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The 'ethylene glycol ethers' (EGE) are a broad family of solvents and hydraulic fluids produced through the reaction of ethylene oxide and a monoalcohol. Certain EGE derived from methanol and ethanol are well known to cause toxicity to the testes and fetotoxicity and that this is caused by the common metabolites methoxy and ethoxyacetic acid, respectively. There have been numerous published claims that EGE fall into the category of 'endocrine disruptors' often without substantiated evidence. This review systematically evaluates all of the available and relevant in vitro and in vivo data across this family of substances using an approach based around the EFSA/ECHA 2018 guidance for the identification of endocrine disruptors. The conclusion reached is that there is no significant evidence to show that EGE target any endocrine organs or perturb endocrine pathways and that any toxicity that is seen occurs by non-endocrine modes of action., (Copyright © 2022 The Author. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine whether feeding CircuCare to rats improves blood circulation, metabolism, immune regulation, endocrine activity, and oxidative stress., Methods: 28 eight-week-old male Sprague-Dawley rats were evenly randomized into control and experimental groups. The control group was fed with ordinary drinking water, while the experimental group was fed with CircuCare at a daily dose of 93.75 mg per 300 g of body weight over eight weeks. Both groups were subjected to a swimming test, and blood samples were taken to observe any variations in various biochemical parameters before and after the test. Key Findings . The experimental group's mean swimming exhaustion duration was 53.2% longer and had a significantly higher lactic acid removal ratio. Their mean prostaglandin E2 level and mean glucose, cortisol, and glutathione level (30 minutes after swimming test) were also significantly higher. No undesirable impacts from CircuCare relating to general blood biochemistry values and bone mineral density were reported., Conclusions: The present results show that CircuCare can be safely used to increase stamina and exercise capability, expedite the metabolism of lactic acid, accelerate muscle repair, and promote the antioxidant activity of cells in rats., Competing Interests: The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2021 Kai-Ting Chien et al.)

The mammary gland (MG) and female prostate are plastic reproductive organs which are highly responsive to hormones. Thus, endocrine disruptors, such as bisphenol A (BPA) and exogenous estrogens, negatively affect glandular homeostasis. In addition to previously described alterations, changes in inflammatory markers expression also trigger the development of a microenvironment that contributes to tumor progression. The current work aimed to evaluate the inflammatory responses of the MG and prostate gland to BPA (50 µg/kg) and 17-β estradiol (35 µg/kg) exposure during the perinatal window of susceptibility. The results showed that at 6 months of age there was an increase in the number of phospho-STAT3 (P-STAT3) positive cells in the female prostate from animals perinatally exposed to 50 µg/kg BPA daily. In addition, the number of macrophages increased in these animals in comparison with nonexposed animals, as shown by the F4/80 marker. Despite an increase in the incidence of lobuloalveolar and intraductal hyperplasia, the MG did not show any difference in the expression of the four inflammatory markers evaluated: tumor necrosis factor-α, COX-2, P-STAT3, and F4/80. Analysis of both glands from the same animal led to the conclusion that exposure to endocrine disruptors during the perinatal window of susceptibility leads to different inflammatory responses in different reproductive organs. As the prostate is more susceptible to these inflammatory mechanisms, it is reasonable to affirm that possible neoplastic alterations in this organ are related to changes in the inflammatory pattern of the stroma, a characteristic that is not evident in the MG., (© 2021 International Federation for Cell Biology.)

Introduction: Introduction: propolis and its components influence lipid metabolism; however, its effect on body composition and mineral metabolism remains unknown. Objectives: to determine the effect of natural propolis supplementation on body composition, mineral metabolism, and the endocrine function of adipose tissue. Material and methods: twenty albino male Wistar rats (8 weeks old) were divided into two groups of 10 animals each. The rats were fed two different types of diet for 90 days: a standard diet for the control group (group C) and the same standard diet + 2 % propolis (group P). Thyroid hormones, ghrelin, leptin, adiponectin and insulin, non-esterified fatty acids (NEFA) in plasma, body composition (lean mass, fat mass and body water), and mineral deposition in target organs (spleen, brain, heart, lungs, testicles, kidneys and femur) were assessed. Results: thyroid stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) did not show any differences after supplementation with propolis, while ghrelin and adiponectin decreased (p < 0.01 and p < 0.05, respectively) and insulin (p < 0.01), leptin (p < 0.05) and NEFA (p < 0.05) increased when 2 % propolis was supplied, while weight and body fat were reduced (p < 0.05) and lean mass increased. Lastly, the propolis supplement improves calcium deposition in the spleen, lungs, testes, and femur (p < 0.05). Conclusion: propolis supplementation of the diet (2 %) causes a decrease in the secretion of ghrelin and adiponectin, increasing the release of non-esterified fatty acids and the rate of insulin secretion. In addition, propolis supplementation induces an improvement in calcium deposition in target organs without affecting the rest of minerals, which improves body composition by inducing a reduction in weight and visceral adipose tissue, and improvement in lean mass.

Context: Although stages of reproductive aging for women in the general population are well described by STRAW+10 criteria, this is largely unknown for female adolescent and young adult cancer survivors (AYA survivors)., Objective: This work aimed to evaluate applying STRAW + 10 criteria in AYA survivors using bleeding patterns with and without endocrine biomarkers, and to assess how cancer treatment gonadotoxicity is related to reproductive aging stage., Design: The sample (n = 338) included AYA survivors from the Reproductive Window Study cohort. Menstrual bleeding data and dried-blood spots for antimüllerian hormone (AMH) and follicle-stimulating hormone (FSH) measurements (Ansh DBS enzyme-linked immunosorbent assays) were used for reproductive aging stage assessment. Cancer treatment data were abstracted from medical records., Results: Among participants, mean age 34.0 ± 4.5 years and at a mean of 6.9 ± 4.6 years since cancer treatment, the most common cancers were lymphomas (31%), breast (23%), and thyroid (17%). Twenty-nine percent were unclassifiable by STRAW + 10 criteria, occurring more frequently in the first 2 years from treatment. Most unclassifiable survivors exhibited bleeding patterns consistent with the menopausal transition, but had reproductive phase AMH and/or FSH levels. For classifiable survivors (48% peak reproductive, 30% late reproductive, 12% early transition, 3% late transition, and 7% postmenopause), endocrine biomarkers distinguished among peak, early, and late stages within the reproductive and transition phases. Gonadotoxic treatments were associated with more advanced stages., Conclusions: We demonstrate a novel association between gonadotoxic treatments and advanced stages of reproductive aging. Without endocrine biomarkers, bleeding pattern alone can misclassify AYA survivors into more or less advanced stages. Moreover, a large proportion of AYA survivors exhibited combinations of endocrine biomarkers and bleeding patterns that do not fit the STRAW + 10 criteria, suggesting the need for modified staging for this population., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The present study was designed to evaluate the effects of di- n -hexyl phthalate (DHP) and di-cyclohexyl phthalate (DCHP) on endocrine organs in rats. Oil control, 20-, 100-, and 500 mg/kg dose groups were selected and administered to pregnant rats on gestational days 6-19 by oral gavage. The neonatal stages of rats continued until postnatal day 20 and the- juvenile stages of rats continued until postnatal day of 32. The rats were allowed to mature until the neonatal and juvenile stages and there after, they were divided into four groups corresponding to the treatment levels. Body and organ weights were recorded, serum was collected, and thyroid, pancreas, pituitary gland, and adrenal gland were removed. There was a decrease in body weights in the 20- and 500mg/kg DHP and in the 20-mg/kg DCHP dose groups in neonatal male rats. In contrast, for female rats, there was an increase in body weights in the 100-mg/kg DCHP dose group and there was a decrease in body weights in the 500-mg/kg DHP dose group. Body weights were increased at 20 and 500 mg/kg in the DHP-exposed juvenile male rats. Serum thyroid-stimulating hormone (TSH) levels were increased in neonatal male rats, while they were increased in the 100-mg/kg DHP group of neonatal and juvenile female rats. Serum triiodothyronine (T3) levels were increased at the high dose of DHP for neonatal male rats and at the low and high dose levels of DCHP for female rats. Serum thyroxine (T4) levels were increased in neonatal rats for DHP. Also, some histopathological changes were observed in the thyroid, pancreas, adrenal, and pituitary gland. In conclusion, it was shown that DHP and DCHP caused negative effects on T3, T4, and TSH hormone levels.

The number of patients surviving ≥5 years after initial cancer diagnosis has significantly increased during the last decades due to considerable improvements in the treatment of many cancer entities. A negative consequence of this is that the emergence of long-term sequelae and endocrine disorders account for a high proportion of these. These late effects can occur decades after cancer treatment and affect up to 50% of childhood cancer survivors. Multiple predisposing factors for endocrine late effects have been identified, including radiation, sex, and age at the time of diagnosis. A systematic literature search has been conducted using the PubMed database to offer a detailed overview of the spectrum of late endocrine disorders following oncological treatment. Most data are based on late effects of treatment in former childhood cancer patients for whom specific guidelines and recommendations already exist, whereas current knowledge concerning late effects in adult-onset cancer survivors is much less clear. Endocrine sequelae of cancer therapy include functional alterations in hypothalamic-pituitary, thyroid, parathyroid, adrenal, and gonadal regulation as well as bone and metabolic complications. Surgery, radiotherapy, chemotherapy, and immunotherapy all contribute to these sequelae. Following irradiation, endocrine organs such as the thyroid are also at risk for subsequent malignancies. Although diagnosis and management of functional and neoplastic long-term consequences of cancer therapy are comparable to other causes of endocrine disorders, cancer survivors need individually structured follow-up care in specialized surveillance centers to improve care for this rapidly growing group of patients., (Copyright © 2019 Endocrine Society.)

Bacterial lipopolysaccharide (LPS) can contribute to the pathogenesis and the clinical symptoms of many diseases such as cancer, mental disorders, neurodegenerative as well as metabolic diseases. The asymptomatic carrier state of Salmonella spp. is a very important public health problem. A subclinical single dose of LPS obtained from S. Enteritidis (5 μg/kg, i.v.) was administered to discern the consequences of changes of various brain peptides such as corticotropin-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), galanin (GAL), neuropeptide Y (NPY), somatostatin (SOM), substance P (SP), and vasoactive intestinal polypeptide (VIP) in selected clinically important brain sections and endocrine glands of the hypothalamic-pituitary-adrenal (HPA), -thyroid (HPT), -ovarian (HPO) axes. The study was conducted on ten immature crossbred female pigs. The brain peptides were extracted from the hypothalamus (medial basal hypothalamus, preoptic area, lateral hypothalamic area, mammillary bodies, and the stalk median eminence), and pituitary gland (adenohypophysis and neurohypophysis) sections and from the ovaries and adrenal and thyroid glands. There was no difference in health status between LPS and the control groups during the period of the experiment. Nevertheless, even a low single dose of LPS from S. Enteritidis that did not result in any clinical symptoms of disease induced dysregulation of various brain peptides, such as CRH, GnRH, TRH, GAL, NPY, SOM, SP, and VIP in selected brain sections of hypothalamus, pituitary gland and in the endocrine glands of the HPA, HPO, and HPT axes. In conclusion, the obtained results clearly show that subclinical LPS from S. Enteritidis can affect the brain chemistry structure and dysregulate bioactive substance from selected brain sections and glands of the neuroendocrine axes. The exact mechanisms by which LPS can influence major neuroendocrine axes are not fully understood and require further studies.

Oligomers of styrene have been identified in polystyrene (PS) polymer samples intended for food packaging. Such oligomers contribute to nonintentionally added substances (NIAS) that may migrate into food or food simulants and therefore have to be assessed for the potential risk to health. No oligomers larger than dimers and trimers of styrene have been found to be present in PS. Some in vivo and in vitro information indicative of an endocrine activity for some specific oligomers suggest concerns for their potential for endocrine disruption in humans. Data on endocrine activity available from in vitro and in vivo screening approaches and from non-guideline studies in experimental animals were evaluated. The different test methods were classified according to the OECD Conceptual Framework for Testing and Assessment of Endocrine Disruptors (OECD) and the ranking system of Borgert et al. proposed in 2014. The quality and reliability of each study is further assessed by professional judgment. The integration of the total information supports the conclusion that neither specific oligomers, nor their mixtures, potentially migrating into food are endocrine disruptors according to the definition of EFSA and WHO/IPCS.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, because ICIs block coinhibitory molecules on T cells and other immune cells, unleashing them to mediate tumor cell killing, they also can disrupt the maintenance of immunological tolerance to self-antigens. Compared with chemotherapy, ICIs have a different toxicity profile, especially the occurrence of autoimmune-like manifestations against multiple organ systems, including endocrine glands, commonly referred to as immune-related adverse events. The aim of this review was to provide practical recommendations regarding the proper assessment and clinical management related to the new onset of endocrinopathies after the use of ICIs in patients with cancer. Cancer 2018;124:1111-21. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Importance: If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune checkpoint inhibitor (ICI) regimens are unknown., Objective: To compare the incidence and risk of endocrine AEs following treatment with US Food and Drug Administration-approved ICI regimens., Data Sources: A PubMed search through July 18, 2016, using the following keywords was performed: "ipilimumab," "MDX-010," "nivolumab," "BMS-963558," "pembrolizumab," "MK-3475," "atezolizumab," "MPDL3280A," and "phase.", Study Selection: Thirty-eight randomized clinical trials evaluating the usage of these ICIs for treatment of advanced solid tumors were identified, resulting in a total of 7551 patients who were eligible for a meta-analysis. Regimens were categorized by class into monotherapy with a PD-1 (programmed cell death protein 1) inhibitor, a CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) inhibitor, or a PD-L1 (programmed cell death 1 ligand 1) inhibitor, and combination therapy with PD-1 plus CTLA-4 inhibitors., Data Extraction and Synthesis: The data were extracted by 1 primary reviewer (R.B.-S.) and then independently reviewed by 2 secondary reviewers (W.T.B. and A.C.G.-C.) following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inferences on the incidence of AEs were made using log-odds random effects models., Main Outcomes and Measures: Incidence of all-grade hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and insulin-deficient diabetes., Results: Overall, 38 randomized clinical trials comprising 7551 patients were included in this systematic review and meta-analysis. The incidence of both hypothyroidism and hyperthyroidism was highest in patients receiving combination therapy. Patients on the combination regimen were significantly more likely to experience hypothyroidism (odds ratio [OR], 3.81; 95% CI, 2.10-6.91, P < .001) and hyperthyroidism (OR, 4.27; 95% CI, 2.05-8.90; P = .001) than patients on ipilimumab. Compared with patients on ipilimumab, those on PD-1 inhibitors had a higher risk of developing hypothyroidism (OR, 1.89; 95% CI, 1.17-3.05; P = .03). The risk of hyperthyroidism, but not hypothyroidism, was significantly greater with PD-1 than with PD-L1 inhibitors (OR, 5.36; 95% CI, 2.04-14.08; P = .002). While patients who received PD-1 inhibitors were significantly less likely to experience hypophysitis than those receiving ipilimumab (OR, 0.29; 95% CI, 0.18-0.49; P < .001), those who received combination therapy were significantly more likely to develop it (OR, 2.2; 95% CI, 1.39-3.60; P = .001). For primary adrenal insufficiency and insulin-deficient diabetes no statistical inferences were made due to the smaller number of events., Conclusions and Relevance: Our study provides more precise data on the incidence of endocrine dysfunctions among patients receiving ICI regimens. Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis.

Amphibians inhabiting montane riparian zones in the Neotropics are particularly vulnerable to decline, but the reasons are poorly understood. Because environmental contaminants, endocrine disruption, and pathogens often figure prominently in amphibian declines it is imperative that we understand how these factors are potentially interrelated to affect montane populations. One possibility is that increased precipitation associated with global warming promotes the deposition of contaminants in montane regions. Increased exposure to contaminants, in turn, potentially elicits chronic elevations in circulating stress hormones that could contribute to montane population declines by compromising resistance to pathogens and/or production of sex steroids regulating reproduction. Here, we test this hypothesis by examining contaminant levels, stress and sex steroid levels, and nematode abundances in male drab treefrogs, Smilisca sordida, from lowland and montane populations in Costa Rica. We found no evidence that montane populations were more likely to possess contaminants (i.e., organochlorine, organophosphate and carbamate pesticides or benzidine and chlorophenoxy herbicides) than lowland populations. We also found no evidence of elevational differences in circulating levels of the stress hormone corticosterone, estradiol or progesterone. However, montane populations possessed lower androgen levels, hosted more nematode species, and had higher nematode abundances than lowland populations. Although these results suggested that nematodes contributed to lower androgens in montane populations, we were unable to detect a significant inverse relationship between nematode abundance and androgen level. Our results suggest that montane populations of this species are not at greater risk of exposure to contaminants or chronic stress, but implicate nematodes and compromised sex steroid levels as potential threats to montane populations.

Phytochemicals are non-nutrient bioactive compounds occurring in plants and food, which possess the capacity to modulate one or more metabolic processes or pathways in the body, resulting to health benefits and promotion of well-being. The interest of the scientific community continues to grow, powered by progressive research efforts to identify properties and potential applications of bioactive substances, and coupled with public interest and consumer demand. However, the natural derivation of these compounds is not a feature of harmlessness, over that of therapeutic efficacy, to which is also added the absence of post-marketing monitoring which does not allow to evaluate the occurrence of adverse effects related to the use of their related products. The literature is particularly rich of studies concerning phytochemicals as environmental estrogens, which result in infertility, reproductive abnormalities, and tumors but also in some endocrine-related health effects. Nevertheless, further studies have been performed to better understand the bioavailability, pharmacokinetics and mode of action of these compounds which seems to go beyond their ability to bind to oestrogen receptors and either stimulate or inhibit the activity of endogenous oestrogens, highlighting new interesting target molecules and signaling pathways. The present review summarizes the latest developments and knowledge concerning the assessment of endocrine activities of dietary phytochemicals focusing on pharmacological aspects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease (IBD)., Objectives: Taking advantage of different mesalamine formulations with/without DBP, we assessed whether DBP from mesalamine (>1000x background) altered serum hormones., Methods: Men (N=73) with IBD participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background) at baseline crossed-over for 4 months to DBP-mesalamine (high) and then crossed-back for 4 months to non-DBP mesalamine (B 1 HB 2 -arm) and vice versa for men on DBP-mesalamine at baseline (H 1 BH 2 -arm). We divided H 1 BH 2 -arm at the median (H 1 <3yrs or H 1 ≥3yrs). We estimated crossover and crossback % changes in serum reproductive hormones using multivariable linear mixed effect models., Results: When B 1 HB 2 -arm (26 men,134 samples) crossed-over, luteinizing hormone decreased 13.9% (95% confidence interval(CI): -23.6,-3.0) and testosterone, inhibin-B, and follicle-stimulating hormone (FSH) marginally decreased; after crossback all increased 8-14%. H 1 BH 2 -arm, H 1 ≥3yrs (25 men,107samples) had no changes at crossover or crossback whereas in H 1 BH 2 -arm,H 1 <3yrs (22 men,100 samples) after crossover, inhibin-B increased 13.2% (CI: 4.2,22.9), FSH decreased 9.9% (CI: -17.9,-1.1) and after crossback, inhibin-B further increased 11.3%, and FSH marginally increased., Conclusions: High-DBP exposure may disrupt pituitary-gonadal hormones that largely reversed after exposure removal, but only in men with no or short previous high-exposure history. Paradoxically, men with longer duration of high-DBP exposure, exposure removal did not change hormone levels, suggesting that long-term high-DBP exposure may alter the pituitary-gonadal axis and make it insensitive to exposure changes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To determine whether adding dehydroepiandrosterone to combined oral contraceptives (COCs) maintains physiological levels of free testosterone., Study Design: A randomized, double-blind, placebo-controlled, two-way crossover study conducted in 81 healthy women (age range: 20-35 years; Body mass index (BMI) range: 18-35 kg/m 2 ) using oral contraceptives. Androgens, sex hormone-binding globulin (SHBG), estradiol (E2) and estrone (E1) were measured, and free testosterone and the free testosterone index were calculated. Subjects discontinued oral contraceptive use for at least one menstrual cycle before being randomized to receive five cycles of ethinyl estradiol (EE) combined with either levonorgestrel (EE/LNG group) or drospirenone (EE/DRSP group) together with either dehydroepiandrosterone (DHEA) (50 mg/day orally) or placebo. Subsequently, all subjects crossed over to the other treatment arm for an additional five cycles., Results: Both COCs decreased the levels of all androgens measured. Significant decreases (p<.05) were found with EE/LNG and EE/DRSP for total testosterone (54.5% and 11.3%, respectively) and for free testosterone (66.8% and 75.6%, respectively). Adding DHEA to the COCs significantly increased all androgens compared to placebo. Moreover, including DHEA restored free testosterone levels to baseline values in both COC groups and total testosterone levels to baseline in the EE/LNG group and above baseline in the EE/DRSP group. SHBG concentrations were significantly higher with EE/DRSP compared to EE/LNG (p<.0001). The addition of DHEA did not affect the levels of SHBG., Conclusions: Taking COCs reduces total and free testosterone levels and increases SHBG concentrations. By coadministration with DHEA, physiological levels of total and free testosterone are restored while using EE/LNG. With EE/DRSP, only the free testosterone level is normalized by DHEA coadministration., Implications: A daily oral dose of 50-mg DHEA maintains physiological free and total testosterone levels in women who are using an EE/LNG-containing COC., (Copyright © 2016 Pantarhei Bioscience. Published by Elsevier Inc. All rights reserved.)

Context: Arecoline is an effective constituent of Areca catechu L. (Arecaceae) with various pharmacological effects. However, investigations also revealed that long use of arecoline could arouse some oral diseases., Objective: The present review gathers the fragmented information available in the literature (before 1 October 2015) regarding pharmacology and toxicology of arecoline. We also discussed the potential developments and applications of arecoline in the future., Methods: All the available information regarding the arecoline is compiled from scientific databases, including Science Direct, PubMed, Web of Science, Scopus, etc., Results: Previous research demonstrated that arecoline is one of the major effective constituents in A. catechu. Additionally, arecoline has a wide spectrum of pharmacological activities including effects on nervous, cardiovascular, digestive and endocrine systems and anti-parasitic effects. What's more, arecoline is reported to be the primary toxic constituent of A. catechu, and the main toxic effects include oral submucous fibrosis (OSF), oral squamous cell carcinoma (OSCC) and genotoxicity., Conclusion: Arecoline has great potential to be a therapeutic drug for various ailments. However, further investigations are needed in the future to reduce or eliminate its toxicities before developing into new drug.

The present study was designed to test the effects of methylphenidate (MPH) exposure on the maturation of endocrine functioning and sexual behavior. Female rat pups received either MPH (2.0mg/kg, i.p.) or saline twice daily between postnatal days 20-35. This period of exposure represents the time just prior to puberty as well as puberty onset. Approximately five weeks after the last injection of MPH or saline, female subjects were hormone-primed and tested during their first sexual experience. Subjects were given the choice to interact with a sexually active male or a sexually receptive female rat (i.e., the partner-preference test). The partner-preference paradigm allows us to assess multiple aspects of female sexual behavior. MPH exposure during peri-adolescence delayed puberty and, when mated for the first time, affected sexual behavior (e.g., increased time spent with the male stimulus and decreased the likelihood of leaving after mounts) during the test of partner preference. When monitoring estrous cyclicity, female subjects treated with MPH during peri-adolescence frequently experienced irregular estrous cycles. The results of the present study suggest that chronic exposure to a therapeutic dose of MPH around the onset of puberty alters long-term endocrine functioning, but with hormone priming, increases sensitivity to sexual stimuli., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The potentiation of the immune system in pregnant rats was performed with Complete Freund's Adjuvant [CFA; 20μl, subcutaneous at gestation day (GD) 18] in experimentally-induced hyperthyroidism by Levo-thyroxine (L-T4; 10μg/100g of b.w., intraperitoneal from GD 2 to 17). The potential effects on the fetal neuroendocrine function were evaluated by observing some histopathological investigations in pregnant rats and measuring some biochemical parameters in dams and their fetuses at GD 20. In hyperthyroid group, an increase in maternofetal serum thyroxine (T4), triiodothyronine (T3) and a decrease in thyrotropin (TSH) levels were noticed, while the concentrations of fetal serum growth hormone (GH) and insulin-like growth factor-1 (IGF1) levels were increased at tested GD with respect to control and CFA groups. Moreover, the activity of uterine and placental myeloperoxidase (MPO) was increased (P<0.001) in CFA and CFA-treated hyperthyroid groups in respect to control or hyperthyroid groups, respectively. The gestational thyrotoxicosis led to some histopathological lesions in uterine and placental tissues characterized by severe degeneration in trophoblast spongioblast cell layer with congestion, mild congested blood vessels in the endometrium and deficient in spiral artery remodeling. Although, the elevation in fetal serum transforming growth factor-beta (TGFβ) and cerebellar monoamines [norepineprine (NE), epinephrine (E), dopamine (DA) and 5-hydroxytryptamine (5-HT)] was observed, the reduction in fetal serum tumor necrosis factor-alpha (TNFα) and adipokines (Leptin and adiponectin) was detected. Treatment of dams with CFA showed an obviously reversing and protecting effect against hyperthyroid perturbations. Thus, the maternal CFA can be used in treatment of the fetal neuroendocrine dysfunctions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Near-infrared (NIR) fluorescent contrast agents are emerging in optical imaging as sensitive, cost-effective, and nonharmful alternatives to current agents that emit harmful ionizing radiation. Developing spectrally distinct NIR fluorophores to visualize sensitive vital tissues to selectively avoid them during surgical resection of diseased tissue is of great significance. Herein, we report the synthetic variation of pentamethine cyanine fluorophores with modifications of physicochemical properties toward prompting tissue-specific uptake into sensitive tissues (i.e., endocrine glands). Tissue-specific targeting and biodistribution studies revealed localization of contrast agents in the adrenal and pituitary glands, pancreas, and lymph nodes with dependence on molecular characteristics. Incorporation of hydrophobic heterocyclic rings, alkyl groups, and halogens allowed a fine-tuning capability to the hydrophobic character and dipole moment for observing perturbation in biological activity in response to minor structural alterations. These NIR contrast agents have potential for clinical translation for intraoperative imaging in the delineation of delicate glands.

Trifloxystrobin is a systemic broad-spectrum foliar strobilurin fungicides that enters the aquatic environment during agricultural application. It is highly toxic and poses a potential risk to aquatic organisms, whereas the effect on the development of early life stages of fish are unclear. In this study, hatchability, time to hatching, and larval mortality were measured. Additionally, the expression of biomarker genes, including those involved in sex hormone pathways (er, vtg, cyp17, and cyp19a), thyroid hormone pathways (trα and dio2), and aryl hydrocarbon receptor pathways (ahr and cyp1a), was determined after embryos of medaka (Oryzias latipes) were exposed to different levels of trifloxystrobin (0, 0.1, 1, 10, and 100 μg/L) for 28 days. The results showed that there were significant differences between controls and the 100 μg/L treatment group in both hatchability and time to hatching of fertilized eggs (p<0.05). Larval mortality was significantly increased in the 0.1, 1, and 10 μg/L treatment groups (p<0.05). These results indicate that embryonic and larval development may be affected by trifloxystrobin exposure. Moreover, the mRNA levels of the er gene were significantly up-regulated at levels of trifloxystrobin above 1 μg/L treatment groups. Up-regulation of vtg, cyp17, and cyp19a mRNA levels was observed in the larvae at the lower concentration treatment groups. The mRNA levels of cyp1a genes were significantly up-regulated at all of the treatment groups. These results suggest that trifloxystrobin is a potential endocrine disruptor through effects on the sex hormone pathway and xenobiotic metabolism. The changes in cyp1a expression can be used as a highly sensitive biomarker to assess trifloxystrobin contamination in the early life stages of fish., (© 2013 Wiley Periodicals, Inc.)

The European Commission lists styrene (S) as an endocrine disruptor based primarily on reports of increased prolactin (PRL) levels in S-exposed workers. The US Environmental Protection Agency included S in its list of chemicals to be tested for endocrine activity. Therefore, the database of S for potential endocrine activity is assessed. In vitro and in vivo screening studies, as well as non-guideline and guideline investigations in experimental animals indicate that S is not associated with (anti)estrogenic, (anti)androgenic, or thyroid-modulating activity or with an endocrine activity that may be relevant for the environment. Studies in exposed workers have suggested elevated PRL levels that have been further examined in a series of human and animal investigations. While there is only one definitively known physiological function of PRL, namely stimulation of milk production, many normal stress situations may lead to elevations without any chemical exposure. Animal studies on various aspects of dopamine (DA), the PRL-regulating neurotransmitter, in the central nervous system did not give mechanistic explanations on how S may affect PRL levels. Overall, a neuroendocrine disruption of PRL regulation cannot be deduced from a large experimental database. The effects in workers could not consistently be reproduced in experimental animals and the findings in humans represented acute reversible effects clearly below clinical and pathological levels. Therefore, unspecific acute workplace-related stress is proposed as an alternative mode of action for elevated PRL levels in workers.

Aspirin (ASP) is the most commonly used non-steroidal anti-inflammatory drug in the world. Recent clinical and preclinical evidence suggests that ASP may also exert psychoactive effects. It remains unclear whether ASP has antidepressant-like activity, and any molecular mechanisms underlying such activity have yet to be elucidated. Using the forced swimming test (FST), a well-established animal model of depression widely used to screen potential antidepressants in rodents, we investigated the effects of subacute treatment with ASP (0, 6, 12, 25, and 50mg/kg, i.p.) on immobility in the FST, and on FST-induced changes in endocrine and immune parameters in rats, in comparison to the clinical antidepressants imipramine (IMI) and fluoxetine (FLU). Serum levels of corticosterone, pro-inflammatory cytokine interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. ASP dose-dependently decreased immobility in the FST, without altering the locomotor activity in the open-field test. The inhibitory effects of higher doses (25 and 50mg/kg) of ASP on immobility were similar to that of FLU and IMI at a dose of 10mg/kg. In addition, the levels of corticosterone, IL-6, and TNF-α in peripheral blood were significantly increased after the FST exposure. IMI, but not FLU and ASP at any dose tested, significantly attenuated corticosterone responses in the FST. Both FLU and IMI treatment reduced the increase of IL-6 and TNF-α levels following the FST exposure. ASP dose-dependently decreased FST-induced increase of cytokine levels, as manifested by significantly stronger effects on IL-6 and TNF-α levels at higher doses (25 and 50mg/kg) than the lowest dose of ASP (6 mg/kg). In all, these results indicate that ASP treatment dose-dependently decreased the immobility time and the release of pro-inflammatory cytokines in the FST, suggesting that the anti-inflammatory effects of ASP might be involved in the antidepressant-like effect., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Obesity and high-fructose corn syrup (HFCS)-sweetened beverages are associated with an increased risk of chronic disease, but it is not clear whether obese (Ob) individuals are more susceptible to the detrimental effects of HFCS-sweetened beverages. The purpose of this study was to examine the endocrine and metabolic effects of consuming HFCS-sweetened beverages, and whether weight classification (normal weight (NW) vs. Ob) influences these effects. Ten NW and 10 Ob men and women who habitually consumed ≤355 mL per day of sugar-sweetened beverages were included in this study. Initially, the participants underwent a 4-h mixed-meal test after a 12-h overnight fast to assess insulin sensitivity, pancreatic and gut endocrine responses, insulin secretion and clearance, and glucose, triacylglycerol, and cholesterol responses. Next, the participants consumed their normal diet ad libitum, with 1065 mL per day (117 g·day(-1)) of HFCS-sweetened beverages added for 2 weeks. After the intervention, the participants repeated the mixed-meal test. HFCS-sweetened beverages did not significantly alter body weight, insulin sensitivity, insulin secretion or clearance, or endocrine, glucose, lipid, or cholesterol responses in either NW or Ob individuals. Regardless of previous diet, Ob individuals, compared with NW individuals, had ∼28% lower physical activity levels, 6%-9% lower insulin sensitivity, 12%-16% lower fasting high-density-lipoprotein cholesterol concentrations, 84%-144% greater postprandial triacylglycerol concentrations, and 46%-79% greater postprandial insulin concentrations. Greater insulin responses were associated with reduced insulin clearance, and there were no differences in insulin secretion. These findings suggest that weight classification does not influence the short-term endocrine and metabolic effects of HFCS-sweetened beverages.

SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs. On the other hand, in monkeys, no toxicological events were observed. The goal of this study is to try to understand the reason why only rats, but not monkeys, showed toxicological events following treatment with SMP-028 and to eventually predict the possible toxicological effect of this compound on human endocrine organs. Our results show that SMP-028 inhibits neutral cholesterol esterase more strongly than other steroidogenic enzymes in rats. Although SMP-028 also inhibits monkeys and human neutral cholesterol esterase, this inhibition is much weaker than that of rat neutral cholesterol esterase. These results indicate (1) that the difference in endocrine toxicological events between rats and monkeys is mainly due to inhibition of steroidogenesis by SMP-028 in rats, not in monkeys, and (2) that SMP-028 may not affect steroidogenesis in humans and therefore might cause no endocrine toxicological events in clinical studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: Conflicting results regarding testicular function in adults with type 1 diabetes (T1D) have been reported, but little is known about Leydig and Sertoli cell function during puberty in boys treated with multiple daily insulin doses. Our aim was to assess testicular function in boys with T1D., Methods: Pubertal boys with T1D (n = 71) and healthy control boys (Control group; n = 104) who were 10-18 years were studied. Both groups were matched by pubertal stage, age, and BMI. Total testosterone (TT), calculated free testosterone (cfT), SHBG, inhibin B, AMH, and gonadotropin levels were determined., Results: At the beginning of puberty, the T1D group had higher levels of SHBG (p = 0.003) and similar androgen levels than the Control group. At the end of puberty, higher TT, and cfT were observed in T1D compared to the Control group (p < 0.01 and p < 0.001, respectively). Gonadotropins and AMH were similar in both groups. Regression analysis showed that T1D was a significant factor, even after adjusting for Tanner stage and BMI-SDS, affecting TT, cFT, and SHBG levels. BMI-SDS was a significant factor affecting TT and SHBG levels. Higher HbA1c had a negative effect on total testosterone and cFT and a positive effect on SHBG levels in T1D boys., Conclusion: Adolescents with T1D do not exhibit hypogonadism, as shown by normal gonadotropin, testosterone, inhibin B, and AMH levels. However, in T1D boys, HbA1c and BMI-SDS had a negative association with testosterone levels. Elevated testosterone levels are observed during late puberty, which were not present earlier., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Endogenous hormones have effects on tissue morphology, cell physiology, and behaviors at low doses. In fact, hormones are known to circulate in the part-per-trillion and part-per-billion concentrations, making them highly effective and potent signaling molecules. Many endocrine-disrupting chemicals (EDCs) mimic hormones, yet there is strong debate over whether these chemicals can also have effects at low doses. In the 1990s, scientists proposed the "low-dose hypothesis," which postulated that EDCs affect humans and animals at environmentally relevant doses. This chapter focuses on data that support and refute the low-dose hypothesis. A case study examining the highly controversial example of bisphenol A and its low-dose effects on the prostate is examined through the lens of endocrinology. Finally, the chapter concludes with a discussion of factors that can influence the ability of a study to detect and interpret low-dose effects appropriately., (© 2014 Elsevier Inc. All rights reserved.)

2,4-Dichlorophenoxyacetic acid (2,4-D) was assessed for systemic toxicity, reproductive toxicity, developmental neurotoxicity (DNT), developmental immunotoxicity (DIT), and endocrine toxicity. CD rats (27/sex/dose) were exposed to 0, 100, 300, 600 (female), or 800 (male) ppm 2,4-D in diet. Nonlinear toxicokinetic behavior was shown at high doses; the renal clearance saturation threshold for 2,4-D was exceeded markedly in females and slightly exceeded in males. Exposure was 4 weeks premating, 7 weeks postmating for P1 males and through lactation for P1 females. F1 offspring were examined for survival and development, and at weaning, pups were divided in cohorts, by sex and dose, and by systemic toxicity (10), DNT (10), DIT (20), and reproductive toxicity (≥ 23). Remaining weanlings were evaluated for systemic toxicity and neuropathology (10-12). Body weight decreased during lactation in high-dose P1 females and in F1 pups. Kidney was the primary target organ, with slight degeneration of proximal convoluted tubules observed in high-dose P1 males and in high-dose F1 males and females. A slight intergenerational difference in kidney toxicity was attributed to increased intake of 2,4-D in F1 offspring. Decreased weanling testes weights and delayed preputial separation in F1 males were attributed to decreased body weights. Endocrine-related effects were limited to slight thyroid hormone changes and adaptive histopathology in high-dose GD 17 dams seen only at a nonlinear toxicokinetic dose. 2,4-D did not cause reproductive toxicity, DNT, or DIT. The "No Observed Adverse Effect Level" for systemic toxicity was 300 ppm in both males (16.6 mg/kg/day) and females (20.6 mg/kg/day), which is approximately 6700- to 93 000-fold higher than that reported for 2,4-D exposures in human biomonitoring studies.

Neurotransmitters and neurohormones are agents that control gonad maturation in decapod crustaceans. Of these, serotonin (5-HT) and dopamine (DA) are neurotransmitters with known antagonist roles in female reproduction, whilst gonadotropin-releasing hormones (GnRHs) and corazonin (Crz) are neurohormones that exercise both positive and negative controls in some invertebrates. However, the effects of these agents on the androgenic gland (AG), which controls testicular maturation and male sex development in decapods, via insulin-like androgenic gland hormone (IAG), are unknown. Therefore, we set out to assay the effects of 5-HT, DA, l-GnRH-III, oct-GnRH and Crz, on the AG of small male Macrobrachium rosenbergii (Mr), using histological studies, a BrdU proliferative cell assay, immunofluorescence of Mr-IAG, and ELISA of Mr-IAG. The results showed stimulatory effects by 5-HT and l-GnRH-III through significant increases in AG size, proliferation of AG cells, and Mr-IAG production (P<0.05). In contrast, DA and Crz caused inhibitory effects on the AG through significant decreases in AG size, proliferation of AG cells, and Mr-IAG production (P<0.05). Moreover, the prawns treated with Crz died before day 16 of the experimental period. We propose that 5-HT and certain GnRHs can be now used to stimulate reproduction in male M. rosenbergii, as they induce increases in AG and testicular size, IAG production, and spermatogenesis. The mechanisms by which these occur are part of our on-going research., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Endocrine-active chemicals can potentially have adverse effects on both humans and wildlife. They can interfere with the body's endocrine system through direct or indirect interactions with many protein targets. Estrogen receptors (ERs) are one of the major targets, and many endocrine disruptors are estrogenic and affect the normal estrogen signaling pathways. However, ERs can also serve as therapeutic targets for various medical conditions, such as menopausal symptoms, osteoporosis, and ER-positive breast cancer. Because of the decades-long interest in the safety and therapeutic utility of estrogenic chemicals, a large number of chemicals have been assayed for estrogenic activity, but these data exist in various sources and different formats that restrict the ability of regulatory and industry scientists to utilize them fully for assessing risk-benefit. To address this issue, we have developed an Estrogenic Activity Database (EADB; http://www.fda.gov/ScienceResearch/BioinformaticsTools/EstrogenicActivityDatabaseEADB/default.htm) and made it freely available to the public. EADB contains 18,114 estrogenic activity data points collected for 8212 chemicals tested in 1284 binding, reporter gene, cell proliferation, and in vivo assays in 11 different species. The chemicals cover a broad chemical structure space and the data span a wide range of activities. A set of tools allow users to access EADB and evaluate potential endocrine activity of chemicals. As a case study, a classification model was developed using EADB for predicting ER binding of chemicals.

Stress and/or antidepressants during pregnancy have been implicated in a wide range of long-term effects in the offspring. We investigated the long-term effects of prenatal stress and/or clinically relevant antidepressant exposure on male adult offspring in a model of the pharmacotherapy of maternal depression. Female Sprague-Dawley rats were implanted with osmotic minipumps that delivered clinically relevant exposure to the antidepressant escitalopram throughout gestation. Subsequently, pregnant females were exposed on gestational days 10-20 to a chronic unpredictable mild stress paradigm. The male offspring were analyzed in adulthood. Baseline physiological measurements were largely unaltered by prenatal manipulations. Behavioral characterization of the male offspring, with or without pre-exposure to an acute stressor, did not reveal any group differences. Prenatal stress exposure resulted in a faster return towards baseline following the peak response to an acute restraint stressor, but not an airpuff startle stressor, in adulthood. Microarray analysis of the hippocampus and hypothalamus comparing all treatment groups revealed no significantly-altered transcripts. Real time PCR of the hippocampus confirmed that several transcripts in the CRFergic, serotonergic, and neural plasticity pathways were unaffected by prenatal exposures. This stress model of maternal depression and its treatment indicate that escitalopram use and/or stress during pregnancy produced no alterations in our measures of male adult behavior or the transcriptome, however prenatal stress exposure resulted in some evidence for increased glucocorticoid negative feedback following an acute restraint stress. Study design should be carefully considered before implications for human health are ascribed to prenatal exposure to stress or antidepressant medication., (© 2013.)

Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer with endocrine disrupting properties that is found ubiquitously in the environment as well as in human amniotic fluid, umbilical cord blood, human milk, semen, and saliva. It is used in the industry to add flexibility to polyvinyl chloride-derived plastics and its wide spread use and presence has resulted in constant human exposure through fetal development and postnatal life. Epidemiological studies have suggested an association between phthalate exposures and human reproductive effects in infant and adult populations. The effects of fetal exposure to phthalates on the male reproductive system were unequivocally shown on animal models, principally rodents, in which short term deleterious reproductive effects are well established. By contrast, information on the long term effects of DEHP in utero exposure on gonadal function are scarce, while its potential effects on other organs are just starting to emerge. The present review focuses on these novel findings, which suggest that DEHP exerts more complex and broader disruptive effects on the endocrine system and metabolism than previously thought. This article is part of a Special Issue entitled "CSR 2013"., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

While bisphenol S (BPS) has been frequently detected both in environment and biota, limited information is available on their effects of endocrine system. In the present study, adult zebrafish pairs were exposed to 0.5, 5, and 50 μg/L of BPS for 21 d, and the effects on reproduction, sex steroid hormones, and transcription of the genes belonging to the hypothalamic-pituitary-gonad (HPG) axis were investigated. The adverse effects on performances of F1 generation were further examined with or without subsequent exposure to BPS. Egg production and the gonadosomatic index in female fish were significantly decreased at ≥0.5 μg/L BPS. Plasma concentrations of 17β-estradiol were significantly increased in both male and female fish. In male fish, however, significant decreases of testosterone concentration were observed along with up-regulation of cyp19a and down-regulation of cyp17 and 17βhsd transcripts. Parental exposure to BPS resulted in delayed and lesser rates of hatching even when they were hatched in clean water. Continuous BPS exposure in the F1 embryos resulted in worse hatchability and increased malformation rates compared to those without BPS exposure. Our observations showed that exposure to low level BPS could affect the feedback regulatory circuits of HPG axis and impair the development of offspring.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts the inactive glucocorticoid cortisone and its active form cortisol. It is widely expressed and, although bidirectional, in vivo it functions predominantly as an oxoreductase, generating active glucocorticoid. This allows glucocorticoid receptor activation to be regulated at a prereceptor level in a tissue-specific manner. In this review, we will discuss the enzymology and molecular biology of 11β-HSD1 and the molecular basis of cortisone reductase deficiencies. We will also address how altered 11β-HSD1 activity has been implicated in a number of disease states, and we will explore its role in the physiology and pathologies of different tissues. Finally, we will address the current status of selective 11β-HSD1 inhibitors that are in development and being tested in phase II trials for patients with the metabolic syndrome. Although the data are preliminary, therapeutic inhibition of 11β-HSD1 is also an exciting prospect for the treatment of a variety of other disorders such as osteoporosis, glaucoma, intracranial hypertension, and cognitive decline.

Nanomaterials (NMs) are engineered for commercial purposes such as semiconductors, building materials, cosmetics, and drug carriers, while natural nanoparticles (NPs) already exist in the environment. Due to their unique physicochemical properties, they may interact actively with biological systems. Some of these interactions might be detrimental to human health, and therefore studies on the potential 'nanotoxicity' of these materials in different organ systems are warranted. The purpose of developing the concept of nanotoxicity is to recognize and evaluate the hazards and risks of NMs and evaluate safety. This review will summarize and discuss recent reports derived from cell lines or animal models concerning the effects of NMs on, and their application in, the endocrine system of mammalian and other species. It will present an update on current studies of the effects of some typical NMs-such as metal-based NMs, carbon-based NMs, and dendrimers-on endocrine functions, in which some effects are adverse or unwanted and others are favorable or intended. Disruption of endocrine function is associated with adverse health outcomes including reproductive failure, metabolic syndrome, and some types of cancer. Further investigations are therefore required to obtain a thorough understanding of any potential risk of pathological endocrine disruption from products containing NMs. This review aims to provide impetus for further studies on the interactions of NMs with endocrine functions., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this study, we investigated inhibition of the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) by prothoracicotropic hormone (PTTH) in prothoracic glands of the silkworm, Bombyx mori. We found that treatment with PTTH in vitro inhibited AMPK phosphorylation in time- and dose-dependent manners, as seen on Western blots of glandular lysates probed with antibody directed against AMPKα phosphorylated at Thr172. Moreover, in vitro inhibition of AMPK phosphorylation by PTTH was also verified by in vivo experiments: injection of PTTH into day 7 last instar larvae greatly inhibited glandular AMPK phosphorylation. PTTH-inhibited AMPK phosphorylation appeared to be partially reversed by treatment with LY294002, indicating involvement of phosphatidylinositol 3-kinase (PI3K) signaling. A chemical activator of AMPK (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside, AICAR) increased both basal and PTTH-inhibited AMPK phosphorylation. Treatment with AICAR also inhibited PTTH-stimulated ecdysteroidogenesis of prothoracic glands. The mechanism underlying inhibition of PTTH-stimulated ecdysteroidogenesis by AICAR was further investigated by determining the phosphorylation of eIF4E-binding protein (4E-BP) and p70 ribosomal protein S6 kinase (S6K), two known downstream signaling targets of the target of rapamycin complex 1 (TORC1). Upon treatment with AICAR, decreases in PTTH-stimulated phosphorylation of 4E-BP and S6K were detected. In addition, treatment with AICAR did not affect PTTH-stimulated extracellular signal-regulated kinase (ERK) phosphorylation, indicating that AMPK phosphorylation is not upstream signaling for ERK phosphorylation. Examination of gene expression levels of AMPKα, β, and γ by quantitative real-time PCR (qRT-PCR) showed that PTTH did not affect AMPK transcription. From these results, it is assumed that inhibition of AMPK phosphorylation, which lies upstream of PTTH-stimulated TOR signaling, may play a role in PTTH stimulation of ecdysteroidogenesis.

Objectives: Camurati-Engelmann disease (CED) is a rare form of progressive bone dysplasia due to mutations in the transforming factor gene TGFB1 on chromosome 19q13.1-q13.3. Endocrine complications such as osteoporosis, vitamin D deficiency, delayed puberty and hypogonadotrophic hypogonadism may be present., Methods and Results: Genetic analysis of the TGFB1 gene revealed a heterozygous missense mutation p.R218C in exon 4 of chromosome 19q13.1-q13.3 in a 14-year-old girl who presented with typical symptoms of CED, hyperprolactinaemia and menstrual irregularity. The patient responded well to prednisone 5 mg/kg per day as well as calcium and vitamin D supplements., Conclusions: The role of p.R218C in TGFB1 on the mechanism of the disease itself and the complications of it in bones and endocrine glands remain unclear. Early recognition as well as a detailed understanding of the pathogenesis of the disease is important for future treatment options and better quality of life of such patients.

This study investigated nitric oxide (NO) mediation of carbon disulfide (CS(2)) toxicity that compromised male rat spermatogenesis and endocrine function. Rats were exposed to multiple levels of CS(2) concentration (0, 50, 250, 1250 mg/m(3)). A 1250 mg/m(3) CS(2)+sodium nitroprusside (SNP) group and a 1250 mg/m(3) CS(2)+NG-monomethyl-L-arginine (L-NMMA) group were established to explore the role of NO in mediating CS(2) toxicity. NO concentrations, NO synthase (NOS) activity, and sex hormone levels were measured, and sperm characteristics were observed and analyzed. Our data show that CS(2) exposure decreased: NOS activity; tissue NO concentrations; serum levels of gonadotropin-releasing hormones, luteinizing hormones, and testosterone; and sperm count and activity. In contrast, increased serum follicle-stimulating hormone concentrations and teratospermia were observed with CS(2) exposure. SNP reduced some of the toxic effects of CS(2), while L-NMMA treatment showed no effect. The results suggests that NO mediates compromised reproductive system function caused by CS(2) exposure., (Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.)

This study evaluated the effects of kolaviron, a biflavonoid from Garcinia kola seed, and quercetin on cadmium-induced reproductive toxicity in rats. Adult male rats were administered with either cadmium (15 mg kg(-1)) alone or in combination with kolaviron (200 mg kg(-1)) or quercetin (10 mg kg(-1)) daily for 5 days. Cadmium-treated rats showed (P < 0.05) decrease in the body weight gain, testis and epididymis weights. However, upon co-administration of kolaviron or quercetin, these changes were significantly reversed in cadmium-treated rats. Also, administration of kolaviron or quercetin significantly prevented cadmium-mediated decrease in sperm motility and epididymal sperm concentration and reversed the increased level of sperm abnormality to near control. In testes and sperm, cadmium treatment resulted in significant decrease in the activities of superoxide dismutase, catalase and glutathione peroxidase, whereas it increased glutathione S-transferase activity as well as hydrogen peroxide and malondialdehyde levels. While plasma levels of triiodothyronine and tetraiodothyronine remained unaffected, the levels of testosterone, luteinising hormone and follicle stimulating hormone were decreased in cadmium-treated rats. Cadmium treatment caused mild congestion of interstitial vessels and oedema in the testes. Taken together, kolaviron and quercetin inhibited the adverse effects of cadmium on the antioxidant enzymes, markers of oxidative stress, endocrine and testicular structure in rats., (© 2012 Blackwell Verlag GmbH.)

The unusual pharmacology of McN-A-343 was first described by Roszowski in 1961. The agonist appeared to be a selective stimulant of muscarinic receptors in sympathetic ganglia, now known to be the muscarinic M₁ receptor subtype. However, subsequent research demonstrated that McN-A-343 is a partial agonist with similar affinity at all five muscarinic acetylcholine receptor subtypes and its relative selectivity depends on a higher efficacy at the M₁ (and M₄) subtypes. Being a partial agonist its action is also dependent on factors, such as receptor density and coupling efficacy between receptor activation and tissue response. Nevertheless, the relatively high efficacy at M₁ receptors led to its widespread use as an aid to distinguish responses mediated through M₁ receptors from those utilizing M₂ or M₃ muscarinic receptor subtypes, especially in the CNS. There is also evidence that it has an allosteric action at some receptor subtypes. Recently, it was demonstrated that McN-A-343 can bind to an allosteric site on the M₂ receptor as well as to the orthosteric site and has thus been termed a "bitopic agonist". This allosteric site differs from that occupied by allosteric modulators, such as gallamine. Comparison of comparable mutagenic changes in M₂ and M₄ receptors also suggests that McN-A-343 utilizes different regions of the two receptors for ERK1/2 activation. McN-A-343 has a number of non-muscarinic actions. These include activation of some types of nicotinic acetylcholine receptors, antagonism of serotonin 5-HT₃ and 5-HT₄ receptor subtypes, inhibition of the uptake mechanism and a local anesthetic action., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In previous studies in freshwater tilapia (Oreochromis mossambicus), dietary supplementation with arachidonic acid (ArA; 20:4n - 6) had considerable, opposing effects on the main ion-transporting enzyme Na(+)/K(+)-ATPase in gills and kidneys and changed the release of osmoregulatory hormones, such as cortisol. The present study was performed to assess the influence of dietary ArA on (1) the osmoregulatory capacity of tilapia acclimated to seawater (SW) (34‰) and (2) the osmoregulatory imbalance associated with acute stress. The increased ambient salinity was associated with significant alterations in the tissue fatty acid composition, particularly the n - 6 polyunsaturated fatty acids (PUFAs). Tissue levels of ArA were further increased as a result of dietary supplementation, whereas docosahexaenoic acid (DHA, 22:6n - 3) and eicosapentaenoic acid (EPA, 20:5n - 3) decreased in gills and kidneys. Basal plasma cortisol as well as lactate levels were elevated in the ArA-supplemented SW-acclimated tilapia compared with the control group. The 5 min of confinement (transient stress) increased plasma cortisol, glucose, and lactate levels with significantly higher levels in ArA-supplemented tilapia. Confinement was also associated with significantly elevated plasma osmolality, sodium, chloride, and potassium levels. ArA-supplemented tilapia showed markedly lower ionic disturbances after confinement, suggesting that dietary ArA can attenuate the hydromineral imbalance associated with acute stress. These results emphasize the involvement of ArA and/or its metabolites in the endocrine and osmoregulatory processes and the response to confinement stress.

Testicular Leydig cells are the predominant source of the male sex steroid hormone testosterone (T), which is required to maintain male fertility. There is now growing evidence that environmental stressors, including chemicals present in food, air and water, may affect energy balance. A relationship between energy balance and reproductive capacity has been proposed for a long time. In the present study, developmental exposures of male rats to soy isoflavones in the maternal diet from gestational day 12 to day 21 post-partum enhanced adiponectin expression in adipose tissue and increased serum adiponectin concentrations in adulthood. However, exposure to soy isoflavones caused a decrease in T production and expression of adiponectin and its receptor (adipoR2) in Leydig cells. In separate experiments, incubation of Leydig cells with recombinant adiponectin in the absence of isoflavones caused a decrease in T biosynthesis associated with diminished expression of the cholesterol transporter steroidogenic acute regulatory protein (StAR). Thus, chemical-induced alterations in serum adiponectin concentrations have implication for steroid hormone secretion. The results also imply that changes in adipose tissue metabolism occasioned by exposure to dietary estrogens, and perhaps other estrogenic agents, possibly contribute to deficiencies in reproductive capacity attributed to these compounds., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Hyperandrogenemia is associated with several clinical disorders in which both reproductive dysfunction and metabolic changes may coexist [i.e. polycystic ovary syndrome (PCOS), obesity and congenital adrenal hyperplasia]. Moreover, there is growing evidence that the elevated levels of circulating androgens in obese girls may lead to an increased neuroendocrine drive to the reproductive axis, similar to that associated with PCOS., Methods: To test whether androgen exposure in the childhood and adolescent period could lead to pubertal alterations in LH secretory patterns, female rhesus monkeys received subcutaneous testosterone implants prepubertally beginning at 1 year of age, maintaining a 3.7-fold increase (P = 0.001) in circulating testosterone levels over cholesterol-implant controls (n = 6/group) into the post-pubertal period. In early adulthood, pulsatile secretion of LH was measured over 12 h during the early follicular phase of a menstrual cycle, and responsiveness of the pituitary to gonadotrophin-releasing hormone was determined. In addition, ultrasounds were performed to assess ovarian morphology and glucose tolerance testing was performed to assess insulin sensitivity., Results: The timing of menarche was similar between groups. Testosterone-treated animals had a significantly greater LH pulse frequency during the early follicular phase compared with controls (P = 0.039) when measured at 5 years of age. There was a larger LH response to GnRH when testosterone-treated animals were 4 years of age (P = 0.042), but not when the animals were 5 years old (P = 0.57). No differences were seen in insulin sensitivity or ovarian morphology, and the groups showed similar rates of ovulation in early adulthood., Conclusions: Exposure to increased levels of androgens over the course of pubertal development appears to trigger physiological changes in the neural drive to the reproductive axis that resemble those of obese hyperandrogenemic girls in early adulthood and are characteristic of PCOS.

The steroid hormone 1α,25(OH)(2)-vitamin D(3) (1,25D(3)) regulates gene transcription through a nuclear receptor (VDRnuc) and initiation of rapid cellular responses through a putative plasma membrane-associated receptor (VDRmem). It has been described that successful mating and fertility rates are significantly decreased in vitamin D deficient male rats and a VDR null mutant rodent has decreased sperm count and motility and expresses rare spermatogenesis. Although the Sertoli cells are pointed as the major target of 1,25D(3) in the testis the mechanism of 1,25D(3) action, particularly in Sertoli cells, remains unclear. Several studies undertaken in the testicular cells showed that 1,25D(3) can produce both genomic and nongenotropic actions in those cells. 1,25D(3) can modulate kinase activities and ionic fluxes (Ca(2+) and Cl(-)) at the plasma membrane resulting in the regulation of secretory processes in Sertoli cells. The enormous complexity of the nongenomic actions of 1,25D(3) implies that specific receptor or specific ligand-binding sites located on the plasma membrane or in the nucleus are believed to initiate specific cell responses. Apparently the choice of the signaling pathways to be activated after the interaction of the hormone with cell surface receptors is directly related with the physiological action to be better accomplished. The demonstration that 1,25D(3) can regulate both Sertoli cell and sperm function may be useful for the study and development of new therapeutic strategies to the treatment of male reproductive disorders. This review summarizes recent research on the rapid actions of 1,25D(3) and identifies questions that remain to be answered in this area., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Sesamia nonagrioides (Lepidoptera: Noctuidae) larvae reared under long day (LD; 16L:8D) conditions pupate after 5 or 6 larval instars, whereas under short day (SD; 12L:12D) conditions they undergo up to 12 additional molts before pupating. This extended period of repeated molting is maintained by high levels of juvenile hormone (JH). Previous work demonstrated that both LD and SD larvae decapitated in the 6th instar pupate but further development is halted. By contrast, about one-third of SD larvae from which only the brain has been removed, undergo first a larval molt, then pupate and subsequently developed to the adult stage. Debrained LD larvae molt to larvae exceptionally but regularly pupate and produce adults. Implanted brains may induce several larval molts in debrained recipient larvae irrespectively of the photoperiodic conditions. The results of present work demonstrate that the prothoracic glands (PGs) and the corpora allata (CA) of debrained larvae continue to produce ecdysteroids and JHs, respectively. PGs are active also in the decapitated larvae that lack JH, consistent with the paradigm that CA, which are absent in the decapitated larvae, are the only source of this hormone. Completion of the pupal-adult transformation in both LD and SD debrained insects demonstrates that brain is not crucial for the development of S. nonagrioides but is required for diapause maintenance. Application of JH to headless pupae induces molting, presumably by activating their PGs. It is likely that JH plays this role also in the induction of pupal-adult transformation in debrained insects. Application of the ecdysteroid agonist RH 2485 (methoxyfenozide) to headless pupae also elicits molting: newly secreted cuticle is in some cases thin and indifferent, in other cases it bears distinct pupal or adult features., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The natural product ginger (Zingiber officinale) has active constituents gingerol, Shogaol and Zerumbone, while turmeric (Curcuma longa) contains three active major curcuminoids, namely, curcumin, demethoxycurcumin, and bisdemethoxycurcumin. They have the same scientific classification and are reported to have anti-inflammatory and many therapeutic effects. This article reviews the physiological and therapeutic effects of ginger and turmeric on some endocrine gland functions, and signal pathways involved to mediate their actions. With some systems and adipose tissue, ginger and turmeric exert their actions through some/all of the following signals or molecular mechanisms: (1) through reduction of high levels of some hormones (as: T4, leptin) or interaction with hormone receptors; (2) by inhibition of cytokines/adipokine expression; (3) acting as a potent inhibitor of reactive oxygen species (ROS)-generating enzymes, which play an essential role between inflammation and progression of diseases; (4) mediation of their effects through the inhibition of signaling transcription factors; and/or (5) decrease the proliferative potent by down-regulation of antiapoptotic genes, which may suppress tumor promotion by blocking signal transduction pathways in the target cells. These multiple mechanisms of protection against inflammation and oxidative damage make ginger and curcumin particularly promising natural agents in fighting the ravages of aging and degenerative diseases, and need to be paid more attention by studies.

Losses in physiological function in healthy ageing occur partly as a consequence of reduced protein intake and partly as a consequence of less than 30-min/day of moderate to vigorous physical activity. The current study aimed to compare the effects of two different intensities of resistance training in healthy older adults, whose habitual dietary intake was supplemented with carbohydrate and amino acid preparations. We hypothesised that although intensive exercise with appropriate carbohydrate and amino acid supplementation would result in the most profound impact on in vivo markers of healthy physiologic and endocrine functions in previously sedentary older individuals, the effectiveness of the less intense exercise prescription with supplementation would also result in beneficial adaptations over and above findings of previous studies on low intensity exercise alone. Twenty-nine older adults (out of 32) completed the study after being randomly assigned to low (SUP&#95;LowR, i.e., approximately 40% 1RM; n = 16) versus high resistance training (SUP&#95;HighR, i.e., approximately 80% 1RM; n = 13) for 12 weeks. A carbohydrate supplement was ingested immediately before and during every exercise session and an amino acid cocktail was ingested post-exercise. Neither intervention significantly impacted upon body composition assessed using: Body mass index, waist/hip ratio and bioelectric impedance. Muscle strength increased similarly in the two groups with the SUP&#95;HighR protocol showing 46 +/- 8%, 10.8 +/- 4.4% and 26.9 +/- 4.9% (P < 0.01) improvements in 1-RM strength, unilateral and bilateral knee extension torque, respectively, compared with 39 +/- 2%, 9.4 +/- 3.7% and 29.5 +/- 8.2% (P < 0.01) increments in the same measures in the SUP&#95;LowR group. Lean muscle thickness however, showed a greater benefit of the SUP&#95;LowR protocol (8.7 +/- 3.9% increase, P < 0.05) compared with the SUP&#95;HighR protocol, which elicited no significant change. In terms of functional abilities, only the standing-from-lying (SFL) test exhibited an improvement in rate in the SUP&#95;HighR group (-11.4%, P < 0.05). The SUP&#95;LowR group, on the other hand, showed significant improvements in the get-up-and-go (-8.7 +/- 3.6%, P < 0.05), the SFL (-4.7% change, P = 0.05) and the 6-min walk (7.2 +/- 2.2% increase in distance covered, P < 0.01) tests. Following overnight fasting, serum levels of glucose changed significantly (-13 +/- 4.7% decrease, P < 0.01) in SUP&#95;LowR. Serum levels of insulin (-25 +/- 5.3% decrease, P = 0.05), neuropeptide Y (-24 +/- 15.3% decrease, P = 0.02), and IGFBP-3 (-11 +/- 6.6% decrease, P = 0.03), changed significantly in SUP&#95;HighR. Circulating levels of interleukin-6, tumour necrosis factor-alpha and insulin-like growth factor 1 did not alter significantly in either intervention group. These data suggest that whilst both interventions were beneficial in older persons, the end targets as well as metabolic and hormonal adaptations are different. The supplementation plus low exercise regimen tended to impact on muscle hypertrophy combined with increased habitual function. Supplementation plus high-intensity exercise regimen improved markers of strength, but not to a significantly greater extent than supplementation plus low intensity exercise.