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Arch Gynecol Obstet (2012) 286:1571–1575 DOI 10.1007/s00404-012-2473-5

REPRODUCTIVE MEDICINE

REPRODUCTIVE MEDICINE

Endometriosis in menopause: a single institution experience

Matteo Morotti Valentino Remorgida Pier Luigi Venturini Simone Ferrero

Received: 14 May 2012 / Accepted: 11 July 2012 / Published online: 24 July 2012 Springer-Verlag 2012

Abstract Purpose This study aims to present the clinical charac- teristics of a series of postmenopausal women with endo- metriosis and to evaluate the preferential location, extension and histopathological features of the lesions. Methods We retrospectively examined the clinical records of 72 postmenopausal women with endometriosis who underwent surgery between January 1998 and December 2010. Results The median age of patients at the time of surgery was 58.5 years. Eleven patients (15.3 %) had previous history of endometriosis and five patients had previously undergone surgery for this reason. Only two patients included in the study were using hormone replacement therapy at the time of surgery. The most frequent location of endometriotic lesions was the ovary and among patients with endometriomas, 35 % (20/57) had different grades of metaplasia, hyperplasia, atypia and endometrioid carcinoma arising in endometriosis. The proportions of epithelium, stroma and hemorrhage in en- dometriotic lesions were higher in patients with concomitant endometrial or ovarian cancer. Conclusions Endometriosis should be considered in the differential diagnosis of postmenopausal cystic lesions of the ovary. The administration of exogenous estrogen is not a prerequisite for the presence of endometriosis in post- menopausal women, and histological signs of functionally active lesions were also observed in the absence of exog- enous hormone intake.

Keywords

replacement therapy Menopause

Diagnosis Endometriosis Hormone

M. Morotti ( &) V. Remorgida P. L. Venturini S. Ferrero Department of Obstetrics and Gynecology, San Martino Hospital and University of Genoa, Largo R. Benzi 1, 16132 Genoa, Italy e-mail: dottmatteomorotti@libero.it

Introduction

Endometriosis is a benign gynecological disorder charac- terized by the presence and growth of functional endome- trial-like tissues outside the uterine cavity. It primarily affects between 4 and 10 % of reproductive age women [1, 2]. Endometriosis is an estrogen-dependent condition [3] and, therefore, it usually causes pain symptoms during the fertile period of a woman’s life; in most cases symptoms improve after the menopause [4]. However, endometriosis also occurs in postmenopausal women [5]. In three his- torical studies the prevalence of postmenopausal endome- triosis in a cohort of patients with endometriosis was 2–5 % [6, 7]; however, in the past the prevalence of endometriosis was lower and diagnosis was not imple- mented by radiological instruments, so the exact preva- lence of this disease is not clear. It has been suggested that hormone replacement therapy (HRT) may reactivate residual endometriosis or even pro- duce new implants in climacteric women with history of endometriosis [8, 9]. However, endometriosis may also occur in postmenopausal women who do not receive HRT [10]. The objective of the current study is to evaluate the location, extent and morphology of endometriotic lesions in postmenopausal patients who underwent surgery at our institution.

Methods

This study included all postmenopausal women who underwent surgery at our institution between January 1998 and December 2010 and had histological diagnosis of endometriosis. Subjects of the study were identified using a computerized database including all the pathology reports

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performed at our institution during the study period. The

Statistical analysis

(10 patients, 13.9. %), atypical endometrial hyperplasia

local institutional review board approved the study.

(5

patients, 6.9 %), uterine myomas (5 patients, 6.9 %),

The medical records of the patients were reviewed to

tubo-ovarian abscess (3 patients, 4.2 %), sigmoid cancer

collect the following variables: age, age at menopause,

(2

patients, 2.8 %), uterine prolapse (2 patients, 2.8 %),

parity, body mass index (BMI), previous use of HRT, pre- vious history of endometriosis and preoperative diagnosis. All cases were reviewed by a pathologist that evaluated the proportion of disease consisting of epithelium (0, no epithelium; 1, B50 % epithelium; 2, [50 % epithelium), stroma (0, no stroma; 1, B50 % stroma; 2, [50 % stroma) and hemorrhage (0, no hemorrhage; 1, B25 % hemorrhage; 2,[25 % hemorrhage) as described in a previous study [11]. When more endometriosis localizations were seen in the same patient, only the lesion with a major grade of epithe- lium, stroma and hemorrhage was evaluated histologically.

cervical cancer, vaginal nodule, cholecystitis and appen- dicitis in one patient (1.4 %). The most frequent location of endometriotic lesions was the ovary (57/72, 79.2 %). This was followed by perito- neum (8/72, 11.1 %), right parametria (3/72, 4.2 %) and vagina, appendix, uterosacral ligament and rectum in one case (1/72, 1.4 %). All patients had a preoperative work-up. Only five asymptomatic uniloculated ovarian cysts (mean diameter 5 ± 1.58 cm) in patients with negative ovarian tumor markers were considered suspicious for endometriomas. When considering patients with abdominal pain as main presenting symptom (n = 19), the location of endometri-

The v 2 test was used to compare the proportion of disease consisting of epithelium, stroma and hemorrhage in patients with and without endometrial or ovarian cancer. P \ 0.05 was considered statistically significant.

osis was the ovary in 13 patients (68.4 %), the peritoneum in 4 patients (21.0 %), the uterosacral ligaments and appendix in 1 patient (5.2 %). In patients with abnormal uterine bleeding (n = 19), endometriosis was found in the ovaries in 12 patients (63.1 %), in the peritoneum in 4 patients (21.0 %), in the parametria in 2 patients (10.4 %) and in the vagina in 1

Results

patient (5.2 %). The location of endometriosis was ovary in the two patients with urogynecological symptoms. In the

Clinical findings

Seventy-two postmenopausal women with endometriosis were included in the study. The age of the patients ranged 46–79 years (median, 58.5 years). The median age at menopause was 50 years (range 42–56 years). The median interval between menopause and surgery was 6 years (range 1–32 years). Only 14 women (12/72, 16.7 %) had previous history of endometriosis. The median BMI was

patient with vaginal bleeding that underwent surgery for a cervical cancer, the location of endometriosis was the right parametria. In patients with rectal bleeding that had a sigmoid cancer, the locations of endometriosis were the rectum in one case and the ovary in the other case. The reasons for surgery in the 14 patients with previous history of endometriosis were ovarian cysts (n = 8, 57.1 %), ovarian cancer (n = 3, 21.4 %), atypical endo- metrial hyperplasia (n = 2, 14.2 %), tubo-ovarian abscess

25.0 kg/m 2 (range 18.0–34.3 kg/m 2 ), with 27 patients

(n

= 1, 7.1 %). In these women with previous history of

(19/72, 26.4 %) with BMI C 25 and 12 patients (11/72, 15.3 %) with BMI C 30. Only three patients included in the study were using hormone replacement therapy at the time of surgery (3/72, 4.2 %), while four patients had used HRT before surgery (4/72, 5.6 %). The mean interval between the interruption of HRT and surgery was 34.5 months (12–50 months). Two patients had previously used tamoxifen for breast cancer that was interrupted 2 and 3 years, respectively, before surgery. The most important presenting symptom was abnormal uterine bleeding in 19 patients (26.4 %), abdominal pain in 19 patients (26.4 %), rectal bleeding in 2 patients (2.8 %), urogynecological dysfunction in 2 patients (2.8 %), vaginal bleeding in 1 patient (1.4 %), while asymptomatic pelvic cysts were found in 29 patients (40.3 %). The indications for surgery were ovarian cyst (31 patients, 43.0 %), ovarian cancer (10 patients, 13.9 %), endometrial cancer

endometriosis, the main presenting symptom was abdominal pain in five patients (n = 4, 28.6 %) and abnormal uterine bleeding in two patients (n = 2, 14.2 %); ovarian cysts were diagnosed in seven asymptomatic patients during routine consultations (n = 7, 50.0 %). No differences in presenting symptoms were seen between those women who had a previous history of endometriosis and those with a primary diagnosis of postmenopausal endometriosis (P = 0.677). In the 23 patients with a cancer diagnosis, the finding of postmenopausal endometriosis was an incidental diagnosis during surgery. No patient included in the study received postoperative hormonal therapies for endometriosis. No patient had a recurrence of the disease with a mean follow-up 49.1 months (range 5–125 months). The follow- up data of the patients were available in 49 patients (49/72, 65.3 %).

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Multiple localizations of endometriosis were observed in five patients (6.9 %). One patient had two concomitant peritoneal nodules. Four patients with ovarian cysts had other endometriotic lesions: rectovaginal and sigmoid endometriosis in one patient, parametrial nodule in one patient and tubaric endometriosis in two patients. Out of 57 patients with ovarian endometriotic cysts, 15 had bilateral endometriotic ovarian cysts (26.3 %). Among patients with cystic ovarian endometriosis with or without concurrent ovarian cancer, six women (10.5 %) had more than one endometriotic ovarian cyst in the same ovary.

Pathological findings

The proportions of epithelium, stroma and hemorrhage in endometriotic lesions of postmenopausal women are shown in Table 1. The proportion of disease consisting of epithelium was significantly higher in patients with con-

comitant endometrial (1.10 ± 0.57) or ovarian cancer (1.20 ± 0.42) than in other study subjects (0.44 ± 0.69;

P \ 0.001). Similarly, the proportion of disease consisting

of stroma was significantly higher in patients with ovarian and endometrial cancer (1.6 ± 0.51 and 1.7 ± 0.48, respectively) than in other study subjects (1.28 ± 0.45,

P = 0.007). Grade 2 hemorrhage ([25 %) was observed in

50.0 % (5/10) of women with endometrial and in 40.0 %

(4/10) of women with ovarian cancer, while grade 2 hemorrhage was observed only in two women without endometrial or ovarian cancer (7/52, 13.5 %; P \ 0.001). Grade 2 stroma was observed in 7 and 6 patients with endometrial and ovarian cancer (70.0 and 60.0 %, respec- tively) and in 15 women without cancer (28.8 %,

P = 0.010).

Among patients with cystic ovarian endometriosis, 35.0 % (20/57) had different grade of metaplasia, hyper- plasia, atypia and endometrioid carcinoma arising in endometriosis (Table 2). When considering the 14 patients with previous history of endometriosis, the proportion of disease consisting of epithelium was grade 0 in 9 patients (64.3 %), and grade 1 in 5 patients (35.7 %). The proportion of stroma was grade 1 in 11 patients (78.6 %) and grade 2 in 3 patients

(21.4 %). The proportion of hemorrhage was grade 0 in six patients (42.8 %) grade 1 in seven patients (50.0 %) and grade 2 in one patient (7.1 %). No differences on the proportion of epithelium (P = 0.210), stroma (P = 0.235) and hemorrhage (P = 0.557) were seen between those women who had a previous history of endometriosis and those with a primary diagnosis of postmenopausal endometriosis.

Discussion

Postmenopausal endometriosis is a rare disease; in our study, we identified only 72 postmenopausal women with endometriosis among the patients operated at our institu- tion during 13 years. In most of the patients, endometriosis was incidentally found during surgery performed for other reasons. As observed in previous studies, postmenopausal endometriosis is primarily located in the ovaries [5, 12, 13]; however, various case reports and case series described pelvic or extrapelvic locations of endometriosis includ- ing gastrointestinal, urinary and retroperitoneal lesions

[1416].

Several pathogenetic mechanisms may explain the presence of endometriosis in menopausal women. The adipose tissue and skin are the most important sources of estrogen biosynthesis in menopause [17]. Several studies demonstrated the expression of aromatase P450 in both eutopic and ectopic endometrium of premenopausal patients with endometriosis [18]. Estrogen stimulates the production of cyclooxygenase type 2 enzyme, resulting in elevated levels of prostaglandin E 2 , which is a stimulator of aromatase activity hypothesizing a positive feedback loop in favour of continuous local production of estradiol in endometriotic tissue [19]. Although this hypothesis was recently contradicted by other authors [20], the endogenous production of estradiol may contribute to the pathogenesis of postmenopausal endometriosis. In the current study, high concurrent endometriosis was found during surgery for ovarian and endometrial cancer (15.3 and 12.5 %, respectively). Main scientific interest has been focused on the relationship between endometriosis and epithelial ovarian cancer. Data from large cohort and case–control studies suggest an association between the two diseases although most of the observed effect sizes are modest [21]. Zanetta et al. [22] in a case series of endometriotic women who developed cancer concluded that hyperestrogenism, either endogenous (e.g., obesity) or exogenous, was the only risk factor for the development of cancer in en- dometriotic lesions. These pathogenetic inputs are the same that could explain the maintenance of postmenopausal endometriosis. The current study showed a significantly higher prevalence of epithelium, stroma and grade 2 hemorrhage in lesions of patients with endometriosis and concomitant cancer than in those of the other subjects included in the study. This observation might be consistent with an increase in the activity of these lesions, presumably related to an estrogenic stimulation in these patients. The use of HRT could cause an increased, although undefined, risk of recurrence of endometriosis, especially

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Table 1 Proportions of epithelium, stroma and hemorrhage in endometriotic lesions of postmenopausal women (n = 72)

 

Total (%)

Endometrial cancer (%)

Ovarian cancer (%)

Others (%)

No epithelium present

36 (50.0)

1 (10.0)

0 (0.0)

35 (67.3)

B50 % epithelium

26 (36.1)

7 (70.0)

8 (80.0)

11 (21.1)

[50 % epithelium

10 (13.9)

2 (20.0)

2 (20.0)

6 (11.5)

No stroma present

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

B50 % stroma

44 (61.1)

3 (30.0)

4 (40.0)

37 (71.1)

[50 % stroma

28 (38.9)

7 (70.0)

6 (60.0)

15 (28.8)

No hemorrhage present

29 (40.3)

0

0

29 (55.8)

B25 % hemorrhage

31 (43.0)

5 (50.0)

6 (60.0)

20 (38.4)

[25 % hemorrhage

12 (16.7)

5 (50.0)

4 (40.0)

2 (3.8)

Table 2 Histologically findings in ovarian endometriotic lesions of postmenopausal women (n = 57)

Histological lesions

Number of patients (%)

No hyperplastic lesions

37 (64.9)

Metaplasia

3 (5.3)

Hyperplasia

7 (12.3)

Atypical hyperplasia

6 (10.5)

Endometrioid carcinoma

4 (7.0)

in patients with severe disease and in obese patients [23]. Indeed HRT is a frequent cause of endometriosis-associ- ated symptoms in the postmenopausal population [23]; however, in our series very few patients used HRT at the time of surgery (2/72, 2.8 %) or had used HRT before surgery (4/72, 5.6 %). The role of exogenous or endogenous estrogens in the pathogenesis of postmenopausal endometriosis is sup- ported by the immunohistochemical observation that, in menopause, there is a preservation of receptors for estro- gen, progesterone and CD10 indicating a potential for reactivation of the disease when appropriate stimulation is given to endometriotic lesions [11]. Other investigators suggested a potential role of deficient immune system in the pathogenesis of endometriosis, allowing ectopic endometrial cells to implant and to grow [24]. Postmenopausal women might have a relative immu- nosuppression status allowing the endometriotic lesions to establish or to progress [25]. A suggestive observation in our study was the coexistence in three cases of tubo-ovarian abscesses and ovarian endometriosis. Tubo-ovarian absces- ses are a rather unusual entity in postmenopausal women when compared to those observed in women of reproductive age and, in these patients, a concomitant pelvic pathology appears to be common [26, 27]. A locally impaired immu- nity in the pelvic cavity of women with endometriosis may decrease the host response to infections [28]. Furthermore, the wall of the endometrioma is weaker than the healthy

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ovarian epithelium and, theoretically, it might be susceptible to bacterial invasion [28]. In conclusion, endometriosis is usually diagnosed in postmenopausal women because of other clinical problems. These endometriotic lesions usually have low activity at histology, supposing that they result from the switching-off of past lesions. However, in a little proportion of patients, endometriotic lesions are histologically and/or clinically active, also in patients who never used HRT. Therefore, endometriosis should be considered in the differential diagnosis of ovarian cyst also in postmenopausal patients without previous use of HRT or previous diagnosis of the disease.

Conflict of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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