Search

Objectives. We performed a systematic literature review to analyze the clinical application and the safety of mifepristone, a prominent antiprogesterone agent, in meningioma patients.Materials and Methods. A systematic search was performed through Medline, Cochrane, and clinicaltrials.gov databases from 1960 to 2014.Study Selection. Studies were selected through a PICO approach. Population was meningioma patients, meningioma cells cultures, and animal models. Intervention was mifepristone administration. Control was placebo administration or any other drug tested. Outcomes were clinical and radiological responsiveness, safety profile, and cell growth inhibition.Results. A total of 7 preclinical and 6 clinical studies and one abstract were included. Encouraging results were found in preclinical studies. Concerning clinical studies, the response rate to mifepristone in terms of radiological regression and symptomatic improvement/stability in patients with inoperable meningioma was low. In meningiomatosis, favorable preliminary results were recorded. The safety profile was good. Limitations were as follows. The tumoral expression of progesterone receptors was not analyzed systematically in every study considered.Conclusions. No clear evidence exists to recommend mifepristone in inoperable meningiomas. Preliminary encouraging results were found in diffuse meningiomatosis. Mifepristone is a well-tolerated treatment. Patients’ selection and hormonal profile analysis in meningiomas are fundamental for a better understanding of its benefit. Multicenter placebo-controlled trials are required.

Endometriosis is a common cause of pelvic pain and affects up to 10% of women of reproductive age. Aberrant progesterone signaling in the endometrium plays a significant role in impaired decidualization and establishment of ectopic endometrial implants. Eutopic endometrial cells from women with endometriosis fail to downregulate genes needed for decidualization, such as those involved in cell cycle regulation, leading to unbridled proliferation. Several causes of progesterone resistance in the endometrium have been postulated, including congenital “preconditioning”, whereby the in utero environment renders infants susceptible to neonatal uterine bleeding and endometriosis. Progesterone action is crucial to decreasing inflammation in the endometrium, and deviant progesterone signaling results in a proinflammatory phenotype. Conversely, chronic inflammation can induce a progesterone-resistant state. Repetitive retrograde endometrial shedding begets chronic peritoneal inflammation, which further exacerbates progesterone resistance. Genetic causes of progesterone resistance include progesterone receptor gene polymorphisms, altered microRNA expression, and epigenetic modifications to progesterone receptors and their targets. Environmental toxins such as dioxin play a possible role in the genesis of endometriosis by permitting an inflammatory milieu. A consequence of impaired progesterone action is that hormonal therapy is rendered ineffective for a subset of women with endometriosis. Synthetic progestins, such as dienogest, may overcome this phenomenon by increasing progesterone receptor expression and decreasing proinflammatory cytokines. Other modalities include high dose depot formulations of progestins, medicated intrauterine devices and the likely advent of oral GnRH antagonists. Unearthing root causes of progesterone inaction in endometriosis will aid in the development of novel therapeutics geared toward prevention and treatment.

Norepinephrine (NE) neurons within the nucleus tractus solitarii (NTS; A2 neurons) and ventrolateral medulla (A1 neurons) represent gonadal steroid-dependent components of several neural networks regulating reproduction. Previous studies have shown that both A1 and A2 neurons express estrogen receptors (ERs). Using double labeling immunocytochemistry we report here that substantial numbers of NE neurons located within the NTS express progesterone receptor (PR) immunoreactivity, whereas few PRs are found in ventrolateral medulla. The evaluation of ERα and PR immunoreactivity in NE neurons through the estrous cycle revealed a fluctuating pattern of expression for both receptors within the NTS. The percentage of A2 neurons expressing PR immunoreactivity was low on metestrus and diestrus (3–7%), but increased significantly to approximately 24% on proestrous morning and remained at intermediate levels until estrus. The pattern of ERα immunoreactivity in A2 neurons was more variable, but a similar increment from 11% to 40% of NE neurons expressing ERα was found from diestrus to proestrus. Experiments in ovariectomized, estrogen-treated and estrogen-plus progesterone-treated rats revealed that PR immunoreactivity in A2 neurons was induced strongly by estrogen treatment, whereas progesterone had no significant effect. The numbers of ERα-positive NE neurons were not influenced by steroid treatment. These observations provide direct evidence for PRs in NE neurons of the brainstem and show that cyclical patterns of gonadal steroid receptor expression exist in A2, but not A1, neurons through the rat estrous cycle. The expression of PR in A2 neurons appears to be driven principally by circulating estrogen concentrations. The fluctuating levels of ERα and PR expression in these brainstem NE neurons may help generate cyclical patterns of biosynthetic and electrical activity within reproductive neural networks.

The aim of the present study was to evaluate the effect of anti-Müllerian hormone (AMH), with and without FSH, on the in vitro development of isolated caprine preantral follicles, as well as follicular steroid production and mRNA levels of AMH, hormone receptors (AMH and FSH), CYP19A1 (cytochrome P450, family 19, subfamily A, polypeptide 1), CYP17 (cytochrome P450, family 17, subfamily A, polypeptide 1), HSD3B (3-beta-hydroxysteroid dehydrogenase) and Myc (myelocytomatosis oncogene). Isolated secondary follicles were cultured in minimum essential medium alpha (α-MEM+) alone or supplemented with 50 ng mL–1 AMH and/or 100 ng mL–1 FSH added sequentially on different days of culture. Follicles were cultured for a total of 18 days, with different media during the first (Days 0–9) and second (Days 10–18) halves of the culture period, resulting in six treatment groups, as follows: α-MEM+/α-MEM+, FSH/FSH, AMH/AMH, AMH+FSH/AMH+FSH, AMH/FSH, and FSH/AMH. Follicle development was evaluated on the basis of follicular growth, oocyte maturation and steroid secretion. There was a decrease in follicular growth rate in the AMH, AMH + FSH and AMH/FSH treatment groups compared with α-MEM+ and FSH treatment groups (P 0.05). Moreover, follicles cultured in the presence of FSH had lower levels of AMH receptor type II (AMHRII) mRNA compared with non-cultured control (freshly isolated follicles), and the AMH and AMH/FSH treatment groups. In conclusion, AMH reduces the follicular growth rate of isolated goat preantral follicles in vitro without affecting follicular survival.

The mouse mammary gland develops postnatally under the control of female reproductive hormones. Estrogens and progesterone trigger morphogenesis by poorly understood mechanisms acting on a subset of mammary epithelial cells (MECs) that express their cognate receptors, estrogen receptor α (ERα) and progesterone receptor (PR). Here, we show that in the adult female, progesterone drives proliferation of MECs in two waves. The first, small wave, encompasses PR(+) cells and requires cyclin D1, the second, large wave, comprises mostly PR(−) cells and relies on the tumor necrosis factor (TNF) family member, receptor activator of NF-κB-ligand (RANKL). RANKL elicits proliferation by a paracrine mechanism. Ablation of RANKL in the mammary epithelium blocks progesterone-induced morphogenesis, and ectopic expression of RANKL in MECs completely rescues the PR −/− phenotype. Systemic administration of RANKL triggers proliferation in the absence of PR signaling, and injection of a RANK signaling inhibitor interferes with progesterone-induced proliferation. Thus, progesterone elicits proliferation by a cell-intrinsic and a, more important, paracrine mechanism.

BACKGROUND: Studies on nickel patch test reactivity and reproducibility of positive tests at different points of the menstrual cycle are heterogeneous. OBJECTIVE: To investigate if non-reproducibilities of positive nickel sulphate patch tests in the two different phases of ovulatory menstrual cycles with the endocrine evidence of luteal phase adequacy are statistically different. METHODS: 15 women (group 1) with positive Finn chamber(R) nickel patch test results in the follicular phase of the ovulatory cycle and 13 women (group 2) with positive Finn chamber nickel patch test results in the luteal phase of the ovulatory cycle were tested again in the counter-phases of their ovulatory cycle, with a scheduled interval of 6 weeks following the first tests. Reproducibilities of the tests in the two groups were evaluated statistically. RESULTS: 3 of the positive test results in group 1 (20%) and 2 of the positive test results in group 2 (15.4%) were non-reproducible. The difference was not statistically significant. CONCLUSION: The reproducibility of positive Finn chamber nickel patch tests does not seem to be affected by the changes in the follicular and luteal phases of the ovulatory cycle.

Eight ligands were used in this study, four basic, three neutral and one acidic. Their binding to serum alpha 1-acid glycoprotein (orosomucoid) was measured at several temperatures, and the data were analysed together by a general model with three unknowns, number of binding sites, delta H0 and delta S0. The partition coefficients of the ligands were measured in octanol/water and heptane/water systems (log Poct. and log Phep.), and their molecular volumes were calculated by molecular modelling techniques. These structural properties allow determination of polarity parameters (delta log Poct.-hep., lambda oct. and lambda hep.) which encode in different proportions the various polar interactions between the solute and the aqueous and organic phases, i.e. hydrogen-bonding capacity and dipolarity/polarizability. This study shows that good correlations exist between delta H0 or delta S0 and polarity parameters, such that the enthalpic contribution to binding increases with increasing polarity of the ligands, mainly hydrogen-bond-donor acidity, whereas their entropic contribution to binding decreases.

The epitope H contains an O-linked Nacetylglucosamine residue in a specific conformation and/or environment recognized by the monoclonal antibody H (mAbH). mAbH stains two bands with Mr x10-3 of 209 and 62 in lysates of cultured rat astrocytes. In addition, in extracts of cultured MCF-7 breast carcinoma cell line cells it stains cytokeratin 8 and five polypeptides originating from Triton X-100-soluble (Mr x10-3 of 232, 67 and 37) and from the Triton X-100- insoluble (Mr x10-3 of 51 and 50) fractions, respectively. In our previous studies we used the mAbH to investigate by immunostaining the expression of the epitope H in normal human brains, human brains with a variety of lesions, astrocytic tumors, infiltrating ductal breast carcinomas, fibroadenomas, and mitochondria-rich normal, metaplastic and neoplastic cells. In order to gain further insight into the expression patterns of the epitope H in human tissues we used the mAbH to investigate the immunohistochemical expression of the epitope H in normal human endometrium, including 30 cases of proliferative endometrium, 30 cases of early secretory endometrium, 30 cases of mid secretory endometrium, 30 cases of late secretory endometrium and 30 cases of decidual tissues. The main results were the following: 1) The decidual stromal cells presented in all cases high cytoplasmic expression of the epitope H; 2) The predecidual stromal cells presented in all cases of late secretory endometrium significant cytoplasmic expression of the epitope H ranging from moderate to high expression; 3) The non pre-decidual stromal cells of the functional endometrial layer presented in all cases insignificant cytoplasmic expression of the epitope H ranging from null to low expression; 4) The stromal cells of the basal layer of the endometrium and decidua did not express the epitope H in any case; 5) The endometrial stromal granulocytes did not express the epitope H in any case and 6) The blood vessel wall cells (endothelial and smooth muscle) of the endometrium through the whole duration of the menstrual cycle and of the decidua presented high cytoplasmic expression of the epitope H. It is concluded that decidualized and predecidualized human normal endometrial stromal cells show increased expression of the O-linked Nacetylglucosamine containing epitope H compared to non-decidualized endometrial stromal cells. These findings suggest that the expression of the epitope H may be under positive progesteronic control in normal human endometrium. Further investigation of the antigens bearing the epitope H might help to gain further insight into the histophysiology and the pathology of human endometrium.