Endometrial hyperplasia as a risk factor of endometrial cancer

Endometrial hyperplasia (EH) is the precursor lesion for endometrioid adenocarcinoma of the endometrium (EC), which represents the most common malignancy of the female reproductive tract in industrialized countries. The most important risk factor for the development of EH is chronic exposure to unopposed estrogen. Histopathologically, EH can be classified into EH without atypia (benign EH) and atypical EH/endometrial intraepithelial neoplasia (EIN). Clinical management ranges from surveillance or progestin therapy through to hysterectomy, depending on the risk of progression to or concomitant EC and the patient´s desire to preserve fertility. Multiple studies support the efficacy of progestins in treating both benign and atypical EH. This review summarizes the evidence base regarding risk factors and management of EH. Additionally, we performed a systematic literature search of the databases PubMed and Cochrane Controlled Trials register for studies analyzing the efficacy of progestin treatment in women with EH.

PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling

In previous studies, we reported that progesterone receptor membrane component 1 (PGRMC1) is implicated in progestin signaling and possibly associated with increased breast cancer risk upon combined hormone replacement therapy. To gain mechanistic insight, we searched for potential PGRMC1 interaction partners upon progestin treatment by co-immunoprecipitation and mass spectrometry. The interactions with the identified partners were further characterized with respect to PGRMC1 phosphorylation status and with emphasis on the crosstalk between PGRMC1 and estrogen receptor α (ERα). We report that PGRMC1 overexpression resulted in increased proliferation of hormone receptor positive breast cancer cell lines upon treatment with a subgroup of progestins including norethisterone and dydrogesterone that promote PGRMC1-phosphorylation on S181. The ERα modulators prohibitin-1 (PHB1) and prohibitin-2 (PHB2) interact with PGRMC1 in dependency on S181-phosphorylation upon treatment with the same progestins. Moreover, increased interaction between PGRMC1 and PHBs correlated with decreased binding of PHBs to ERα and subsequent ERα activation. Inhibition of either PGRMC1 or ERα abolished this effect. In summary, we provide strong evidence that activated PGRMC1 associates with PHBs, competitively removing them from ERα, which then can develop its transcriptional activities on target genes. This study emphasizes the role of PGRMC1 in a key breast cancer signaling pathway which may provide a new avenue to target hormone-dependent breast cancer.

Analysis of the causes of unsuccessful hormonal treatment of non-atypical endometrial hyperplasia in premenopousal women

Annotation. Non-atypical endometrial hyperplasia (NEH), despite of benign morphology, may be insensitive to the hormonal treatment and has a tendency to recurrence and progression to atypia in some cases. The study purpose was the investigation of different type of progestins treatment results and comparison of progesterone receptors (PGR) and Е-cadherin expression in the sensitive NEH(+) and resistant NEH(–) to progestin treatment type of NEH. Prospective study of three groups of women with histologically confirmed NEH, who took different progestins during 6 months was done: І group – 96 women, who took micronized progesterone orally 200 mg per day continually, ІІ group – 161 women, who took dydrogesterone 20 mg per day continually, ІІІ group – 54 women, who were inserted LNG-IUD 52 mg. Control histopathological investigations of the endometrial samplings at 3 and 6 months were done. Expression of PGR and Е-cadherin by immunohistochemistry were investigated in the start samples of endometrium for all 63 NEH(–) women, 48 NEH(+) women and 20 control samples of normal proliferative and secretory endometrium. In the result of the study only nonsignificant and unreliable differences between different progestins efficacy were found. It was 75% normal endometrium samples till 6 months for micronized progesterone, 81.4% for dydrogesterone and 83.3% for LNG-IUD. Data analysis of PGR expression in the NEH(–) endometrium has shown significantly less week expression as for glandular cells (50.82±0.73), as for stromal cells (47.34±0.82) in comparison to the NEH(+) endometrial samples (glandular – 183.7±3.1; stroma 166.4±2.3; р<0.05) and normal proliferative (193.2±8.5 і 178.7±6.3 respectively; р<0.05) and secretory (140.2±4,4 і 116.6±3,1 respectively; р<0.05) endometrium. Е-cadherin expression in the glandular endometrial cells NEH(–) mostly was negative (86.4%) and 13.6% cells only demonstrated its week expression. NEH(+) women cells predominantly showed a positive reaction. It was often enough week (49.2%) and moderate (34.4%), but only in the 16.4% samples were negative. Thus, the use of progestogens for the treatment of NEH in women with low expression of PGR and negative expression of E-cadherin in the endometrium is inappropriate. Investigations of PGR та Е-cadherin expression in the endometrium of women with NEH before starting treatment may provide an opportunity to predict negative result in advance and chose alternative therapeutical approach.