptives are less expensive and have a different side-effect spectrum. The additive use of these drugs should be considered after adjuvant treatment in order to further prolong the recurrence- free interval. Possibilities of Long-T erm T reatment Extensive and/or progressive cases as well as deeply infiltrating forms of endo- metriosis are often problematic. In these cases, even primary intervention is often technically difficult and confronts the surgeon with many problems. This is all the more true in cases of recurrence. Since substantial fibrosis and myohyper- plasia lead to tumorous changes, exten- sive resection is necessary but fraught with the problem of incomplete removal and the risk of intra- and postoperative complications. In order to achieve an improvement of the symptoms of this type of endometriosis, various forms of treatment such as oral contraceptives, progestins, GnRH analogues as depot drugs, physical therapy or homeopathy as well as the intrauterine release of pro- gestins can be attempted permanently or intermittently alongside surgical re- moval while taking the chronicity of the disease into account (Fig. 22). A particu- lar advantage of GnRH analogues is the possibility to reduce side-effects through add-back medication, which explains their increasing importance as a very ef- fective long-term treatment [85]. A pro- gressive reduction of the pain symptoms has been achieved by the long-term ad- ministration of dienogest over a period of 15 months [86]. Recurrence If the patient has recurrent complaints and/or a recurrence is diagnosed, she can be offered another surgical intervention or another course of drug treatment or a combination of both (Fig. 23). Since endometriosis is a chronic disease, a therapeutic approach must be discussed with the patient which is acceptable for her, has the least possible side-effects, is cost-efficient and, in particular, is what the patient herself asks for after having been appropriately informed. Although repeat operations cannot always be avoided, it is absolutely paramount to choose a medicinal treatment concept after such an operation. The spectrum of possible drug therapies has been listed above. Progestins as permanent medica- tion or continuous oral contraceptives are often used primarily as a symptom- atic treatment in view of the costs. If this is not sufficient, GnRH agonists are ef- fective even when used repeatedly in cases of recurrence. Combined with add- back medication, they also have few side-effects. Another option is the titration of the “therapeutic estrogen window” in which low-dosed GnRH analogues are used [87]. A still further possibility is to carry out intermittent 3-monthly treatment epi- sodes with a GnRH agonist and a low- dose continuous combined estrogen/ progestin add-back medication. This is an inexpensive and well-tolerated treat- Figure 23. General principle of therapy for recurrent endometriosis. An individual therapy plan must be discussed and defined with each patient. Figure 22. Results of various long-term treatments for recurrent endometriosis. Mod. from [84]. Endometriosis J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 117 ment form. Whether these long-term therapies can be discontinued after 2–3 years of freedom from symptoms and followed with a long-cycle oral contra- ceptive is still unclear. Recommendations for Cases of Infertility Caused by Endo- metriosis The management of infertile patients suffering from chronic recurrent endo- metriosis is discussed controversially. In severe cases with excessive endometrio- sis, organic damage and adhesions lead to mechanical infertility; in mild or mod- erate endometriosis, however, the dis- ease can be associated with functional infertility or it can be an irrelevant addi- tional finding. Drug-based therapies alone will not improve fertility. A few years ago, a Chochrane analysis clearly showed that the suppression of the ova- rian function by minimal or mild endo- metriosis does not influence the infertil- ity [88]. It should be borne in mind that this statement is based on studies with low case numbers. There is a lack of in- ternational multicenter studies which would produce sufficient case numbers and result in scientifically robust find- ings. Down-regulation with GnRH agonists prior to the stimulation phase in IVF pro- tocols prevents the premature LH peak, leads to more oocytes and improves pregnancy rates compared with therapy protocols in which no GnRH agonist was used [89]. The positive effect of GnRH agonists used up to 6 months before an IVF cycle irrespective of the stage of endometriosis (ultra-long protocol) needs to be discussed carefully on a case by case basis. Especially in older pa- tients, prolonged suppression cannot be a useful therapy option since the subse- quent stimulation can be compromised in view of the age-related low ovarian reserve [90]. The same is true for women who have been operated for ovarian endometriomas repeatedly or bilaterally. So far, there is no consensus in the litera- ture about how long the GnRH medica- tion should be carried out in the ultra- long protocol. In the case of low-grade peritoneal endo- metriosis – especially if macroscopic and microscopic aspects suggest that the implants are inactive – the endometriosis should not be a factor determining the infertility treatment. Once other infertil- ity factors have been excluded or treated successfully and the stimulation of the ovaries does not lead to pregnancy after 6–12 cycles, the endometriosis can be accepted as the cause of infertility and should be treated as such. In this situa- tion, the endoscopic excision or vapori- sation of all lesions is recommended since this has resulted in improved preg- nancy rates in at least one prospective randomised study [48]. In advanced stages, endoscopic surgery must be performed to resect the implants and cysts, and the reproductive organs must be repaired microsurgically as far as possible. If extensive adhesiolysis is necessary, if the surgical intervention is incomplete and insufficient or if a repeat operation is required, assisted reproduc- tion offers the best chance of achieving pregnancy if GnRH agonists are used in the ultra-long protocol. Treatment with GnRH analogues alone after surgical in- tervention for endometriosis does not improve the chances of achieving preg- nancy.    Conclusion/Relevancy to Pr actice This review of the surgical and medici- nal therapies suggests recommendations based on scientific literature and Ger- man as well as European (ESHRE) guidelines. On the one hand, surgical ex- cellence is required in order to ad- equately perform the often difficult in- terventions for endometriosis endo- scopically but also to recognise the lim- its of surgery. Even well-trained and ex- perienced surgeons are sometimes only partially successful, and recurrence may require adequate medication, possibly over prolonged periods. For this reason, precise knowledge of the different mechanisms of action and side-effects of the available drugs is required in order to use them in a targeted way, sometimes in combination. While non-steroidal anti- inflammatory drugs, oral contraceptives and many progestins have proven worth- while empirically in the treatment of pain, GnRH agonists with add-back medication are currently the standard treatment to effect regression of active endometriosis. New progestins in an ap- propriate dosage are an equivalent, inex- pensive option with a different side-ef- fect spectrum. The patient must always be comprehen- sively informed and involved in the deci- sion-making process about the most suitable therapy. Merely applying the guidelines in a standardised way would not be a responsible medical approach. As the network of certified endometrio- sis centres is growing in Germany, Aus- tria and Switzerland [91], doctors should not be afraid to consult their experienced colleagues in particularly difficult cases or refer patients to specialised centres in order to develop a customised and effec- tive treatment strategy.    Conflicts of Interest In the last three years, the corresponding author has worked as a speaker for the companies BayerHealthCare, Solvay and Takeda Thomas Rabe: has held talks for Jenapharm receiving payment and travel expenses. Mona Langhardt: no conflict of interest Jörg Woziwodzki: no conflict of interest Ludwig Kiesel: has held talks for BayerHealthCare receiving payment and travel expenses. Felice Petraglia: no conflict of interest.

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