Endocrine Adverse Effects Research Articles

Transcriptome analysis of fetal rat testis following intrauterine exposure to the azole fungicides triticonazole and flusilazole reveals subtle changes despite adverse endocrine effects

Azoles are used in agriculture and medicine to combat fungal infections. We have previously examined the endocrine disrupting properties of the agricultural azole fungicides triticonazole and flusilazole. Triticonazole displayed strong androgen receptor (AR) antagonism in vitro, whereas in utero exposure resulted in anti-androgenic effects in vivo evidenced by shorter anogenital distance (AGD) in fetal male rats. Flusilazole displayed strong AR antagonism, but less potent than triticonazole, and disrupted steroidogenesis in vitro, whereas in utero exposure disrupted fetal male plasma hormone levels. To elaborate on how these azole fungicides can disrupt male reproductive development by different mechanisms, and to investigate whether feminization effects such as short AGD in males can also be detected at the transcript level in fetal testes, we profiled fetal testis transcriptomes after in utero exposure to triticonazole and flusilazole by 3′Digital Gene Expression (3′DGE). The analysis revealed few transcriptional changes after exposure to either compound at gestation day 17 and 21. This suggests that the observed influence of flusilazole on hormone production may be by directly targeting steroidogenic enzyme activity in the testis at the protein level, whereas observations of shorter AGD by triticonazole may primarily be due to disturbed androgen signaling in androgen-sensitive tissues. Expression of Calb2 and Gsta2 was altered by flusilazole but not triticonazole and may pinpoint novel pathways of disrupted testicular steroid synthesis. Our findings have wider implication for how we integrate omics data in chemical testing frameworks, including selection of non-animal test methods and building of Adverse Outcome Pathways for regulatory purposes.

Biomonitoring of emerging DINCH metabolites in pregnant women in charleston, SC: 2011–2014

Due to the mounting evidence that phthalates, specifically di-2-ethylhexyl phthalate and dibutyl phthalate, produce adverse endocrine effects in humans and wildlife, the use of other chemicals as replacements has increased. One of the most commonly encountered phthalate replacements is di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH). Currently, little is known about the prevalence of human exposure, bioactivity, and endocrine disrupting potential of DINCH. We sampled urine from 100 pregnant women during the second trimester of pregnancy living in Charleston, SC between 2011 and 2014 and measured the following DINCH metabolites by LC-MS/MS: cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester (OH-MINCH), cyclohexane-1,2-dicarboxylic acid-mono(oxo-isononyl) ester (oxo-MINCH), and cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl ester (cx-MINCH). These metabolites were also tested on human estrogen receptor alpha and progesterone receptor beta transactivation assays in vitro. OH-MINCH was detected in 98% of urine samples. The specific gravity-adjusted median (interquartile range) OH-MINCH concentration was 0.20 (0.25) ng/mL, and concentrations were significantly higher in African American women compared to Caucasian women (p = 0.01). DINCH metabolite concentrations were consistent between years, and they did not exhibit estrogenic or progestogenic activity in vitro. Human exposure to these emerging compounds should continue to be monitored, especially in vulnerable populations, to ensure the replacement of phthalates by DINCH is not a case of regrettable substitution.

Structure-based discovery of the endocrine disrupting effects of hydraulic fracturing chemicals as novel androgen receptor antagonists

Hydraulic fracturing (HF) technology is increasingly utilized for oil and gas extraction operations. The widespread use of HF has led to concerns of negative impacts on both the environment and human health. Indeed, the potential endocrine disrupting impacts of HF chemicals is one such knowledge gap. Herein, we used structure-based molecular docking to assess the binding affinities of 60 HF chemicals to the human androgen receptor (AR). Five HF chemicals had relatively high predicted AR binding affinity, suggesting the potential for endocrine disruption. We next assessed androgenic and antiandrogenic activities of these chemicals in vitro. Of the five candidate AR ligands, only Genapol®X–100 significantly modified AR transactivation. To better understand the structural effect of Genapol®X–100 on the potency of AR inhibition, we compared the antiandrogenic activity of Genapol®X–100 with that of its structurally similar chemical, Genapol®X–080. Interestingly, both Genapol®X–100 and Genapol®X–080 elicited an antagonistic effect at AR with 20% relative inhibitory concentrations of 0.43 and 0.89 μM, respectively. Furthermore, we investigated the mechanism of AR inhibition of these two chemicals in vitro, and found that both Genapol®X–100 and Genapol®X–080 inhibited AR through a noncompetitive mechanism. The effect of these two chemicals on the expression of AR responsive genes, e.g. PSA, KLK2, and AR, was also investigated. Genapol®X–100 and Genapol®X–080 altered the expression of these genes. Our findings heighten awareness of endocrine disruption by HF chemicals and provide evidence that noncompetitive antiandrogenic Genapol®X–100 could cause adverse endocrine health effects.

SAT-722 Structure-Based Discovery of Hydraulic Fracturing Chemicals as Novel Androgen Receptor Antagonists

Hydraulic fracturing (HF) technology is increasingly utilized for oil and gas extraction operations. The widespread use of HF has led to concerns of potential negative impacts on both the environment and human health. Indeed, the potential endocrine disrupting impacts of HF chemicals is one such knowledge gap. Herein, we used structure-based molecular docking to assess the binding affinities of 60 HF chemicals used in California to the human androgen receptor (AR). Five HF chemicals had relatively high AR binding affinity, suggesting the potential to disrupt AR effects. We next assessed androgenic and antiandrogenic activities of these chemicals in vitro. Of the five candidate AR ligands, only Genapol® X–100 was found to significantly reduce the AR transactivation by 22%. To better understand the structural effect of Genapol® X–100 on the potency of receptor inhibition, we compared the antiandrogenic activity of Genapol® X–100 with that of its structurally similar chemical, Genapol® X–080. Interestingly, both Genapol® X–100 and Genapol® X–080 elicited a significant antagonistic effect with 20% relative inhibitory concentrations (RIC20) of 0.43 and 0.89 μM, respectively. This indicated that Genapol® X–100 was more potent in inhibiting AR than Genapol® X–080, consistent with longer Genapol® X–100 chain length causing greater potency of AR activity inhibition. Furthermore, we investigated the mechanism of AR inhibition of these two chemicals in vitro. The result revealed that both Genapol® X–100 and Genapol® X–080 inhibited AR through noncompetitive binding mechanism. The effects of these two chemicals on the expression of AR responsive genes such as PSA, KLK2, and AR were also investigated. Genapol® X–100 and Genapol® X–080 notably altered the expression of these genes at relatively low concentrations of 0.5 µM to 1 µM. Using these integrated in vitro and in silico approaches, we identified HF chemicals as novel noncompetitive AR antagonists. Our findings heighten awareness of endocrine disruption by HF chemicals and provide evidence that noncompetitive antiandrogenic Genapol® X–100 could possibly cause adverse endocrine health effects in humans.

Hyponatremia in a Patient With Cancer

Hyponatremia in a Patient With Cancer

Assessment of the endocrine disrupting properties of Bisphenol AF according to the EU criteria and ECHA/EFSA guidance.

Endocrine disruptors (EDs) are exogenous compounds that interfere with the hormone system, affecting human health and environment. Specific legislative obligations have been introduced in the European Union (EU) to gradually eliminate EDs in water, industrial chemicals and pesticides. However, identification of EDs is the first and essential step towards regulation and appropriate risk management. Scientific criteria and guidance for ED assessment have recently been established for pesticides in the EU. In this project, the ED properties of the non‐pesticide chemical Bisphenol AF (BPAF), analogue and potential substitute of Bisphenol A were evaluated by the application of the EU criteria and guidance in the frame of human health risk assessment. A data dossier was built by a systematic literature review (WOS, Scopus, Pubmed, Embase), title/abstract screening (RAYYAN) and full‐text examination. All relevant information was extracted and systematically reported, and reliability and relevance of data were assessed (SciRAP). Data were synthesised into lines of evidence for (i) endocrine activity, (ii) adversity and (iii) general toxicity, and weight of evidence evaluation was applied. The initial analysis of the evidence showed potential endocrine adverse effects and endocrine activity, meeting the ED criteria and leading the assessment to the mode of action (MoA) analysis. The biological plausibility of the link between the adverse effects and the endocrine activity was investigated based on current scientific knowledge. Empirical support for dose–response and temporal concordance was evaluated, and the key events were assessed in terms of essentiality, consistency, analogy and specificity. Finally, an overall conclusion of the ED properties of BPAF was drawn. The EU criteria and guidance for EDs assessment were successfully applied to BPAF demonstrating its endocrine activity and adversity based on weight of evidence methodology and MoA analysis. The Fellow greatly increased her knowledge and hands‐on experience on ED assessment in the EU regulatory context contributing to implement transparency and structure in health risk assessment.

SUN-388 Immune Checkpoint Inhibitor Nivolumab in Advanced or Recurrent Adrenocortical Carcinoma

Introduction: Adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy. Due to the rarity of this malignancy, controlled trials investigating efficacy of chemotherapy or immunotherapy are uncommon. Newer therapy with immune check point inhibitor Nivolumab, a monoclonal antibody of the programmed cell death 1 receptor ( PD 1) is investigational for the treatment of advanced or refractory ACC. Here we present a case of advanced stage IV ACC which was treated with nivolumab, and the disease showed response with shrinkage of the visceral metastatic lesions. Case: A 22-year-old female presented with vague abdominal pain and was found on US scan of the abdomen to have a mass in the left adrenal area. CT scan, PET scan followed by biopsy, confirmed ACC with bilateral lower lobe pulmonary nodules. Adrenal hormone evaluation was unremarkable. She underwent left adrenalectomy of a 20 cm tumor with radical nephrectomy and also bilateral wedge resections of lower lobe pulmonary nodules, all of which was positive for metastatic ACC. Surgical resection was followed by adjuvant chemotherapy (Adriamycin, Cis-platinum, Etoposide along with mitotane) and local radiation therapy to the primary tumor bed. Over the following months, she started to have worsening low back pain, and subsequently found to have a metastatic spinal lesion at the T12 vertebral body, which was treated with radiosurgery. She was also found to have liver metastases which were resected surgically. Despite chemotherapy, her disease continued to progress with recurrence of metastases in the lungs, liver and bone. Sunitinib was initiated without any response. Eventually she was started on off-label investigational single-agent nivolumab 3 years from the time of initial presentation. Follow-up CT scan 3 months post treatment with nivolumab showed radiological evidence of interval decrease in size of known metastatic lesions likely representing a response to therapy with nivolumab. The use of nivolumab was complicated by thyroiditis. Conclusion: Nivolumab, an immune checkpoint PD-1 inhibitor not currently approved for the treatment of ACC, may slow progression of ACC. Nivolumab has may many immune-related endocrine adverse effects, including hypophysitis, thyroiditis, autoimmune diabetes, and adrenal insufficiency. Our patient developed painless thyroiditis followed by hypothyroidism. In our patient, treatment with nivolumab showed a stabilization of visceral disease for > 6 months. Nivolumab may be a treatment option for patients with advanced or recurrent ACC

SUN-413 Dual Endocrinopathies Following Single Dose of Pembrolizumab Therapy

Introduction: Immune related endocrine adverse effects (IReAs) caused by checkpoint inhibitors (CI) used in the treatment of advanced cancers are rare and often under recognized, but they can be potentially life-threatening. Case: A 69 y/o male with stage 4 metastatic colon cancer was evaluated 10 days following the receipt of a single dose of Pembrolizumab (P). He reported extreme fatigue, syncope, nausea, cold intolerance and constipation. Exam: Orthostasis and HR = 104/min. Biochemical evaluation before P: Am cortisol 12 (5-23 mcg/dl), TSH 3.4 (0.4 -4 UIU/ml). Post P: Am cortisol < 1.8, ACTH 4 (6-50 pg/ml), FT4 0.7 (0.76 -1.46 ng/dl),TT3 57.5 (60-180 ng/dl), TSH 7.31,Total T 200 (240-827 ng/dl), Free T 17.4 (46-224 pg/ml), FSH 12.7 (1.4 -18.1 mIU/ml ), LH 5.6 (1.5 -9.3 mIU/ml), PRL102 (2.1-17 ng/ml).IGF-1 and renin/aldosterone were WNL. Na 139, K 3.6, BG 103. TPO, TSI, TRAB, GAD65 and 21 alpha hydroxylase antibodies were negative. ACTH stimulation test showed baseline, 30, 60 mins cortisol of < 1.8, 12, and 19 respectively. A pituitary MRI revealed enlarged pituitary gland 12 mm (baseline 4 mm), 4 weeks after receiving P. Physiologic hydrocortisone (15/10 mg) PO and Levothyroxine 50 mcg daily were initiated. 3 weeks later, he required ventilator support for P induced pneumonitis resulting in respiratory failure. This warranted IV methyl prednisone 2mg/kg, followed by rapid prednisone taper to a maintenance dose of 20 mg daily lifelong and P was discontinued indefinitely. At the 6 week follow-up, hypotension and fatigue improved, FT4 was WNL, and pituitary enlargement had resolved. Unfortunately, he transitioned to inpatient hospice care on account of progression of the underlying cancer off P. Conclusions: 1. The incidence of P induced hypophysitis is 0.5 -1.1 %, whereas primary hypothyroidism occurs in 3.9 % of patients.1 2. Our patient developed primary hypothyroidism and secondary AI, simultaneously. The reported time for onset of hypophysitis and primary hypothyroidism, after exposure to P is 4-10 weeks and 6 weeks respectively, and is attributed to cumulative dose toxicity. In this case, it was observed within 10 days of receipt of a single dose.1 3. Active surveillance of patients receiving CI presenting with evidence of hormone deficiency and/or focal neurological findings facilities prompt recognition and timely management of IReAs. Endocrine evaluation prior to starting CI should be considered. 4. In contrast to other causes of hypophysitis, the adrenal, thyroid and gonadal axes are affected in descending order of frequency, in P treated patients. Diabetes insipidus is infrequently noted.1 5. Check point inhibitors can be continued in most cases if underlying endocrinopathies are adequately treated.

Effects of clozapine and haloperidol treatment on plasma concentrations of androgen hormones and androgendependent organ changes in rats.

OBJECTIVES:Metabolic and endocrine adverse effects are among the most concerning unfavorable consequences of commonly used psychotropic drugs. The present research was planned to assess and determine the effects of haloperidol and clozapine on testosterone, cortisol, and corticosterone levels and also their influence on androgen-dependent organs in adult male Wistar rats.MATERIALS AND METHODS:Animals were casually distributed into three groups (n = 10 in each group). Drugs were administered intraperitoneally for 28 days. The control group received 2 mL of physiological saline, the second group received haloperidol (0.5 mg/kg), and the third group received clozapine (0.5 mg/kg). The subsequent testosterone, cortisol, and corticosterone plasma concentration levels were analyzed with chemiluminescent immunoassay.RESULTS:Clozapine and haloperidol treatments altered testosterone hormone levels. Testosterone mean values in both the clozapine (1.00–0.58) and haloperidol (0.65–0.62) groups were found to be lower than compared to controls (P = 0.003, P < 0.001). Histomorphometric analysis results also showed reduced testes size and reduced weight of androgen-dependent organs in drug-treated rats.CONCLUSION:It can be suggested that clozapine and haloperidol are effective in reducing the testosterone plasma concentration level and androgen-dependent organ sizes; therefore, clinicians should be aware of these effects when considering the use of antipsychotic drugs.

Cancer Immunotherapy Related Endocrine Adverse Effects

Cancer Immunotherapy Related Endocrine Adverse Effects

Host Developmental Toxicity of BPA and BPA Alternatives Is Inversely Related to Microbiota Disruption in Zebrafish

Host-associated microbiota can biotransform xenobiotics, mediate health effects of chemical exposure, and play important roles in early development. Bisphenol A (BPA) is a widespread environmental chemical that has been associated with adverse endocrine and neurodevelopmental effects, some of which may be mediated by microbiota. Growing public concern over the safety of BPA has resulted in its replacement with structurally similar alternatives. In this study, we evaluated whether BPA and BPA alternatives alter microbiota and modulate secondary adverse behavioral effects in zebrafish. Zebrafish were developmentally exposed to BPA, Bisphenol AF (BPAF), Bisphenol B (BPB), Bisphenol F (BPF), or Bisphenol S (BPS). At 10 days post fertilization (dpf), toxicity assessments were completed and 16S rRNA gene sequencing was performed to evaluate potential chemical-dependent shifts in microbial community structure and predicted function. A standard light/dark behavioral assay was used to assess locomotor activity. Based on developmental toxicity assessments at 10 dpf, a range of potencies was observed: BPAF > BPB > BPF ∼ BPA > BPS. Analysis of 16S rRNA gene sequencing data showed significant concentration-dependent disruption of microbial community structure and enrichment of putative microbial functions with exposure to BPS, BPA, or BPF, but not BPB or BPAF. Interestingly, microbial disruption was inversely related to host developmental toxicity and estrogenicity. Exposure to BP analogs did not cause behavioral effects at 10 dpf. Our findings indicate that some BP analogs disrupt host microbiota early in life and demonstrate novel chemical-microbiota interactions that may add important context to current hazard identification strategies.

Severe chronic pain following spinal cord damage: a pragmatic perspective for prescribing opioids.

The controversial issue of prescribing opioids to people with spinal cord damage who have severe pain is discussed in this paper. The reasons for concern regarding the increase in opioid prescription over recent years are outlined, along with a summary of the major potential adverse outcomes associated with opioids, such as falls, respiratory suppression, adverse endocrine effects, cognitive impairment, and the potential for opioid abuse, addiction and death. Situations when opioids are more appropriate are considered to be in the immediate post-trauma or post-operative periods. More controversial is the use of opioids in chronic non-cancer pain. A brief review of the evidence regarding opioids in chronic non-cancer pain is presented, and strategies outlined for reducing the risk of adverse consequences from opioid use in chronic non-cancer pain. These strategies include considerations before starting opioids, during initiation, monitoring activities and the cessation process. A vital consideration before starting opioids includes ensuring that all alternatives to opioids have been fully considered and trialled. Finally, some pragmatic proposals for prescribing opioids in people with SCD are suggested. It is recommended that before opioids are commenced, that the informed consent process should be complimented by a treatment agreement, with an initial 4-week trial period, and close monitoring of established goals.

Urinary biomarkers of exposure to the mycoestrogen zearalenone and its modified forms in German adults.

Zearalenone (ZEN), a mycotoxin with estrogenic activity, can exert adverse endocrine effects in mammals and is thus of concern for humans. ZEN is found in cereal crops and grain-based foods, often along with modified ('masked') forms usually not detected in routine contaminant analysis, e.g., ZEN-O-β-glucosides and ZEN-14-sulfate. These contribute to mycoestrogen exposure, as they are cleaved in the gastrointestinal tract to ZEN, and further metabolized in animals and humans to α- and β-zearalenol (α-ZEL and β-ZEL). ZEN and its metabolites are mainly excreted as conjugates in urine, allowing to monitor human exposure by a biomarker-based approach. Here, we report on a new study in German adults (n = 60) where ZEN, α-ZEL, and β-ZEL were determined by LC-MS/MS analysis after enzymatic hydrolysis and immunoaffinity column clean-up of the aglycones in urines. Biomarkers were detected in all samples: ZEN ranges 0.04-0.28 (mean 0.10 ± 0.05; median 0.07) ng/mL; α-ZEL ranges 0.06-0.45 (mean 0.16 ± 0.07; median 0.13) ng/mL, and β-ZEL ranges 0.01-0.20 (mean 0.05 ± 0.04; median 0.03) ng/mL. Notably, average urinary levels of α-ZEL, the more potent estrogenic metabolite, are higher than those of ZEN, while β-ZEL (less estrogenic than ZEN) is found at lower levels than the parent mycotoxin. Similar results were found in ten persons who collected multiple urine samples to gain more insight into temporal fluctuations in ZEN biomarker levels; here some urines had higher maximal concentrations of total ZEN (the sum of ZEN, α-ZEL, and β-ZEL) with 1.6 and 1.01ng/mL, i.e., more than those found in the majority of other urines. A preliminary approach to translate the new urinary biomarker data into dietary mycotoxin intake suggests that exposure of most individuals in our cohort is probably below the tolerable daily intake (TDI) of 0.25µg/kg b.w. set by EFSA as group value for ZEN and its modified forms while that of some individuals exceed it. In conclusion, biomonitoring can help to assess consumer exposure to the estrogenic mycotoxin ZEN and its modified forms and to identify persons at higher risk.

Performance-enhancing drugs and adverse endocrine effects

Performance-enhancing drugs and adverse endocrine effects

Endocrinological aspects of HIV infection.

Patients with human immunodeficiency virus (HIV) are living longer with effective antiretroviral therapies and are enjoying near normal life span. Therefore, they are encountering endocrine issues faced by the general population along with those specific to HIV infection. The purpose of this article is to review the common endocrine aspects of HIV infection, and the early detection and management strategies for these complications. Recent literature on HIV and endocrine disease was reviewed. HIV can influence endocrine glands at several levels. Endocrine glandular function may be altered by the direct effect of HIV viral proteins, through generation of systemic and local cytokines and the inflammatory response and via glandular involvement with opportunistic infections and HIV-related malignancies. Endocrine disorders seen in people with HIV include metabolic issues related to obesity such as diabetes, hyperlipidemia, lipohypertrophy, lipoatrophy and lipodystrophy and contribute significantly to quality of life, morbidity and mortality. In addition, hypogonadism, osteopenia and osteoporosis are also more prevalent in the patients with HIV. Although disorders of hypothalamic-pituitary-adrenal axis resulting in adrenal insufficiency can be life threatening, these along with thyroid dysfunction are being seen less commonly in the antiretroviral therapy (ART) era. ARTs have greatly improved life expectancy in people living with HIV but can also have adverse endocrine effects. Clinicians need to have a high index of suspicion for endocrine abnormalities in people with HIV as they can be potentially life threatening if untreated. Endocrine evaluation should be pursued as in the general population, with focus on prevention, early detection and treatment to improve quality of life and longevity.

Endocrine adverse effects after immune checkpoint inhibitor therapy in patients with metastatic melanoma: Experience from a single tertiary level centre

Endocrine adverse effects after immune checkpoint inhibitor therapy in patients with metastatic melanoma: Experience from a single tertiary level centre

Effects of methomyl on steroidogenic gene transcription of the hypothalamic-pituitary-gonad-liver axis in male tilapia

Male tilapia were exposed to sub-lethal methomyl concentrations of 0, 0.2, 2, 20 or 200 μg/L for 30 d, and were subsequently cultured in methomyl-free water for 18 d. Relative transcript abundance of steroidogenic genes involved in the HPGL axis of male tilapia was examined at 30 d in the exposure test and at 18 d in the recovery test. The results revealed that low concentrations of methomyl (0.2 and 2 μg/L) did not cause significant changes in gene mRNA levels in the HPGL axis of male tilapia; thus, we considered 2 μg/L concentrations as the level that showed no apparent adverse endocrine disruption effects. However, higher concentrations of methomyl (20 and 200 μg/L) disrupted the endocrine system and caused significant increase in the levels of GnRH2, GnRH3, ERα, and ERβ genes in the hypothalamus, GnRHR and FSHβ genes in the pituitary, CYP19a, FSHR, and ERα genes in the testis, and VTG and ERα genes in the liver, and significantly decreased the levels of LHR, StAR, 3β-HSD, and ARα genes in the testis and LHβ gene in the pituitary, leading to changes in sex steroid hormone and vitellogenin levels in the serum and ultimately resulting in reproductive dysfunction in male tilapia. The recovery tests showed that the toxicity effect caused by 20 μg/L methomyl was reversible; however, the toxicity effect at 200 μg/L of methomyl was irreversible after 18 d. Therefore, we concluded that 200 μg/L was the threshold concentration for methomyl-induced irreversible endocrine disruption in male tilapia.

Transcriptional changes in steroidogenesis by perfluoroalkyl acids (PFOA and PFOS) regulate the synthesis of sex hormones in H295R cells

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are two of the most widely used perfluoroalkyl acids (PFAAs). Because of their strong persistence, they have become widely distributed throughout the environment and human bodies. PFOA and PFOS are suspected to disrupt the endocrine system based upon many in vivo studies, but the underlying mechanisms are currently unclear. In this study, we investigated the endocrine-related effects of PFOA and PFOS using in vitro estrogen receptor (ER) and androgen receptor (AR) transactivation assays and steroidogenesis assay. The results showed that PFOA and PFOS exhibited weak antagonistic ER transactivation but did not exhibit agonistic ER or AR transactivation. In the steroidogenesis assay, PFOA and PFOS induced 17β-estradiol (E2) level and reduced testosterone level, which would be caused by the induction of aromatase activity. The qPCR analysis of genes involved in steroidogenesis indicates that PFOA and PFOS associate with sex hormone synthesis by the transcriptional induction of two genes, cyp19 and 3β-hsd2. Moreover, the transcriptional induction of cyp11b2 by PFOS suggests that this chemical may underlie the disruption of several physiological functions related to aldosterone. The results of the current study suggest that PFOA and PFOS are potential endocrine disrupting chemicals (EDCs) and provide information for further studies on the molecular events that initiate the adverse endocrine effects.

Endocrine Effects of Inhaled Corticosteroids in Children.

Inhaled corticosteroids (ICSs) are widely used as first-line treatment for various chronic respiratory illnesses. Advances in devices and formulations have reduced their local adverse effects. However, as delivery of ICSs to the lungs improves, the systemic absorption increases, and an adverse effect profile similar to, although milder than, oral corticosteroids has emerged. The most serious potential adverse effect is adrenal insufficiency, which can be life threatening. Adrenal insufficiency occurs most in patients taking the highest doses of ICSs but is reported with moderate or even low doses as well. Our recommendations include greater vigilance in testing adrenal function than current standard practice. In patients with diabetes mellitus (types 1 and 2), an increase in glucose levels is likely, and diabetes medication adjustment may be needed when initiating or increasing ICSs. The risk of linear growth attenuation and adverse effects on bone mineral density is generally low but should be considered in the face of additional risk factors. On behalf of the Pediatric Endocrine Society Drugs and Therapeutics Committee, we present a review of the endocrine adverse effects of ICSs in children and offer recommendations relating to testing and referral. Limited data in particular realms diminish the strength of certain recommendations, and clinical judgment continues to be paramount.

Serum Triamcinolone Levels Following Interlaminar Epidural Injection.

Lumbar interlaminar epidural steroid injections (ESIs) are one of the most commonly performed procedures in pain medicine, but little is known about the serum levels of steroids following injection into the epidural space. The primary objective of this study was to investigate the pharmacokinetics of fluoroscopy-guided epidural-administered triamcinolone acetonide in a cohort of patients with chronic low-back pain seeking treatment in a pain medicine clinic. The study cohort included 10 patients undergoing a fluoroscopically guided L4-L5 or L5-S1 lumbar interlaminar ESI at a pain medicine specialty clinic. Blood was collected prior to the ESI and on days 1, 2, 4, 6, 8, 14, 21, 28, 35, and 42 following the injection. The sample extract was analyzed by tandem mass spectrometry. The terminal elimination half-life of epidural-administered triamcinolone in a noncompartmental analysis was 523 hours. In the noncompartmental analysis, peak triamcinolone concentrations of 4.1 ng/mL were detected within 24 hours after administration. The pharmacokinetics of epidural-administered triamcinolone is consistent with previously observed adverse effects of the drug on endocrine function. The pharmacokinetics of other epidural-administered steroids should be determined and incorporated in clinical trials to investigate the potential associations between serum levels, clinical outcomes, and potential adverse endocrine effects.