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Seminars in Cell & Developmental Biology Mar 2022Postmenopausal osteoporosis is a systemic disease characterized by the loss of bone mass and increased bone fracture risk largely resulting from significantly reduced... (Review)
Review
Postmenopausal osteoporosis is a systemic disease characterized by the loss of bone mass and increased bone fracture risk largely resulting from significantly reduced levels of the hormone estrogen after menopause. Besides the direct negative effects of estrogen-deficiency on bone, indirect effects of altered immune status in postmenopausal women might contribute to ongoing bone destruction, as postmenopausal women often display a chronic low-grade inflammatory phenotype with altered cytokine expression and immune cell profile. In this context, it was previously shown that various immune cells interact with osteoblasts and osteoclasts either via direct cell-cell contact, or more likely via paracrine mechanisms. For example, specific subtypes of T lymphocytes express TNFα, which was shown to increase osteoblast apoptosis and to indirectly stimulate osteoclastogenesis via B cell-produced receptor-activator of NF-κB ligand (RANKL), thereby triggering bone loss during postmenopausal osteoporosis. T17 cells release interleukin-17 (IL-17), which directs mesenchymal stem cell differentiation towards the osteogenic lineage, but also indirectly increases osteoclast differentiation. B lymphocytes are a major regulator of osteoclast formation via granulocyte colony-stimulating factor secretion and the RANKL/osteoprotegerin system under estrogen-deficient conditions. Macrophages might act differently on bone cells dependent on their polarization profile and their secreted paracrine factors, which might have implications for the development of postmenopausal osteoporosis, because macrophage polarization is altered during disease progression. Likewise, neutrophils play an important role during bone homeostasis, but their over-activation under estrogen-deficient conditions contributes to osteoblast apoptosis via the release of reactive oxygen species and increased osteoclastogenesis via RANKL signaling. Furthermore, mast cells might be involved in the development of postmenopausal osteoporosis, because they store high levels of osteoclastic mediators, including IL-6 and RANKL, in their granules and their numbers are greatly increased in osteoporotic bone. Additionally, bone fracture healing is altered under estrogen-deficient conditions with the increased presence of pro-inflammatory cytokines, including IL-6 and Midkine, which might contribute to healing disturbances. Consequently, in addition to the direct negative influence of estrogen-deficiency on bone, immune cell alterations contribute to the pathogenesis of postmenopausal osteoporosis.
Topics: Bone Resorption; Bone and Bones; Cell Differentiation; Estrogens; Female; Humans; Osteoblasts; Osteoclasts; Osteoporosis, Postmenopausal
PubMed: 34024716
DOI: 10.1016/j.semcdb.2021.05.014 -
International Journal of Molecular... Dec 2020Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and... (Review)
Review
Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but are also highly involved in a wide range of brain functions, such as cognition, memory, neurodevelopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and anti-inflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further, in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated to suggest a future direction in identifying novel treatment strategies in psychiatric disorders.
Topics: Animals; Estrogens; Humans; Mental Disorders; Neuroprotection; Receptors, Estrogen; Signal Transduction
PubMed: 33396472
DOI: 10.3390/ijms22010373 -
Nutrients Jan 2023Phytoestrogens are literally estrogenic substances of plant origin. Although these substances are useful for plants in many aspects, their estrogenic properties are... (Review)
Review
Phytoestrogens are literally estrogenic substances of plant origin. Although these substances are useful for plants in many aspects, their estrogenic properties are essentially relevant to their predators. As such, phytoestrogens can be considered to be substances potentially dedicated to plant-predator interaction. Therefore, it is not surprising to note that the word phytoestrogen comes from the early discovery of estrogenic effects in grazing animals and humans. Here, several compounds whose activities have been discovered at nutritional concentrations in animals and humans are examined. The substances analyzed belong to several chemical families, i.e., the flavanones, the coumestans, the resorcylic acid lactones, the isoflavones, and the enterolignans. Following their definition and the evocation of their role in plants, their metabolic transformations and bioavailabilities are discussed. A point is then made regarding their health effects, which can either be beneficial or adverse depending on the subject studied, the sex, the age, and the physiological status. Toxicological information is given based on official data. The effects are first presented in humans. Animal models are evoked when no data are available in humans. The effects are presented with a constant reference to doses and plausible exposure.
Topics: Humans; Animals; Phytoestrogens; Isoflavones; Plants; Estrogens; Models, Animal
PubMed: 36678189
DOI: 10.3390/nu15020317 -
Pathology Oncology Research : POR Jan 2020Rapid advance in oncology leads to increasing survival of oncologic patients. More and more of them live long enough to reach either the natural age of menopause or, as... (Review)
Review
Rapid advance in oncology leads to increasing survival of oncologic patients. More and more of them live long enough to reach either the natural age of menopause or, as a side effect of their oncotherapy, experience the cessation of gonadal function, leading to premature ovarian insufficiency, with disturbing vasomotor symtoms and long-term negative cardiovascular and skeletal effects. Thus, an ever increasing number of cancer survivors search endocrinologic help in the form of hormone replacement therapy (HRT). The misinterpretation of the WHI (Women's Health Initiative) Study has lead to an irrational fear of female hormone replacement, both by the general population and medical professionals. It has seemed the logical and safe conclusion to many physicians to avoid HRT, supposing that this attitude definitely causes no harm, whereas the decision of prescribing estrogen alone or with progestins might bear oncologic and thromboembolic risks and may even lead to litigation in case of a potentially related complication. However, it was known even before the WHI results that premature menopause and hypogonadism decreases the life expectancy of women by years through its skeletal and cardiovascular effects, and this negative effect correlates with the length of the hypoestrogenaemic period. Therefore, the denial of HRT also needs to be supported by evidence and should be weighed againts the risks of HRT. Yet, the oncologic risk of HRT is extremely difficult to assess. In this work we review the latest evidence from in vitro experiments to clinical studies, regarding HRT in survivors of gynecologic and non-gynecologic cancers. Based on our literature research, we group tumours regarding the oncologic risk of properly chosen female hormone replacement therapy in cancer survivors as follows: 'HRT is advanageous' (e.g. endometrial cancer type I, cervical adenocarcinoma, haematologic malignancies, local cutaneous malignant melanoma, colorectal cancer, hepatocellular cancer); 'HRT is neutral' (e.g. BRCA 1/2 mutation carriers without cancer, endometrial cancer type II, uterinal carcinosarcoma and adenosarcoma, certain types of ovarian cancer, cervical, vaginal and vulvar squamous cell carcinoma, prolactinoma, kidney cancer, pancreatic cancer, thyroid cancer); 'HRT is relatively contraindicated' for various reasons (e.g. leiomyosarcoma, certain types of ovarian tumours, brain tumours, advanced metastatic malignant melanoma, lung cancer, gastric cancer, bladder cancer); 'HRT is diasadvantageous and thus contraindicated' (e.g. breast cancer, endometrial stroma sarcoma, meningioma, glioma, hormone receptor positive gastric and bladder cancer).
Topics: Breast Neoplasms; Cancer Survivors; Estrogens; Female; Genital Neoplasms, Female; Hormone Replacement Therapy; Humans; Neoplasms; Neoplasms, Second Primary; Progesterone
PubMed: 30617760
DOI: 10.1007/s12253-018-00569-x -
Redox Biology Apr 2020Sex-based differences in human disease are caused in part by the levels of endogenous sex steroid hormones which regulate mitochondrial metabolism. This review updates a... (Review)
Review
Sex-based differences in human disease are caused in part by the levels of endogenous sex steroid hormones which regulate mitochondrial metabolism. This review updates a previous review on how estrogens regulate metabolism and mitochondrial function that was published in 2017. Estrogens are produced by ovaries and adrenals, and in lesser amounts by adipose, breast stromal, and brain tissues. At the cellular level, the mechanisms by which estrogens regulate diverse cellular functions including reproduction and behavior is by binding to estrogen receptors α, β (ERα and ERβ) and G-protein coupled ER (GPER1). ERα and ERβ are transcription factors that bind genomic and mitochondrial DNA to regulate gene transcription. A small proportion of ERα and ERβ interact with plasma membrane-associated signaling proteins to activate intracellular signaling cascades that ultimately alter transcriptional responses, including mitochondrial morphology and function. Although the mechanisms and targets by which estrogens act directly and indirectly to regulate mitochondrial function are not fully elucidated, it is clear that estradiol regulates mitochondrial metabolism and morphology via nuclear and mitochondrial-mediated events, including stimulation of nuclear respiratory factor-1 (NRF-1) transcription that will be reviewed here. NRF-1 is a transcription factor that interacts with coactivators including peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) to regulate nuclear-encoded mitochondrial genes. One NRF-1 target is TFAM that binds mtDNA to regulate its transcription. Nuclear-encoded miRNA and lncRNA regulate mtDNA-encoded and nuclear-encoded transcripts that regulate mitochondrial function, thus acting as anterograde signals. Other estrogen-regulated mitochondrial activities including bioenergetics, oxygen consumption rate (OCR), and extracellular acidification (ECAR), are reviewed.
Topics: DNA, Mitochondrial; Estrogens; Humans; Mitochondria; Nuclear Respiratory Factor 1; Transcription Factors
PubMed: 32001259
DOI: 10.1016/j.redox.2020.101435 -
Neurotherapeutics : the Journal of the... Jul 2019There are 3 common physiological estrogens, of which estradiol (E2) is seen to decline rapidly over the menopausal transition. This decline in E2 has been associated... (Review)
Review
There are 3 common physiological estrogens, of which estradiol (E2) is seen to decline rapidly over the menopausal transition. This decline in E2 has been associated with a number of changes in the brain, including cognitive changes, effects on sleep, and effects on mood. These effects have been demonstrated in both rodent and non-human preclinical models. Furthermore, E2 interactions have been indicated in a number of neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. In normal brain aging, there are a number of systems that undergo changes and a number of these show interactions with E2, particularly the cholinergic system, the dopaminergic system, and mitochondrial function. E2 treatment has been shown to ameliorate some of the behavioral and morphological changes seen in preclinical models of menopause; however, in clinical populations, the effects of E2 treatment on cognitive changes after menopause are mixed. The future use of sex hormone treatment will likely focus on personalized or precision medicine for the prevention or treatment of cognitive disturbances during aging, with a better understanding of who may benefit from such treatment.
Topics: Animals; Brain; Cognitive Aging; Estrogens; Humans
PubMed: 31364065
DOI: 10.1007/s13311-019-00766-9 -
Cells Dec 2019The microbiome is undoubtedly the second genome of the human body and has diverse roles in health and disease. However, translational progress is limited due to the... (Review)
Review
The microbiome is undoubtedly the second genome of the human body and has diverse roles in health and disease. However, translational progress is limited due to the vastness of the microbiome, which accounts for over 3.3 million genes, whose functions are still unclear. Numerous studies in the past decade have demonstrated how microbiome impacts various organ-specific cancers by altering the energy balance of the body, increasing adiposity, synthesizing genotoxins and small signaling molecules, and priming and regulating immune response and metabolism of indigestible dietary components, xenobiotics, and pharmaceuticals. In relation to breast cancer, one of the most prominent roles of the human microbiome is the regulation of steroid hormone metabolism since endogenous estrogens are the most important risk factor in breast cancer development especially in postmenopausal women. Intestinal microbes encode enzymes capable of deconjugating conjugated estrogen metabolites marked for excretion, pushing them back into the enterohepatic circulation in a biologically active form. In addition, the intestinal microbes also break down otherwise indigestible dietary polyphenols to synthesize estrogen-like compounds or estrogen mimics that exhibit varied estrogenic potency. The present account discusses the potential role of gastrointestinal microbiome in breast cancer development by mediating metabolism of steroid hormones and synthesis of biologically active estrogen mimics.
Topics: Adiposity; Breast Neoplasms; Dysbiosis; Estrogens; Female; Gastrointestinal Microbiome; Humans; Microbiota; Obesity; Risk Factors
PubMed: 31847455
DOI: 10.3390/cells8121642 -
Clinical and Experimental Dermatology Dec 2022In this second part of a four-part review, we examine the effect of menopause on the skin. Menopause and the associated hypo-oestrogenic state have implications for the... (Review)
Review
In this second part of a four-part review, we examine the effect of menopause on the skin. Menopause and the associated hypo-oestrogenic state have implications for the structure and function of the skin. We performed a literature review to investigate the impact of the menopause on common dermatoses. There is evidence that oestrogen is implicated in transepidermal water loss and reduction in dermal collagen. There are associations with menopause and multiple common dermatoses, including xerosis and pruritus, hidradenitis suppurativa and psoriasis. Menopause has a clear impact on the skin and common dermatological conditions. Further research to understand the mechanisms and explore therapeutic options is needed.
Topics: Humans; Female; Skin; Menopause; Psoriasis; Estrogens; Hidradenitis Suppurativa
PubMed: 35727900
DOI: 10.1111/ced.15308 -
Clinical and Experimental Dermatology Dec 2022Menopause, which usually occurs between the age of 45 and 55 years, is associated with falling oestrogen levels due to ovarian follicle depletion. The impact on the... (Review)
Review
Menopause, which usually occurs between the age of 45 and 55 years, is associated with falling oestrogen levels due to ovarian follicle depletion. The impact on the cardiovascular system and bone density are well documented; however, further research required to establish the impact on the skin and hair. In this first part of a four-part review, we examine the effect of menopause on the hair. We performed a literature review on dermatology and hair in menopause. Androgens and oestrogens are involved with regulation of the hair cycle, with a reduction in anagen hairs seen in postmenopausal women. Female pattern hair loss and frontal fibrosing alopecia have both been associated with the perimenopausal and postmenopausal states. It is clear that menopause and the change in hormone levels have an impact on the hair cycle and common hair conditions. However, further research is required, particularly to understand the therapeutic targets and role of hormonal therapy.
Topics: Female; Humans; Middle Aged; Alopecia; Hair Diseases; Hair; Menopause; Skin; Estrogens
PubMed: 35796569
DOI: 10.1111/ced.15327 -
International Journal of Molecular... Oct 2021Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose... (Review)
Review
Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose tissue predominantly in the lower body. The onset of lipedema pathophysiology is thought to occur during periods of hormonal fluctuation, such as puberty, pregnancy, or menopause. Although the identification and characterization of lipedema have improved, the underlying disease etiology remains to be elucidated. Estrogen, a key regulator of adipocyte lipid and glucose metabolism, and female-associated body fat distribution are postulated to play a contributory role in the pathophysiology of lipedema. Dysregulation of adipose tissue accumulation via estrogen signaling likely occurs by two mechanisms: (1). altered adipocyte estrogen receptor distribution (ERα/ERß ratio) and subsequent metabolic signaling and/or (2). increased release of adipocyte-produced steroidogenic enzymes leading to increased paracrine estrogen release. These alterations could result in increased activation of peroxisome proliferator-activated receptor γ (PPARγ), free fatty acid entry into adipocytes, glucose uptake, and angiogenesis while decreasing lipolysis, mitochondriogenesis, and mitochondrial function. Together, these metabolic alterations would lead to increased adipogenesis and adipocyte lipid deposition, resulting in increased adipose depot mass. This review summarizes research characterizing estrogen-mediated adipose tissue metabolism and its possible relation to excessive adipose tissue accumulation associated with lipedema.
Topics: Adipose Tissue; Animals; Estrogens; Humans; Lipedema; Receptors, Estrogen; Signal Transduction
PubMed: 34769153
DOI: 10.3390/ijms222111720