The 10 most-cited articles in Endocrinology, 2022

Oxytocin and vasopressin are peptide hormones secreted from the pituitary that are well known for their peripheral endocrine effects on childbirth/nursing and blood pressure/urine concentration, respectively. However, both peptides are also released in the brain, where they modulate several aspects of social behaviors. Oxytocin promotes maternal nurturing and bonding, enhances social reward, and increases the salience of social stimuli. Vasopressin modulates social communication, social investigation, territorial behavior, and aggression, predominantly in males. Both peptides facilitate social memory and pair bonding behaviors in monogamous species. Here we review the latest research delineating the neural circuitry of the brain oxytocin and vasopressin systems and summarize recent investigations into the circuit-based mechanisms modulating social behaviors. We highlight research using modern molecular genetic technologies to map, monitor activity of, or manipulate neuropeptide circuits. Species diversity in oxytocin and vasopressin effects on social behaviors are also discussed. We…

Adipose tissue secretions are depot-specific and vary based on anatomical location. Considerable attention has been focused on visceral (VAT) and subcutaneous (SAT) adipose tissue with regard to metabolic disease, yet our knowledge of the secretome from these depots is incomplete. We conducted a comprehensive analysis of VAT and SAT secretomes in the context of metabolic function. Conditioned media generated using SAT and VAT explants from individuals with obesity were analyzed using proteomics, mass spectrometry, and multiplex assays. Conditioned media were administered in vitro to rat hepatocytes and myotubes to assess the functional impact of adipose tissue signaling on insulin responsiveness. VAT secreted more cytokines (IL-12p70, IL-13, TNF-α, IL-6, and IL-8), adipokines (matrix metalloproteinase-1, PAI-1), and prostanoids (TBX2, PGE2) compared with SAT. Secretome proteomics revealed differences in immune/inflammatory response and extracellular matrix components. In vitro, VAT-conditioned media decreased hepatocyte and myotube insulin sensitivity, hepatocyte glucose handling,…

The pathogeneses of the 2 major forms of diabetes, type 1 and type 2, differ with respect to their major molecular insults (loss of immune tolerance and onset of tissue insulin resistance, respectively). However, evidence suggests that dysfunction and/or death of insulin-producing β-cells is common to virtually all forms of diabetes. Although the mechanisms underlying β-cell dysfunction remain incompletely characterized, recent years have witnessed major advances in our understanding of the molecular pathways that contribute to the demise of the β-cell. Cellular and environmental factors contribute to β-cell dysfunction/loss through the activation of molecular pathways that exacerbate endoplasmic reticulum stress, the integrated stress response, oxidative stress, and impaired autophagy. Whereas many of these stress responsive pathways are interconnected, their individual contributions to glucose homeostasis and β-cell health have been elucidated through the development and interrogation of animal models. In these studies, genetic models and pharmacological compounds have enabled the…

The practice of oncology has dramatically changed in the last decade with the introduction of molecular tumor profiling into routine tumor diagnostics and the extraordinary progress in immunotherapies. However, there remains an unmet need to explore personalized dosing strategies that take into account the patient's sex and gender to optimize the balance between efficacy and toxicity for each individual patient. In this mini-review, we summarize the evidence on sex and gender differences in toxicity of anticancer therapies and present data on dose reduction and dose discontinuation rates for selected chemotherapies and targeted therapies. Finally, we propose the investigation of body composition (specifically fat-free muscle mass) as a viable approach for personalized treatment dosage.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women. A common symptom of PCOS is hyperandrogenism (AE); however, the source of these androgens is uncertain. Aldo-keto reductase family 1 member C3 (AKR1C3) catalyzes the formation of testosterone (T) and 5α-dihydrotestosterone (DHT) in peripheral tissues, which activate the androgen receptor (AR). AKR1C3 is induced by insulin in adipocytes and may be central in driving the AE in PCOS. We elucidated the conversion of both classical and 11-oxygenated androgens to potent androgens in a model of PCOS adipocytes. Using high-performance liquid chromatography (HPLC) discontinuous kinetic assays to measure product formation by recombinant AKR1C3, we found that the conversion of 11-keto-Δ4-androstene-3,17-dione (11K-4AD) to 11-ketotestosterone (11K-T) and 11-keto-5α-androstane-3,17-dione (11K-5AD) to 11-keto-5α-dihydrotestosterone (11K-DHT) were superior to the formation of T and DHT. We utilized a stable isotope dilution liquid chromatography high resolution mass spectrometric (SID-LC-HRMS) assay for the…

Despite advances in treatment strategies, breast cancer (BC) remains one of the most prevalent cancers worldwide. Recent studies implicate the gut microbiome as a potential risk factor for BC development. Alterations in gut microbial diversity resulting in dysbiosis have been linked to breast carcinogenesis by modulating host immune responses and inflammatory pathways, favoring tumorigenesis and progression. Moreover, gut microbiota populations are different between women with BC vs those that are cancer free, further implicating the role of the gut microbiome in cancer development. This alteration in gut microbiota is also associated with changes in estrogen metabolism, which strongly correlates with BC development. Gut microbiota that express the enzyme β-glucuronidase (GUS) may increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties enabling reabsorption into circulation. Increased circulating estrogens may, in turn, drive estrogen receptor-positive BC. GUS-expressing microbiota also affect cancer therapy efficacy and toxicity by modifying…

The zonation of liver metabolic processes is well-characterized; however, little is known about the cell type-specificity and zonation of sexually dimorphic gene expression or its growth hormone (GH)-dependent transcriptional regulators. We address these issues using single-nucleus RNA-sequencing of 32 000 nuclei representing 9 major liver cell types. Nuclei were extracted from livers from adult male and female mice; from males infused with GH continuously, mimicking the female plasma GH pattern; and from mice exposed to TCPOBOP, a xenobiotic agonist ligand of the nuclear receptor CAR that perturbs sex-biased gene expression. Analysis of these rich transcriptomic datasets revealed the following: 1) expression of sex-biased genes and their GH-dependent transcriptional regulators is primarily restricted to hepatocytes and is not a feature of liver nonparenchymal cells; 2) many sex-biased transcripts show sex-dependent zonation within the liver lobule; 3) gene expression is substantially feminized both in periportal and pericentral hepatocytes when male mice are infused with GH…

In women, excess androgen causes polycystic ovary syndrome (PCOS), a common fertility disorder with comorbid metabolic dysfunctions including diabetes, obesity, and nonalcoholic fatty liver disease. Using a PCOS mouse model, this study shows that chronic high androgen levels cause hepatic steatosis while hepatocyte-specific androgen receptor (AR)-knockout rescues this phenotype. Moreover, through RNA-sequencing and metabolomic studies, we have identified key metabolic genes and pathways affected by hyperandrogenism. Our studies reveal that a large number of metabolic genes are directly regulated by androgens through AR binding to androgen response element sequences on the promoter region of these genes. Interestingly, a number of circadian genes are also differentially regulated by androgens. In vivo and in vitro studies using a circadian reporter [Period2::Luciferase (Per2::LUC)] mouse model demonstrate that androgens can directly disrupt the hepatic timing system, which is a key regulator of liver metabolism. Consequently, studies show that androgens decrease H3K27me3, a gene…

Differentiated thyroid cancer and breast cancer account for a significant portion of endocrine-related malignancies and predominately affect women. As hormonally responsive tissues, the breast and thyroid share endocrine signaling. Breast cells are responsive to thyroid hormone signaling and are affected by altered thyroid hormone levels. Thyroid cells are responsive to sex hormones, particularly estrogen, and undergo protumorigenic processes upon estrogen stimulation. Thyroid and sex hormones also display significant transcriptional crosstalk that influences oncogenesis and treatment sensitivity. Obesity-related adipocyte alterations-adipocyte estrogen production, inflammation, feeding hormone dysregulation, and metabolic syndromes-promote hormonal alterations in breast and thyroid tissues. Environmental toxicants disrupt endocrine systems, including breast and thyroid homeostasis, and influence pathologic processes in both organs through hormone mimetic action. In this brief review, we discuss the hormonal connections between the breast and thyroid and perspectives on hormonal…

Preterm birth worldwide remains a significant cause of neonatal morbidity and mortality, yet the exact mechanisms of preterm parturition remain unclear. Preterm birth is not a single condition, but rather a syndrome with a multifactorial etiology. This multifactorial nature explains why individual predictive measures for preterm birth have had limited sensitivity and specificity. One proposed pathway for preterm birth is via placentally synthesized corticotrophin-releasing hormone (CRH). CRH is a peptide hormone that increases exponentially in pregnancy and has been implicated in preterm birth because of its endocrine, autocrine, and paracrine roles. CRH has actions that increase placental production of estriol and of the transcription factor nuclear factor-κB, that likely play a key role in activating the myometrium. CRH has been proposed as part of a placental clock, with early activation of placental production resulting in preterm birth. This article will review the current understanding of preterm birth, CRH as an initiator of human parturition, and the evidence regarding the…