“We have argued against this attribution as, in our view, there are three conditions that must be met before credit can be given for having identified the two pathologies: (i) to have found the presence of epithelial structures outside the uterine cavity; (ii) to have identified these as endometrial glands and stroma; and (iii) to have clearly understood that this invasion was ‘benign’ (and therefore, ‘non neoplastic’) in nature. Using these criteria, there is no doubt that it was the surgeon Thomas Cullen who described for the first time the full morphological and clinical picture of endometriosis and adenomyosis.”

“In 1920, he drew a scheme with the classic sites of adenomyotic lesions in the pelvis. He correctly mentioned that the condition, called in these days adenomyoma, involved the presence of ectopic endometrial-like tissue in the myometrial wall, rectovaginal septum, hilus of the ovary, uterine ligaments, rectal wall and umbilicus. Cullen considered uterine adenomyoma, ovarian endometriosis and deep endometriosis as one disease characterized by the presence of adeno-myomatous tissue outside the uterine cavity and today there is increasing evidence that he may have been right.”

“It was John A. Sampson who created the name endometriosis seven years after his fundamental paper on ovarian endometriomas.”

“His original observation came when he operated women at the time of menstruation and found that the peritoneal lesions were bleeding, similarly to what happens in eutopic endometrium, proving to him that the tissue outside the uterus was of endometrial origin. In 1927, Sampson postulated that presence of endometrial cells outside the uterus was due to tubal regurgitation and dissemination of menstrual shedding.”

“In 1932, Hill Jr. reported the presence of aberrant endometrium at microscopy in a series of 135 patients who were operated-upon for some pelvic pathology. Amongst these cases, 20 had adenomyomas of the uterus and 115 had peritoneal endometriosis. The majority of the patients were between 20 and 45 yr of age, with the youngest being 16 yr old and the oldest 61. Pelvic pain related to menstruation was the principal reason for seeking relief through surgery and this usually happened some ten-years after the onset of disease; in addition he mentioned that symptoms were progressive.”

“The first suggestion came from Geist and Salmon who, in 1941 advocated the use of androgens in gynaecological disorders.”

“In 1944, Miller wrote: ‘testosterone propionate can be used in diminishing the activity and decreasing the size of the lesions in endometriosis so that radical surgery can be performed with less danger.’ In spite of the positive results obtained, the undesirable side effects of hirsutism, acne, and deepening of the voice occurred sufficiently often to cause the clinician and the patient considerable concern. For this reason, androgen therapy never really took off.”

“The first to do so was Karnaky who, in 1945, reported apparently good results, achieving amenorrhoea with increasing daily doses of up 100 mg/day of diethylstilbestrol (DES). In his report he reached at an intriguing conclusion: ‘endometriosis is not stimulated to grow by large continuous doses of stilbestrol, but small doses of stilbestrol may stimulate it.’ In his series, five patients became pregnant after stilbestrol was discontinued.”

“In 1948 Novak and de Lima linked them again hypothesising a specific local hormonal reaction in ectopic endometrium. They wrote: ‘one cannot resist the feeling that there is some common denominator between endometrial hyperplasia and adenomyosis, and possibly also pelvic endometriosis.’ Their statement was based on the observation that, of a total of 134 women with adenomyosis, endometriosis was also present in 42 (31.3%).”

“New pelvic endoscopic techniques were introduced in gynaecology in the late 1940s. Culdoscopy was a new procedure for pelvic visualization in gynaecology and it was claimed that the procedure was invaluable in the investigation of pelvic tumours, small ovarian disease, endometriosis, ectopic pregnancy and especially helpful in the detailed study of primary and secondary sterility in females.”

“In 1953, Meigs recommended early and frequent childbearing as prophylaxis and even exhorted patients to subsidise their sons and daughters so that this approach may become financially feasible. He wrote: ‘It is the author’s belief that avoidance of endometriosis through early marriage and frequent childbearing is the most important method of prophylaxis.’ Obviously, Meigs was not referring to peritoneal endometriosis; rather he was attempting to solve the challenges of those days: painful rectovaginal adenomyomas and cystic ovarian endometriomas in young women for whom at that time hysterectomy and castration were the only surgical cure.”

“This concept bears striking similarity to the approach taken by Rock et al approximately the same time in their quest for a hormonal contraceptive.” (Reference 27: Garcia CR, Pincus G, Rock J. “Effects of certain 19-nor steroids on the human menstrual cycle.” Science. 1956;124:891–3.)

“In a detailed study of 29 ovary specimens with chocolate cysts, Hughesdon found that in 90 per cent of them the ovarian endometrioma was formed by a pseudocyst. The surface of the ovary is adherent, usually to the posterior side of the parametrium and part of the ovarian cortex is invaginated... Hughesdon concluded that ectopic endometrium does not simply erode its way into the ovary: the ovary is actively invaginated, thus, providing a pseudocyst mimicking a uterus.”

“The idea led Kistner to propose, in 1958, a more practical alternative: induce a state of ‘pseudopregnancy’ to reproduce the improvement noted in endometriosis during and after pregnancy. He postulated that the positive effect of pregnancy was due to decidualization that results in necrosis and elimination of superficial endometriotic implants... His first experimental treatments involved 12 patients to whom large doses of a number of oestrogenic compounds and two progestins were administered in a ‘graduate scale’ for periods of time up to 7 months to produce amenorrhoea, as well as a decidual reaction in the endometrium.” Elsewhere: “In 1958, commenting on the use of androgens Kistner noted that ‘androgenic substances... probably exert their effect through inhibition of gonadotropic substances.’” And: “In 1958 Kistner wrote: ‘the unpredictability of permanent relief in endometriosis following the use of oestrogenic substances alone’ and the fact that ‘oestrogen therapy also has the disadvantage of occasionally resulting in rather profuse break-through bleeding, endometrial hyperplasia and hypermenorrhea...’ make this treatment unwise.”

“Two researchers Kistner and Andrews share the credit for the advent of ‘pseudo-pregnancy’ as a treatment for endometriosis.” (Reference 41: Andrews MC, Andrews WC, Strauss AF. “Effects of progestin-induced pseudopregnancy on endometriosis: clinical and microscopic studies.” 1959.)

“The first oral contraceptive ever marketed, Enovid (norethinodrel plus mestranol) was administered to 23 women with endometriosis. Decidual transformation was consistently demonstrated in the eutopic endometrium and was present in the ectopic endometrium in all of the five instances in which it was obtained for study. Clinical improvement during therapy was observed in 14 of the 17 patients treated because of pain.”

“To improve the effectiveness of the pseudo-pregnancy regimen, long-acting steroid hormones were introduced in the 1960s. Patients developed amenorrhoea, which persisted throughout the period of hormone administration, and most of them experienced considerable to complete relief of their symptoms... pregnancy rates in women who complained of infertility in addition to endometriosis ranged from 10 to 53 per cent. It is unfortunate that, although extensively utilized, oestrogen-progestin combinations have not been properly tested. Indeed, a 2007 Cochrane systematic review... found only one study that met the inclusion criteria.”

“Starting in 1967, Semm, transformed what was called at the time ‘peritoneoscopy’ into modern laparoscopy by improving the optical system, removing the source of light from the abdominal cavity and creating an automatic control of gas insufflations into the abdomen.”

“The first being an antigonadotropic steroid, danazol. Its introduction in 1971 by Greenblatt et al brought back the clock, since this compound has definite androgenic properties and may produce symptoms not very different from those reported in the forties.”

“In the early 1970s leading gynaecologists in Europe and US concluded that laparoscopy is the preferred tool for diagnosis and surgery of endometriosis... especially when, in the early 1970s, endoscopic methods for haemostasis, ligature and suture during surgical pelviscopy were introduced.” Elsewhere: “Clearly, peritoneal endometriosis became the signature of endometriosis... and research became focused on how fragments of menstrual endometrium implant on peritoneal surfaces and invade the underlying tissues.”

“In 1975 Kistner noted that approximately 40 to 50 per cent of patients who are desirous of childbearing and who have had conservative surgical treatment will become pregnant. Such pregnancy usually occurs within the first 24 months, although in a few patients, the delay may be of 3 or even 4 years. Kistner observed that pregnancy rates were influenced by 5 factors: the extent of disease; the age; the history of additional prior surgery for endometriosis; the duration of infertility before surgery; and the length of post-surgical follow up.”

“A few years later, Buttram reported pregnancy rates of 73, 56 and 40 per cent respectively, for patients with mild, moderate and severe endometriosis. As surgery was most beneficial in the early post-operative period he recommended that, if medical suppressive therapy is to be used in conjunction with conservative surgery to enhance fertility, it should be instituted preoperatively rather than postoperatively.”

“Dmowski and collaborators were the first to advocate, in 1981, a role of the immune system in the pathogenesis of endometriosis. This Group demonstrated that rhesus monkeys with spontaneous endometriosis have an altered cellular immune response to autologous antigens... Haney et al in 1981 demonstrated that endometriosis is accompanied by a chronic intraperitoneal inflammatory process, as shown by the increased number of peritoneal macrophages in infertile women with endometriosis compared with normal women or women with other causes of infertility.”

“A first major finding was an increased activation of peritoneal macrophages in infertile women with mild endometriosis.” Elsewhere: “This was made possible thanks to the increasing use of laparoscopy for tubal sterilisation, or the exploration of infertility: peritoneal fluid could easily be collected for research purposes and carefully analysed. This resulted in an avalanche of publications on the pathogenesis of endometriosis.”

“Halme et al demonstrated that retrograde menstruation through the fallopian tubes into the peritoneal cavity is a very common physiologic event in most menstruating women with patent tubes and, therefore, additional factors must be implicated in the genesis of endometriosis.”

“The clinical importance of even very small lesions was suggested when, in a prospective study of artificial insemination in women with minimal endometriosis, Jansen found reduced fecundability. Awareness of the existence of subtle peritoneal endometriosis produced an increase in the diagnosis of endometriosis, although clinical significance of early lesions remained controversial.”

“Nezhat et al introduced carbon dioxide laser for the removal of endometriotic implants, excision of endometrioma capsules, and lysis of adnexal adhesions. In a series of 102 patients, they reported a pregnancy rate of 60 per cent within 24 months after laser surgery without additional hormonal therapy. Laparoscopic vaporisation with carbon dioxide laser became a popular treatment modality for endometriosis-associated infertility, yet little data existed regarding the effectiveness of such an approach.”

“Fedele and co-workers were the first to compare the clinical effects of gestrinone and danazol, observing a significant decrease of pain-related symptoms (dysmenorrhoea, pelvic pain, deep dyspareunia) in both groups, without any significant difference. The same year Venturini and co-workers showed that gestrinone significantly reduces serum concentrations of total testosterone and sex hormone binding globulin (SHBG), whereas free testosterone is slightly, but significantly, increased.”

“In 1994 Adamson and Pasta carried out a meta-analysis and concluded that either no treatment or surgery is superior to medical treatment for minimal and mild endometriosis associated with infertility; in addition, in moderate and severe disease, surgery seems to yield comparable results with both operative laparoscopy or laparotomy... One such study was published in 1994 by Sutton et al who concluded that laser laparoscopy was a safe, simple and effective treatment in alleviating pain in women with stage I, II and III endometriosis.”

“In 1997, Marcoux et al published a second randomised, controlled trial and concluded that laparoscopic surgery enhanced fecundity in infertile women with minimal and mild endometriosis.” Elsewhere: “In a review published in 1997, Ryan and Taylor concluded that three general concepts steered during the late 20th century research in endometriosis. First, there is evidence of a local peritoneal inflammatory process... Second, there is a role for angiogenic factors in the establishment of ectopic implants. Third, there is evidence for biochemical differences of eutopic and ectopic endometrium in endometriosis patients.”

“In the late 1990s rectal endoscopic ultrasonography was proposed to diagnose the presence of deep bowel infiltration and select patients for surgery.” Elsewhere: “A strong correlation between pelvic pain and the depth of invasion was described in the presence of implants more than 10 mm deep.”

“A recent prospective, randomised, controlled clinical trial compared the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena) with a depot formulation of a GnRHa in the control of endometriosis-related chronic pelvic pain (CPP) in patients with severe endometriosis. Both treatment modalities showed comparable effectiveness... Among the additional advantages of the LNG-IUS is the fact that it does not provoke hypoestrogenism and requires only one medical intervention (for its introduction) every 5 years. This device could, therefore, become the treatment of choice for CPP-associated endometriosis in women who do not wish to conceive.”

“A 2007 Cochrane systematic review aimed at assessing the effects on pain-related symptoms of oral contraceptives when compared to other treatments, found only one study that met the inclusion criteria.” Elsewhere: “Because the Cochrane review concluded that there remains a paucity of information regarding the long-term benefits of COCs in the treatment of endometriosis, prospective randomised studies using a pseudo-pregnancy scheme should be performed in adolescents with the presumptive clinical diagnosis of early endometriosis.”

“Leyendecker et al proposed a new unified concept... found circumstantial evidence suggesting that endometriosis and adenomyosis are caused by trauma. In other words, chronic uterine peristaltic activity or phases of hyper-peristalsis induce, at the endometrial-myometrial interface, micro traumas with the activation of the mechanism of ‘tissue injury and repair’, followed by the local production of oestrogen; in due course, this results in permanent hyper-peristalsis and a self-perpetuation of the disease process.” Elsewhere: “It is tempting to speculate that endometriosis is primarily a disease of exaggerated endometrial preconditioning, which not only confers protection against hyper-inflammation and oxidative stress associated with pregnancy, but also endows endometrial cells with the mechanisms to survive in unfavourable ectopic locations.”

“Today we are proposing a new theory, namely that adenomyosis and endometriosis are phenotypes of the same disorder: the ‘Endometrium and Inner Myometrium Dysfunction Syndrome’ (EIMDS)... the dysfunction results in a spectrum of pregnancy disorders involving infertility, miscarriage and major pregnancy complications such as preterm rupture of the membranes, preterm birth, small for gestation age and pre-eclampsia.” Elsewhere: “Rather than surgery, a ‘symptom-oriented’ treatment based on 6-month pseudopregnancy regimen, can be a first line recommendation... In the absence of severe endometriosis a ‘problem-orientated’ rather than ‘lesion-orientated’ treatment may be indicated.”