{"paper_id":"21ff406c-ac04-4d7f-8f20-d9f53ef3756d","body_text":"O R I G I N A L A R T I C L E Open Access\nSymptomatic endometriosis developing\nseveral years after menopause in the\nabsence of increased circulating estrogen\nconcentrations: a systematic review and\nseven case reports\nFernanda de Almeida Asencio 1, Helizabet Abdalla Ribeiro 1, Paulo Ayrosa Ribeiro 1, Mario Malzoni 2, Leila Adamyan 3,\nAnastasia Ussia 4,5, Victor Gomel 6, Dan C. Martin 7,8 and Philippe R. Koninckx 4,5,9,10,11*\nAbstract\nBackground: To review women with symptomatic and clinically progressive endometriosis after menopause in the\nabsence of estrogen intake or excessive systemic endogenous production.\nDesign: Seven case reports and a systematic review of the literature from 1995 till February 2018.\nResults: O n l y7c a s er e p o r t sf r o mt h ea u t h o r sa n d2 9c a s e sf r o mt h el i t e r a t u r ed e s c r i b e dw o m e nw i t he i t h e rc y s t i c\novarian or deep endometriosis. Severity, symptoms, and localization are highly variable. No case report describes\nsymptomatic superficial typical lesions. In 22 of 36 women (61%), symptoms started more than 10 years after menopause.\nConclusions:Symptomatic and clinically progressive endometriosis after menopause in the absence of increased\nsystemic estrogen concentrations or exogenous estrogen intake starts more than 10 years after menopause in the\nmajority of women. This observation suggests that a genetic and/or epigenetic incident caused estrogen-independent\nprogression, increased sensitivity to estrogens or increased local production of estrogens. This observation is important for\nunderstanding the pathophysiology of endometriosis, forthe management of postmenopausal endometriosis, and for\nindividualization of medical therapy of endometriosis since estrogen-independent endometriosis growth probably also\noccurs before menopause.\nKeywords: Endometriosis, Pathophysiology of endometriosis, Postmenopausal endometriosis, Genetics, Epigenetics\nIntroduction\nSymptomatic endometriosis starting several years after\nmenopause in women not taking hormone replacement\ntherapy (HRT) is a rare condition. Case reports only de-\nscribe women with increasing pain, ovarian masses, or\nintestinal symptoms suspicious of a cancer. This is con-\nsistent with Kempers ’ [1] observations in 1960 on post-\nmenopausal endometriosis. This was before estrogen\nassays, laparoscopy or ultrasound. Of all postmenopausal\nwomen operated for clinical symptoms between 1945\nand 1958 in the Mayo clinic, endometriosis was found in\n136 women, of whom 41 had symptoms compatible with\nendometriosis, 35 had an endometrioma, and 4 had pro-\ngressive severe pain and/or bowel symptoms. The article\nin addition reported that in a control group of 50 hyster-\nectomies, 8 atrophic endometriosis lesions were found.\nEndometriosis is considered a hormonally responsive\nendometrium-like tissue where estrogens stimulate growth\nand progestins stop growth and eventually cause deciduali-\nzation. It seems logical that after menopause endometriosis\nwill become less active [2–4] since endometriosis is defined\nas (normal) endometrium-like tissue outside the uterus\nresulting from implantation of cells or endometrial frag-\nments following retrograde menstruation [5]. However, the\n* Correspondence: pkoninckx@gmail.com\n4Gruppo Italo Belga, Villa del Rosario, Rome, Italy\n5Università Cattolica, Rome, Italy\nFull list of author information is available at the end of the article\nGynecological Surgery\n© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0\nInternational License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and\nreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to\nthe Creative Commons license, and indicate if changes were made.\nAlmeida Asencio et al. Gynecological Surgery            (2019) 16:3 \nhttps://doi.org/10.1186/s10397-019-1056-x\n\npathophysiology of endometriosis [6] is unclear and endo-\nmetriosis may result from dislocation of basal endomet-\nrium [7] and metaplasia of peritoneal mesothelial cells [ 8]\nor of peritoneal or endometrial stem cells [ 9]. That endo-\nmetriosis is phenotypically different from endometrium is\naccording to the implantation/metaplasia theory, consid-\nered to be the consequence of the environmental factors in\nthe peritoneal cavity, and of immunologic or of other pre-\ndisposing factors.\nThe concept that endometriosis is a normal endometrium\noutside the uterus is not consistent with all clinical observa-\ntions. The clinical, histologic, and immuno-cytochemical\ndifferences suggested that peritoneal, ovarian, and deep\nendometriosis are three different diseases [ 10]. The nor-\nmal endometrium theory is not compatible with the clonal\naspect of deep and cystic endometriosis [ 6]. Therefore, the\nendometriotic disease theory (EDT) [ 6, 11] and recently\nthe genetic–epigenetic theory [ 12] suggest that the endo-\nmetriotic cells are cells with a series of genetic or epigen-\netic transformations with epigenetic defined as “heritable\nchanges in gene function that do not involve changes in\nthe DNA sequence. ” These changes can occur in either\nmature adult or neonatal endometrium [ 13] following\nretrograde menstruation, or in stem/progenitor cells from\nthe endometrium [ 13] or from the peritoneal cavity or\neven in bone marrow cells [ 14–16]. The specific combin-\nation of genetic and epigenetic incidents will determine\nthe development into typical, cystic, or deep endometri-\nosis. Subtle lesions are considered a mixture of implanted\nnormal endometrium and of early endometriosis which\nafter additional genetic and/or epigenetic incidents can\ndevelop into more severe lesions.\nStimulated by the observation of two women with pro-\ngressively increasing symptoms of endometriosis after\nmenopause in the absence of increased estrogen secre-\ntion or intake, we decided to perform a systematic\nreview of symptomatic postmenopausal endometriosis in\nthe absence of increased systematic endogenous estro-\ngen production or estrogen intake. The aim was to es-\ntablish its prevalence and clinical presentation.\nMaterials and methods\nCase reports and systematic review\nThe aim of the study was to find women with progres-\nsively increasing symptoms caused by endometriosis\nafter menopause and in the absence of estrogen intake\nor increased estrogen production. PubMed (comprising\nMEDLINE and Cochrane) and Scopus were searched ac-\ncording to the PRISMA checklist for publications in\nEnglish between 1995 and February 2018 with “endo-\nmetriosis” AND ( “postmenopause” OR “menopause” OR\n“menopausal” OR “postmenopausal”) in the title and for\n“endometriosis” AND “postmenopause” AND NOT\n“cancer” in the title, keywords, or abstract respectively.\nThe 102 and 241 articles found, respectively, were\nmanually screened for the absence of increased systemic\nendogenous estrogen production or estrogen intake in\nwomen with progressively increasing symptoms after\nmenopause likely caused by endometriosis. The 29 re-\nports found were searched for the age when the diagno-\nsis was made and for the number of years since surgical\nor spontaneous menopause. When the exact age of\nmenopause was not available, we used 50 years (10 case\nreports, Table 1, indicated as *50*) to calculate years\nsince menopause. A variation of a few years or omitting\nthese reports did not change the conclusions. Years\nsince menopause was considered important since inter-\nmittently increased ovarian estrogen secretion can occur\nduring the first years after menopause. In addition, the\nfollowing items were recorded: previous surgery espe-\ncially endometriosis surgery, drug intake, the presenting\nsymptoms, the indication to start the investigation,\npre-operative biochemistry and imaging, findings during\nsurgery, and the final diagnosis by pathology. The sys-\ntematic review was submitted to PROSPERO but not ac-\ncepted since only a limited number of case reports were\nfound. Our case reports were scrutinized in addition for\nthe clinical exam with special attention to the presence\nor absence of vaginal atrophy, defined as an atrophic va-\nginal appearance with para-basal cells on a wet smear.\nThe quality of evidence described in these case reports\n[17] is high since the descriptions have comprehensive\ndetails written by clinicians noting the uncommon find-\ning during surgery in postmenopausal women of severe\nendometriosis in the absence of increased circulating es-\ntrogen concentrations. However, the reports obviously\ncarry a publication bias, since only women with symp-\ntoms sufficiently severe to perform surgery and in whom\nsevere endometriosis was found were published. This re-\nview does not draw conclusions on the prevalence of\nsymptomatic endometriosis after menopause, which is\nlikely much higher. We know that unexpected endomet-\nriosis is frequent in women undergoing surgery after\nmenopause [ 1].\nWe asked our colleagues (see the “Acknowledgments”\nsection) with a known interest and a large experience of\nsevere endometriosis surgery to retrieve all women in\nwhom they had performed surgery for postmenopausal\nendometriosis without increased estrogen production or\nestrogen intake. This resulted in five additional cases and\nin a few cases of whom the records could not be retrieved.\nTypes of endometriosis: definitions used\nEndometriosis, defined as “endometrial-like glands and\nstroma outside the uterus, ” can present as small micro-\nscopical lesions and macroscopically as subtle, typical,\ncystic, and deep lesions. Although the case reports of\npostmenopausal lesions described in this manuscript are\nAlmeida Asencio et al. Gynecological Surgery            (2019) 16:3 Page 2 of 11\n\nTable 1 Women with progressive endometriosis after menopause in the absence of estrogens\nPatient Age Menopause BMI,\nkg/m2\nPrevious surgery Medication Indication for diagnosis Final diagnosis Comorbidities\nAge Age Type Endo Type Months Pain type Pain increasing Finding E2, pg/ml CA125, U/mL CT MRI US Surgery\nCase report 1 72 54 Spt 65 4 0 0 3 1 1 –– – 3 3 Diverticulitis\nCase report 2 64 51 Surg 37 51 2 3 0 3 1 1 + 2 + 3 –– – 33 3 D i a b e t e s ,\nhypertension,\nobesity\nCase report 3 62 45 Spt 31 57 3 1 3 3 1 1 + 3 –– – 33 – Hypertension,\nobesity\nCase report 4 43 36 Spt 24 36 2 3 0 3 1 1 –– – 00 3 + 4\nCase report 5 37 32 Spt 27 32 4 3 1 6 3 1 1 –– – 33 – Adenomyosis\nCase report 6 52 48 Spt – 50 1 5 0 – 11 –– – – 22\nCase report 7 67 52 Spt 32 No 0 – 1+3 –– – 3 3 3 Diverticulitis\nMaeda [27] 65 *50* Spt – 34 1 0 1 6 –– 4< 1 0 – 66 – 3\nManero [28] 62 47 Spt – No 0 –– 1 – 0 –– 22\nMatsushima [29] 56 50 Spt 31 No 0 – 1 3 12.6 48 – 66 2\nRose e Silva 1 [ 30] 62 48 Spt –– 0 –– 1 – 8 –– 22\nRose e Silva 1 [ 30] 78 58 Spt – 58 1 0 0 –– 0 – 66 – 65\nRose e Silva 1 [ 30] 54 48 Spt –– 0 –– 1 – 30 –– 3 3 Hypertension\nMedina [31] 74 54 Spt 29 No 0 1 1 – 0 –– 63\nBellina [32] 54 47 Surg – 47 1 0 0 –– 52 5 –– – 62\nIzuishi [33] 54 52 Spt – No 0 –– 1 – Normal 6 –– 3\nPopoutchi [34] 74 52 Spt – 71 2 0 0 –– 3 –– 6 –– 3 Obesity\nTorres-Rincón [35] 49 *50* –– No –– 5 –– – – – –\nDeval [36] 69 *50* Spt 32 No 0 1 1 1 + 3 – 0 – 66 3\nBidarmaghz [37] 63 49 Spt – No 0 5 –– 6 –– 3\nGudla [38] 63 48 Surg – 48 2 0 0 – 15 – 19 6 –– 3\nBailey [39] 53 45 Surg 37 45 2 3 0 –– 01 6 – 66 – 3 Hypertension,\nobesity\nKhong [40] 62 50 Surg – 50 2 2 + 5 0 –– 4 –– – – 3 3 Hypertension\nZhuang [41] 62 *50* Spt – No 0 4 –– 6 –– 3\nRabinerson [42] 58 52 Spt – 43 4 0 0 3 – 15 –– 33\nJakhmola [43] 50 *48* Spt – No 0 2 1 1 –– 6 –– 4\nBhat [44] 50 *48* Surg – ?2 3 0 1 1 0 – 596 3 –– 3\nSuchonska [45] 84 50 Spt – No 0 4 – 6 – 6 3 Hypertension\nAgarwal Sharma [ 46] 69 *50* Spt – No 0 –– 5 – 120 6 – 62\nAlmeida Asencio et al. Gynecological Surgery            (2019) 16:3 Page 3 of 11\n\nTable 1 Women with progressive endometriosis after menopause in the absence of estrogens (Continued)\nPatient Age Menopause BMI,\nkg/m2\nPrevious surgery Medication Indication for diagnosis Final diagnosis Comorbidities\nAge Age Type Endo Type Months Pain type Pain increasing Finding E2, pg/ml CA125, U/mL CT MRI US Surgery\nMohamed [47] 60 *50* Spt – No 0 1 1 5 – 06 –– 3\nPlodeck [48] 72 *50* Spt – ?1 0 0 2 1 5 – 06 –– 3 Hypertension\nFlyckt [49] 59 43 Surg 33 43 2 0 1 + 2 4 –– 11 9 – 6 –– –\nCameron [50] 66 50 Surg 50 2 0 2 9 0 –– 6 –– 5\nSasson [51] 61 45 Spt 38 59 4 4 2 3 – 15 3 9 7 5 – 55\nJaegle [52] 62 *50* Spt 41 No 3 43 4 – 38 6 – 6 4 Hypertension,\ndiabetes 2,\nobesity\nBese [53] 74 50 Spt 30 61 5 3 3 + 5 24 – 0 – 64 6 –– 3+6\nAge of menopause (if not mentioned or unknown because of a previous hysterectomy or tamoxifen *50* or *48* are used to calculate time since menopause). Type of menopause: spontaneous or surgical. Type of\nprevious surgery (0, no or not mentioned; 1, hysterectomy; 2, hysterectomy and bilateral adnexectomy; 3, bowel resection; 4, others; 5, subtotal hysterectomy and bilateral salpingo-oophorectomy). Endometriosis\nduring previous surgery (0, no; 1, superficial; 2, cystic ovarian; 3, deep; 4, abdominal wall; 5, adenomyosis). Medical therapy before surgery (0, no; 1, GnRha; 2, aromatase inhibitors; 3, tamoxifen). Indication for\ninvestigation: severe pain (1 –2–3), increasing pain (1), or cyst (2), finding during clinical exam (0, accidental finding; 1, chronic pain; 2, dyspareunia; 3, bowel symptoms; 4, urinary symptoms; 5, abdominal pain). Final\ndiagnosis (1, typical endo; 2, cystic ovarian endo; 3, deep endo; 4, deep cystic; 5, abdominal wall; 6, malignancy; 7, normal)\nAlmeida Asencio et al. Gynecological Surgery            (2019) 16:3 Page 4 of 11\n\nlimited to cystic ovarian endometriosis and larger nod-\nules of deep endometriosis, the definitions used in this\nmanuscript are as follows. Typical lesions are superficial\n(less than 5 mm) “powder burn ” black dots in a fibrotic\narea. Subtle lesions are non-colored superficial lesions\n[18]. A discussion of the exact depth of subtle lesions, of\ntheir clinical significance [ 19], of the histological con-\nfirmation of biopsies [ 20], of Müllerianosis [ 21], and of\nthe significance of larger areas with subtle lesions is be-\nyond the scope of this article. Cystic endometrioses are\nthe (larger) chocolate cysts of the ovary but not the\nsmaller (3 –6 mm) cysts under the peritoneum or close\nto the vagina in deep endometriosis. Deep endometriosis\nis defined as endometriosis deeper than 5 mm under the\nperitoneal surface [ 22]. A discussion of the limitations of\ndepth to define deep endometriosis [ 12] is beyond the\nscope of this manuscript.\nResults\nCase reports of postmenopausal endometriosis in women\nwithout estrogen intake or signs of endogenous estrogen\nproduction\nOnly seven case reports could be collected, and ten sur-\ngeons did not remember having seen such cases.\nCase 1 (FA)\nA 72-year-old woman with spontaneous menopause at\nage 54 was referred for increasing pelvic pain. She had\nher menarche at 11 years and did not have antecedents\nof dysmenorrhea, dyspareunia, dysuria, dyschezia, endo-\nmetriosis, nor infertility. Her medical, surgical, and\ngynecological history was uneventful except a diverticu-\nlitis and a volvulus 6 years before. She had never taken\nhormone replacement therapy (HRT), and the vaginal\nepithelium was atrophic. The gynecological exam and a\ntransvaginal ultrasound confirmed a normal uterus and\novaries. However, it also showed a 1-cm arciform thicken-\ning at the insertion of the right uterosacral ligament and a\n24-mm nodule at 11 cm from the anus, on the\nrecto-sigmoid, infiltrating the muscularis and affecting 15%\nof the circumference of the bowel. In the absence of other\nsigns of malignancy, a laparoscopy was performed with a\ntotal hysterectomy, bilateral salpingo-oophorectomy, a seg-\nmental resection of the bowel, and a resection of the\nretro-cervical and right pararectal nodule. The pathology\nrevealed active endometriotic glands and stroma in the\nretro-cervical and right pararectal nodules. The bowel le-\nsion had fibrosis secondary to diverticulitis. Recovery was\nuneventful, and she was discharged on day 5. After 4 weeks,\nshe returned to her normal activities and is pain free.\nCase 2 (FA)\nA 64-year-old woman with spontaneous menopause at\nage 50 was referred for increasing pelvic pain,\ndyspareunia, dyschezia, and repetitive constipation\nwhich had started some 5 years ago. She was a G3 P1 A2\nwith menarche at 11 years of age and a BMI of 37. At\nage 51, she had been operated for abdominal pain, nau-\nsea, and a large endometriotic mass close to the left kid-\nney with signs of renal failure. An abdominal total\nhysterectomy with bilateral salpingo-oophorectomy and\nleft nephrectomy had confirmed the diagnosis of endo-\nmetriosis. She never had taken HRT, and the vaginal epi-\nthelium was atrophic. Clinical exam revealed a large\npainful nodule. MRI showed two nodules: one large nod-\nule in the pouch of Douglas, invading the vaginal cuff\nand left parametrium and extending up to the hypogas-\ntric plexus and the left sacral nerves (S3 and S4); an-\nother nodule of 37 × 32 × 14 mm was seen in the rectum\nat 7.9 cm from the anal border, infiltrating the muscu-\nlaris and submucosa. Transvaginal ultrasound examin-\nation confirmed a 35 × 28 × 23 mm nodule in the\nvaginal cuff and a 41 × 10 × 19 mm nodule in the\nrecto-sigmoid, compromising 50% of the circumference, in-\nfiltrating the muscularis a nd submucosa at 9 cm from the\nanal border. A laparoscopic segmental bowel resection and\nresection of the deep endometriosis nodule invading the\npelvic floor, the sacral nerves, and the left sciatic nerve con-\nfirmed the diagnosis of endometriosis. Postoperative recov-\nery was uneventful, and she was discharged on day 5 and is\npain free for 5 months.\nCase 3 (FA)\nA 62-year-old woman with spontaneous menopause at\nage 45 was seen for increasing severe pelvic pain (10/10)\nand rectal pain with tenesmus. She was a P3G3 with me-\nnarche at age 13, a BMI of 31, and hypertension. She\nhad not taken HRT since menopause, and the vagina\nwas atrophic. Four years before, she had undergone a\nrecto-sigmoidectomy with resection of an endometriosis\nnodule from the right uterosacral ligament and rectovagi-\nnal septum. Not responding to treatment with GnRha after\nsurgery, she returned in 2017. At MRI, a retro-cervical\nnodule infiltrating the apical portion of the vagina and a\nnodule (17 × 06 mm) in the sigmoid were found. Ultrason-\nography confirmed the rectovaginal (15 × 4 mm) and the\nrecto-sigmoid nodule (17 × 7 × 3 mm), compromising 25%\nof the circumference and infiltrating the muscularis. She is\nplanned for surgery.\nCase 4 (AU)\nA 43-year-old woman with surgical menopause at age 36\nvisited for increasing severe pain symptoms for 2 years.\nShe was a P2G2 with menarche at 11 years and a BMI of\n24. She had undergone a hysterectomy at age 34 for pain\nand a bilateral adnexectomy at age 36 for pain and endo-\nmetriosis, after which she was pain free for 5 years. She\nhad not taken HRT postoperatively, and her vagina was\nAlmeida Asencio et al. Gynecological Surgery            (2019) 16:3 Page 5 of 11\n\natrophic. The gynecological examination, MRI, and\nultrasound were negative. A diagnostic laparoscopy re-\nvealed a large pelvic endometriosis plaque (5 × 4 cm)\nwith small cystic spots (3 –5 mm) in the pouch of\nDouglas and a deep endometriosis (1 × 1 cm) nodule\naround the right ureter, all of which were removed dur-\ning the procedure. Pathology confirmed the diagnosis of\nendometriosis. The postoperative recovery was unevent-\nful, and she is pain free for 1 year.\nCase 5 (AU)\nA 37-year-old woman with spontaneous menopause at\nage 32 visited for increasing pain symptoms for 1 year.\nShe was a P0G0 with a menarche at age 9 and a BMI of\n27. At 23 years of age, she had undergone an adnexect-\nomy for pain, and at age 27, we removed a rectovaginal\ndeep endometriosis nodule extending around the left ur-\neter (3 × 2 × 2 cm) and a cystic ovarian endometriosis\nfrom the remaining ovary. At age 32, a hysterectomy\nwithout ovariectomy was performed. Postoperatively, she\nbecame menopausal with increased FSH concentrations\nand a 17b-estradiol concentration of 80 pgr/ml, which is\ninsufficient for endometrial proliferation. Following hys-\nterectomy, she was pain free for 4 years, after which she\nhad progressively increasing pelvic pain on no hormonal\ntherapy. Her clinical examination, MRI, and ultrasound\ndemonstrated a 4 × 4 cm deep endometriosis nodule of\nthe cecum. In order to avoid a fourth surgical interven-\ntion, she was treated with GnRha without success. We\nplan to try an aromatase inhibitor.\nCase 6 (LA)\nA 52-year-old woman with spontaneous menopause at\nage 48 visited for increasing pain symptoms for 1 year.\nShe was a P3G8. At age 50, she had undergone a total\nlaparoscopic hysterectomy because of pain and an ade-\nnomyotic uterus. She had not taken HRT, and clinical\nexamination demonstrated vaginal atrophy. A large cys-\ntic ovarian endometriosis was diagnosed. The pathology\nof the excised cyst confirmed the endometriosis. The\npostoperative recovery was uneventful, and she now is\npain free for 4 months.\nCase 7 (MM)\nA 67-year-old woman with spontaneous menopause at\nage 52 was referred because of chronic pelvic pain, dys-\nchezia, dyspareunia intermittent diarrhea since several\nyears, and a suspicion of vaginal fornix endometriosis.\nShe was a P0G0 with menarche at 12 years, a BMI of 32,\nand a history of sigmoid diverticulosis. She had not been\ntaking HRT since menopause. The clinical examination\nrevealed a vaginally visible retro-cervical nodule extend-\ning to the left parametrium. By ultrasonography, this\nnodule (18 × 11 × 29 mm) was confirmed together with\nanother nodule (16 × 5 × 12 mm) at 8-cm distance from\nthe anal verge. In addition to adenomyosis, a thickened\nendometrial layer suggestive for a polypoid hyperplasia,\nnormal ovaries, and severe adnexal adhesions were\nfound. MRI confirmed the retro-para-cervical nodule.\nAfter confirmation of endometrial hyperplasia without\natypia on endometrial biopsy, a laparoscopic adhesioly-\nsis, total hysterectomy, bilateral salpingo-oophorectomy,\nureterolysis with resection of the retro-para-cervical and\nvaginal bowel nodule, and shaving of a small rectal nod-\nule were performed. Adenomyosis and deep infiltrating\nendometriosis were confirmed at histopathologic evalu-\nation. The postoperative recovery was uneventful, and\nshe was discharged on day 2. She is pain free for 2 years\nwithout signs of recurrence both clinically and at US.\nA systematic review of clinically progressive\npostmenopausal endometriosis without estrogen intake\nor increased production\nWe did not review postmenopausal women who under-\nwent surgery and in whom endometriosis was found in\nthe absence of hormone replacement therapy. In this\ngroup of women, endometriosis was found in 2 to 5%\n[23]. The reported studies had either been published in\n1955 and 1960 before the introduction of HRT [ 1], or the\nabsence of HRT treatment had been explicitly stated [ 24].\nThe article of Kempers [1] described that of the 41 women\nafter menopause, 25 had cystic ovarian endometriosis, 7\ndiffuse pelvic endometriosis, 8 intestinal, and 1 vaginal\nendometriosis. The prevalence seems to decrease with age\nsince 5, 11, 13, 7, 2, 2, and 1 women were 45 –49, 50 –54,\n55–59, 60–64, 65–69, 70–74, and 75–80 years old respect-\nively (Fig. 1). The number of years since menopause was\nnot available. More recently, a review from Genua [ 25]\nconfirmed that 69 out of 72 postmenopausal women who\nunderwent surgery between 1998 and 2010 and in whom\nendometriosis was found had not taken hormone replace-\nment therapy. The interval between menopause and sur-\ngery ranged from 1 to 32 years (median 6 years). Only\n16.7% had a previous history of endometriosis, and the\nmedian BMI was 25.0 kg/m 2. The presenting symptoms\nwere abnormal uterine bleeding in 26.4%, abdominal pain\nin 26.4%, rectal bleeding in 2.8%, urogynecological dys-\nfunction in 2.8%, vaginal bleeding in 1.4%, and an asymp-\ntomatic pelvic cyst in 40.3%. The indications for surgery\nwere ovarian cyst (43.0%), ovarian cancer (13.9%), endo-\nmetrial cancer (13.9. %), atypical endometrial hyperplasia\n(6.9%), uterine myomas (6.9%), tubo-ovarian abscess\n(4.2%), sigmoid cancer (2.8%), uterine prolapse (2.8%), and\ncervical cancer, vaginal nodule, cholecystitis, and appendi-\ncitis (1.4%). The type of endometriosis found was cystic\novarian endometriosis in 79.2%, superficial endometriosis\nin 11.1%, and endometriosis of the right parametrium, va-\ngina, appendix, uterosacral ligament, and rectum in 5.6%.\nAlmeida Asencio et al. Gynecological Surgery            (2019) 16:3 Page 6 of 11\n\nOur review found 29 women (Table 1) with progres-\nsively increasing symptoms after menopause in whom\nendometriosis was diagnosed in the absence of HRT in-\ntake or an increased endogenous estrogen production.\nThe symptoms are variable and comprise increasing pain\nwith urinary symptoms [ 26], an asymptomatic cystic\novarian endometrioma or a cystic ovarian endometrioma\nwith pain [ 27–31], a small bowel obstruction [ 32, 33], a\nrectovaginal deep endometriosis [ 29, 34], a sigmoid deep\nendometriosis [ 35], even a sigmoid obstruction more\nthan 10 years after menopause [ 36], a deep endometriosis\nwith progressive hydronefrosis [37], with renal failure [ 38]\nand with severe hypertension [ 39], urinary bleeding with\nan hydronephrosis and a polypoid intra-ureteral lesion\n[40], a vaginal endometriotic cyst [ 41], a lesion mimicking\nab o w e lt u m o r[42], or an abdominal hemorrhage [ 43].\nSome women were preoperatively suspected to have a can-\ncer either an adenocarcinoma [44] or a disseminated ovar-\nian cancer although during surgery only superficial\nendometriosis lesions together with bilaterally large endo-\nmetriomas were found [45]. Even endometriosis suspicious\nof a gastric cancer [ 46] or of a pancreatic tumor in a\n69-year-old woman [47], endometriosis with inferior vena\ncava involvement [48], and endometriosis in the abdominal\nwall were described. A nodular wall endometriosis devel-\noped in a woman without ovarian function treated with an\naromatase inhibitor for breast cancer [ 49]. A new cystic\nendometrioma in the wall appeared spontaneously after\nthe excision of two previous cysts. Plasma concentrations\nof 17b-estradiol were low (20–40 pg/ml); cyst fluid concen-\ntrations were 80 pg/ml returning to normal after GnRha\ntreatment [ 50]. A series of reports describe progressive\nendometriosis in women taking tamoxifen [51–54].\nFigure 1 illustrates that a majority of women were over\n60 years old and more than 10 years after menopause.\nThe treatment of symptomatic postmenopausal endo-\nmetriosis seems to be surgical excision. If this cannot be\nperformed, a treatment with aromatase inhibitors was\nsuggested [ 55].\nDiscussion\nThe article of Kempers [ 1] and the three reviews on\nendometriosis found in women undergoing surgery after\nmenopause [ 23–25] describe postmenopausal women\nwho did not take HRT. It is not surprising that the\nprevalence decreases with age (Fig. 1) since the age of\nmenopause is variable and since ovarian activity can be\nintermittently increased in the first years after meno-\npause. Unfortunately, the number of years since meno-\npause is not always available. In addition, it is difficult to\nknow whether the indication for surgery had been endo-\nmetriosis, whether pain was caused by endometriosis, or\nwhether endometriosis was a plausible explanation after\nsurgery. They remain, however, remarkable documents\nwith a detailed description of the clinical importance of\nendometriosis in women undergoing surgery after\nmenopause [ 1]. The importance of postmenopausal\nendometriosis is also emphasized in this review of con-\ntemporary articles. Endometriosis was considered to be\nthe cause of postmenopausal surgery in 13 women out\nof 516 surgeries by Scott and Te Linde [ 56] and in 37\nout of 1000 by Henriksen [ 57]. To interpret these data\ncollected more than 60 years ago, we should remember\nthat this was before the introduction of hormone re-\nplacement therapy, estrogen assays, or ultrasound and\nwith little knowledge of endocrinology such as\nFig. 1 Women with progressive and symptomatic endometriosis after menopause (this series) and women operated after menopause in whom\nendometriosis was found (Kempers). The frequency distribution of the years after menopause and/or the age of the women is indicated\nAlmeida Asencio et al. Gynecological Surgery            (2019) 16:3 Page 7 of 11\n\nperipheral conversion to estrogens and the intermittent\nand variable ovarian activity during the first years after\nmenopause. This explains Kempers ’ conclusion that\nthese women must have had estrogen production some-\nwhere. He also clearly demonstrates that most women\nwere young and (probably) early after menopause. Dif-\nferences in life expectancy cannot explain the differences\nbetween the data in the Kempers ’ article and in this art-\nicle since life expectancy after menopause was estimated\nto be 27 years in 1955 and 33 years today [ 58].\nOur series describe women with progressive symptoms\nafter menopause in whom endometriosis was diagnosed in\nthe absence of estrogen intake or increased endogenous\nproduction. This is a rare condition, limited to case reports.\nNotwithstanding all limitations imposed by a recall bias,\nthis also seems to be a rare condition when asking sur-\ngeons with a large experience in endometriosis surgery.\nThe biphasic frequency distribution of age and years after\nmenopause moreover suggests two different endometriosis\npopulations. The high incidence of endometriosis in\nwomen younger than 55 years old or early after menopause\nand decreasing thereafter is compatible with an estrogen-\nresponsive tissue. The second group after 60 years or more\nthan 10 years after menopause can only be explained by\ncirculating estrogen-independent progression of endomet-\nriosis or a change in estrogen sensitivity or local produc-\ntion of estrogens. In more than half of the women,\nsymptoms started more than 10 years after menopause.\nThat women clearly remember when symptoms started\nmoreover suggests that the progression of these endometri-\nosis lesions started abruptly at a specific point in time after\nmenopause. This observation in postmenopausal women\ncan be explained by the occurrence of a new genetic or epi-\ngenetic incident as postulated by the genetic –epigenetic\ntheory to be the pathophysiology of endometriosis [ 12].\nThat such an incident is more likely to occur in women\nwith a predisposition and with previous genetic–epigenetic\nincidents is supported by the observation that most of these\nwomen had been diagnosed with endometriosis before\nmenopause. This genetic–epigenetic instability also is fully\ncompatible with the rare occu rrences of malignant trans-\nformation of endometriosis after menopause [59].\nIt is surprising that all repor ts of clinically progressive\npostmenopausal endometriosis lesions were either cystic\novarian endometriosis or d eep endometriosis, without a\nsingle case report of clinically progressive superficial endo-\nmetriosis. This contrasts with the high prevalence of typical\nlesions in premenopausal women who undergo a diagnostic\nlaparoscopy for chronic pain. It is unclear, whether these\nwomen have less severe pain, and thus is not reported. The\nabsence of reports thus can be a publication bias. An alter-\nnative explanation could be that after menopause typical le-\nsions no longer cause pain. Only deep and cystic ovarian\nendometriosis seem to carry the risk that additional genetic\nor epigenetic incidents cause them to start proliferation in\nthe absence of increased circulating estrogens.\nOur series permits the conclusion that (some) cystic or\ndeep endometriosis lesions can progress notwithstanding\nthe low postmenopausal estrogen concentrations which\nare insufficient to stimulate the endometrium or to lubri-\ncate the vagina. Conversion of precursor steroids to estro-\ngens in peripheral tissue, especially fat, might have played\na role in some cases, as in the seventh case report with\nendometrial hyperplasia and obesity. In most cases, how-\never, peripheral conversion as a cause of endometriosis\nprogression is unlikely considering the absence of endo-\nmetrial stimulation and the onset of symptoms many\nyears after menopause in non-obese women. An alterna-\ntive explanation could be a local estrogen production\nwithin the endometriosis lesions. Aromatase activity with\nlocal estrogen production and/or progesterone resistance\nin endometriosis lesions of young women are well known,\nalthough not yet described in postmenopausal endometri-\nosis. The mechanism and pathways for this aromatase\nactivity and local estrogen production and lack of apop-\ntosis are moreover increasingly viewed as the result of\ngenetic and/or epigenetic incidents or genetic polymorph-\nism [2, 60–62]. The case report of the wall endometrioma\nin a postmenopausal woman [ 50] confirms aromatase\nactivity because of the increased, although still below\n100 pg/ml, estrogen concentration in the cyst fluid.\nThese endometriosis lesions with progressive symp-\ntoms and starting often more than 10 years after meno-\npause strongly suggest heterogeneity of cystic and deep\nendometriosis. Indeed, most cystic and deep endometri-\nosis lesions are stimulated by estrogens and growth will\nbe inhibited by progestins. This is moreover indirectly\nconfirmed by the many reports of endometriosis in post-\nmenopausal women taking hormone replacement therapy.\nHowever, some lesions grow in the absence of increased\nestrogen concentrations in plasma. The frequency of these\ncirculating estrogen-independent lesions before meno-\npause is unknown since they will only be diagnosed after\nmenopause. This heterogeneity in cystic and deep endo-\nmetriosis moreover is consistent with clinical observations\nduring surgery. Heterogeneity of endometriosis lesions is\nalso consistent with the variable response to medical\ntherapy. Whereas the response of the endometrium to es-\ntrogens and progestins is predictable, pain relief of endo-\nmetriosis by medical therapy is much more variable. The\noccasional progression of deep endometriosis [ 63]o rt h e\nsevere bleedings [ 64] during pregnancy also supports het-\nerogeneity of lesions.\nThese rare symptomatic and progressive cases of endo-\nmetriosis after menopause, starting more than 10 years\nafter menopause, and the heterogeneity of cystic and deep\nendometriosis lesions and the heterogeneity in aromatase\nactivity and progesterone resistance in endometriosis\nAlmeida Asencio et al. Gynecological Surgery            (2019) 16:3 Page 8 of 11\n\nlesions can be explained with the genetic–epigenetic theory\n[6, 12], postulating a cumulative series of genetic or epigen-\netic incidents in the pathophysiology of endometriosis. Pre-\ndisposition or susceptibility of endometriosis is considered\nto be caused by genetic and epigenetic incidents transmit-\nted at birth. The transmitted incidents are insufficient to\nexpress the disease, but a woman with more severe trans-\nmitted incidents is at higher risk to develop the disease\nwhen additional incidents occur later. The many differences\nin the endometrium of women with and without endomet-\nriosis can be considered as the expression of these incidents\ntransmitted at birth. The variable genetic and/or epigenetic\nincidents can explain that endometriosis is heterogeneous.\nIt also can explain that the growth of endometriosis can\noccur notwithstanding low circulating estrogen concentra-\ntions as evidenced by this series and by endometriosis in a\nman [65] not taking estrogens (the other six reported cases\nof endometriosis were in men who had been taking estro-\ngens for prostate cancer [ 66]). The onset of these progres-\nsive and symptomatic lesions more than 10 years after\nmenopause suggests that new or additional incidents did\noccur. This poly-genetic and p oly-epigenetic concept of\npathophysiology of endometriotic disease also is fully com-\npatible with recent histochemical profiling of endometriosis\n[67] and the induction of epigenetic changes in endometri-\nosis [68].\nAlready in 1960 [ 1], Kempers described a series of\nwomen with active adenomyosis after menopause.\nAlthough the relationship between adenomyosis and\nendometriosis remains unclear, a similar pathogenesis of\na combination of a series of genetic and/or epigenetic in-\ncidents can be postulated [ 69].\nIn conclusion, postmenopausal endometriosis progres-\nsing in the absence of estrogen intake or of a systemic\nincreased production is an argument for the genetic –\nepigenetic theory to explain the pathophysiology of\nendometriosis. These lesions thus should be considered\na benign tumor and no longer as normal endometrium\nor as “normal” metaplastic cells with an abnormal be-\nhavior because of the environment or of the immun-\nology. The direct clinical consequences of endometriosis\nprogressing after menopause in the absence of increased\nestrogen concentrations are the heterogeneity of endomet-\nriosis lesions with a variable reaction during pregnancy\nand a variable response to medical therapy. Since this cir-\nculating estrogen-independent growth probably also oc-\ncurs before menopause, women with medical therapy\nneed an individual follow-up and therapy should be recon-\nsidered when lesions grow. After menopause, it is import-\nant to recognize these lesions as different from a cancer.\nConclusions\nPostmenopausal endometriosis can start to progress\nmore than 10 years after menopause in the absence of\nestrogen intake or of a systemic increased production.\nThis suggests that an acute genetic or epigenetic inci-\ndent happened. The exact mechanism is not known, and\nit is unclear whether the growth of these lesions is estro-\ngen independent or the consequence or an altered estro-\ngen sensitivity or of an altered estrogen production\nwithin the lesion. It is unclear whether these are new le-\nsions or a change in existing lesions. This observation\ncan be explained by the genetic –epigenetic theory which\nconsiders the pathophysiology of endometriosis as a cu-\nmulative series of genetic or epigenetic incidents. That\nthe specific set of incidents is specific for each lesion can\nexplain the heterogeneity of endometriosis lesions. After\nmenopause, only incidents which stimulate growth in\nthe absence of increased circulating estrogens will be-\ncome clinically symptomatic. These lesions thus should\nbe considered a benign tumor and not as “normal”\nmetaplastic cells with an abnormal behavior because of\nthe environment or of the immunology.\nAcknowledgements\nWe thank Mauricio Abrao (Sao Paulo), Jacques Donnez (Belgium), Victor\nGomel (Canada), Jörg Keckstein (Austria), Ceana and Camran Nezhat (USA),\nAntonio Setubal (Lisbon), Charles Koh (USA), Harry Reich and Assia Stepanian\n(USA) Arnaud Wattiez (Dubai) and Errico Zupi (Italy). Unfortunately they\ncould not retrieve additional case reports.\nFunding\nNo funding\nAvailability of data and materials\nRecords of case reports are available with the authors as indicated\nAuthors’ contributions\nFAA, PK, and AU contributed to the conception and design of the study. FAA,\nPA, and PK contributed to the acquisition of the data. All authors contributed to\nthe drafting and revision and final approval of the manuscript.\nEthics approval and consent to participate\nNot applicable\nConsent for publication\nAll authors agreed for publication\nCompeting interests\nThe authors declare that they have no competing interests.\nPublisher’sN o t e\nSpringer Nature remains neutral with regard to jurisdictional claims in\npublished maps and institutional affiliations.\nAuthor details\n1Laparoscopy and Endometriosis Group Department, Santa Casa School of\nMedical Sciences of São Paulo, São Paulo, Brazil. 2Endoscopica Malzoni,\nCenter for Advanced Endoscopic Gynecologic Surgery, Via C. Errico 2, 83100\nAvellino, Italy. 3Department of Operative Gynecology, Federal State Budget\nInstitution V. I. Kulakov Research Center for Obstetrics, Gynecology, and\nPerinatology, Ministry of Health of the Russian Federation, Moscow, Russia;\nand e Department of Reproductive Medicine and Surgery, Moscow State\nUniversity of Medicine and Dentistry, Moscow, Russia. 4Gruppo Italo Belga,\nVilla del Rosario, Rome, Italy. 5Università Cattolica, Rome, Italy. 6Department\nof Obstetrics and Gynecology, University of British Columbia Women ’s\nHospital, Vancouver, BC, Canada. 7School of Medicine, University of\nTennessee Health Science Center, Memphis, TN, USA. 8Institutional Review\nBoard, Virginia Commonwealth University, Richmond, VA, USA. 9KU Leuven,\nAlmeida Asencio et al. Gynecological Surgery            (2019) 16:3 Page 9 of 11\n\nVuilenbos 2, 3360 Bierbeek, Belgium. 10University of Oxford, Oxford, UK.\n11Moscow State University, Moscow, Russia.\nReceived: 23 September 2018 Accepted: 10 January 2019\nReferences\n1. 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