ABSTRACT
In utero exposure to glucocorticoids in late gestation programs changes in cardiovascular function. The objective of this study was to determine the degree to which angiotensin II mediates sex-biased changes in autonomic function as well as basal and stress-responsive cardiovascular function following in utero glucocorticoid exposure. Pregnant rats were administered the synthetic glucocorticoid dexamethasone (Dex; 0.4 mg/kg/day sc) or vehicle on gestation days 18-21. Mean arterial pressure, heart rate, and heart rate variability (HRV) were measured via radiotelemetry in freely moving, conscious adult rats. To evaluate the impact of stress, rats were placed in a restraint tube for 20 min. In a separate cohort of rats, restraint stress was performed before and after chronic treatment with the angiotensin type 1 receptor antagonist, losartan (30 mg/kg/day ip). Frequency domain analysis of HRV was evaluated, and data were integrated into low-frequency (LF, 0.20-0.75 Hz) and high-frequency (HF, 0.75-2.00 Hz) bands. Prenatal Dex resulted in an exaggerated pressor and heart rate response to restraint in female offspring that was attenuated by prior losartan treatment. HF power was higher in vehicle-exposed female rats compared with Dex females. Following losartan, HF power was equivalent between female vehicle and Dex-exposed rats. In utero exposure to Dex produced female-biased alterations in stress-responsive cardiovascular function, which may be indicative of a reduction in parasympathetic activity. Moreover, these findings suggest this autonomic dysregulation may be mediated, in part, by long-term changes in renin-angiotensin signaling.NEW & NOTEWORTHY Our findings reveal the involvement of angiotensin II on sex-selective cardiovascular function and autonomic changes in adult offspring exposed to dexamethasone during the last 4 days of gestation. We show that angiotensin II receptor blockade reverses the exaggerated pressor and heart rate response to acute restraint stress and the autonomic dysregulation observed in female, but not male, offspring exposed to dexamethasone in utero.
Subject(s)
Angiotensin II Type 2 Receptor Blockers , Prenatal Exposure Delayed Effects , Angiotensin II/pharmacology , Angiotensin II Type 2 Receptor Blockers/pharmacology , Animals , Blood Pressure/physiology , Dexamethasone/toxicity , Female , Male , Pregnancy , Rats , Receptor, Angiotensin, Type 1ABSTRACT
CONTEXT: In preclinical studies, high androgen levels during pregnancy are associated with low birth weight and rapid postnatal weight gain in the offspring. However, human data linking prenatal androgens with birth weight and early life weight gain in the offspring are scarce. DESIGN: We evaluated 516 mother-child pairs enrolled in the New England birth cohorts of the Collaborative Perinatal Project (1959-1966). We assayed androgen bioactivity in maternal sera during third-trimester using a receptor-mediated luciferase expression bioassay. Age and sex-specific BMI Z-scores (BMIz), defined using established standards, were assessed at birth, 4 months, 1 year, 4 years, and 7 years. We used linear mixed models to evaluate the relation of maternal androgens with childhood BMIz overall and by sex. We examined the association of maternal androgens with fetal growth restriction. The association of weight trajectories with maternal androgens was examined using multinomial logistic regression. RESULTS: Higher maternal androgen levels associated with lower BMIz at birth (ß = - 0.39, 95% CI: - 0.73, - 0.06); this relation was sex-dependent, such that maternal androgens significantly associated with BMIz at birth in girls alone (ß = - 0.72, 95% CI: - 1.40, - 0.04). The relation of maternal androgens with fetal growth restriction revealed dose threshold effects that differed by sex. There was no significant association between maternal androgens and weight trajectory overall. However, we found a significant sex interaction (p = 0.01); higher maternal androgen levels associated with accelerated catch-up growth in boys (aOR = 2.14, 95% CI: 1.14, 4.03). CONCLUSION: Our findings provide evidence that maternal androgens may have differential effects on the programming of intrauterine growth and postnatal weight gain depending on fetal sex.
Subject(s)
Androgens/blood , Body-Weight Trajectory , Pregnancy Trimester, Third/blood , Prenatal Care , Adult , Androgens/analysis , Birth Weight , Body Mass Index , Child , Child Development/physiology , Child, Preschool , Cohort Studies , Correlation of Data , Female , Humans , Infant, Newborn , New England/epidemiology , Pregnancy , Prenatal Care/methods , Prenatal Care/statistics & numerical data , Sex Factors , Weight Gain/physiologyABSTRACT
Estrogens exert profound effects on the expression of anxiety in humans and rodents; however, the directionality of these effects varies considerably within both clinical and preclinical literature. It is believed that discrepancies regarding the nature of estrogens' effects on anxiety are attributable to the differential effects of specific estrogen receptor (ER) subtypes. In this chapter we will discuss the relative impact on anxiety and anxiety-like behavior of each of the three main ERs: ERα, which has a generally anxiogenic effect, ERß, which has a generally anxiolytic effect, and the G-protein-coupled ER known as GPR30, which has been found to both increase and decrease anxiety-like behavior. In addition, we will describe the known mechanisms by which these receptor subtypes exert their influence on emotional responses, focusing on the hypothalamic-pituitary-adrenal axis and the oxytocinergic and serotonergic systems. The impact of estrogens on the expression of anxiety is likely the result of their combined effects on all of these neurobiological systems.
Subject(s)
Anxiety Disorders/metabolism , Anxiety/metabolism , Estrogen Receptor alpha/agonists , Estrogen Receptor beta/agonists , Estrogens/metabolism , Neurons/metabolism , Receptors, G-Protein-Coupled/agonists , Active Transport, Cell Nucleus/drug effects , Animals , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Anxiety/drug therapy , Anxiety Disorders/drug therapy , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Estrogens/pharmacology , Estrogens/therapeutic use , Humans , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/metabolism , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Oxytocin/metabolism , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/metabolism , Receptors, Estrogen/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Oxytocin/agonists , Receptors, Oxytocin/metabolism , Serotonergic Neurons/drug effects , Serotonergic Neurons/metabolismABSTRACT
Prenatal stress and overexposure to glucocorticoids (GC) during development may be associated with an increased susceptibility to a number of diseases in adulthood including neuropsychiatric disorders, such as depression and anxiety. In animal models, prenatal overexposure to GC results in hyper-responsiveness to stress in adulthood, and females appear to be more susceptible than males. Here, we tested the hypothesis that overexposure to GC during fetal development has sex-specific programming effects on the brain, resulting in altered behaviors in adulthood. We examined the effects of dexamethasone (DEX; a synthetic GC) during prenatal life on stress-related behaviors in adulthood and on the tryptophan hydroxylase-2 (TpH2) gene expression in the adult dorsal raphe nucleus (DRN). TpH2 is the rate-limiting enzyme for serotonin (5-HT) synthesis and has been implicated in the etiology of human affective disorders. Timed-pregnant rats were treated with DEX from gestational days 18-22. Male and female offspring were sacrificed on the day of birth (postnatal day 0; P0), P7, and in adulthood (P80-84) and brains were examined for changes in TpH2 mRNA expression. Adult animals were also tested for anxiety- and depressive- like behaviors. In adulthood, prenatal DEX increased anxiety- and depressive- like behaviors selectively in females, as measured by decreased time spent in the center of the open field and increased time spent immobile in the forced swim test, respectively. Prenatal DEX increased TpH2 mRNA selectively in the female caudal DRN at P7, whereas it decreased TpH2 mRNA selectively in the female caudal DRN in adulthood. In animals challenged with restraint stress in adulthood, TpH2 mRNA was significantly lower in rostral DRN of prenatal DEX-treated females compared to vehicle-treated females. These data demonstrated that prenatal overexposure to GC alters the development of TpH2 gene expression and these alterations correlated with lasting behavioral changes found in adult female offspring.
Subject(s)
Dexamethasone/toxicity , Glucocorticoids/toxicity , Prenatal Exposure Delayed Effects/physiopathology , Sex Characteristics , Aging , Animals , Anxiety/physiopathology , Behavior, Animal , Depression/physiopathology , Disease Models, Animal , Dorsal Raphe Nucleus/physiopathology , Female , Male , Pregnancy , Radioimmunoassay , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Serotonin/metabolism , Stress, Psychological/complications , Stress, Psychological/physiopathology , Tryptophan Hydroxylase/analysisABSTRACT
Comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) represents the fourth leading cause of morbidity and mortality worldwide, and women have a two times greater risk than men. Thus understanding the pathophysiology has widespread implications for attenuation and prevention of disease burden. We suggest that sex-dependent MDD-CVD comorbidity may result from alterations in fetal programming consequent to the prenatal maternal environments that produce excess glucocorticoids, which then drive sex-dependent developmental alterations of the fetal hypothalamic-pituitary-adrenal (HPA) axis circuitry impacting mood, stress regulation, autonomic nervous system (ANS), and the vasculature in adulthood. Evidence is consistent with the hypothesis that disruptions of pathways associated with gamma aminobutyric acid (GABA) in neuronal and vascular development and growth factors have critical roles in key developmental periods and adult responses to injury in heart and brain. Understanding the potential fetal origins of these sex differences will contribute to development of novel sex-dependent therapeutics.
Subject(s)
Cardiovascular Diseases/metabolism , Depression/metabolism , Fetal Development/physiology , Sex Characteristics , Stress, Physiological , Animals , Cardiovascular Diseases/physiopathology , Depression/physiopathology , Female , Humans , Male , RiskABSTRACT
There is a strong and growing literature showing that key aspects of brain development may be critical antecedents of adult physiology and behavior or may lead to physiological and psychiatric disorders in adulthood. Many are significantly influenced by sex-dependent factors. Neurons of the paraventricular nucleus (PVN) of the hypothalamus occupy a key position in regulating homeostatic, neuroendocrine, and behavioral functions. This brain area is a critical link for our understanding of the etiology of a number of disorders with components ranging from mood to feeding and energy balance and to autonomic nervous system regulation. Thus, based on common brain circuitry, the PVN may be a critical anatomical intersection for understanding comorbidities among depression, obesity, and cardiovascular risk. Historically, the majority of approaches to brain development examine neuronal, glial, and vascular factors independently, with notably less emphasis on vascular contributions. The realization that the PVN undergoes a unique vascular developmental process places added value on discerning the cellular and molecular mechanisms that drive its late-onset angiogenesis and further implications for neuronal differentiation and function. This has ramifications in humans for understanding chronic, and sometimes fatal, comorbidities that share sex-dependent biological bases in development through functional and anatomical intersections with the hypothalamus.
Subject(s)
Cardiovascular Diseases/physiopathology , Depressive Disorder, Major/physiopathology , Sex Characteristics , Brain/metabolism , Cardiovascular Diseases/epidemiology , Comorbidity , Depressive Disorder, Major/epidemiology , Female , Humans , MaleABSTRACT
The neurotrophin, brain-derived neurotrophic factor (BDNF), is recognized as a key component in the regulation of CNS ontogeny, homeostasis and adult neuroplasticity. The importance of BDNF in CNS development and function is well documented by numerous reports from animal studies linking abnormal BDNF signaling to metabolic disturbances and anxiety or depressive-like behavior. Despite the diverse roles for BDNF in nearly all aspects of CNS physiology, the regulation of BDNF expression, as well as our understanding of the signaling mechanisms associated with this neurotrophin, remains incomplete. However, links between sex hormones such as estradiol and testosterone, as well as endogenous and synthetic glucocorticoids (GCs), have emerged as important mediators of BDNF expression and function. Examples of such regulation include brain region-specific induction of Bdnf mRNA in response to estradiol. Additional studies have also documented regulation of the expression of the high-affinity BDNF receptor Tropomyosin-Related Kinase B by estradiol, thus implicating sex steroids not only in the regulation of BDNF expression, but also in mechanisms of signaling associated with it. In addition to gonadal steroids, further evidence also suggests functional interaction between BDNF and GCs, such as in the regulation of corticotrophin-releasing hormone and other important neuropeptides. In this review, we provide an overview of the roles played by selected sex or stress hormones in the regulation of BDNF expression and signaling in the CNS.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Brain/physiology , Glucocorticoids/metabolism , Gonadal Steroid Hormones/metabolism , Signal Transduction/physiology , Animals , HumansABSTRACT
AIM: Recurrent aphthous ulcers (RAU) are one of the most common and poorly understood mucosal disorders. Most of the literature suggests that stress has a causal role in RAU and it is estimated that at least 1 in 5 individuals is afflicted with RAU. Review of literature reveals that nutritional and stress factors may be of paramount importance in the occurrence and severity of RAU. To test this hypothesis we have derived a study to explore definitive relationship between nutrition, stress and RAU in professional undergraduate students. METHODS: A total of 80 undergraduate students were selected randomly for the study from professional colleges. On evaluation 50 subjects were identified to be RAU positive and the rest 30 never had ulcers. All the subjects were evaluated during their university examinations and the 50 RAU positive subjects were later evaluated for the stress levels after the examinations. The major variables that were compared were simplified oral hygiene index, body mass index, hemoglobin percentage, mid upper arm circumference and malnutrition universal screening tool, Hamilton anxiety rating scale and general health questionnaire. RESULTS: The stress level was measured using Hamilton anxiety scale (HAS) and a highly significant difference was determined between during exams and post exam period in the students who tested positive for RAU. The General Health Questionnaire (GHQ) also appeared to be a sensitive instrument to determine the stress levels and statistically significant differences were recorded in the RAU positive students during exams and post exam period. General health is also poor during exams as compared after exams. The hematological factor as denoted by HB measurement showed significant statistical difference between patients who had RAU (present and history) and those who did not. Nutritional indicator (Malnutrition Universal Screening Tool) MUST also showed that it was a sensitive measure for detecting nutritional compromise and the statistically significant difference was shown between RAU positive and negative. The BMI, OHI-S and MUAC had no statistical differences shown in our analysis. CONCLUSION: A number of conditions and diseases have been shown to lead to the onset of RAU. However, RAU can occur in the absence of any diagnosable disease or physical condition. According to our evaluation, stress emerged as having a causal role on RAU, along with hematinic deficiencies and poor nutritional status in professional undergraduate college students.
Subject(s)
Stomatitis, Aphthous/etiology , Stress, Psychological/complications , Students , Educational Measurement , Female , Humans , India , Male , Prospective Studies , Recurrence , Universities , Young AdultABSTRACT
The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design.
Subject(s)
Adrenal Cortex Hormones/metabolism , Gonadal Hormones/metabolism , Mood Disorders/complications , Mood Disorders/metabolism , Sex Characteristics , Stress, Psychological/complications , Stress, Psychological/metabolism , Antidepressive Agents/therapeutic use , Female , Humans , Male , Mood Disorders/drug therapy , Stress, Psychological/drug therapyABSTRACT
Oestradiol exerts a profound influence upon multiple brain circuits. For the most part, these effects are mediated by oestrogen receptor (ER)α. We review here the roles of ERß, the other ER isoform, in mediating rodent oestradiol-regulated anxiety, aggressive and sexual behaviours, the control of gonadotrophin secretion, and adult neurogenesis. Evidence exists for: (i) ERß located in the paraventricular nucleus underpinning the suppressive influence of oestradiol on the stress axis and anxiety-like behaviour; (ii) ERß expressed in gonadotrophin-releasing hormone neurones contributing to oestrogen negative-feedback control of gonadotrophin secretion; (iii) ERß controlling the offset of lordosis behaviour; (iv) ERß suppressing aggressive behaviour in males; (v) ERß modulating responses to social stimuli; and (vi) ERß in controlling adult neurogenesis. This review highlights two major themes; first, ERß and ERα are usually tightly inter-related in the oestradiol-dependent control of a particular brain function. For example, even though oestradiol feedback to control reproduction occurs principally through ERα-dependent mechanisms, modulatory roles for ERß also exist. Second, the roles of ERα and ERß within a particular neural network may be synergistic or antagonistic. Examples of the latter include the role of ERα to enhance, and ERß to suppress, anxiety-like and aggressive behaviours. Splice variants such as ERß2, acting as dominant negative receptors, are of further particular interest because their expression levels may reflect preceeding oestradiol exposure of relevance to oestradiol replacement therapy. Together, this review highlights the predominant modulatory, but nonetheless important, roles of ERß in mediating the many effects of oestradiol upon adult brain function.
Subject(s)
Brain/physiology , Estrogen Receptor beta/physiology , Neurons/physiology , Aggression/physiology , Animals , Neurogenesis/physiology , Sexual Behavior, Animal/physiologyABSTRACT
Exposure to glucocorticoids (GCs) in early development can lead to long-term changes in brain function and behavior, although little is known about the underlying neural mechanisms. Perinatal exposure to GCs alters adult anxiety and neuroendocrine responses to stress. Therefore, we investigated the effects of either late gestational or neonatal exposure to the GC receptor agonist dexamethasone (DEX), on apoptosis within the amygdala, a region critical for emotional regulation. DEX was administered to timed-pregnant rat dams from gestational day 18 until parturition, or postnatal day 4-6. Offspring were sacrificed the day following the last DEX treatment, and tissue was processed for immunohistochemical detection of cleaved caspase-3, a marker for apoptotic cells. Prenatal DEX treatment significantly increased the number of cleaved caspase-3-positive cells in the amygdala of both sexes, largely due to increases within the medial and basomedial subregions. Postnatal DEX treatment also increased cleaved caspase-3 immunoreactivity within the amygdala, although effects reached significance only in the central nucleus of females. Overall, DEX induction of cleaved caspase-3 in the amygdala was greater following prenatal compared with postnatal treatment, yet in both instances, elevations in cleaved caspase-3 correlated with an increase in pro-apoptotic Bax mRNA expression. Dual-label immunohistochemistry of cleaved caspase-3 and the neuronal marker NeuN confirmed that virtually all cleaved caspase-3-positive cells in the amygdala were neurons, and a subset of these cells (primarily following postnatal treatment) expressed a GABAergic calcium-binding protein phenotype (calbindin or calretinin). Together these results indicate that early developmental GC exposure induces neuronal apoptosis within the amygdala in an age-, sex-, and region-dependent manner.
Subject(s)
Amygdala/drug effects , Amygdala/pathology , Apoptosis/drug effects , Dexamethasone/toxicity , Glucocorticoids/toxicity , Age Factors , Amygdala/metabolism , Animals , Caspase 3/metabolism , Female , Immunohistochemistry , Male , Neurons/drug effects , Neurons/pathology , Pregnancy , Prenatal Exposure Delayed Effects/metabolism , Prenatal Exposure Delayed Effects/pathology , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Sex FactorsABSTRACT
BACKGROUND: Currently there is no reliable diagnostic marker to distinguish between the subgroups of idiopathic inflammatory myopathies (IIMs), i.e. dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). Membrane attack complex (MAC) has been shown to be involved in the pathogenesis of dermatomyositis but its role as a diagnostic marker has not been evaluated. AIM: To assess the diagnostic utility of MAC deposition in distinguishing dermatomyositis from other neuromuscular disorders. MATERIAL AND METHODS: Immunohistochemical detection of MAC deposition on endomysial microvessels was carried out on 127 muscle biopsies comprising of 21 cases of dermatomyositis, 42 other IIMs and 64 non-IIM neuromuscular diseases. RESULTS: MAC deposition showed a high sensitivity (80.9%) and specificity (85%) to differentiate DM from other IIMs. Its specificity was higher (98.4%) in discriminating DM from non-IIM muscular diseases and IIM from non-IIMs. CONCLUSION: MAC deposition can serve as a reliable marker to distinguish DM from other IIMs (i.e. PM and IBM) as well as from non-IIM diseases. It can also serve as a useful adjunct in diagnosis of IIMs when there is diagnostic dilemma with their morphologic similarities. These results provide further credence to the long-standing view that MAC-mediated capillary destruction is involved in the immunopathogenesis of DM.
Subject(s)
Complement Membrane Attack Complex/metabolism , Dermatomyositis/diagnosis , Dermatomyositis/metabolism , Adolescent , Adult , Age Factors , Aged , Biopsy/methods , Child , Child, Preschool , Female , Humans , Male , Microvessels/metabolism , Middle Aged , Muscles/pathology , Myositis/diagnosis , Myositis/metabolism , Myositis, Inclusion Body/diagnosis , Myositis, Inclusion Body/metabolism , Polymyositis/diagnosis , Polymyositis/metabolism , Reproducibility of Results , Young AdultABSTRACT
Introduction. Serial objective assessment of disease activity in Rheumatoid Arthritis (RA) is imperative to achieve remission. The CDAI score appears more practical than DAS-28 in routine assessment of disease activity in RA patients. Objective. To evaluate correlation and agreement of the DAS-28 with CDAI in RA patients. Methods. A total of 200 patients of RA were evaluated by DAS-28 and CDAI and divided into 4 categories of disease activity i.e. Group-I: Remission (DAS-28 < 2.6; CDAI < 2.8), Group II: Low disease activity (DAS-28 = 2.6-3.2; CDAI = 2.8-10), Group III: Moderate disease activity (DAS-28 = 3.2- 5.1; CDAI = 10-22), Group IV: High disease activity (DAS-28 > 5.1; CDAI > 22). DAS-28 was compared to CDAI in each group using spearman correlation coefficient and kappa statistics. Results. Group I shows mean DAS-28 of 1.99 ± 0.38; mean CDAI of 0.90 ± 0.65, (P = 0.0001). Group II shows mean DAS-28 of 3.04 ± 0.17; mean CDAI of 6.45 ± 02.35, (P = 0.0001). Group III shows mean DAS-28 of 4.25 ± 0.58; mean CDAI of 16.46 ± 3.31 (P < 0.0001). Group IV shows mean DAS-28 of 6.38 ± 0.87; mean CDAI of 38.56 ± 11.88 (P < 0.0001). Kappa statistics (κ) of the above comparison was 0.533. Conclusion. Our findings indicate that CDAI-a composite score that employs only clinical variables and omits assessment of Acute Phase Reactant (APR), has moderate to good correlation (Kappa value = 0.533) to DAS-28 for assessment of disease activity in RA patients.
ABSTRACT
Immuno-inflammatory diseases like lupus are associated with premature atherosclerosis. With improved survival, atherosclerotic cardiovascular disease has emerged as an important late complication of systemic lupus erythematosus. The burden of this co-morbidity in Asian patients is not fully known but is likely to be high. We review the literature available and draw attention to this oft overlooked problem.
Subject(s)
Asian People , Cardiovascular Diseases/ethnology , Lupus Erythematosus, Systemic/ethnology , Models, Theoretical , Comorbidity/trends , HumansABSTRACT
Androgens influence many aspects of reproductive behavior, including sexual preference of females for males. In oophorectomized women with sexual desire disorder, testosterone patches improve libido, but their use is limited because of adverse side effects. Selective androgen receptor modulators offer an improved safety profile for both sexes: enhancing libido and muscle and bone growth in a manner similar to steroidal androgens but with fewer adverse effects, such as hirsutism, acne, and prostate growth. The current study investigated the action of a novel selective androgen receptor modulator (LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one]) on male-directed sexual preference, proceptivity, and lordosis behavior of female rats. LGD-3303 is a nonsteroidal, nonaromatizable, highly selective ligand for the androgen receptor and effectively crosses the blood-brain barrier. Gonadectomized female rats were treated with LGD-3303 (3-30 mg/kg) or vehicle by daily oral gavage. Results showed that LGD-3303 treatment enhanced sexual preference of females for males but only if females had previous sexual experience. This occurred after 1 or 7 d of treatment. In contrast, preference for males was inhibited by LGD-3303 treatments of sexually naive females. The LGD-3303 increase in male preference was blocked by pretreatment with the androgen receptor antagonist flutamide. LGD-3303 treatment increased lordosis and proceptivity behaviors in ovariectomized females primed with suboptimal doses of estradiol benzoate plus progesterone. These data support the concept that LGD-3303 can stimulate aspects of female sexual behavior and may serve as a potential therapeutic for women with sexual desire disorders.
Subject(s)
Androgen Receptor Antagonists , Androgens , Sexual Behavior, Animal/drug effects , Animals , Dihydrotestosterone/pharmacology , Estradiol/analogs & derivatives , Estradiol/pharmacology , Female , Flutamide/pharmacology , Male , Ovariectomy , Progesterone/pharmacology , Pyrroles/pharmacology , Quinolones/pharmacology , Random Allocation , Rats , Rats, Sprague-DawleyABSTRACT
INTRODUCTION: Disease-modifying anti-rheumatic drugs (DMARDs) currently form the mainstay of treatment of rheumatoid arthritis (RA). We aimed to evaluate the retention rates of "therapeutic segments" of DMARDs in patients with RA. METHODS: This was a cross-sectional study of RA patients with at least one year of follow-up. A therapeutic segment is said to begin when one DMARD combination is instituted and it ends with a subsequent change. The disability index for each patient was calculated using a modified health assessment questionnaire. Retention rates were calculated using the Kaplan Meier survival analysis. RESULTS: 375 DMARD courses in 102 patients were analysed. 99 courses were being continued at the time of the study and hence were censored for the purposes of analysis. The respective median (interquartile range [IQR]) retention period for segments containing methotrexate (MTX), sulfasalazine, hydroxychloroquine and leflunomide was 28 (15-45), 12 (3-20), 18 (9-24), 15 (4-32) months. The log-rank statistical test indicated that MTX was retained longer singly (median [IQR] 43 [32-70] months) than in combination (median [IQR] 19 [10-24] months) (p-value is 0.001). The commonest reason for the discontinuation of the DMARD segment was the disease "slipping out" of control (51.1 percent) followed by adverse effects (24.3 percent). Treatment termination on account of disease control was encountered in 16.3 percent of courses only. As many as 63 percent of single DMARD segments were changed because of disease "slip out" as compared to 41 percent of combination DMARD segments. Adverse effects were a more frequent cause of termination of the combination segments (32 vs. 15 percent). CONCLUSION: MTX, used singly, had the highest retention rates among all the DMARDs used in RA patients. Disease "slip out" and adverse effects frequently required a change of the therapeutic segment.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Adult , Cross-Sectional Studies , Disability Evaluation , Female , Humans , Male , Medication Adherence , Methotrexate/therapeutic use , Middle Aged , Retrospective Studies , Surveys and Questionnaires , Time Factors , Treatment OutcomeABSTRACT
Dysfunctions of the brain 5-HT system are often associated with affective disorders, such as depression. The raphe nuclei target the limbic system and most forebrain areas and constitute the main source of 5-HT in the brain. All 5-HT neurons express tryptophan hydroxylase-2 (TPH2), the brain specific, rate-limiting enzyme for 5-HT synthesis. Estrogen receptor (ER) beta agonists have been shown to attenuate anxiety- and despair-like behaviors in rodent models. Therefore, we tested the hypothesis that ER beta may contribute to the regulation of gene expression in 5-HT neurons of the dorsal raphe nuclei (DRN) by examining the effects of systemic and local application of the selective ER beta agonist diarylpropionitrile (DPN) on tph2 mRNA expression. Ovariectomized (OVX) female rats were injected s.c. with DPN or vehicle once daily for 8 days. In situ hybridization revealed that systemic DPN-treatment elevated basal tph2 mRNA expression in the caudal and mid-dorsal DRN. Behavioral testing of all animals in the open field (OF) and on the elevated plus maze (EPM) on days 6 and 7 of treatment confirmed the anxiolytic nature of ER beta activation. Another cohort of female OVX rats was stereotaxically implanted bilaterally with hormone-containing wax pellets flanking the DRN. Pellets contained 17-beta-estradiol (E), DPN, or no hormone. Both DPN and E significantly enhanced tph2 mRNA expression in the mid-dorsal DRN. DPN also increased tph2 mRNA in the caudal DRN. DPN- and E-treated rats displayed a more active stress-coping behavior in the forced-swim test (FST). No behavioral differences were found in the OF or on the EPM. These data indicate that ER beta acts at the level of the rat DRN to modulate tph2 mRNA expression and thereby influence 5-HT synthesis in DRN subregions. Our results also suggest that local activation of ER beta neurons in the DRN may be sufficient to decrease despair-like behavior, but not anxiolytic behaviors.
Subject(s)
Estrogen Receptor beta/metabolism , Neurons/metabolism , Raphe Nuclei/metabolism , Serotonin/metabolism , Tryptophan Hydroxylase/metabolism , Adaptation, Psychological/drug effects , Animals , Anxiety/drug therapy , Anxiety/metabolism , Depression/drug therapy , Depression/metabolism , Estradiol/administration & dosage , Estradiol/pharmacology , Estrogen Receptor beta/agonists , Estrogens/administration & dosage , Estrogens/pharmacology , Female , Maze Learning , Neurons/drug effects , Nitriles/administration & dosage , Nitriles/pharmacology , Ovariectomy , Propionates/administration & dosage , Propionates/pharmacology , RNA, Messenger/metabolism , Raphe Nuclei/drug effects , Rats , Rats, Sprague-Dawley , Stress, Psychological/drug therapy , Stress, Psychological/metabolismABSTRACT
Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a basic response of animals to environmental perturbations that threaten homeostasis. These responses are regulated by neurones in the paraventricular nucleus of the hypothalamus (PVN) that synthesise and secrete corticotrophin-releasing hormone (CRH). Other PVN neuropeptides, such as arginine vasopressin and oxytocin, can also modulate activity of CRH neurones in the PVN and enhance CRH secretagogue activity of the anterior pituitary gland. In rodents, sex differences in HPA reactivity are well established; females exhibit a more robust activation of the HPA axis after stress than do males. These sex differences primarily result from opposing actions of sex steroids, testosterone and oestrogen, on HPA function. Ostreogen enhances stress activated adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) secretion, whereas testosterone decreases the gain of the HPA axis and inhibits ACTH and CORT responses to stress. Data show that androgens can act directly on PVN neurones in the male rat through a novel pathway involving oestrogen receptor (ER)beta, whereas oestrogen acts predominantly through ERalpha. Thus, we examined the hypothesis that, in males, testosterone suppresses HPA function via an androgen metabolite that binds ERbeta. Clues to the neurobiological mechanisms underlying such a novel action can be gleaned from studies showing extensive colocalisation of ERbeta in oxytocin-containing cells of the PVN. Hence, in this review, we address the possibility that testosterone inhibits HPA reactivity by metabolising to 5alpha-androstane-3beta,17beta-diol, a compound that binds ERbeta and regulates oxytocin containing neurones of the PVN. These findings suggest a re-evaluation of studies examining pathways for androgen receptor signalling.