Symptomatic endometriosis developing several years after menopause in the absence of increased circulating estrogen concentrations: a systematic review and seven case reports

The aim of the study was to find women with progressively increasing symptoms caused by endometriosis after menopause and in the absence of estrogen intake or increased estrogen production. PubMed (comprising MEDLINE and Cochrane) and Scopus were searched according to the PRISMA checklist for publications in English between 1995 and February 2018 with “endometriosis” AND (“postmenopause” OR “menopause” OR “menopausal” OR “postmenopausal”) in the title and for “endometriosis” AND “postmenopause” AND NOT “cancer” in the title, keywords, or abstract respectively. The 102 and 241 articles found, respectively, were manually screened for the absence of increased systemic endogenous estrogen production or estrogen intake in women with progressively increasing symptoms after menopause likely caused by endometriosis. The 29 reports found were searched for the age when the diagnosis was made and for the number of years since surgical or spontaneous menopause. When the exact age of menopause was not available, we used 50 years (10 case reports, Table 1, indicated as *50*) to calculate years since menopause. A variation of a few years or omitting these reports did not change the conclusions. Years since menopause was considered important since intermittently increased ovarian estrogen secretion can occur during the first years after menopause. In addition, the following items were recorded: previous surgery especially endometriosis surgery, drug intake, the presenting symptoms, the indication to start the investigation, pre-operative biochemistry and imaging, findings during surgery, and the final diagnosis by pathology. The systematic review was submitted to PROSPERO but not accepted since only a limited number of case reports were found. Our case reports were scrutinized in addition for the clinical exam with special attention to the presence or absence of vaginal atrophy, defined as an atrophic vaginal appearance with para-basal cells on a wet smear.

The quality of evidence described in these case reports [17] is high since the descriptions have comprehensive details written by clinicians noting the uncommon finding during surgery in postmenopausal women of severe endometriosis in the absence of increased circulating estrogen concentrations. However, the reports obviously carry a publication bias, since only women with symptoms sufficiently severe to perform surgery and in whom severe endometriosis was found were published. This review does not draw conclusions on the prevalence of symptomatic endometriosis after menopause, which is likely much higher. We know that unexpected endometriosis is frequent in women undergoing surgery after menopause [1].

We asked our colleagues (see the “Acknowledgments” section) with a known interest and a large experience of severe endometriosis surgery to retrieve all women in whom they had performed surgery for postmenopausal endometriosis without increased estrogen production or estrogen intake. This resulted in five additional cases and in a few cases of whom the records could not be retrieved.

Endometriosis, defined as “endometrial-like glands and stroma outside the uterus,” can present as small microscopical lesions and macroscopically as subtle, typical, cystic, and deep lesions. Although the case reports of postmenopausal lesions described in this manuscript are limited to cystic ovarian endometriosis and larger nodules of deep endometriosis, the definitions used in this manuscript are as follows. Typical lesions are superficial (less than 5 mm) “powder burn” black dots in a fibrotic area. Subtle lesions are non-colored superficial lesions [18]. A discussion of the exact depth of subtle lesions, of their clinical significance [19], of the histological confirmation of biopsies [20], of Müllerianosis [21], and of the significance of larger areas with subtle lesions is beyond the scope of this article. Cystic endometrioses are the (larger) chocolate cysts of the ovary but not the smaller (3–6 mm) cysts under the peritoneum or close to the vagina in deep endometriosis. Deep endometriosis is defined as endometriosis deeper than 5 mm under the peritoneal surface [22]. A discussion of the limitations of depth to define deep endometriosis [12] is beyond the scope of this manuscript.

Only seven case reports could be collected, and ten surgeons did not remember having seen such cases.

We did not review postmenopausal women who underwent surgery and in whom endometriosis was found in the absence of hormone replacement therapy. In this group of women, endometriosis was found in 2 to 5% [23]. The reported studies had either been published in 1955 and 1960 before the introduction of HRT [1], or the absence of HRT treatment had been explicitly stated [24]. The article of Kempers [1] described that of the 41 women after menopause, 25 had cystic ovarian endometriosis, 7 diffuse pelvic endometriosis, 8 intestinal, and 1 vaginal endometriosis. The prevalence seems to decrease with age since 5, 11, 13, 7, 2, 2, and 1 women were 45–49, 50–54, 55–59, 60–64, 65–69, 70–74, and 75–80 years old respectively (Fig. 1). The number of years since menopause was not available. More recently, a review from Genua [25] confirmed that 69 out of 72 postmenopausal women who underwent surgery between 1998 and 2010 and in whom endometriosis was found had not taken hormone replacement therapy. The interval between menopause and surgery ranged from 1 to 32 years (median 6 years). Only 16.7% had a previous history of endometriosis, and the median BMI was 25.0 kg/m². The presenting symptoms were abnormal uterine bleeding in 26.4%, abdominal pain in 26.4%, rectal bleeding in 2.8%, urogynecological dysfunction in 2.8%, vaginal bleeding in 1.4%, and an asymptomatic pelvic cyst in 40.3%. The indications for surgery were ovarian cyst (43.0%), ovarian cancer (13.9%), endometrial cancer (13.9. %), atypical endometrial hyperplasia (6.9%), uterine myomas (6.9%), tubo-ovarian abscess (4.2%), sigmoid cancer (2.8%), uterine prolapse (2.8%), and cervical cancer, vaginal nodule, cholecystitis, and appendicitis (1.4%). The type of endometriosis found was cystic ovarian endometriosis in 79.2%, superficial endometriosis in 11.1%, and endometriosis of the right parametrium, vagina, appendix, uterosacral ligament, and rectum in 5.6%.

Our review found 29 women (Table 1) with progressively increasing symptoms after menopause in whom endometriosis was diagnosed in the absence of HRT intake or an increased endogenous estrogen production. The symptoms are variable and comprise increasing pain with urinary symptoms [26], an asymptomatic cystic ovarian endometrioma or a cystic ovarian endometrioma with pain [27‐31], a small bowel obstruction [32, 33], a rectovaginal deep endometriosis [29, 34], a sigmoid deep endometriosis [35], even a sigmoid obstruction more than 10 years after menopause [36], a deep endometriosis with progressive hydronefrosis [37], with renal failure [38] and with severe hypertension [39], urinary bleeding with an hydronephrosis and a polypoid intra-ureteral lesion [40], a vaginal endometriotic cyst [41], a lesion mimicking a bowel tumor [42], or an abdominal hemorrhage [43]. Some women were preoperatively suspected to have a cancer either an adenocarcinoma [44] or a disseminated ovarian cancer although during surgery only superficial endometriosis lesions together with bilaterally large endometriomas were found [45]. Even endometriosis suspicious of a gastric cancer [46] or of a pancreatic tumor in a 69-year-old woman [47], endometriosis with inferior vena cava involvement [48], and endometriosis in the abdominal wall were described. A nodular wall endometriosis developed in a woman without ovarian function treated with an aromatase inhibitor for breast cancer [49]. A new cystic endometrioma in the wall appeared spontaneously after the excision of two previous cysts. Plasma concentrations of 17b-estradiol were low (20–40 pg/ml); cyst fluid concentrations were 80 pg/ml returning to normal after GnRha treatment [50]. A series of reports describe progressive endometriosis in women taking tamoxifen [51‐54].

Figure 1 illustrates that a majority of women were over 60 years old and more than 10 years after menopause.

The treatment of symptomatic postmenopausal endometriosis seems to be surgical excision. If this cannot be performed, a treatment with aromatase inhibitors was suggested [55].