The role of X-chromosome inactivation in female predispositionto autoimmunity

Background Manipulation of the follicular phase uterine epithelium in women undergoing infertility treatment, has not generally shown differing morphological effects on uterine epithelial characteristics using Scanning Electron Microscopy (SEM) and resultant pregnancy rates have remained suboptimal utilising these manipulations. The present study observed manipulation of the proliferative epithelium, with either 7 or 14 days of sequential oestrogen (E) therapy followed by progesterone (P) and assessed the appearance of pinopods (now called uterodomes) for their usefulness as potential implantation markers in seven women who subsequently became pregnant. Three endometrial biopsies per patient were taken during consecutive cycles: day 19 of a natural cycle - (group 1), days 11/12 of a second cycle after 7 days E then P - (group 2), and days 19/22 of a third cycle after 14 days E then P - (group 3). Embryo transfer (ET) was performed in a subsequent long treatment cycle (as per Group 3). Results Seven pregnancies resulted in seven viable births including one twins and one miscarriage. Analysis of the individual regimes showed 5 days of P treatment to have a higher correlation for uterodomes in all 3 cycles observed individually. It was also observed that all 7 women demonstrated the appearance of uterodomes in at least one of their cycles. Conclusions We conclude that manipulation of the follicular phase by shortening the period of E exposure to 7 days, does not compromise uterine epithelial morphology and we add weight to the conclusion that uterodomes indicate a receptive endometrium for implantation.

In order to explore the possible role of E-cadherin in familial cancer, 19 familial breast cancer patients, whose tumours demonstrated loss of heterozygosity (LOH) at the E-cadherin locus, were screened for germline mutations. No pathogenic germline alterations were detected in these individuals. However, a somatic mutation was found (49-2A→C) in one of the tumours. This tumour showed a pattern of both ductal and lobular histology. Another 10 families with cases of breast, gastric and colon cancer were also screened for germline mutations, and no mutations were found. A missense mutation in exon 12 of E-cadherin (1774G→A; Ala592Thr) was previously found in one family with diffuse gastric cancer, and colon and breast cancer. An allelic association study was performed to determine whether the Ala592Thr alteration predisposes to breast cancer. In total, we studied 484 familial breast cancer patients, 614 sporadic breast cancer patients and 497 control individuals. The frequencies of this alteration were similar in these groups. However, a correlation between the Ala592Thr alteration and ductal comedo-type tumour was seen. These results, together with previously reported studies, indicate that germline mutations and, more commonly, somatic mutations in E-cadherin may have an influence on the behaviour of the tumours, rather than predispose to breast cancer.

Background Manipulation of the uterine epithelium utilising standard dose exogenous oestrogen (E2) and progesterone (P4) has been shown to achieve a mature secretory morphological response. However, in an in vitro fertilisation (IVF) setting, frozen embryo transfer (ET) has had a low success rate. We propose that in patients with previously failed ET attempts, the uterine epithelium can be directly visualised by biopsy and Scanning Electron Microscopy (SEM) and that with an individualised fine tuning of the hormone supplementation regime, based on the SEM examination of sequential uterine biopsies, it is possible to provide a uterine environment conducive to successful ET. Methods A 47 year old women was chosen for endometrial biopsy, histopathological dating and endometrial observation utilising SEM to determine the integrity of her secretory uterine epithelium because of her age and several previously failed attempts at frozen ET. Exogenous E2 and P4 supplementation was administered in modified doses according to the SEM result, in consecutive cycles until the epithelial response appeared satisfactory for potential implantation. Results This case study demonstrates the dramatic change in epithelial characteristics that can be achieved as a response to these altered doses of E2 and P4. The uterine morphology changed from a hypotrophic to a mature, receptive epithelium such that ET resulted in the birth of healthy twin boys. Conclusion The comparison between the consecutive biopsies in direct response to the SEM analysis and tailored modification of E2 and P4 dose clearly demonstrates, in this case, the effectiveness of individual morphological monitoring to maximise the successful outcome of ET.

Background Previous work by our group and others has implicated a role for kinins in the ovulatory process. The purpose of the present study was to elucidate whether endogenous progesterone, which is an intraovarian regulator of ovulation, might be responsible for induction of the kinin system in the ovary during ovulation. The gonadotropin-primed immature rat was used as the experimental model, and the role of endogenous progesterone was explored using the antiprogestin, RU486. Results The results of the study revealed that RU486 treatment, as expected, significantly attenuated ovulation. Activity of the kinin-generating enzyme, kallikrein, was elevated in the ovary in control animals prior to ovulation with peak values observed at 4 h post hCG, only to fall to low levels at 10 h, with a recovery at 20 h post hCG. RU486 treatment had no significant effect on ovarian kallikrein activity as compared to the control group. Total ovarian kininogen levels in control animals increased significantly at 12–14 h after hCG – coinciding with initiation of ovulation. Thereafter, ovarian kininogen levels fell to low levels at 20 h, only to show a rebound from 24–38 h post-hCG. RU486 treatment had no significant effect on the rise of total ovarian kininogen levels from 12–14 h after hCG; however, from 30–40 h post hCG, RU486-treated animals had significantly higher total ovarian kininogen levels versus control animals, suggesting that endogenous progesterone may act to restrain elevations of kininogens in the post-ovulatory ovary. This robust elevation of ovarian kininogen levels by RU486 was found to be primarily due to an increase in T-kininogen, which is a potent cysteine protease inhibitor. Conclusions Taken as a whole, these results suggest that endogenous progesterone does not regulate kallikrein activity or kininogens prior to ovulation, but may provide a restraining effect on T-kininogen levels in the post-ovulatory ovary.

,The database contains a set of answers from 1,500 respondents to a study carried out at the Generation Institute entitled: "Research on the causes of childlessness and low fertility among women." As part of the research, qualitative research was conducted and then a survey was conducted in July-August 2023. Based on the collected data, the report "What's holding women back" Instytut Pokolenia Warsaw 2023 was created.,

Table 1. Antibodies used for immunohistochemistry. Table 2. Incidence of uterine glandular epithelial lesions over time following neonatal estrogen exposure (GEN or DES) Table 3. Immunohistochemical expression of differentiation markers in the uterine epithelium following neonatal estrogen exposure (GEN or DES). This dataset is associated with the following publication: Suen, A., W. Jefferson, C. Williams, and C. Wood. Differentiation patterns of uterine carcinomas and precursor lesions induced by neonatal estrogen exposure in mice. TOXICOLOGIC PATHOLOGY. Society of Toxicology, RESTON, VA, 46(5): 574-596, (2018).

Background Germline mutations in the tumor suppressor PTEN predispose human beings to breast cancer, and genetic and epigenetic alterations of PTEN are also detected in sporadic human breast cancer. Germline Pten mutations in mice lead to the development of a variety of tumors, but mammary carcinomas are infrequently found, especially in mice under the age of six months. Results To better understand the role of PTEN in breast tumor development, we have crossed Pten heterozygous mice to MMTV-Wnt-1 transgenic mice that routinely develop ductal carcinomas in the mammary gland. Female Wnt-1 transgenics heterozygous for Pten developed mammary tumors earlier than Wnt-1 transgenics that were wild type for Pten. In most tumors arising in Pten heterozygotes, the Pten wild-type allele was lost, suggesting that cells lacking Pten function have a growth advantage over cells retaining a wild type allele. Tumors with LOH contained high levels of activated AKT/PKB, a downstream target of the PTEN/PI3K pathway. Conclusions An animal model has been developed in which the absence of Pten collaborates with Wnt-1 to induce ductal carcinoma in the mammary gland. This animal model may be useful for testing therapies specific for tumors deregulated in the PTEN/PI3K/AKT pathway.