Progesterone Resistance and Adult Stem Cells’ Genomic and Epigenetic Changes in the Puzzle of Endometriosis

Endometriosis is a chronic inflammatory disease under hormonal/non-hormonal regulation, and microenvironment influences, originating in adult stem cells (mainly of bone marrow/endometrial progenitor mesenchymal type), and their exosomes, with special migratory and adhesion capacities. The postmenstrual repair with regeneration of eutopic and ectopic endometrium has similar genetic and epigenetic changes versus disease-free women. The competition between ectopic and eutopic endometrium for a limited supply of stem cells, and the depletion of normal stem cells flux to the uterus is considered the novel mechanism through which endometriosis interferes with endometrial functions and fertility. The gene expression DNA/RNA or microRNA changes/dysregulation of estrogen and progesterone receptors represent a possible explanation of progesterone resistance or loss of progesterone signalling in ectopic, and eutopic endometrium versus normal. The genes’ changes involved in hormonal/non-hormonal pathways control of eutopic/ectopic endometrial cells, and of invaded tissues/organs may explain the disease persistency, progression and severity. Deficient DNA methylation of ERβ, the initial genomic event is followed by pathologic over-expressed ERβ in ectopic stromal cells, and it dictates the decline of PR isoforms, PRB being significantly lower in ectopic and eutopic endometrium. Altered expression of ERα, ERβ, and PRs accompanies the conversion of resident normal endometrial cells to ectopic lesions

Endometrial Histology and Safety on Non-Oral Routes of Hormone Therapy for Perimenopausal/Early Menopausal Women: Transdermal Estrogens and Vaginal Micronized Progesterone

The Women’s Health Initiative issues, confusions, and misunderstandings regarding women’s and medical staff’s fears about coronary heart disease; stroke; venous thromboembolism; breast cancer; metabolic, cognitive and mood disorders; and general mortality have driven many attempts to promote other safe regimens for perimenopause/early menopause and midlife health. Perimenopause/early menopause climacteric syndrome may be safely treated with sequential transdermal/percutaneous estrogens and progestogens/vaginal progesterone or continuous transdermal estrogen plus intrauterine system medicated with progestogen/progesterone or with continuous combined transdermal estrogen-vaginal progesterone regimen, when menopause since 3 years. Endometrial safety is assessed in terms of endometrial hyperplasia and carcinoma prevention. Transvaginal sonography, hysteroscopy, and endometrial biopsy at 6/12 months ensure about secretory and atrophy/inactive endometrial aspects as markers for endometrial safety. The majority of endometrial carcinomas depicted after MHT are high grade, not estrogen dependent, developed on an atrophic endometrium. The histologic, genomic, and transcriptomic assessments with immunohistochemistry are diagnoses adjunct for cell proliferation/mitosis and apoptosis presence. Proteins, growth factors, cytokines as PAX2, PTEN and its genetic aberrations, microRNA-binding protein family (IMP, IGF-BP, progesterone dependent), bcl 2, Ki-67, K-ras, p53, p16, and steroid (estrogen and progesterone) receptors are markers for differentiation between benign hyperplasia/endometrial intraepithelial neoplasia, type 1/type 2 endometrial carcinomas, and long-term outcome

Neuroprotection in Perimenopausal Women

Endocrine and neural senescence overlap in time, by intertwined complex feedback loops. Womens’ brain is genetically more prone to suffer during life, and perimenopause is a “critical period” in neuroaging, when the degenerative processes begin. Many hypotheses on the multifactorial nature of women’s brain aging are elaborated, and tested in high-tech research centers. The most analyzed Alzheimer’s disease (AD) is characterized not only by Aβ oligomers and fibrils accumulation, but also by metabolic and inflammatory changes, with the onset during menopausal transition and early years of menopause. Deep analysis of endocrine, neural, and metabolic pathways are giving new insights to the sequential view of Aβ-centric in AD pathogenesis, prevention, and treatment from perimenopause, for maintaining women’s neurological health

New Insights for Hormone Therapy in Perimenopausal Women Neuroprotection

Perimenopause is a mandatory period in women’s life, when the medical staff may initiate hormone therapy with sex steroids for the delay of brain aging and neurodegenerative diseases, during the so-called “window of opportunity.” Animals’ models are helpful to sustain the still controversial results of human clinical observational and/or randomized controlled studies. Estrogens, progesterone, and androgens, with their nuclear and membrane receptors, genes, and epigenetics, with their connections to cholinergic, GABAergic, serotoninergic, and glutamatergic systems are involved in women’s normal brain or in brain’s pathology. The sex steroids are active through direct and/or indirect mechanisms to modulate and/or to protect brain plasticity, and vessels network, fuel metabolism—glucose, ketones, ATP, to reduce insulin resistance, and inflammation of the aging brain through blood-brain barrier disruption, microglial aberrant activation, and neural cell survival/loss

Potential Therapeutic Options and Perspectives for Alleviation of Endometrial Estrogen Dominance and Progesterone Resistance in Endometriosis

Endometriosis is a chronic disease, influenced by internal and external environment, with long duration from intrauterine life with acme during childbearing, when it is associated to chronic pelvic pains, and infertility/subfertility. DNA hypermethylation of endometrial promoter PRs Hox genes and DNA hypomethylation of promoter ERβ gene is a possible explanation of estrogen dominance, progressive loss of progesterone signaling, followed by progesterone resistance in ectopic, and progesterone attenuance in eutopic endometrium, for failure of hormone therapy (HT), repeated recurrences after surgery, cancers after long time evolution. Animal models, human trials demonstrated progesterone (P4) and progestins influences over progression of disease pathological characteristics, associated to endometrial ER, PR aberrant expressions: ERα loss, and abnormal PRB/PRA ratio. P4 supplementation before mice induced-endometriosis protected from PRs depletion, action that can be translated in women according to the difference of 7 to 12 years between histologic onset and clinical symptoms/signs, parallel to progressive loss of PRs and PR-mediated signaling in ectopic and eutopic endometria. The animal studies have shown that a DNA methylation inhibitor alleviates lesion growth, and induces PRs target gene expression restoration. Continuous/extended contraceptives, dienogest- a new progestin, GnRH agonists/antagonists, aromatase inhibitors, SERM, SPRM, combinated molecules are therapeutic options/perspectives aiming restoration endometrial estrogen-progesterone balance, without disease’s cure. HT may be active alone, or surgery associated

A New Cell Stem Concept for Pelvic Floor Disorders Prevention and Treatment. Endometrial Mesenchymal Stem Cells

High rate complications and recurrences in reconstructive surgery using in situ synthetic/polypropylene (PP) meshes have driven to a new concept based on mesenchymal stem cells (MSCs) for homeostasis repair in pelvic floor disorders (PFD). Prevention and therapy with MSCs are up to date analyzed on small and large animal models, less in women trials. Cell based-vaginal/intraurethral, or systemically introduced, tissue engineering (TE) with new generation meshes/scaffolds MSCs seeded-bone marrow, adipose tissue and recently proposed the endometrial/menstrual MSCs (eMSCs/MenSCs) for PFDs, management. Easy collected, isolated with specific markers, cultured for number harvesting, without ethic and immune compatibility issues, with unique biologic properties eMSCs/MenSCs differentiate in many cellular types—smooth muscle, and fibroblast-like cells, preserving cell shape, and phenotype, without oncogenic risks, and collagen, elastin fibers; eMSCs/MenSCsare appropriate for PFDs management, respecting good protocols for human safety. The quick appeared regenerative effect-mediated by angiogenesis, apoptosis inhibition, cell proliferation, no chronic inflammation and low/no foreign body reactions, less thick collagen fibers, and fibrosis improve connective/neuromuscular tissues; less pelvic structures stiffness with more elasticity are advantages for new meshes/scaffolds generation in TE. Human eSMCs/MenSCs deliver bioactive factors by their exosomes/microvesicles/secretome for paracrine effects to injury site, facilitating in vivo tissue repair

Breast and Cervix Uteri: Rare Locations for Mycobacterium Tuberculosis Infections and Complications-Cases Report and Literature Review

Breast and cervix uteri are rare locations for Mycobacterium tuberculosis (MbT) infection and MbT association to cervical cancer is more rare in European countries. This chapter analyses two cases of rare locations of tuberculosis (TB) in young Romanian women. The first patient presented a chronic primary TB breast abscess, non-pregnancy related with periods of apparent healing and repeated areolar fistula formation. In the second case, the unexpected discovery of secondary TB endocervical granulomatous inflammation with caseous necrosis on a radical hysterectomy specimen, performed after chemoradiotherapy for squamous non-keratinizing cell carcinoma is presented. Worldwide incidence, risk factors, hypothetic mechanisms of primary/secondary breast and cervix uteri MbT infection, the association to high-risk HPV, microbiological diagnosis difficulties, the differentials to pyogenic abscesses, other chronic granulomas and breast cancer treatment issues are presented in the reviewed literature, focusing on the peculiarities of these rare locations and complications. It is recalled an old concept of “therapeutic antitubercular” test when all other assessments steps are usefulness

Abnormal Cervical Remodeling Early Depiction by Ultrasound Elastography: Potential Opportunities for Preterm Birth Prevention and Delay

Early depiction of abnormal cervical remodeling (CR) is a prime information source with days/even weeks to uterine contractions for preterm birth (PTB) risks. CR phases, softening-ripening-dilation, are distinctive by molecular, and timing in preterm/term: integrity loss in ripening and dilation. Changes in extracellular matrix, cellular content, water retention drive progressively to resistance reduction, rising elasticity, relaxing cervical smooth muscle cells (CSMCs) are organized like a sphincter at internal os. Shear Wave Elasticity Imaging-SWEI (dynamic elastography) based on objectively measurable cervical response to deformability is more accurate for early CR depiction from 8–12 weeks vs. conventional ultrasound cervical length (CL) measurements (16–23+6days weeks). SWEI quantifies tissue microstructure, constant fractional stiffness reduction (~ 4%/week), and spatial gradient in Shear Wave Speed (SWS) along cervix, and CL serial measurements in addition offers better strategies for prolongation, actual/future fetal safety, when cervical softness/shortness progresses. Vaginal progesterone (P4) from early pregnancy to complete 37 weeks is preventive: controls CR, indicated by SWS prior to CL 28, 34, 37 weeks) in asymptomatic cases, with characteristic history/actual abnormal CR/shortness, a small better efficacy for vaginal P4, and cerclage vs. pessary, when separately analyzed; few retrospective studies exist on triple association efficacy for PTB prevention/delay and neonatal outcomes