Hormone Action Research Articles

Hypoparathyroidism: diagnosis, management and emerging therapies.

Hypoparathyroidism is characterized by inadequate parathyroid hormone (PTH) secretion or action and results in hypocalcaemia, and canlead tohyperphosphataemia and hypercalciuria. Most cases of hypoparathyroidism occur as a complication of surgery, with the remainder due to causes including autoimmune disease, genetic causes, infiltrative diseases, mineral deposition or due to abnormalities in serum levels of magnesium. Hypoparathyroidism can cause multisystem disease, with long-term complications resulting from ectopic calcification as well as renal complications with nephrocalcinosis, nephrolithiasis and renal impairment in addition to respiratory, cardiac or neurological manifestations. Conventional therapy consists of oral calcium salts and active vitamin D but it has limitations, including fluctuations in serum levels of calciumand a high pill burden, and can increase therisk of long-term complications. By contrast, PTH replacement therapy can effectively achieve normal serum levels of calcium, and lower serum levels of phosphate.The long-acting PTH analogue, palopegteriparatide, has been shown to normalize urine levels of calcium. In addition, PTH replacement therapy reduces the pill burden. Palopegteriparatide is alsoassociated with improved quality of life in comparison toconventional therapy. This Review summarizes currentrecommendations regarding the pathophysiology, evaluation and management of hypoparathyroidism and also referencesthe 2022 international hypoparathyroidism guidelines. Palopegteriparatide hasnow been approved as PTH replacement therapy for hypoparathyroidism. Emerging therapies will also be presented in this Review.

Variable transduction of thyroid hormone signaling in structures of the mouse brain

L-thyroxine (L-T4) monotherapy is the standard treatment for hypothyroidism, administered daily to normalize TSH levels. Once absorbed, T4 is converted to T3 to alleviate most symptoms. However, this treatment abnormally elevates plasma T4 levels in over 50% of patients. Using L-T4-treated Thyroid Hormone (TH) Action Indicator mice, which express a T3-regulated luciferase (Luc) reporter, we examined whether these T4 elevations disrupt TH signaling. Hypothyroid mice exhibited reduced Luc expression across brain regions, and L-T4 treatment failed to restore T3 signaling uniformly. There was also variability in the activity of type 2 deiodinase (D2), the enzyme that generates most brain T3. Intracerebroventricular T4 administration achieved higher elevation of Luc expression in the mediobasal hypothalamus compared to the cortex, and studies on cultured cortical astrocytes and hypothalamic tanycytes revealed cell-type-specific responses to T4. In tanycytes, exposure to T4 sustained D2 activity, leading to progressive T3 signaling, whereas in astrocytes, T4 exposure triggered a drop in D2 activity, limiting T3 production through a ubiquitin-dependent, self-limiting mechanism. The sustained D2 activity in tanycytes was linked to rapid deubiquitination by USP33, as confirmed using a ubiquitin-specific protease (USP) pan-inhibitor and USP33 knockout mice. In conclusion, the brain's response to L-T4 treatment is heterogeneous, influenced by cell-specific regulation of D2-mediated T3 production. While cortical astrocytes exhibit limited T3 signaling due to D2 ubiquitination, tanycytes coexpressing USP33 amplify T3 signaling by rescuing ubiquitinated D2 from proteasomal degradation. These findings provide mechanistic insights into the limitations of L-T4 therapy and highlight the need for tailored approaches to managing hypothyroidism.

Thyroid function during COVID-19 and post-COVID complications in adults: a systematic review

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has presented multifaceted health challenges. COVID-19 primarily targets the respiratory system but also affects multiple organ systems, including the endocrine system. Emerging evidence suggests interactions between thyroid function, the acute phase of COVID-19, and the prolonged symptoms known as post-COVID sequalae or long COVID. Several studies have reported that COVID-19 can induce thyroid dysfunction, leading to conditions such as thyroiditis and alterations in thyroid hormone levels. The mechanisms through which SARS-CoV-2 affects the thyroid include direct viral infection of thyroid cells, leading to viral thyroiditis, which causes inflammation and transient or sustained thyroid dysfunction, as well as an excessive systemic immune response (cytokine storm). This is associated with elevated levels of cytokines, such as IL-6, that disrupt thyroid function and lead to nonthyroidal illness syndrome (NTIS). Medications administered during the acute illness phase, such as corticosteroids and antiviral drugs, can also impact thyroid hormone actions. The involvement of the thyroid gland in long COVID, or postacute sequelae of SARS-CoV-2 infection, is an area not well defined, with potential implications for understanding and managing this condition. Persistent low-grade inflammation affecting thyroid function over time can lead to ongoing thyroiditis or exacerbate pre-existing thyroid conditions. Viral infections, including SARS-CoV-2, can trigger or worsen autoimmune thyroid diseases, such as Hashimoto’s thyroiditis and Graves’ disease. Long COVID may disrupt the hypothalamic–pituitary–adrenal (HPA) axis, which can, in turn, affect the hypothalamic-pituitary-thyroid (HPT) axis, leading to abnormal thyroid function. This review was designed to systematically capture recent literature on COVID-19-related thyroid dysfunction in the adult population, the prognostic consequences of thyroid dysfunction during COVID-19, and the effects of thyroid dysfunction on patients with long COVID. A comprehensive search of PubMed and EMBASE databases was conducted. The systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Study quality was assessed using the Critical Appraisal Skills Programme (CASP). A total of 53 studies met the inclusion criteria. The review summarises recent findings and provides an update of the current understanding of thyroid dysfunction in COVID-19-related spectrum of disorders, underscoring the complex nature of SARS-CoV-2 infection and its far-reaching impacts on human health.

Expression of genes involved in thyroid hormone action in human induced pluripotent stem cells during differentiation to insulin-producing cells: Effects of iopanoic acid on differentiation

Expression of genes involved in thyroid hormone action in human induced pluripotent stem cells during differentiation to insulin-producing cells: Effects of iopanoic acid on differentiation

Peripubertal antagonism of corticotropin-releasing factor receptor 1 results in sustained changes in behavioral plasticity and the transcriptomic profile of the amygdala.

Peripuberty is a significant period of neurodevelopment with long-lasting effects on the brain and behavior. Blocking type 1 corticotropin-releasing factor receptors (CRFR1) in neonatal and peripubertal rats attenuates detrimental effects of early-life stress on neural plasticity, behavior, and stress hormone action, long after exposure to the drug has ended. CRFR1 antagonism can also impact neural and behavioral development in the absence of stressful stimuli, suggesting sustained alterations under baseline conditions. To investigate this further, we administered the CRFR1 antagonist (CRFR1a) R121919 to young adolescent male and female rats across 4 days. Following each treatment, rats were tested for locomotion, social behavior, mechanical allodynia, or prepulse inhibition (PPI). Acute CRFR1 blockade immediately reduced PPI in peripubertal males, but not females. In adulthood, each assay was repeated without CRFR1a exposure to test for persistent effects of the adolescent treatment. Males continued to experience deficits in PPI while females displayed altered locomotion, PPI, and social behavior. The amygdala was collected to measure long-term effects on gene expression. In the adult amygdala, peripubertal CRFR1a induced alterations in pathways related to neural plasticity and stress in males. In females, pathways related to central nervous system myelination, cell junction organization, and glutamatergic regulation of synaptic transmission were affected. Understanding how acute exposure to neuropharmacological agents can have sustained impacts on brain and behavior, in the absence of further exposures, has important clinical implications for developing adolescents.

TRα1mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertility.

Thyroid hormone receptors (TRs) mediate the genomic actions of thyroid hormone. Mutations of THRA gene cause a human disease known as resistance to thyroid hormone (RTHα). We created a mouse model expressing a dominant negative mutated TRα1 (Thra1PV/+ mice) that exhibits growth retardation, bone abnormalities, constipation, and anemia, as found in RTHα patients. In addition, female Thra1PV/+ mice exhibit decreased fertility. In the present study, we aimed to characterize the molecular events leading to infertility. Histologically, there was progressive uterine atrophy in Thra1PV/+ mutant mice, characterized by squamous metaplasia of the endometrial mucosa and endometrial fibrosis. RNA-seq analysis of laser-captured micro-dissected endometrium and spatial transcriptomics revealed a key role for Krüppel-like factor (Klf9), a directly-regulated TR target gene, in normal endometrial differentiation. Klf9 was suppressed in the endometrium of mice harboring mutated TRα1 and pathway analysis revealed that deficient Klf9 signaling was associated with squamous differentiation, consistent with the endometrial metaplasia observed histologically. Further, we showed that this metaplastic endometrial mucosa was the source of ectopic IL-33, which was associated with increased T-cell infiltrates, destruction of glands, and endometrial fibrosis. Our studies provide new insights to understand uterine epithelial morphogenesis and how thyroid dysfunction could lead to female infertility.

Complementary Strategies to Identify Differentially Expressed Genes in the Choroid Plexus of Patients with Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a neurological disease causing myelin and axon damage through inflammatory and autoimmune processes. Despite affecting millions worldwide, understanding its genetic pathways remains limited. The choroid plexus (ChP) has been studied in neurodegenerative processes and diseases like MS due to its dysregulation, yet its role in MS pathophysiology remains unclear. Our work re-evaluates the ChP transcriptome in progressive MS patients and compares gene expression profiles using diverse methodological strategies. Samples from patient and healthy control RNASeq sequencing of brain tissue from post-mortem patients (GEO: GSE137619) were used. After an evaluation and quality control of these data, they had their transcripts mapped and quantified against the reference transcriptome GRCh38/hg38 of Homo sapiens using three strategies to identify differentially expressed genes in progressive MS patients. Functional analysis of genes revealed their involvement in immune processes, cell adhesion and migration, hormonal actions, amino acid transport, chemokines, metals, and signaling pathways. Our findings can offer valuable insights for progressive MS therapies, suggesting specific genes influence immune cell recruitment and potential ChP microenvironment changes. Combining complementary approaches maximizes literature coverage, facilitating a deeper understanding of the biological context in progressive MS.

Digenic Inheritance Mode in Congenital Hypothyroidism due to Thyroid Dysgenesis: HYPOTYGEN translational cohort study.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and is chiefly caused by thyroid dysgenesis (CHTD). The inheritance mode of the disease remains complex. Gain insight into the inheritance mode of CHTD. Prospective multicenter nationwide translational study in France. We prospectively included 514 patients with CH diagnosed through systematic newborn screening (HYPOTYGEN cohort). We focused on CHTD cases and studied their clinical and molecular phenotypes. Targeted next-generation sequencing using a 78-gene panel, including genes involved in thyroid development, function, transport, metabolism and action of thyroid hormones. Statistical analysis, familial segregation and in vitro functional studies focusing on cell migration have been performed. We analyzed the clinical phenotypes of 458 patients with CH. Cardiac and renal malformations were present in 7.7%(14/182) and 3.9%(7/178) of patients, respectively. Genetic analysis was performed on 292 patients of the cohort, based on criteria for ethnicity and availability of DNA samples for index cases and their parents. A disease-causing mutation in one of the 10 known genes for CHTD was identified in 20/292 (6.8%) patients. We found a digenic mode of inheritance in 16 (5.5%) patients, each carrying a variant in a thyroid development gene and a variant in the H2O2 generation complex gene DUOX2/DUOXA2. Familial segregation analysis and in vitro functional studies supported this model. This work expands our understanding of the molecular causes of CHTD by demonstrating that digenic inheritance can be implicated, with deleterious variants in thyroid development and DUOX2/DUOXA2 genes. The complexity of this model implies a revision of the genetic landscape of CHTD and specific clinical care of patients during long-term follow-up. NCT01916018.

Noncanonical RGS14 structural determinants control hormone-sensitive NPT2A-mediated phosphate transport.

The sodium phosphate cotransporter-2A (NPT2A) mediates basal and parathyroid hormone (PTH)- and fibroblast growth factor-23 (FGF23)-regulated phosphate transport in proximal tubule cells of the kidney. Both basal and hormone-sensitive transport require sodium hydrogen exchanger regulatory factor-1 (NHERF1), a scaffold protein with tandem PDZ domains, PDZ1 and PDZ2. NPT2A binds to PDZ1. RGS14 persistently represses hormone action by binding to PDZ2. The RGS14 canonical RGS domain, Ras/Rap-binding domains, and G protein regulatory motif cannot explain its regulatory effects on hormone-sensitive phosphate transport because these actions are mediated not only by the PTH receptor, a G protein-coupled receptor (GPCR), but also by the fibroblast growth factor receptor-1, a receptor tyrosine kinase that is not governed by G protein activity. Here, we identify the structural elements of RGS14 that mutually control the action of PTH and FGF23. RGS14 truncation constructs lacking upstream sequence and the RGS domain were fully functional. Removing the linker sequence between the RGS and RBD1 domains abolished RGS14 action. Examination of the alpha-helical linker region suggested candidate serine residues that might facilitate regulatory activities. RGS14 Ser266 and Ser269 are phosphorylated in response to PTH and FGF23, and replacement of these residues by Ala eliminated the actions of RGS14 on hormone-sensitive phosphate transport. PTH stimulated the phosphorylation of a peptide construct harboring the sites of purported phosphorylation and full-length RGS14. Mutating Ser266Ala and Ser269Ala abolished phosphorylation. The results establish that RGS14 regulation of phosphate transport requires targeted phosphorylation within the linker and an intact PDZ ligand.

Hypoparathyroidism: Similarities and differences between Western and Eastern countries.

Hypoparathyroidism (hypoPT) is characterized by acute and chronic complications due to insufficient parathyroid hormone (PTH) production or action. Several management guidelines have been developed, but mostly based on evidence from Western countries. Data from Eastern countries have not been systematically compared with those from Western countries. Literatures regarding to the epidemiology, genetics, risk factors, clinical manifestations and therapies for hypoPT in Easten and Western countries, including China, South Korea, Japan, India, and USA, Canada, Italy, and etc., were searched through PubMed and CNKI. This review was officially endorsed by European Calcified Tissue Society (ECTS) board. Postoperative hypoPT is the major form of hypoPT in both Western and Eastern countries. The genetic profiles and clinical features of hypoPT are similar in Eastern and Western countries. The most commonly used medications in Eastern countries are calcium and native vitamin D or active vitamin D analogues, similar to their Western counterparts. While PTH replacement therapy is not available and approved to use in most Eastern countries. Physicians and surgeons should follow the guidelines on the management of thyroid nodules, taking more care of protecting parathyroid glands during surgery. The cross-talk between East and West in the management of hypoPT should be continued. Direct comparisons of the management strategies in patients with hypoPT between Eastern and Wester countries regarding to the morbidity, mortality, quality of life, optimal dosage, efficacies and side-effects of conventional therapies or newer medications, as well as pharmacogenetics and pharmacoeconomics, would be valuable.

Peripubertal antagonism of corticotropin-releasing factor receptor 1 results in sustained changes in behavioral plasticity and the transcriptomic profile of the amygdala.

Peripuberty is a significant period of neurodevelopment with long-lasting effects on the brain and behavior. Blocking type 1 corticotropin-releasing factor receptors (CRFR1) in neonatal and peripubertal rats attenuates detrimental effects of early-life stress on neural plasticity, behavior, and stress hormone action, long after exposure to the drug has ended. CRFR1 antagonism can also impact neural and behavioral development in the absence of stressful stimuli, suggesting sustained alterations under baseline conditions. To investigate this further, we administered the CRFR1 antagonist (CRFR1a) R121919 to young adolescent male and female rats across 4 days. Following each treatment, rats were tested for locomotion, social behavior, mechanical allodynia, or prepulse inhibition (PPI). Acute CRFR1 blockade immediately reduced PPI in peripubertal males, but not females. In adulthood, each assay was repeated without CRFR1a exposure to test for persistent effects of the adolescent treatment. Males continued to experience deficits in PPI while females displayed altered locomotion, PPI, and social behavior. The amygdala was collected to measure long-term effects on gene expression. In the adult amygdala, peripubertal CRFR1a induced alterations in pathways related to neural plasticity and stress in males. In females, pathways related to central nervous system myelination, cell junction organization, and glutamatergic regulation of synaptic transmission were affected. Understanding how acute exposure to neuropharmacological agents can have sustained impacts on brain and behavior, in the absence of further exposures, has important clinical implications for developing adolescents.

Structure of an LGR dimer - an evolutionary predecessor of glycoprotein hormone receptors.

The glycoprotein hormones of humans, produced in the pituitary and acting through receptors in the gonads to support reproduction and in the thyroid gland for metabolism, have co-evolved from invertebrate counterparts 1,2 . These hormones are heterodimeric cystine-knot proteins; and their receptors bind the cognate hormone at an extracellular domain and transmit the signal of this binding through a transmembrane domain that interacts with a heterotrimeric G protein. Structures determined for the human receptors as isolated for cryogenic electron microscopy (cryo-EM) are all monomeric 3-6 despite compelling evidence for their functioning as dimers 7-10 . Here we describe the cryo-EM structure of the homologous receptor from a neuroendocrine pathway that promotes growth in a nematode 11 . This structure is an asymmetric dimer that can be activated by the hormone from that worm 12 , and it shares features especially like those of the thyroid stimulating hormone receptor (TSHR). When studied in the context of the human homologs, this dimer provides a structural explanation for the transactivation evident from functional complementation of binding-deficient and signaling-deficient receptors 7 , for the negative cooperativity in hormone action that is manifest in the 1:2 asymmetry of primary TSH:TSHR complexes 8,9 , and for switches in G-protein usage that occur as 2:2 complexes form 9,10 .

Thyroid Hormones and Co-workers: An Overview.

The hypothalamus secretes the thyroid-releasing hormone(TRH) that induces the pituitary gland to release the thyroid-stimulating hormone(TSH) which stimulates thyroid follicular cells to release the thyroid hormones(THs), thyroxine (T4), and triiodothyronine (T3). The process of synthesizing T3 and T4 hormones involves various enzymatic steps, starting with the iodination of L-tyrosine residues present in the protein thyroglobulin. Thyroid hormones are released into the bloodstream, where they bind to thyroid hormone distributor proteins (THDPs) which transport them in the circulation. The conversion of T4 to T3 (the more biologically active hormone) in target tissues is facilitated by selenoprotein enzymes known as deiodinases. THscan bind to different molecules located on the plasma membrane, such as integrin αvβ3, through which they exercise regulatory non-genomic control. Nevertheless,most of thyroid hormone's actions are mediated intracellularly by binding to thyroid hormone receptors(TRs). Thyroid hormone receptors act as ligand-dependent transcription factors, Thyroid hormone receptors activate thyroid hormone response elements on gene promoters through canonical signaling. Thyroid hormones mediate several critical physiological processes including organ development, cell differentiation, metabolism, and cell growth and maintenance.

Recent advances in research on common targets of neurological and sex hormonal influences on asthma.

Asthma is currently one of the most common of respiratory diseases, severely affecting the lives of patients. With the in-depth study of the role of the nervous system and sex hormones on the development of asthma, it has been found that the nervous system and sex hormones are related to each other in the pathway of asthma. To investigate the effects of sex hormones and the nervous system on the development of asthma. In this review, we searched for a large number of relevant literature to elucidate the unique mechanisms of sex hormones and the nervous system on asthma development, and summarized several common targets in the pathways of sex hormones and the nervous system on asthma. We summarize several common important targets in the pathways of action of sex hormones and the nervous system in asthma, provide new directions and ideas for asthma treatment, and discuss current therapeutic limitations and future possibilities. Finally, the article predicts future applications of several important targets in asthma therapy.

Thyroid Hormone Action by Genomic and Nongenomic Molecular Mechanisms.

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are pivotal in regulating various physiological processes including growth, development, and metabolism. The biological actions of thyroid hormones are primarily initiated by binding to nuclear thyroid hormone receptors (TRs). These receptors, belonging to the superfamily of nuclear receptors, act as ligand-dependent transcription factors. Transcriptional regulation by TRs is mediated by the recruitment of coregulators, governing activation and repression of target genes, thereby modulating cellular responses to thyroid hormones. Beyond this canonical genomic pathway, TH can regulate the expression of genes not directly bound by TRs through cross-talk mechanisms with other transcription factors and signaling pathways. Thyroid hormones can also elicit rapid non-genomic effects, potentially mediated by extranuclear TR proteins or by interactions with membrane receptors such as integrin αvβ3. This non-genomic mode of action adds another layer of complexity to the diverse array of physiological responses orchestrated by thyroid hormones, expanding our understanding of their multifaceted actions.

Up-regulated mitochondrial biogenesis associated with GH/IGF axis in the ovaries of muskrats (Ondatra zibethicus)

Mitochondria play a critical role in follicular development and ovulation, at least in part through the actions of growth hormone (GH)/insulin-like growth factor-1 (IGF-1) on mitochondrial biogenesis. This study aimed to identify seasonal alterations in the GH/IGF-1 system and mitochondrial biogenesis in muskrat (Ondatra zibethicus) ovaries. We utilized the muskrat, a typical seasonal breeder, to clarify the potential impact of the GH/IGF-1 system on mitochondrial biogenesis across different breeding seasons using immunohistochemistry, gene expression and high-throughput sequencing. Alterations in follicular development existed in muskrat ovaries between the breeding season (BS) and non-breeding season (NBS), accompanied by a striking decrease in circulating and ovarian GH and IGF-1 concentrations. GH, GHR, IGF-1, IGF-1R, and mitochondrial biogenesis markers were localized in the ovarian cells of muskrats during both seasons. In contrast, Gh, Ghr, Igf-1, Igf-1r, Ppargc1a, Ppargc1b, Tfam, and Nrf1/2 mRNA levels were higher in BS. The relative levels of GH and IGF-1 in circulation and ovaries were positively associated with mitochondrial biogenesis markers. Additionally, RNA-seq analysis demonstrated that differentially expressed genes might be associated with insulin and PI3K/Akt signaling pathways, as well as mitochondrial function-related pathways. These findings suggest that the intra-ovarian GH/IGF-1 system, which is associated with seasonal changes in mitochondrial biogenesis, is activated in muskrat ovaries in BS.

Transcriptome and metabolome analysis of osteoblasts identifies disrupted purine metabolism and parathyroid hormone associated pathway induced by P. gingivalis infection.

Porphyromonas gingivalis (P. gingivalis), a major pathogenic bacterium of chronic periodontitis and central player in the onset and subsequent progression of periodontitis, can cause alveolar bone resorption. The osteoblast dysfunction induced by P. gingivalis infection is a crucial pathological process causing bone loss. However, the comprehensive responses of osteoblasts, especially metabolism processes involved in osteoblast dysfunction under P. gingivalis invasion are largely unknown. In the present study, to profile the molecules switched in osteoblast dysfunction caused by P. gingivalis infection, the effect of P. gingivalis invasion on osteoblast differentiation was assessed and investigated through transcriptomics and metabolomics approaches. We found that P. gingivalis infection dramatically impaired osteoblast function. P. gingivalis invasion disrupted homeostasis of phosphorus (Pi)/calcium (Ca2+) and induced robust oxidative stress, cell apoptosis and massive activation of inflammatory response in osteoblasts. Notably, the exposure to P. gingivalis induced the inactivation of endocrines pathways, involved in bone formation, which is characterized by downregulated genes and less accumulated metabolites in "Parathyroid hormone synthesis, secretion and action", its downstream "Wnt signaling pathway" and related Pi/Ca2+ transport. Furthermore, we found that disrupted purine metabolism produced less ATP in P. gingivalis-infected osteoblasts and the reduced ATP may directly inhibit phosphorus transport. Collectively, these results provide a new insight into the molecular changes in P. gingivalis-infected osteoblasts in a comprehensive way.

Hormone Signaling in Breast Development and Cancer.

Hormones control normal breast development and function. They also impinge on breast cancer (BC) development and disease progression in direct and indirect ways. The major ovarian hormones, estrogens and progesterone, have long been established as key regulators of mammary gland development in rodents and linked to human disease. However, their roles have been difficult to disentangle because they act on multiple tissues and can act directly and indirectly on different cell types in the breast, and their receptors interact at different levels within the target cell. Estrogens are well-recognized drivers of estrogen receptor-positive (ER+) breast cancers, and the ER is successfully targeted in ER+ disease. The role of progesterone receptor (PR) as a potential target to be activated or inhibited is debated, and androgen receptor (AR) signaling has emerged as a potentially interesting pathway to target on the stage.In this chapter, we discuss hormone signaling in normal breast development and in cancer, with a specific focus on the key sex hormones: estrogen, progesterone, and testosterone. We will highlight the complexities of endocrine control mechanisms at the organismal, tissue, cellular, and molecular levels. As we delve into the mechanisms of action of hormone receptors, their interplay and their context-dependent roles in breast cancer will be discussed. Drawing insights from new preclinical models, we will describe the lessons learned and the current challenges in understanding hormone action in breast cancer.

Absence of cholesterol gallstone formation in male C57BL/6 mice by abrogation of hepatic thyroid hormone action

Absence of cholesterol gallstone formation in male C57BL/6 mice by abrogation of hepatic thyroid hormone action

The neurobiology of parenting and infant-evoked aggression.

Parenting behavior comprises a variety of adult-infant and adult-adult interactions across multiple timescales. The state transition from nonparent to parent requires an extensive reorganization of individual priorities and physiology and is facilitated by combinatorial hormone action on specific cell types that are integrated throughout interconnected and brainwide neuronal circuits. In this review, we take a comprehensive approach to integrate historical and current literature on each of these topics across multiple species, with a focus on rodents. New and emerging molecular, circuit-based, and computational technologies have recently been used to address outstanding gaps in our current framework of knowledge on infant-directed behavior. This work is raising fundamental questions about the interplay between instinctive and learned components of parenting and the mutual regulation of affiliative versus agonistic infant-directed behaviors in health and disease. Whenever possible, we point to how these technologies have helped gain novel insights and opened new avenues of research into the neurobiology of parenting. We hope this review will serve as an introduction for those new to the field, a comprehensive resource for those already studying parenting, and a guidepost for designing future studies.