Abstract Estrogen receptor beta (ERbeta, encoded by ESR2 gene) and cytochrome P450 aromatase (encoded by CYP19A1 gene) play critical roles in endometriosis, and the levels of insulin-like growth ...factor-I (IGF-I) in the peritoneal fluid are significantly higher in patients with endometriosis compared with those in normal women. However, the effects and mechanisms of IGF-I on ERbeta and aromatase expression remain to be fully elucidated. In this study, human endometriotic stromal cells (ESCs) and endometrial cells (EMs) derived from ovarian endometriomas and eutopic endometrial tissues. ESCs were cultured with IGF-I, signal pathway inhibitors, and siRNAs. ERbeta and aromatase expression were measured by real-time PCR and Western, respectively. The binding of c-Jun and CREB to the ESR2 and CYP19A1 promoters was assessed by chromatin immunoprecipitation assay. Animal experiments were performed in a xenograft mouse model. Levels of IGF-I mRNA in ESCs were markedly higher than those in EMs. IGF-I upregulated ERbeta and aromatase expression in ESCs after stimulation of the IGF1R/PI3K/AKT pathway. Following IGF-I treatment, a marked increase in c-Jun and CREB phosphorylation occurred, enhancing binding to the ESR2 and CYP19A1 promoters. An IGF1R inhibitor in vivo reduced IGF-I-induced endometriosis graft growth and ERbeta and aromatase expression. In conclusion, this is the first report to describe a mechanistic analysis of ERbeta and aromatase expression regulated by IGF-I in ESCs. Moreover, an IGF1R inhibitor impeded ectopic lesion growth in nude mice. These findings suggest that an inhibitor of IGF1R might have therapeutic potential as an antiendometriotic drug. Key messages Level of IGF-I mRNA in ESCs is markedly higher than that in EMs. IGF-I up-regulates ERbeta and aromatase expression via IGF1R/PI3K/AKT pathway. C-Jun and CREB are recruited to ESR2 or CYP19A1 promoter by IGF-I stimulation. IGF-1R inhibitors in vivo impede the growth of ectopic lesions in nude mice.
Background
The malignant transformation of endometriosis within the ovary is a recognised condition. There is less literature surrounding the malignant transformation of extra‐ovarian endometriosis ...(MEOE).
Aims
We report our experience with MEOE in ten patients and present a review of the literature regarding this rare malignancy.
Materials and Methods
For this retrospective case series, patients were identified from a practice‐based database. Where required, operative notes and pathology reports were reviewed.
Results
Ten patients diagnosed with MEOE between 1991 and 2014 were identified. In each case, the tumour was localised to the pelvis and centred on the pouch of Douglas, broad ligament, obturator fossa, parametrium and rectovaginal septum. Tumour histology was endometrioid adenocarcinoma (six), clear cell carcinoma (two), and adenosarcoma (two). Five patients had a history of endometriosis and four had received oestrogen‐only hormone replacement therapy after hysterectomy and bilateral salpingo‐oophorectomy. Treatments included surgery (one), surgery and radiotherapy (one), surgery and chemotherapy (one), surgery, radiotherapy and chemotherapy (three), and radiotherapy and chemotherapy (four). Maintenance hormonal therapy was also used in three patients. Curative doses of radiotherapy 45 Gy or more resulted in in‐field control in five patients. Six patients had no evidence of disease at a mean follow up period of 15 years (5.5–24 years). Severe G3 long‐term bladder morbidity occurred in three patients after radical surgery and radiotherapy.
Conclusion
MEOE is a rare condition for which treatment needs to be individualised. Multicentre studies and registries will hopefully define optimal treatment.