Endometrioid endometrial carcinoma, the most common form of endometrial cancer, usually develops out of a typical sequence of endometrial hyperplasias. The underlying cause of these hyperplasias is a relative predominance of estrogen combined with insufficient progesterone levels. Typical causes include corpus luteum insufficiency/anovulatory cycles (premenopause), polycystic ovary syndrome and obesity with metabolic syndrome (aromatase conversion of ovarian androgens in adipose tissue), inappropriate hormone therapy post menopause (insufficient dosage of gestagens) or an estrogen or androgen-producing tumor [1]. Even in patients with Lynch syndrome (formerly known as HNPCC), tumorigenesis of hereditary endometrioid carcinoma usually follows the usual progression with development of the respective hyperplasias [1]. Up to now, the correct clinical evaluation of endometrial hyperplasias was made more difficult by the different classification systems still in use: in Germany hyperplasias are sometimes still differentiated according to the classification “glandular-cystic hyperplasia” and “adenomatous hyperplasia grade I to III”. In 1994, the WHO classified endometrial hyperplasias into 4 categories: While categories 1, 2 and 4 were generally accepted, pathologists continued to debate the existence of group 3-type hyperplasias. Hyperplasias without atypia (categories 1 and 2) are considered benign pathologies which will regress with conservative treatment (oral gestagens, gestagen IUD, elimination of the cause of anovulation/corpus luteum insufficiency) [1]. A large percentage (up to 60 %) [3] of atypical endometrial hyperplasias (categories 3 and 4) are found to be coexistent with invasive endometrial carcinoma or develop into invasive endometrial carcinoma within the space of just a few years [1], [2], [4]. Hysterectomy (total hysterectomy, not supracervical hysterectomy!) is therefore the treatment of choice for atypical endometrial hyperplasia [4] or – in selected patients, i.e. younger patients wanting to have children – high-dose gestagen therapy with appropriate close histological monitoring [1], [4]. The WHO classification of 1994 and even more so the parallel use of the older classification system led to confusion among clinicians. The consequence of this was inadequate diagnosis, with hysterectomies performed for hyperplasias without atypia or gestagens administered in HRT dosages for atypical hyperplasia. Pathologists also experienced difficulties with categorization. This was made even more difficult by the development and parallel use of a further classification system: benign hyperplasia and endometrial intraepithelial neoplasia (EIN) [2]. In its latest classification [5] published in 2014, the WHO has clarified the matter: it now only differentiates between 2 categories of endometrial hyperplasia: This reduction to 2 categories was not only due to the need to do away with the confusing multitude of terms currently in use. Rather, it reflects a new understanding of molecular genetic changes. Hyperplasias without atypia exhibit no relevant genetic changes. They are benign changes and will regress again after the endocrine milieu (physiological gestagen levels) has normalized. In a few cases (1–3 %), progression to invasive disease may occur if the endocrine disorder (long-term estrogen dominance or relative or absolute gestagen deficiency) persists over the long term. Atypical endometrial hyperplasias exhibit many of the mutations typical for invasive endometrioid endometrial cancer [7]. In up to 60 % of cases, patients have coexisting invasive cancer or are at extremely high risk of developing invasive cancer ([Table 1]). The implications for treatment are obvious: hyperplasias without atypia should generally be treated conservatively (normalization of the cycle through weight loss, metformin; oral contraceptives; cyclical gestagens; gestagen IUD). Preventive hysterectomy should only be considered in exceptional cases (e.g., extreme obesity without any prospect of weight loss) [1], [4]. The surgery should be done as a total hysterectomy, i.e., it must include removal of the cervix [4]. Treatment of atypical hyperplasia/endometrioid intraepithelial neoplasia should generally consist of total (not supracervical) hysterectomy [1], [4]. Conservative treatment with high-dose gestagens and close histological monitoring should only be considered in exceptional cases (when the patient wants to have children, satisfactory compliance) [1], [4], [6].

There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.

Approximately 80% of human ovarian and endometrial cancers and 50% of breast cancers express GnRH and its receptor as part of an autocrine regulatory system. After binding of its ligand the tumor GnRH receptor couples to G-protein alphai and activates a variety of intracellular signaling mechanisms. (1) Through activation of a protein tyrosine phosphatase, autophosphorylation of growth factor receptors is reverted leading to an inhibition of mitogenic signaling and reduced cell proliferation. (2) Through activation of nuclear factor kappa B antiapoptotic mechanisms are induced protecting tumor cells from apoptosis induced, for example, by doxorubicin. (3) Through activation of the Jun kinase pathway AP-1 is induced, leading to cell cycle arrest in the G0/G1 phase. It seems reasonable to speculate that this system enables the tumor cell to reduce proliferation and to activate repair mechanisms while being protected simultaneously from apoptosis. Interestingly, GnRH antagonists show the same activity in this system as agonists, indicating that the dichotomy GnRH agonist-GnRH antagonist defined in the pituitary gonadotrope is not valid for the tumor GnRH system. Recently, a second type of GnRH receptor, specific for GnRH-II, has been identified in ovarian and endometrial cancers, which transmits significantly stronger antiproliferative effects than the GnRH-I receptor. GnRH antagonists have agonistic effects on this type II receptor. In animal models of human cancers, GnRH antagonists had stronger antitumor effects than GnRH agonists. Therefore, we performed a phase II clinical trial with the GnRH antagonist, cetrorelix (10 mg/day), in patients with ovarian or mullerian carcinoma refractory to platinum chemotherapy. Of 17 evaluable patients treated with cetrorelix, 3 obtained a partial remission (18%) which lasted for 2 to 6 months. Furthermore, 6 patients experienced disease stabilization (35%) for up to 1 year. In this very refractory patient population (median number of prior chemotherapies = 3) these results are quite remarkable when compared with palliative chemotherapy. In addition, cytotoxic GnRH analogs have been developed, where for example doxorubicin was covalently coupled to GnRH analogs. These compounds have superior antitumor effects in cancers expressing GnRH receptors as compared with native doxorubicin and allow for a targeted cytotoxic chemotherapy of gynecologic and breast cancers.

Tamoxifen is a selective estrogen receptor modulator used for the treatment and prevention of estrogen receptor (ER)—positive breast cancer. However, tamoxifen increases the risk of endometrial cancer (EC) by about 2–7 fold, and more aggressive types of EC with poor prognoses are observed in tamoxifen users. On the other hand, tamoxifen is an efficacious treatment for advanced or recurrent EC with low toxicity. The differential agonistic or antagonistic effects of tamoxifen on ERα are explained by the tissue-specific expression profiles of co-activators and co-repressors of the receptor. The estrogen-agonistic effect of tamoxifen in endometrial cancers can also be explained by the expression of G-protein coupled estrogen receptor 1 (GPER-1), a membrane-bound estrogen receptor for which tamoxifen and other “antiestrogens” are pure agonists.

The expression of GnRH (GnRH-I, LHRH) and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the ovary. The proliferation of human ovarian cancer cell lines is time- and dose-dependently reduced by GnRH and its superagonistic analogs. The classical GnRH receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH analogs in these cancer cells. The GnRH receptor rather interacts with the mitogenic signal transduction of growth-factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in downregulation of cancer cell proliferation. In addition GnRH activates nucleus factor kappaB (NFkappaB) and protects the cancer cells from apoptosis. Furthermore GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (JNK/AP-1) pathway independent of the known AP-1 activators, protein kinase (PKC) or mitogen activated protein kinase (MAPK/ERK). Recently it was shown that human ovarian cancer cells express a putative second GnRH receptor specific for GnRH type II (GnRH-II). The proliferation of these cells is dose- and time-dependently reduced by GnRH-II in a greater extent than by GnRH-I (GnRH, LHRH) superagonists. In previous studies we have demonstrated that in ovarian cancer cell lines except for the EFO-27 cell line GnRH-I antagonist Cetrorelix has comparable antiproliferative effects as GnRH-I agonists indicating that the dichotomy of GnRH-I agonists and antagonists might not apply to the GnRH-I system in cancer cells. After GnRH-I receptor knock down the antiproliferative effects of GnRH-I agonist Triptorelin were abrogated while the effects of GnRH-I antagonist Cetrorelix and GnRH-II were still existing. In addition, in the ovarian cancer cell line EFO-27 GnRH-I receptor but not putative GnRH-II receptor expression was found. These data suggest that in ovarian cancer cells the antiproliferative effects of GnRH-I antagonist Cetrorelix and GnRH-II are not mediated through the GnRH-I receptor.