Basal Neuroendocrine Research Articles

Dynamic Changes of Molecular Subtype Classification and Genomic Classifier Scores in High-Risk Prostate Cancer Patients Undergoing Pre-Operative Stereotactic Body Radiation Therapy

The radiobiology of irradiated human prostate cancer (PCa) remains poorly understood as irradiated tissues often remain in situ. PREPARE-SBRT (NCT03663218) is a clinical trial testing the safety of neoadjuvant MRI-guided stereotactic body radiation therapy (SBRT) for men with high-risk PCa. We leveraged paired samples from pre-treatment biopsy and irradiated prostatectomy (RP) specimens to evaluate transcriptomic changes in irradiated tumors at acute timepoints following SBRT. Tumor RNA expression profiles were generated using Decipher GRID by Veracyte on 12 subjects enrolled on NCT03663218 with paired pre/post-SBRT tissues (n = 24). Descriptive statistics using Decipher Genomic Classifier (GC) Score [0-1] and GC risk group (low/int/high) were generated from a validated 22-gene GC. Tumor biology signatures reported as dichotomous variables evaluated changes in androgen receptor (AR) activity [higher v lower] and cell cycle progression (CCP) [lower v higher]. Decipher prostate subtype classifier [PSC, luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), basal neuroendocrine like (BN)] classification and PAM50 molecular subtype [luminal A (lumA), luminal B (lumB), basal] at pre/post-SBRT timepoints were reported. A control cohort of transcriptomic profiles of 803 matched untreated biopsy and RP samples from the same patients were used to control for signature differences attributable to sample type. The median pre- and post-SBRT GC scores were 0.55 and 0.72 (Δ+0.17), respectively. By comparison, median GC scores in a control cohort (n = 803) of biopsy and RP specimens were 0.50 and 0.56 (Δ+0.06), respectively. SBRT increased GC score in 9/12 subjects (75%) with a median increase of 0.3. Changes in GC score resulted in reclassification of baseline GC risk in 7 of 12 subjects with 71% of reclassified subjects (5/7) transitioning to a higher genomic risk. 92% of subjects (11/12) had higher AR activity scores at baseline. Of this subgroup, 5/11 (45%) converted to lower AR activity score after SBRT. CCP signatures remained stable in 9 of 12 subjects (75%) with 7/12 subjects exhibiting lower CCP score at baseline and only 1 subject transitioning from lower to higher CCP score. Distribution of PAM50 molecular subtype at baseline and after SBRT was lumA (33>53%), lumB (25>17%), basal (42>25%) resulting in 83% of subjects (10/12) annotated to a different PAM50 molecular subtype at pre/post-SBRT assessment. PSC subtype distribution at baseline was LD (33%), LP (25%), BI (33%) and BN (8%). Strikingly, after SBRT, 92% (11/12) of subjects were classified as BI molecular subtype with several immune activation signatures also increased after SBRT. A majority of subjects demonstrate a post-SBRT increase in GC score with reclassification of genomic-prognostic risk group in 58%. An enrichment of the basal-immune molecular subtype was observed following SBRT suggesting a convergence towards this biology in irradiated tumors.

A novel prostate cancer subtyping classifier based on luminal and basal phenotypes.

Prostate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression-based subtyping model based on prostate-specific biological processes was sought. Unsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n=32,000; evaluation, n=68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts. Clustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01-0.71; n=855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n=108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09-0.51). With the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features. Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors-the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management.

MP17-01 DIFFERENTIAL TRANSCRIPTOMIC INDICATORS OF POTENTIAL THERAPEUTIC RESPONSE TO TARGETED THERAPY FOR AJCC IIC+ LOCALIZED PROSTATE CANCER WITH DECIPHER ≥0.95

You have accessJournal of UrologyCME1 Apr 2023MP17-01 DIFFERENTIAL TRANSCRIPTOMIC INDICATORS OF POTENTIAL THERAPEUTIC RESPONSE TO TARGETED THERAPY FOR AJCC IIC+ LOCALIZED PROSTATE CANCER WITH DECIPHER ≥0.95 Eric Li, James Proudfoot, Alex Hakansson, Xin Zhao, Yang Liu, Adam Weiner, Edward Schaeffer, Elai Davicioni, and Ashley Ross Eric LiEric Li More articles by this author , James ProudfootJames Proudfoot More articles by this author , Alex HakanssonAlex Hakansson More articles by this author , Xin ZhaoXin Zhao More articles by this author , Yang LiuYang Liu More articles by this author , Adam WeinerAdam Weiner More articles by this author , Edward SchaefferEdward Schaeffer More articles by this author , Elai DavicioniElai Davicioni More articles by this author , and Ashley RossAshley Ross More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003237.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Among patients with AJCC Stage IIC+ cancer, a subset of patients are genomically at highest risk of progression with very high Decipher ≥0.95 scores. This group of patients is distinct and not present with AJCC I-IIB prostate cancer. As genomic changes may predict potential benefit from molecular based therapies, we sought to identify incidence of genomic alterations in this population. METHODS: We analyzed the transcriptomes of 13,117 men diagnosed with AJCC stage IIC+ localized prostate cancer. We compared signature readouts for androgen receptor activity (AR-A), PTEN loss, homologous repair deficiency, Rb loss, immune activity, and PSMA (FOLH1) expression, as well as prostate subtyping classifier (PSC) based on cell of origin and molecular pathways. Standardized mean differences (SMD) were calculated to compare size effect, with significant effect size defined as 0.2. RESULTS: 1767 men with AJCC Stage IIC+ cancer were found to have Decipher score ≥0.95. Patients with Decipher ≥0.95 possessed lower AR activity, as well as higher rates of PTEN loss and HR deficiency compared to men with high Decipher 0.6-0.95 (SMD 0.32, 0.40, and 0.43). There was a lower incidence of luminal differentiated (LD), and higher incidence of basal immune (BI) and basal neuroendocrine (BN) subtypes among those with Decipher ≥0.95. Rates of Rb loss remained low across all Decipher subgroups, and there was no significant difference in FOLH1 expression comparing men with Decipher 0.6-0.95 and Decipher ≥0.95. CONCLUSIONS: Patients with very high Decipher ≥0.95 localized prostate cancer have a distinct molecular profile, and may benefit from PARP inhibitors. Further investigation is required to understand how these molecular signatures may drive progression and metastasis in patients who are identified as very high risk on genomic classifier testing. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e212 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eric Li More articles by this author James Proudfoot More articles by this author Alex Hakansson More articles by this author Xin Zhao More articles by this author Yang Liu More articles by this author Adam Weiner More articles by this author Edward Schaeffer More articles by this author Elai Davicioni More articles by this author Ashley Ross More articles by this author Expand All Advertisement PDF downloadLoading ...

Hormone contraceptive use in young women: Altered mood states, neuroendocrine and inflammatory biomarkers

Oral contraceptives are used by millions of women worldwide, yet there are questions regarding the psychological and biological consequences of these medications. Considering that sex steroid hormones can regulate neuroendocrine and behavioral responses to stress, the current study examined mood and stress symptomatologies, as well as circulating levels of cortisol and inflammatory biomarkers among young women (N = 388), of whom, 47.0 % (n = 182) were using a form of hormonal contraception. Women using hormone contraceptives displayed significantly higher depressive and stress scores compared to non-users, whereas no differences were found for anxiety symptoms. Moreover, contraceptive users had markedly elevated plasma cortisol and C-reactive protein levels in comparison to non-users. Upon assessing women at different phases of their menstrual cycle, hormone contraceptive users displayed higher levels of cortisol compared to women in the follicular and luteal phases, in addition to higher levels of CRP levels compared to women in the luteal phase. Together, these findings suggest that hormone contraceptive use is linked to exaggerated basal neuroendocrine and inflammatory profiles, which could potentially increase sensitivity to the impacts of stressors and mood disturbances.

PD07-07 MOLECULAR SUBTYPING OF >80,000 PROSTATE CANCER TRANSCRIPTOMES IDENTIFIES FOUR CLASSES WITH DISTINCT BIOLOGICAL AND CLINICAL CHARACTERISTICS WITH IMPLICATIONS FOR TARGETED THERAPIES

You have accessJournal of UrologyCME1 May 2022PD07-07 MOLECULAR SUBTYPING OF >80,000 PROSTATE CANCER TRANSCRIPTOMES IDENTIFIES FOUR CLASSES WITH DISTINCT BIOLOGICAL AND CLINICAL CHARACTERISTICS WITH IMPLICATIONS FOR TARGETED THERAPIES Adam Weiner, Yang Liu, Ashley Ross, Felix Feng, Phuoc Tran, Nicholas Zaorsky, Angela Jia, Xin Zhao, Alex Hakansson, Vinnie Liu, James Proudfoot, Ewan Gibb, Elai Davicioni, Daniel Spratt, and Edward Schaeffer Adam WeinerAdam Weiner More articles by this author , Yang LiuYang Liu More articles by this author , Ashley RossAshley Ross More articles by this author , Felix FengFelix Feng More articles by this author , Phuoc TranPhuoc Tran More articles by this author , Nicholas ZaorskyNicholas Zaorsky More articles by this author , Angela JiaAngela Jia More articles by this author , Xin ZhaoXin Zhao More articles by this author , Alex HakanssonAlex Hakansson More articles by this author , Vinnie LiuVinnie Liu More articles by this author , James ProudfootJames Proudfoot More articles by this author , Ewan GibbEwan Gibb More articles by this author , Elai DavicioniElai Davicioni More articles by this author , Daniel SprattDaniel Spratt More articles by this author , and Edward SchaefferEdward Schaeffer More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002526.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We used molecular subtyping to characterize the largest prostate cancer transcriptome database to understand the tumor behavior and help guide treatment decision making. METHODS: Whole transcriptome analyses was performed on de-identified tumor samples from biopsies or radical prostatectomy from the clinical use of the Decipher prostate genomic classifier (Decipher Biosciences, San Diego, CA; n=32,000, training cohort, n=48,703, testing cohort). We grouped these patients based on expression patterns of a curated panel of signatures and biomarkers relevant to systemic therapies for prostate cancer (n=21), from which we identified 4 clusters with distinct biological characteristics. A multinomial logistic regression was trained to reproduce the clusters as a single sample classifier. RESULTS: Luminal-Differentiating (LD) tumors had the highest AR-activity scores, upregulation of canonical AR transcriptional targets (i.e., PSA and PSMA; Fig). Luminal Proliferating (LP) tumors had the highest expression of AR, and cell proliferation genes (e.g., MKI67 and TOP2A) and pathways. Basal Immune (BI) tumors possessed significant immune infiltration and T-effector cell activity and low levels of immune suppressor signatures. Basal Neuroendocrine (BN) tumors were characterized by low AR-activity expression, low immune infiltration, and enrichment with neuronal gene expression. LP and BI tumors tended to possess more aggressive clinical characteristics: high proportions of grade group 4-5, node positive disease (BI only), and high Decipher score. In a cohort of patients treated with radical prostatectomy (n=855), patients with LD tumors experienced longer metastasis-free survival compared to LP (HR=3.56 [1.83-6.93]), BI (HR=2.55 [1.29-5.01]) and BN (HR=3.30 [1.03-10.61]) with Cox regression adjusting for age, PSA, stage and Gleason score. CONCLUSIONS: This molecular subtyping model for prostate cancer, derived from the largest reported transcriptome analysis of primary tumors segments tumors by relevant biological processes with potential implications for targeting systemic therapies. Source of Funding: Decipher Biosciences © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e101 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Adam Weiner More articles by this author Yang Liu More articles by this author Ashley Ross More articles by this author Felix Feng More articles by this author Phuoc Tran More articles by this author Nicholas Zaorsky More articles by this author Angela Jia More articles by this author Xin Zhao More articles by this author Alex Hakansson More articles by this author Vinnie Liu More articles by this author James Proudfoot More articles by this author Ewan Gibb More articles by this author Elai Davicioni More articles by this author Daniel Spratt More articles by this author Edward Schaeffer More articles by this author Expand All Advertisement PDF DownloadLoading ...

Sex-specific associations of basal steroid hormones and neuropeptides with Conduct Disorder and neuroendocrine mediation of environmental risk

Conduct Disorder (CD) is characterized by severe aggressive and antisocial behavior. The stress hormone system has frequently been investigated as a neurobiological correlate of CD, while other interacting neuroendocrine biomarkers of sex hormone or neuropeptide systems have rarely been studied, especially in females. We examined multiple basal neuroendocrine biomarkers in female and male adolescents with CD compared to healthy controls (HCs), and explored whether they mediate effects of environmental risk factors on CD. Within the FemNAT-CD study, salivary cortisol, alpha-amylase, testosterone, dehydroepiandrosterone-sulfate (DHEA-S), estradiol, progesterone, oxytocin, and arginine-vasopressin were measured under basal conditions in 166 pubertal adolescents with CD, and 194 sex-, age-, and puberty-matched HCs (60% females, 9–18 years). Further, environmental risk factors were assessed. Single hormone analyses showed higher DHEA-S, and lower estradiol and progesterone levels in both females and males with CD relative to HCs. When accounting for interactions between neuroendocrine systems, a male-specific sex hormone factor (testosterone/DHEA-S) predicted male CD, while estradiol and a stress-system factor (cortisol/alpha-amylase) interacting with oxytocin predicted female CD. Estradiol, progesterone, and oxytocin partly explained associations between early environmental risk and CD. Findings provide evidence for sex-specific associations between basal neuroendocrine measures and CD. Especially altered sex hormones (androgen increases in males, estrogen reductions in females) robustly related to CD, while basal stress-system measures did not. Early environmental risk factors for CD may act partly through their effects on the neuroendocrine system, especially in females. Limitations (e.g., basal neuroendocrine assessment, different sample sizes per sex, pubertal participants, exploratory mediation analyses) are discussed.

Chronic fluoxetine treatment of juvenile zebrafish (Danio rerio) does not elicit changes in basal cortisol levels and anxiety-like behavior in adulthood.

Exposure to selective serotonin reuptake inhibitors (SSRIs) during development may elicit long-term neuroadaptive changes that could alter the basal regulation of stress-associated physiological and behavioral processes later in life. Currently, the effects of juvenile fluoxetine exposure in rodent models appear to be dependent on the developmental window targeted as well as the duration of drug exposure. The zebrafish (Danio rerio) model is rapidly becoming a useful tool in pharmacological research and can be used to help elucidate some of the long-term effects of fluoxetine exposure prior to sexual maturation on neuroendocrine and behavioral stress markers. In the current study, juvenile zebrafish were chronically exposed to fluoxetine hydrochloride (0 or 100 μg/L) for 14 days (31–44 days post-fertilization (dpf)), then were left untreated until young adulthood. Starting at 90 dpf, basal neuroendocrine stress and behavioral responses of zebrafish were assessed. Cortisol was extracted from the young adult zebrafish body (trunk) and quantified via enzyme-linked immunosorbent assay (ELISA). Anxiety-like behaviors were assessed in response to introduction to the novel tank test. It was expected that juvenile exposure to fluoxetine would (1) reduce basal cortisol levels and (2) elicit anxiolytic effects in the novel tank test in adulthood. However, fluoxetine exposure during the juvenile period was not associated with alterations in basal levels of cortisol nor were there any significant changes in anxiety-like behavior in the young adult zebrafish. Thus, in zebrafish, it does not appear that SSRI exposure during the juvenile period has a long-term adverse or maladaptive impact on the basal expression of cortisol and anxiety-like behavior in adulthood. Further studies are needed to determine if SSRI exposure during this developmental window influences neuroendocrine and behavioral responses to acute stress.

Basal neuroendocrine status and cocaine craving measurements in active cocaine-dependent volunteers at admission and after 8 weeks of abstinence

Basal neuroendocrine status and cocaine craving measurements in active cocaine-dependent volunteers at admission and after 8 weeks of abstinence

Decreased cortisol response to awakening is associated with cognitive vulnerability to depression in a nonclinical sample of young adults

Due to its high intraindividual stability, the cortisol awakening response (CAR) may be regarded as a trait measure of the dynamics of the HPA-axis activity. The present study aimed at investigating associations of the CAR with rumination as a cognitive vulnerability marker for depression assessed by both a trait measure and by experimental manipulation. After induction of sad mood by viewing a sad sequence of a movie, 42 healthy university students were randomly induced to either ruminatively self-focus on their feelings or to distract themselves from their mood by concentrating on respective text cards for 8min. Trait rumination and distraction were measured by the Response Styles Questionnaire (RSQ) at baseline (T0), while current mood was recorded before (T1) and after (T2) the mood induction as well as after the rumination/distraction induction (T3) using the Positive and Negative Affect Schedule (PANAS). Basal saliva cortisol levels were measured independently on a different day. After mood induction, levels of mood were lowered significantly. Participants subsequently induced to ruminate kept their negative mood whereas participants induced to distract themselves showed a reduction in negative mood. Self-focused trait rumination amplified low mood in both induction conditions. A decreased CAR was associated with self-focused rumination and with less improvement of sad mood after induced distraction. We conclude that the two variables apparently share specific vulnerability qualities towards depression by hampering the adaptive shift of attention to external cues during dysphoric moods, probably involving lowered disinhibition of task-irrelevant negative emotional processing. The present study provided first indications of a possible relationship between a cognitive vulnerability marker for depression and characteristics of basal neuroendocrine activity regarding their association with the course of experimentally induced dysphoric mood.

Impaired hypothalamic-pituitary-adrenocortical (HPA) system is related to severity of benzodiazepine withdrawal in patients with depression

A concatenation of data indicates that the pathogenesis of depression is related to an increased production and secretion of corticotropin-releasing hormone (CRH). Benzodiazepines profoundly suppress the basal and stress-related activation of the hypothalamic-pituitary-adrenocortical (HPA) system and discontinuation of these drugs results in rebound activation. We therefore investigated whether the extent of HPA system dysregulation is related to the severity of benzodiazepine withdrawal in patients with depression. We performed the combined dexamethasone/CRH test before benzodiazepine discontinuation (taper-off max. 5 mg diazepam-equivalents/week) in 14 depressed patients (13 f, 1 m, mean age 54.6 +/- 14.6) who responded to the antidepressant treatment. The severity of withdrawal symptoms was measured using the Clinical Institute Withdrawal Assessment-Benzodiazepines (CIWA-B) questionnaire. The depressive psychopathology was monitored using the Hamilton Depression Rating Scale, Montgomery Asberg Depression Rating Scale and Beck Depression Inventory. Patients with more severe benzodiazepine withdrawal (CIWA-B-increase > 14 pts; n = 7) showed a significant higher cortisol and ACTH response in the dexamethasone/CRH test preceding the discontinuation of benzodiazepines than patients displaying less severe withdrawal symptoms (CIWA-B-increase <14 pts.; n = 7) (ANCOVA, p < 0.05). Both groups did not differ in the pre-taper psychopathology ratings and their basal neuroendocrine activity. In view of the GABAergic inhibition of HPA system activity and the anxiogenic effect of CRH, benzodiazepine withdrawal symptoms may be partly due to a disinhibition of the HPA system during discontinuation of benzodiazepines.

Impaired hypothalamic-pituitary-adrenocortical (HPA) system is related to severity of benzodiazepine withdrawal in patients with depression

A concatenation of data indicates that the pathogenesis of depression is related to an increased production and secretion of corticotropin-releasing hormone (CRH). Benzodiazepines profoundly suppress the basal and stress-related activation of the hypothalamic-pituitary-adrenocortical (HPA) system and discontinuation of these drugs results in rebound activation. We therefore investigated whether the extent of HPA system dysregulation is related to the severity of benzodiazepine withdrawal in patients with depression. We performed the combined dexamethasone/CRH test before benzodiazepine discontinuation (taper-off max. 5 mg diazepam-equivalents/week) in 14 depressed patients (13 f, 1 m, mean age 54.6 ± 14.6) who responded to the antidepressant treatment. The severity of withdrawal symptoms was measured using the Clinical Institute Withdrawal Assessment-Benzodiazepines (CIWA-B) questionnaire. The depressive psychopathology was monitored using the Hamilton Depression Rating Scale, Montgomery Asberg Depression Rating Scale and Beck Depression Inventory. Patients with more severe benzodiazepine withdrawal (CIWA-B-increase > 14 pts.; n=7) showed a significant higher cortisol and ACTH response in the dexamethasone/CRH test preceding the discontinuation of benzodiazepines than patients displaying less severe withdrawal symptoms (CIWA-B-increase <14 pts.; n = 7) (ANCOVA, p < 0.05). Both groups did not differ in the pre-taper psychopathology ratings and their basal neuroendocrine activity. In view of the GABAergic inhibition of HPA system activity and the anxiogenic effect of CRH, benzodiazepine withdrawal symptoms may be partly due to a disinhibition of the HPA system during discontinuation of benzodiazepines.

Metabolic, Neuroendocrine and Immune Functions in Basal Conditions and during the Acute-Phase Response to Endotoxic Shock in Undernourished Rats

Chronic malnutrition is one of the most important causes of several metabolic, immune and neuroendocrine dysfunctions. The aim of the present study was to determine the influence of chronic food restriction on basal neuroendocrine, immune and adipocyte functions and during the acute-phase response to endotoxic shock in female rats. The effect of refeeding of undernourished rats on the above-mentioned functions was also investigated. For these purposes, plasma total protein, glucose, triglycerides, ACTH, corticosterone, tumor necrosis factor-α (TNF) and leptin (LEP) levels were determined in basal condition and 2 h after endotoxin (LPS; 180 µg/kg body weight, i.p.) administration in 3 different groups: (1) well-nourished (WN) controls; (2) undernourished (UN) rats as a consequence of chronic food restriction, and (3) UN rats re-fed to restoration of their body weights in the WN rat range. The results indicate that UN rats, in comparison with WN controls, developed an arrest in body weight gain as well as in basal hypoglycemia, hypotriglyceridemia, hypoleptinemia, hypercorticosteronemia and enhanced adrenal glucocorticoid content; however, no changes in basal total protein, ACTH and TNF plasma levels and in anterior pituitary ACTH concentrations were found. When endotoxic shock was induced, the LPS-induced hypoglycemia developed in WN rats was abolished in UN animals, and both ACTH and TNF plasma concentrations after endotoxin, albeit significantly (p < 0.05) higher than the respective basal values, were significantly (p < 0.05) lower in UN than in WN control rats. Despite the high basal plasma corticosterone concentration in UN vs. WN rats, the LPS-induced glucocorticoid release was similar in WN and UN rats. Additionally, LPS treatment did not modify basal plasma LEP levels, regardless of the group. Interestingly, UN rats fed ad libitum for 15 days restored their body weight to WN rat range values, and the various metabolic dysfunctions seen in UN rats in both basal and post-LPS conditions were fully normalized. Our results clearly indicate that chronic undernutrition not only affects, as earlier described, reproductive function but also metabolic, neuroendocrine, immune and adipocyte functions, and that the effects induced by undernutrition can be fully reversed after recovery of normal body weight. The present study strongly supports the involvement of the metabolic status in the effectiveness of the defense mechanisms developed in patients in inflammatory stress conditions.

Effects of maternal iodine deficiency and thyroidectomy on basal neuroendocrine function in rat pups.

We have used in situ hybridization histochemistry to investigate the effects of maternal thyroidectomy and chronic maternal iodine deficiency on basal neuroendocrine function in rat pups. Specifically, we have measured hypothalamic thyrotrophin-releasing hormone (TRH) and pituitary thyroid-stimulating hormone (TSH) expression together with circulating levels of tri-iodothyronine (T3) in rat pups delivered from and suckled by thyroidectomized or iodine-deficient dams. Because of the close interaction between the thyroid, adrenal and growth hormone axes, we have also examined hypothalamic corticotrophin-releasing hormone (CRH) and growth hormone-releasing hormone (GRH) transcripts at the same time points: birth, 1 month and 2 months of age. Three weeks after surgical thyroidectomy, adult female Sprague-Dawley rats proved unable to carry pups to term and lactate successfully. Pups delivered from thyroidectomized dams given a small replacement dose of T3 during pregnancy were significantly lighter than controls (84 +/- 3%) and had markedly depressed plasma T3 levels (36 +/- 6% of control). Hypothalamic CRH and GRH transcript levels were significantly decreased in pups at birth (to 8 +/- 2.5% and 24 +/- 8% of control respectively) but had returned to normal by 1 month after delivery. Pituitary TSH transcript levels and hypothalamic levels of TRH transcripts, however, were similar to those of controls. Only one of seven dams fed a low-iodine diet for 6 months produced live pups, and these were too few in number to produce significant data. Dams fed a low-iodine diet from 4 months before mating, however, did produce live pups and although they were not significantly lighter than control pups at birth, by 1 month after birth, they were significantly lighter (72 +/- 3% of controls). Circulating T3 levels were not significantly different from control at any time point examined. Hypothalamic TRH levels were significantly elevated at birth (451 +/- 138% of control), but this difference was not maintained at 1 or 2 months after birth despite the lactating dams being maintained on the low-iodine diet. Pituitary TSH levels showed an upward trend at all time points that reached significance at 1 month after birth (204 +/- 19%; P < 0.05). Hypothalamic CRH and GRH transcript levels were not different from controls at any time point. In summary, chronic iodine deficiency or thyroidectomy with low-level T3 replacement in Sprague-Dawley rats markedly impaired fertility and the ability to carry pups to term, and produced an unexpectedly modest up-regulation of the hypothalamo-pituitary-thyroid axis and down-regulation of the hypothalamo-pituitary-adrenal axis.