Search

Studies in people and animal models suggest that depression is influenced by natural fluctuations in the levels of 17beta-oestradiol (E(2)), as well as administration of E(2)-based therapies, such as selective oestrogen receptor modulators (SERMs). Elucidating the effects and mechanisms of E(2) is important to improve future E(2)-based therapeutics. An important question is whether effects of E(2) or SERMs for mood regulation act at the alpha or beta isoform of the oestrogen receptor (ER) because some of the unwanted trophic effects of E(2)-based therapies may involve actions at ERalpha, rather than ERbeta. In the present study, whether there are sex differences in depression-like behaviour of adult mice (experiment 1), and the effects of natural fluctuations in E(2) (experiment 2), or administration of E(2) or a SERM that has higher affinity for ERbeta than for ERalpha (diarylpropionitrile; DPN) to ovariectomised (experiment 3) wildtype and ERbeta knockout (betaERKO) mice were investigated. Results of this study supported our hypotheses that: there would be sex differences favouring males for depression-like behaviour and endogenous increases in, or exogenous administration of, E(2) or administration of an ERbeta SERM would decrease depression-like behaviour in wildtype, but not betaERKO, mice. In experiment 1, adult male mice spent less time immobile in the forced swim test (i.e., showed less depression-like behaviour) compared with female mice. In experiment 2, pro-oestrous (higher circulating E(2) levels), compared with dioestrous (lower circulating E(2) levels), mice had reduced immobility in the forced swim test; this effect was not observed in betaERKO mice. In experiment 3, administration of E(2) or DPN to ovariectomised wildtype, but not betaERKO, mice decreased immobility compared with vehicle administration, these data suggest that ERbeta may be required for some of the anti-depressant-like effects of E(2). [ABSTRACT FROM AUTHOR]

Routine gynecological care is important for the maintenance of good health and integral to early detection and treatment of sexually transmitted diseases and cancer. Research indicates that both patients and clinicians find this examination anxiety provoking and, therefore, may fail to comply with optimal guidelines for routine care. Training techniques, effective for attenuating providers' and patients' anxiety, are reviewed. These include medical school programs for providers and seminars on women's health designed for lay people. In addition to providing training when there are fewer immediate stressors, methods for reducing anxiety may be employed proximate to exams. Providing informative, behavioral, and cognitive-behavioral techniques, emphasizing greater patient control, may be useful in decreasing anxiety associated with pelvic examinations. These latter techniques may be incorporated into providers' protocol for routine pelvic examinations and thereby may serve to enhance compliance for routine gynecological care. [ABSTRACT FROM AUTHOR]

Background: Masculine sexual behaviors are dependent on androstane-derived steroids; however, the modulatory effects of mating, and of mating control, on androstane neurosteroidogenesis remain largely unknown., Objective: Herein, we investigated the effects of mating control, prior sexual experience, and age on brain region specific neurosteroidogenic responses in male rats., Methods: Effects of acute sexual experience were tested in naïve male rats that either remained sexually- naïve, were exposed to a standard mating chamber, or were either given control of the mating pace in a standard mating chamber (male control) or mated wherein the female stimulus rat controlled the mating pace in a paced-mating chamber (female control). Aged (10-12 months) sexually responsive male rats were similarly euthanized from the homecage or engaged in male controlled or female controlled mating. All rats were euthanized immediately following exposure conditions for radioimmunoassay of steroids in midbrain, hypothalamus, hippocampus and cortex., Results: Consummatory sexual behavior in male vs. female-controlled mating paradigms was altered by age and prior sexual experience. Male-controlled mating increased androstane neurosteroid metabolism, such that complementary increases in the testosterone (T) metabolite 5α-androstane-3α-17β- diol (3α-diol) in the midbrain and hypothalamus of male rats corresponded to decreases in the prohormone, T. 3α-diol were increased in the hippocampus in response to the context alone, and to a lesser degree in response to mating. Mating diminished neurosteroidogenesis in the cortex. Neurosteroidogenesis was overall reduced in aged male rats compared to naïve controls, however, these effects were more prominent in sexually non-responsive aged male rats., Conclusion: Extending previous findings, these results indicate differential production of androstane neurosteroids in a mating exposure, age and brain region dependent manner., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Neuroactive steroids have rapid, nongenomic effects on neuronal excitability. The effects in humans are less clear. We compared seizure control and concentrations of neuroactive steroids, known to influence neuroexcitability in animal studies, in pregnant women. Participants were prospectively followed throughout pregnancy with seizure-medication diaries and blood samples, assayed for steroid concentrations with gas chromatography-mass spectrometry. Baseline seizure frequency was calculated for the preconception year, and it was determined if seizure frequency was increased in each trimester. The Wilcoxon rank-sum test was used to compare neuroactive steroid concentrations in between the group with increased frequency to the group without, as calculated for the respective trimester, with the Holm-Bonferroni method to correct for multiple comparisons. Among eighty-three pregnancies included, twenty-eight had increased seizure frequency during at least one trimester (15, 18 and 10, respectively) compared to preconception seizure frequency. Allopregnanolone concentrations were lower in the 3rd trimester (p < 0.001), with a similar trend in the 1st (p = 0.08), for pregnancies with increased compared to those with stable seizure frequency. Other neuroactive steroid concentrations were similar. Our findings suggest that lower allopregnanolone concentrations are associated with increased seizure frequency during pregnancy. Validation of these finding in a larger cohort has potential important clinical applications., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Progestogens' (e.g., progesterone and its neuroactive metabolite, allopregnanolone), cognitive effects and mechanisms among males are not well-understood. We hypothesized if progestogen's effects on cognitive performance are through its metabolite allopregnanolone, and not actions via binding to traditional progestin receptors (PRs), then progesterone administration would enhance performance in tasks mediated by the hippocampus and cortex, coincident with increasing allopregnanolone concentrations, brain derived neurotrophic factor (BDNF) and/or muscimol binding of PR knock out (PRKO) and wild-type PR replete mice. Experiment 1 : Progesterone (4 mg/kg, subcutaneously (SC; n = 12/grp), or oil vehicle control, was administered to gonadally-intact adult male mice PRKO mice and their wild-type counterparts and cognitive behaviors in object recognition, T-maze and water maze was examined. Progesterone, compared to vehicle, when administered post-training increased time investigating novel objects by the PRKO and wild-type mice in the object recognition task. In the T-maze task, progesterone administration to wild-type and PRKO mice had significantly greater number of spontaneous alternations compared to their vehicle-administered counterparts. In the water maze task, PRKO mice administered vehicle spent significantly fewer seconds in the quadrant associated with the escape platform on testing compared to all other groups. Experiment 2 : Progesterone administered to wild-type and PRKO mice increased plasma progesterone and allopregnanolone levels ( n = 5/group). PRKO mice had higher allopregnanolone levels in plasma and hippocampus, but not cortex, when administered progesterone and compared to wild-type mice. Experiment 3 : Assessment of PR binding revealed progesterone administered wild-type mice had significantly greater levels of PRs in the hippocampus and cortex, compared to all other groups ( n = 5/group). Wild-type mice administered progesterone, but not vehicle, had increased BDNF levels in the hippocampus, but not the cortex, compared to PRKOs. Wild-type as well as PRKO mice administered progesterone experienced significant increases in maximal GABA A agonist, muscimol, binding in hippocampus and cortex, compared to their vehicle-administered counterparts. Thus, adult male mice can be responsive to progesterone for cognitive performance, and such effects may be independent of PRs trophic actions of BDNF levels in the hippocampus and/or increases in GABA A activity in the hippocampus and cortex., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Frye, Lembo and Walf.)

Among female rats, mating enhances neurosteroid formation in the midbrain ventral tegmental area (VTA; independent of peripheral steroid-secreting glands, ovaries, and adrenals). The sources/targets for these actions are not well understood. In Experiment 1, proestrous rats engaged in a mating paradigm, or did not, and the midbrains had been assessed via the Affymetrix rat genome microarrays. In Experiment 2, the influence of gonadal and adrenal glands on the expression of these genes was assessed in rats that were proestrous, ovariectomized (OVX), or OVX and adrenalectomized (ADX). The microarrays revealed 53 target genes that were significantly up-regulated (>2.0-fold change) in response to mating. Mating significantly enhanced the midbrain mRNA expression of genes involved in hormonal and trophic actions: Gh1, S100g, and Klk1b3 in proestrous, but not OVX and/or ADX, rats; Fshb in all but OVX/ADX rats; and lutenizing hormone β and thyroid-stimulating hormone (TSH) β in all rats. Thus, mating enhances midbrain gene expression independent and dependent of peripheral glands., (Copyright © 2020 Frye and Chittur.)

Engagement in sexual behavior can impact neurosteroidogenesis, in particular production of the prohormone testosterone (T) and likely its subsequent metabolism to 5α-androstane-3α-17β-Diol (3α-Diol) or aromatization to estradiol (E 2 ). Androgens and their metabolites vary across the lifespan and impact many behaviors, including cognition, anxiety, and sexual behavior. Thus, we hypothesized that mating may alter cognitive performance via androstane neurosteroids in an age- and experience-dependent manner. We first investigated if exposure to mating during memory consolidation could enhance performance in the novel object recognition task (NOR). Male rats were trained in NOR and then immediately exposed to mating-relevant or control stimuli. Following a 4 h inter-trial interval (ITI), male rats were tested for object memory. Male rats that were exposed to a receptive female during the ITI had better performance in NOR. We then investigated if these effects were due to novelty associated with mating. Male rats were exposed to mating-relevant stimuli and identified as sexually responsive (SR) or sexually non-responsive (SNR) based on a median split of engagement in mating with the stimulus female. We found that a brief history (10 min session daily for five consecutive days) of sexual history substantially influenced performance in the NOR task, such that SR males had better performance in the NOR task, but only when presented with the opportunity to mate during the ITI. As T levels substantially decrease with age in male rodents, we investigated whether the effects of long-term sexual experience (10 months) influenced neurosteroids and NOR performance in mid-aged (12 months old) males. Mid-aged SR males maintain neural T; however, they have decreased neural E 2 and decreased cognitive performance at 12 months compared to mid-aged SNR rats. In sexually experienced rats, those with better cognitive performance had greater levels of T metabolites (e.g., 3α-Diol in mated SR males, E 2 in mid-aged SNR rats). While naïve males that were mated during the ITI had better cognitive performance, T metabolites were decreased compared to controls. These findings suggest that T metabolites, but not the prohormone, may influence learning dependent on sexual proclivity, experience, and proximate opportunity to mate., (Copyright © 2020 Kohtz and Frye.)

Prenatal stress (PNS) can influence behaviors associated with cognition, reward and emotional regulation, which are controlled by brain areas such as the cortex, hippocampus, hypothalamus, midbrain and cerebellum. Allopregnanolone in these regions modulates behavioral and parasympathetic effects. The current study tested whether exposing pregnant dams to 5 days of resident-intruder stress on prenatal days 15-20 for 10 min altered the levels of allopregnanolone in cortex, hypothalamus, hippocampus, midbrain, and cerebellum of male and female juvenile offspring. In cortex, hypothalamus, and midbrain of male rats exposed to prenatal stress, levels of allopregnanolone were significantly lower compared to all other groups. In the hippocampus and cerebellum, among females exposed to prenatal stress levels were significantly higher compared to all other groups. These differences in allopregnanolone levels varying by prenatal stress, sex and brain regions provide insight in potential mechanism of stress regulation and etiopathophysiology of stress-related disorders., Competing Interests: No conflicts of interest declared., (© 2020 The Authors.)

The neurosteroid, 5α-pregnan-3α-ol-20-one (known as "allopregnanolone" or 3α,5α-THP), is produced in the midbrain ventral tegmental area (VTA), independent of peripheral sources of progestogens, where it has potential actions at N-methyl-D-aspartate (NMDA) and GABA A receptors to facilitate rodent sexual behavior. Progestogens can also have anti-anxiety effects, but whether these involve actions of centrally-derived 3α,5α-THP or these receptors to support reproductively-relevant behavior is not well understood. We investigated the extent to which 3α,5α-THP's actions via NMDA and/or GABA A receptors in the midbrain VTA influence reproductive behaviors. Estradiol-primed, ovariectomized/adrenalectomized (OVX/ADX) rats received midbrain VTA infusions of vehicle, an NMDA receptor blocker (MK-801; 200 ng), or a GABA A receptor blocker (bicuculline; 100 ng) followed by a second infusion of vehicle or 3α,5α-THP (100 ng). Reproductively-relevant behaviors were assessed: sexual (paced mating), anxiety-like (elevated plus maze), and social (partner preference, social interaction) behavior. Compared to vehicle, intra-VTA infusions of MK-801 exerted anxiolytic-like effects on elevated plus maze behavior and enhanced lordosis. Unlike prior observations in gonadally-intact rats, intra-VTA bicuculline had no effect on the behavior of OVX/ADX rats (likely due to a floor effect). Subsequent infusions of 3α,5α-THP reversed effects on lordosis and infusions of bicuculline inhibited 3α,5α-THP-facilitated lordosis. Thus, NMDA and GABA A receptors may act as mediators for reproductive behavioral effects of 3α,5α-THP in the midbrain VTA., (Copyright © 2020 Frye, Qrareya, Llaneza and Paris.)

Finasteride (FIN) is the prototypical inhibitor of steroid 5α-reductase (5αR), the enzyme that catalyzes the rate-limiting step of the conversion of progesterone and testosterone into their main neuroactive metabolites. FIN is clinically approved for the treatment of benign prostatic hyperplasia and male baldness; while often well-tolerated, FIN has also been shown to cause or exacerbate psychological problems in vulnerable subjects. Evidence on the psychological effects of FIN, however, remains controversial, in view of inconsistent clinical reports. Here, we tested the effects of FIN in a battery of tests aimed at capturing complementary aspects of mood regulation and stress reactivity in rats. FIN reduced exploratory, incentive, prosocial, and risk-taking behavior; furthermore, it decreased stress coping, as revealed by increased immobility in the forced-swim test (FST). This last effect was also observed in female and orchiectomized male rats, suggesting that the mechanism of action of FIN does not primarily reflect changes in gonadal steroids. The effects of FIN on FST responses were associated with a dramatic decrease in corticotropin release hormone (CRH) mRNA and adrenocorticotropic hormone (ACTH) levels. These results suggest that FIN impairs stress reactivity and reduces behavioral activation and impulsive behavior by altering the function of the hypothalamus-pituitary-adrenal (HPA) axis.

One of the hallmarks of drug abuse is a reduction in the salience of, and motivation for, natural rewards, such as mating. The effects of psychostimulants on male sexual interest and performance are conflicting; use of psychostimulants can produce increases in risky sexual behaviors but have detrimental effects on sexual ability. We hypothesize that these conflicting effects on sexual behavior are due to interactions between cocaine and androgens, such as testosterone and its neuroactive metabolite, 3α-androstanediol (3α-diol). Male rats were administered saline or cocaine (5, 10, or 20mg/kg, i.p.). Motor behavior was observed in the first 30min following drug-administration, and then sexual responding was assessed for 15min. Levels of androgens (testosterone, 3ɑ-diol, and testosterone's aromatized metabolite, estradiol) were measured in circulation and brain regions (frontal cortex, hippocampus, hypothalamus/striatum (hypo/str), and midbrain). Cocaine had no effect on measures of sexual interest (i.e. anogenital investigation). However, cocaine had substantial effects on consummatory sexual behaviors, such as the latency to mount/intromit and the number of sexual contacts. Frontal cortex and hypo/str 3α-diol levels were strongly correlated with consummatory behaviors in saline administered rats; however, this relationship was disrupted by cocaine at all dosages, concomitant with impaired sexual behaviors. Additionally, there was a shift in metabolism at low dosages of cocaine to push testosterone metabolism in the midbrain towards 3α-diol. On the contrary, moderate and high dosages of cocaine shifted testosterone metabolism towards estradiol. These data demonstrate that the association between cortical and hypo/str 3α-diol levels and sexual behavior of male rats is disrupted by non-contingent cocaine and that there may be dose-dependent effects of acute cocaine on androgen metabolism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Drug use influences sexual behavior, performance, and can be associated with increased sexual risk-taking. Our prior results using an animal model indicate that progestogens contribute to hormonally-mediated changes in sexual behavior of female rodents during acute cocaine exposure. Androgens, such as testosterone, and its metabolite 3ɑ-androstanediol (3α-diol), and estradiol, are known to influence male sexual behavior, but can also alter the expression of sexual behavior of female rodents. As such, we investigated the influence of endogenous androgen and estradiol fluctuations on cocaine-mediated changes in motor behavior and sexual receptivity of rats during diestrous or proestrous phases of the estrous cycle. Female rats were administered saline or cocaine (5, 10, or 20mg/kg, i.p.). Motor behavior was observed in the first 30min following drug administration, and then sexual responding was assessed for 15min. Cocaine decreased aggressive behavior in response to attempted mounts by a male among non-receptive (diestrous) rats and inhibited sexual behavior among sexually receptive (proestrous) rats. Cocaine dose-dependently altered concentrations of testosterone metabolites (estradiol and 3α-diol), but not testosterone, which correlated to motor and sexual behaviors of diestrous and proestrous rats, respectively. These data suggest that actions of 3α-diol may be involved in female sexual and motor behavior in response to cocaine, in a cycle-dependent manner., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Our research objective is to understand more, through subjective, self-reports on discussion boards/forums, persons' experiences associated with the use of drugs that alter androgen metabolism, such as finasteride. Finasteride is an orally active, specific inhibitor of 5α-reductase, which is localized to many androgen-dependent tissues. Finasteride inhibits the conversion of testosterone (T) to dihydrotestosterone (DHT), and is commonly used to treat benign prostatic hypertrophy (BPH) and male pattern baldness (MPB), both disorders associated with elevated DHT levels and 5α-reductase activity in the prostate and hair follicles, respectively. It is now acknowledged that long-term use and discontinuation of finasteride has adverse effects (AEs); however, these claims have not been well documented. In this study, discussion board posts (forums) were analyzed as self-reports of what finasteride users indicate is problematic for them. Reports were categorized by the age of subjects as well as the types of AEs described: antiandrogenic, estrogenic, central, and nonspecific/severe. A total of 244 cases were recorded and analyzed on the discussion forum on propeciahelp.com . Among these, 74 (32%) cases reported antiandrogenic affects, 43 (19%) reported estrogenic effects, 70 (30%) reported central effects, 11 (5%) reported nonspecific/severe AEs, and 31 (14%) reported AEs in all categories. The categorization of AEs may prompt further investigation into the pathophysiology of post-finasteride syndrome (PFS). Also, subjective reports may engender greater understanding of the perceived lasting AEs of finasteride.

Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the GABAA receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases. Neuroactive steroids regulate many physiological functions, such as the stress response, puberty, the ovarian cycle, pregnancy and reward. Their levels are altered in several neuropsychiatric and neurological diseases and both preclinical and clinical studies emphasise a therapeutic potential of neuroactive steroids for these diseases, whereby symptomatology ameliorates upon restoration of neuroactive steroid concentrations. However, direct administration of neuroactive steroids has several challenges, including pharmacokinetics, low bioavailability, addiction potential, safety and tolerability, which limit its therapeutic use. Therefore, modulation of neurosteroidogenesis to restore the altered endogenous neuroactive steroid tone may represent a better therapeutic approach. This review summarises recent approaches that target the neuroactive steroid biosynthetic pathway at different levels aiming to promote neurosteroidogenesis. These include modulation of neurosteroidogenesis through ligands of the translocator protein 18 kDa and the pregnane xenobiotic receptor, as well as targeting of specific neurosteroidogenic enzymes such as 17β-hydroxysteroid dehydrogenase type 10 or P450 side chain cleavage. Enhanced neurosteroidogenesis through these targets may be beneficial not only for neurodegenerative diseases, such as Alzheimer's disease and age-related dementia, but also for neuropsychiatric diseases, including alcohol use disorders., (© 2015 British Society for Neuroendocrinology.)

This review explores the effects of female reproductive hormones, estrogens and progestogens, with a focus on progesterone and allopregnanolone, on object memory. Progesterone and its metabolites, in particular allopregnanolone, exert various effects on both cognitive and non-mnemonic functions in females. The well-known object recognition task is a valuable experimental paradigm that can be used to determine the effects and mechanisms of progestogens for mnemonic effects across the lifespan, which will be discussed herein. In this task there is little test-decay when different objects are used as targets and baseline valance for objects is controlled. This allows repeated testing, within-subjects designs, and longitudinal assessments, which aid understanding of changes in hormonal milieu. Objects are not aversive or food-based, which are hormone-sensitive factors. This review focuses on published data from our laboratory, and others, using the object recognition task in rodents to assess the role and mechanisms of progestogens throughout the lifespan. Improvements in object recognition performance of rodents are often associated with higher hormone levels in the hippocampus and prefrontal cortex during natural cycles, with hormone replacement following ovariectomy in young animals, or with aging. The capacity for reversal of age- and reproductive senescence-related decline in cognitive performance, and changes in neural plasticity that may be dissociated from peripheral effects with such decline, are discussed. The focus here will be on the effects of brain-derived factors, such as the neurosteroid, allopregnanolone, and other hormones, for enhancing object recognition across the lifespan., (Copyright © 2015. Published by Elsevier B.V.)

Purpose: Our primary objective was to assess associations between urine cortisol as a biomarker of psychological stress and in vitro fertilization (IVF) outcomes. A secondary objective was to assess associations between toxic metals and cortisol., Methods: Urine and blood specimens were collected from 52 women and 28 male partners completing a first IVF procedure, on the day of oocyte retrieval. Urine cortisol was measured with an enzyme-linked immunosorbent assay. Mercury (Hg), cadmium (Cd), and lead (Pb) were determined in blood and Cd in urine by inductively coupled plasma-mass spectrometry., Results: No associations were indicated for cortisol with IVF outcomes in multivariable regression models adjusted for covariates. However, we detected positive linear associations for cortisol and urine Cd (β = 9.96, 95%CI 1.52, 21.44) and blood Hg (β = 1.44, 95%CI 0.31, 3.18). An exploratory stratified analysis suggested a potential inverse association between urine cortisol and oocyte fertilization among women with low, but not high blood Hg., Conclusion: While limited, these preliminary data suggest that psychological stress may not play a major role in IVF outcomes, which therefore could be one less concern for couples and their clinicians. Our data also raise the possibility for toxic metals to modify associations between cortisol and IVF outcomes among women. However, these preliminary results require corroboration in an experimental animal model and confirmation in a larger, more definitive observational study.

Rationale: Given that the pregnane neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP), is increased following behavioral challenges (e.g., mating), and that there is behavioral-induced biosynthesis of 3α,5α-THP in midbrain and mesocorticolimbic structures, 3α,5α-THP likely has a role in homeostasis and motivated reproduction and reproduction-related behaviors (e.g., affect, affiliation). The role of pregnane xenobiotic receptor (PXR), involved in cholesterol metabolism, for these effects is of continued interest., Objectives: We hypothesized that there would be differences in brain levels of 3α,5α-THP following varied behavioral experiences, an effect abrogated by knockdown of PXR in the midbrain., Methods: Proestrous rats were infused with PXR antisense oligonucleotides (AS-ODNs) or vehicle to the ventral tegmental area before different behavioral manipulations and assessments. Endpoints were expression levels of PXR in the midbrain, 3α,5α-THP, and ovarian steroids (estradiol, progesterone, dihydroprogesterone) in the midbrain, striatum, hippocampus, hypothalamus, prefrontal cortex, and plasma., Results: Across experiments, knocking down PXR reduced PXR expression and 3α,5α-THP levels in the midbrain and hippocampus. There were differences in terms of the behavioral manipulations, such that paced mating had the most robust effects to increase 3α,5α-THP levels and reduce open field exploration and social interaction. An additional question that was addressed is whether brain-derived neurotrophic factor (BDNF) is a downstream factor for regulating effects of behavioral-induced 3α,5α-THP biosynthesis. Rats infused with PXR AS-ODNs had lower levels of BDNF in the hippocampus., Conclusion: Thus, PXR may be a regulator of mating-induced 3α,5α-THP formation and behavioral changes and neural plasticity, such as BDNF.

Chronic stress can influence behaviors associated with medial prefrontal cortex (mPFC) function, such as cognition and emotion regulation. Dopamine in the mPFC is responsive to stress and modulates its behavioral effects. The current study tested whether exposure to 10 days of chronic unpredictable stress (CUS) altered the effects of acute elevation stress on dopamine release in the mPFC and on spatial recognition memory. Male rats previously exposed to CUS or nonstressed controls were tested behaviorally, underwent microdialysis to assess mPFC dopamine levels or underwent blood sampling for corticosterone analysis. Dopamine in the mPFC significantly increased in both groups during acute elevation stress compared with baseline levels, but the level was attenuated in CUS rats compared with controls. Control rats exposed to elevation stress immediately before the T-maze test showed impaired performance, whereas CUS rats did not. No group differences were observed in general motor activity or plasma corticosterone levels following elevation stress. The present results indicate that prior exposure to this CUS procedure reduced dopamine release in the mPFC during acute elevation stress and prevented the impairment of performance on a spatial recognition test following an acute stressor. These findings may contribute to an understanding of the complex behavioral consequences of stress.

Rationale: Progesterone and its metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), have actions in the ventral tegmental area (VTA) that are required for lordosis, a characteristic mating posture of female rodents. 17β-estradiol (estradiol) co-varies with progestogens over natural cycles, enhances production of 3α,5α-THP, and is required for successful reproductive behavior., Objectives: A question of interest is the role of pregnane xenobiotic receptor (PXR), a nuclear receptor that regulates enzymes needed for the production of 3α,5α-THP, for estradiol-mediated lordosis. The hypothesis tested was that if PXR is involved in estradiol-mediated biosynthesis of 3α,5α-THP and reproductive behavior, knocking down expression of PXR in the VTA of estradiol-primed, but not vehicle-primed, rats should decrease lordosis and midbrain 3α,5α-THP; effects may be attenuated by 3α,5α-THP administered to the VTA., Methods: Ovariectomized rats were administered subcutaneous injections of oil vehicle or estradiol. Rats were then administered PXR antisense oligonucleotides (PXR AS-ODNs; which are expected to locally knock down expression of PXR), or control (saline), infusions to the VTA. Rats were administered 3α,5α-THP or vehicle via infusions to the VTA. Reproductive behavior (paced mating task) of rats was determined in addition to exploratory (open field), affective (elevated plus maze), and pro-social (social interaction task) behavior., Results: Reproductive behavior (i.e., increased lordosis) was enhanced with estradiol-priming and infusions of 3α,5α-THP to the VTA. Infusions of PXR AS-ODNs to the VTA attenuated responses in estradiol-, but not vehicle-, primed rats, compared to control infusions., Conclusions: PXR may be involved in a neuroregulatory response involving biosynthesis of 3α,5α-THP in the midbrain VTA of estradiol-primed rats.

Objective: To determine whether allopregnanolone (AP) may mediate seizure reduction in progesterone-treated women with epilepsy., Methods: The NIH Progesterone Trial compared the efficacy of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects, randomized 2:1 to progesterone or placebo, stratified by catamenial vs noncatamenial designation. Treatments were compared on proportions of 50% responders, and changes in seizure frequency from 3 baseline to 3 treatment cycles. Serum AP levels were measured by radioimmunoassay from 155 women with intractable focal-onset seizures who had baseline and treatment-phase midluteal serum samples drawn each cycle for hormone measurements., Results: There was no significant correlation between percentage changes in AP levels and seizure frequencies from baseline to treatment for either the catamenial or noncatamenial stratum. There was a significant correlation for the subset of subjects who showed a significantly greater responder rate in the post hoc analysis of the trial, i.e., subjects who had a 3-fold or greater increase in average daily seizure frequency perimenstrually compared with the midfollicular and midluteal phases (C1 ≥ 3: r = -0.442, p = 0.013, and specifically for C1 ≥ 3 progesterone-treated subjects [r = -0.452, p = 0.035], but not other groups [C1 ≥ 3 placebo: r = -0.367; C1 <3 progesterone: r = 0.099; C1 <3 placebo: r = 0.131; p = not significant])., Conclusions: The findings support AP as a mediator of seizure reduction in progesterone-treated women who have a substantial level of perimenstrually exacerbated seizures., (© 2014 American Academy of Neurology.)

The capacity to form progesterone (P₄)'s 5α-reduced metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP; a.k.a. allopregnanolone), in the brain may be related to facilitation of lordosis among estrogen-primed (E₂) mice. We investigated this idea further by comparing effects of endogenous and exogenous progestogens in mice that are deficient in the Type One 5α-reductase enzyme (5α-reductase knockout mice; 5α-RKO), and their wildtype counterparts for sexual behavior. Comparisons were made following administration of progestogens that are expected to increase 3α,5α-THP or not. Sexual receptivity of 5α-RKO mice and their wildtype counterparts was examined when mice were naturally-cycling (Experiment 1); ovariectomized (OVX), E₂-primed (10 μg, subcutaneous; SC) and administered P₄ (0, 125, 250, or 500 μg SC; Experiment 2); and OVX, E₂-primed and administered P₄, medroxyprogesterone acetate (MPA, 4 mg/kg, SC, which does not convert to 3α,5α-THP) or 3α,5α-THP (4 mg/kg, SC; Experiment 3). The percentage of mounts that elicited lordosis (lordosis quotient) or aggression/rejection behavior (aggression quotient), as well as the quality of lordosis (lordosis rating), was scored. Wildtype, but not 5α-RKO, mice in behavioral estrus demonstrated significantly greater lordosis quotients and lordosis ratings, but similar aggression quotients, compared to their diestrous counterparts. Among OVX and E₂-primed mice, P₄ facilitated lordosis of wildtype, but not 5α-RKO, mice. MPA neither facilitated lordosis of wildtype, nor 5α-RKO mice. 3α,5α-THP administered to wildtype or 5α-RKO mice increased lordosis quotients and lordosis ratings and decreased aggression quotients. 3α,5α-THP levels in the midbrain, one brain region important for sexual behavior, were increased during behavioral estrus, with P4 administered to WT, but not 5α-RKO mice, and 3α,5α-THP administered to WT and 5α-RKO mice. MPA did not increase 3α,5α-THP. Thus, deletion of Type One 5α-reductase among female mice may attenuate reproductive responding during the estrous cycle and after hormone-priming., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A novel factor of interest for growth/plasticity in the brain is pregnane xenobiotic receptor (PXR). PXR is a liver factor known for its role in xenobiotic clearance and cholesterol metabolism. It is expressed in the brain, suggesting a potential role for plasticity, particularly involving cholesterol-based steroids and neurosteroids. Mating induces synthesis of neurosteroids in the midbrain Ventral Tegmental Area (VTA) of female rodents, as well as other "plastic" regions of the brain, including the hippocampus, that may be involved in the consolidation of the mating experience. Reducing PXR in the VTA attenuates mating-induced biosynthesis of the neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP). The 18 kDA translocator protein (TSPO) is one rate-limiting factor for 3α,5α-THP neurosteroidogenesis. The hypothesis tested was that PXR is an upstream factor of TSPO for neurosteroidogenesis of 3α,5α-THP in the VTA for lordosis, independent of peripheral glands. First, proestrous rats were administered a TSPO blocker (PK11195) and/or 3α,5α-THP following infusions of PXR antisense oligonucleotides (AS-ODNs) or vehicle to the VTA. Inhibiting TSPO with PK11195 reduced 3α,5α-THP levels in the midbrain and lordosis, an effect that could be reversed with 3α,5α-THP administration, but not AS-ODN+3α,5α-THP. Second, proestrous, ovariectomized (OVX), or ovariectomized/adrenalectomized (OVX/ADX) rats were infused with a TSPO enhancer (FGIN 1-27) subsequent to AS-ODNs or vehicle to the VTA. PXR AS-ODNs blocked actions of FGIN 1-27 for lordosis and 3α,5α-THP levels among proestrous > OVX > OVX/ADX rats. Thus, PXR may be upstream of TSPO, involved in neurosteroidogenesis of 3α,5α-THP in the brain for plasticity. This novel finding of a liver factor involved in behavioral/neural plasticity substantiates future studies investigating factors known for their prominent actions in the peripheral organs, such as the liver, for modulating brain function and its augmentation.

Neurosteroids are cholesterol-based hormones that can be produced in the brain, independent of secretion from peripheral endocrine glands, such as the gonads and adrenals. A focus in our laboratory for over 25 years has been how production of the pregnane neurosteroid, allopregnanolone, is regulated and the novel (i.e., non steroid receptor) targets for steroid action for behavior. One endpoint of interest has been lordosis, the mating posture of female rodents. Allopregnanolone is necessary and sufficient for lordosis, and the brain circuitry underlying it, such as actions in the midbrain ventral tegmental area (VTA), has been well-characterized. Published and recent findings supporting a dynamic role of allopregnanolone are included in this review. First, contributions of ovarian and adrenal sources of precursors of allopregnanolone, and the requisite enzymatic actions for de novo production in the central nervous system will be discussed. Second, how allopregnanolone produced in the brain has actions on behavioral processes that are independent of binding to steroid receptors, but instead involve rapid modulatory actions via neurotransmitter targets (e.g., γ-amino butyric acid-GABA, N-methyl-D-aspartate- NMDA) will be reviewed. Third, a recent focus on characterizing the role of a promiscuous nuclear receptor, pregnane xenobiotic receptor (PXR), involved in cholesterol metabolism and expressed in the VTA, as a target for allopregnanolone and how this relates to both actions and production of allopregnanolone will be addressed. For example, allopregnanolone can bind PXR and knocking down expression of PXR in the midbrain VTA attenuates actions of allopregnanolone via NMDA and/or GABAA for lordosis. Our understanding of allopregnanolone's actions in the VTA for lordosis has been extended to reveal the role of allopregnanolone for broader, clinically-relevant questions, such as neurodevelopmental processes, neuropsychiatric disorders, epilepsy, and aging.

Evidence is emerging of the role of membrane progestin receptors (referred to as mPRs herein: members of Progestin and AdipoQ Receptor (Paqr) family) as a novel brain target in mammals, such as rats. In the present study, the role of mPRs in mice was assessed to further elucidate the conservation of this mechanism across species. The brain target investigated was the midbrain ventral tegmental area (VTA) given its described role for rapid actions of progestins for reproduction. Studies tested the hypothesis that if mPRs are required for progestin-facilitated lordosis through actions in the VTA, then knockdown of mPRs in the VTA will attenuate lordosis. Ovariectomized (OVX) mice were subcutaneously injected with estradiol (E2) and progesterone (P4), and infused with antisense oligodeoxynucleotides (AS-ODNs) to mPRα (Paqr7) and/or mPRβ (Paqr8) or vehicle to the lateral ventricle or VTA. Mice were assessed for reproductive behavior (lordosis and aggression/rejection quotients) in a standard mating task. Results supported our hypothesis. E2+P4-facilitated lordosis was significantly reduced, and aggression/rejection increased, with infusions of mPRα, mPRβ, or mPRαβ AS-ODNs to the lateral ventricle, compared to vehicle. E2+P4-facilitated lordosis was significantly decreased, and aggression/rejection increased, with mPRβ or mPRαβ AS-ODNs to the VTA of C57/BL6 mice. Both mPRɑ and mPRβ AS-ODNs reduced lordosis, and increased aggression/rejection, of wildtype (C57/BL6x129) mice, but not nuclear PR knockout mice. Thus, mPRs may be a novel target of progestins for reproductive behavior of mice., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Endocrine-disrupting chemicals (EDCs) are diverse and pervasive and may have significant consequence for health, including reproductive development and expression of sex-/gender-sensitive parameters. This review chapter discusses what is known about common EDCs and their effects on reproductively relevant end points. It is proposed that one way that EDCs may exert such effects is by altering steroid levels (androgens or 17-estradiol, E₂) and/or intracellular E₂ receptors (ERs) in the hypothalamus and/or hippocampus. Basic research findings that demonstrate developmentally sensitive end points to androgens and E₂ are provided. Furthermore, an approach is suggested to examine differences in EDCs that diverge in their actions at ERs to elucidate their role in sex-/gender-sensitive parameters., (© 2014 Elsevier Inc. All rights reserved.)

Progestogens have actions in the midbrain ventral tegmental area (VTA) to mediate motivated behaviours, such as those involved in reproductive processes, among female rodents. In the VTA, the formation and actions of one progestogen, 5α-pregnan-3α-ol-20-one (3α,5α-THP), are necessary and sufficient to facilitate sexual responding (measured by lordosis) of female rodents. Although 3α,5α-THP can be produced after metabolism of ovarian progesterone, 3α,5α-THP is also a neurosteroid produced de novo in brain regions, such as the VTA. There can be dynamic changes in 3α,5α-THP production associated with behavioural experience, such as mating. Questions of interest are the sources and targets of 3α,5α-THP. Regarding sources, the pregnane xenobiotic receptor (PXR) may be a novel factor involved in 3α,5α-THP metabolism in the VTA (as well as a direct target of 3α,5α-THP). We have identified PXR in the midbrain of female rats, and manipulating PXR in this region reduces 3α,5α-THP synthesis and alters lordosis, as well as affective and social behaviours. Regarding targets, recent studies have focused on the role of membrane progestin receptors (mPRs). We have analysed the expression of two of the common forms of these receptors (mPRα/paqr7 and mPRβ/paqr8) in female rats. The expression of mPRα was observed in peripheral tissues and brain areas, including the hypothalamus and midbrain. The expression of mPRβ was only observed in brain tissues and was abundant in the midbrain and hypothalamus. To our knowledge, studies of these receptors in mammalian models have been limited to expression and regulation, instead of function. One question that was addressed was the functional effects of progestogens via mPRα and mPRβ in the midbrain of hormone-primed rats for lordosis. Studies to date suggest that mPRβ may be an important target of progestogens in the VTA for lordosis. Taken together, the result of these studies demonstrate that PXR is involved in the production of 3α,5α-THP in the midbrain VTA. Moreover, mPRs may be a target for the actions of progestogens in the VTA for lordosis., (© 2013 British Society for Neuroendocrinology.)

Progesterone (P4) facilitates exploration, anxiety and social behaviors in estrogen (E2)-primed mice. Some of these effects may be due to actions of its 5α-reduced metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP). In order to address the role of P4 and its metabolite, 3α,5α-THP, a mouse model was utilized. We hypothesized that if P4's metabolism to 3α,5α-THP is essential to facilitate exploratory, anti-anxiety and social behaviors of mice, then wildtype, but not 5α-reductase knockout (5α-RKO), mice will have greater expression of these behaviors. Experiment 1: Mice were ovariectomized (ovx), E2-primed and administered P4 (0, 125, 250, or 500μg) subcutaneously and then tested 4h later in a battery of tasks: open field, elevated plus maze, and social interaction. Experiment 2: Ovx, E2-primed mice were administered P4 (4mg/kg), 3α,5α-THP (4mg/kg), medroxyprogesterone acetate (MPA, which does not convert to 3α,5α-THP; 4mg/kg), or vehicle subcutaneously and tested 4h later. There was a dose-dependent effect of P4 to wildtype, but not 5α-RKO, mice. Neither wildtype, nor 5α-RKO, mice had increased exploration, anti-anxiety or pro-social behavior with MPA administration. Progesterone only exerted effects on anti-anxiety behavior, and increased 3α,5α-THP in the prefrontal cortex and hippocampus, when administered to wildtype mice. 3α,5α-THP to both WT and 5α-RKO mice increased exploration, anti-anxiety and social interaction and 3α,5α-THP levels in the hippocampus and prefrontal cortex. Thus, metabolism of P4 by the 5α-reductase enzyme may be essential for enhancement of these behaviors., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Progesterone (P4) may influence cognition in part through actions of its 5α-reduced metabolite, allopregnanolone. Ovariectomized mice that were C57BL/6 wildtype (WT), or deficient in the 5α-reductase Type 1 enzyme (5α-reductase knockout; 5αRKO), were administered vehicle, P4, allopregnanolone, or medroxyprogesterone acetate (MPA) after training in the object recognition or placement tasks. WT mice administered P4 or allopregnanolone performed significantly better in the object recognition and placement tasks than did WT mice administered vehicle or MPA. 5αRKO mice administered allopregnanolone, but not P4, MPA, or vehicle showed enhanced performance in the object recognition and placement tasks. Levels of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex and hippocampus were lowest among mice administered MPA. Thus, some of P4s effects to enhance cognitive performance may be incumbent upon its 5α-reduction., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Progesterone (P₄) and its metabolites, rapidly facilitate lordosis of rats partly through actions in the ventral tegmental area (VTA). The study of membrane progestin receptors (mPRs), of the Progestin and AdipoQ Receptor (PAQR) superfamily, has been limited to expression and regulation, instead of function. We hypothesized that if mPRs are required for progestin-facilitated lordosis in the VTA, then mPRs will be expressed in this region and knockdown will attenuate lordosis. First, expression of mPR was examined by reverse-transcriptase polymerase chain reaction (RT-PCR) in brain and peripheral tissues of proestrous Long-Evans rats. Expression of mPRα (paqr7) was observed in peripheral tissues and brain areas, including hypothalamus and midbrain. Expression of mPRβ (paqr8) was observed in brain tissues and was abundant in the midbrain and hypothalamus. Second, ovariectomized rats were estrogen (E₂; 0.09 mg/kg, SC), and P₄ (4 mg/kg, SC) or vehicle-primed, and infused with antisense oligodeoxynucleotides (AS-ODNs) targeted against mPRα and/or mPRβ intracerebroventricularly or to the VTA. Rats were assessed for motor (open field), anxiety (elevated plus maze), social (social interaction), and sexual (lordosis) behavior. P₄-facilitated lordosis was significantly reduced with administration of AS-ODNs for mPRα, mPRβ, or co-administration of mPRα and mPRβ to the lateral ventricle, compared to vehicle. P₄-facilitated lordosis was reduced, compared to vehicle, by administration of mPRβ AS-ODNs, or co-administration of mPRα and mPRβ AS-ODNs, but not mPRα AS-ODNs alone, to the VTA. No differences were observed for motor, anxiety, or social behaviors. Thus, mPRs in the VTA are targets of progestin-facilitated lordosis of rats., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: Progesterone (P4 ) and its product, 5α-pregnan-3α-ol-20-one (3α,5α-THP), act in the midbrain ventral tegmental area (VTA) to alter motivated behaviors, such as mating, and motor and anxiety behavior. Of interest is whether 3α,5α-THP formation requires the pregnane xenobiotic receptor (PXR), which is expressed in the midbrain of rats., Aim: The role of PXR in the midbrain for 3α,5α-THP formation, which precedes modulation of motivated behaviors, was investigated., Methods: Rats had estrous cycle phase determined and were assessed when they were in diestrus or proestrus. Diestrous and proestrous rats were infused with control or antisense oligodeoxyribonucleotides (AS-ODNs) targeted against PXR to the VTA., Main Outcome Measures: In pilot studies, PXR gene and protein expression in the midbrain were determined with quantitative reverse transcriptase polymerase chain reaction and Western blotting, respectively. Diestrous and proestrous rats infused with control or AS-ODNs to the VTA were tested for anxiety (open field and plus maze), social (social interaction), and sexual (paced mating) behavior. Expression of PXR in the midbrain was verified with Western blotting. Plasma estradiol, P4 , dihydroprogesterone (DHP), and 3α,5α-THP levels, and brain P4 , DHP, and 3α,5α-THP levels were measured. We predicted that proestrous rats infused with PXR AS-ODNs would have decreased anti-anxiety, social, and sexual behavior, lower midbrain expression of PXR, and lower midbrain levels of 3α,5α-THP compared with controls., Results: Results supported the hypothesis that formation of 3α,5α-THP requires PXR and may be important for motivated behaviors. PXR AS-ODN, compared with control, infusions to the VTA reduced PXR expression and 3α,5α-THP levels in the midbrain and attenuated sexual receptivity of proestrous rats., Conclusions: Knockdown of PXR in the midbrain reduces 3α,5α-THP levels and sexual receptivity of proestrous rats. Thus, PXR in the midbrain may be required for the observed increase in 3α-5α-THP during proestrus, which has subsequent effects on motivated, reproductive behaviors., (© 2013 International Society for Sexual Medicine.)

Stressors, during early life or adulthood, can alter steroid-sensitive behaviors, such as exploration, anxiety, and/or cognitive processes. We investigated if exposure to acute stressors in adulthood may alter behavioral and neuroendocrine responses of male rats that were exposed to gestational stress or not. We hypothesized that rats exposed to gestational and acute stress may show behavioral inhibition, increased corticosterone, and altered androgen levels in the hippocampus. Subjects were adult, male offspring of rat dams that were restrained daily on gestational days 14-20, or did not experience this manipulation. Immediately before testing, rats were restraint stressed for 20 min or not. During week 1, rats were tested in a battery of tasks, including the open field, elevated plus maze, social interaction, tailflick, pawlick, and defensive burying tasks. During week 2, rats were trained and tested 24 h later in the inhibitory avoidance task. Plasma corticosterone and androgen levels, and hippocampal androgen levels, were measured in all subjects. Gestational and acute restraint stress increased plasma levels of corticosterone, and reduced levels of testosterone's 5α-reduced metabolites, dihydrotestosterone (DHT) and 3α-androstanediol (3α-diol), but not the aromatized metabolite, estradiol (E(2)), in plasma or the hippocampus. Gestational and acute restraint stress reduced central entries made in the open field, and latencies to enter the shock-associated side of the inhibitory avoidance chamber during testing. Gestational stress reduced time spent interacting with a conspecific. These data suggest that gestational and acute restraint stress can have actions to produce behavioral inhibition coincident with increased corticosterone and decreased 5α-reduced androgens of adult male rats. Thus, gestational stress altered neural circuits involved in the neuroendocrine response to acute stress in early adulthood.

Background: This study assessed BRCA1 and BRCA2 mutation prevalence in an unselected cohort of patients with triple-negative breast cancer (BC)., Methods: One hundred ninety-nine patients were enrolled. Triple negativity was defined as <1% estrogen and progesterone staining by immunohistochemistry and HER-2/neu not overexpressed by fluorescence in situ hybridization. Having given consent, patients had BRCA1 and BRCA2 full sequencing and large rearrangement analysis. Mutation prevalence was assessed among the triple-negative BC patients and the subset of patients without a family history of breast/ovarian cancer. Independent pathological review was completed on 50 patients., Results: Twenty-one deleterious BRCA mutations were identified--13 in BRCA1 and 8 in BRCA2 (prevalence, 10.6%). In 153 patients (76.9%) without significant family history (first-degree or second-degree relatives with BC aged <50 years or ovarian cancer at any age), 8 (5.2%) mutations were found. By using prior National Comprehensive Cancer Network (NCCN) guidelines recommending testing for triple-negative BC patients aged <45 years, 4 of 21 mutations (19%) would have been missed. Two of 21 mutations (10%) would have been missed using updated NCCN guidelines recommending testing for triple-negative BC patients aged <60 years., Conclusions: The observed mutation rate was significantly higher (P = .0005) than expected based on previously established prevalence tables among patients unselected for pathology. BRCA1 mutation prevalence was lower, and BRCA2 mutation prevalence was higher, than previously described. Additional mutation carriers would have met new NCCN testing guidelines, underscoring the value of the updated criteria. Study data suggest that by increasing the age limit to 65 years, all carriers would have been identified., (Copyright © 2011 American Cancer Society.)

CD4(+) T cells are the key players of vaccine resistance to fungi. The generation of effective T cell-based vaccines requires an understanding of how to induce and maintain CD4(+) T cells and memory. The kinetics of fungal antigen (Ag)-specific CD4(+) T cell memory development has not been studied due to the lack of any known protective epitopes and clonally restricted T cell subsets with complementary T cell receptors (TCRs). Here, we investigated the expansion and function of CD4(+) T cell memory after vaccination with transgenic (Tg) Blastomyces dermatitidis yeasts that display a model Ag, Eα-mCherry (Eα-mCh). We report that Tg yeast led to Eα display on Ag-presenting cells and induced robust activation, proliferation, and expansion of adoptively transferred TEa cells in an Ag-specific manner. Despite robust priming by Eα-mCh yeast, antifungal TEa cells recruited and produced cytokines weakly during a recall response to the lung. The addition of exogenous Eα-red fluorescent protein (RFP) to the Eα-mCh yeast boosted the number of cytokine-producing TEa cells that migrated to the lung. Thus, model epitope expression on yeast enables the interrogation of Ag presentation to CD4(+) T cells and primes Ag-specific T cell activation, proliferation, and expansion. However, the limited availability of model Ag expressed by Tg fungi during T cell priming blunts the downstream generation of effector and memory T cells.

Progestogens [progesterone (P(4)) and its products] play fundamental roles in the development and/or function of the central nervous system during pregnancy. We, and others, have investigated the role of pregnane neurosteroids for a plethora of functional effects beyond their pro-gestational processes. Emerging findings regarding the effects, mechanisms, and sources of neurosteroids have challenged traditional dogma about steroid action. How the P(4) metabolite and neurosteroid, 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP), influences cellular functions and behavioral processes involved in emotion/affect, motivation, and reward, is the focus of the present review. To further understand these processes, we have utilized an animal model assessing the effects, mechanisms, and sources of 3α,5α-THP. In the ventral tegmental area (VTA), 3α,5α-THP has actions to facilitate affective, and motivated, social behaviors through non-traditional targets, such as GABA, glutamate, and dopamine receptors. 3α,5α-THP levels in the midbrain VTA both facilitate, and/or are enhanced by, affective and social behavior. The pregnane xenobiotic receptor (PXR) mediates the production of, and/or metabolism to, various neurobiological factors. PXR is localized to the midbrain VTA of rats. The role of PXR to influence 3α,5α-THP production from central biosynthesis, and/or metabolism of peripheral P(4), in the VTA, as well as its role to facilitate, or be increased by, affective/social behaviors is under investigation. Investigating novel behavioral functions of 3α,5α-THP extends our knowledge of the neurobiology of progestogens, relevant for affective/social behaviors, and their connections to systems that regulate affect and motivated processes, such as those important for stress regulation and neuropsychiatric disorders (anxiety, depression, schizophrenia, drug dependence). Thus, further understanding of 3α,5α-THP's role and mechanisms to enhance affective and motivated processes is essential.

There are estrous cycle differences in affective behaviors of rodents that are generally attributed to cyclic variations in estradiol, progesterone (P) and its metabolites. A question is the role of the steroid metabolism enzyme, 5α-reductase, for these estrous cycle differences. To address the requirement of 5α-reductase, estrous cycle variations in the behavior of wildtype mice and their littermates that are deficient in the 5α-reductase type 1 enzyme (5αRKO mice) were examined. The hypothesis was that if some of the estrous cycle differences in exploratory (open field) and anxiety (elevated plus maze) are due to P's 5α-reduction to 5α-pregnan-3α-ol-20-one (3α,5α-THP), then wildtype mice will have estrous cycle differences in the expression of these behaviors, but 5αRKO mice will not. Mice were tested in these tasks and then had plasma and brains collected so that steroid levels (estradiol, P, 3α,5α-THP, corticosterone) could be measured in these tissues. Results supported this hypothesis. There were estrous cycle differences among wildtype, but not 5αRKO, mice. Proestrous wildtype mice made more central entries in the open field and spent more time on the open arms of the plus maze, coincident with higher 3α,5α-THP levels in plasma and brain regions important for these behaviors, such as the hippocampus and cortex, compared to their diestrous counterparts. Variability in the open field and elevated plus maze could be explained by circulating and hippocampus levels of 3α,5α-THP, respectively. Thus, 5α-reductase may be required for the estrous cycle variations in affective behavior and 3α,5α-THP levels of female mice., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Some environmental contaminants interact with hormones and may exert adverse consequences as a result of their actions as endocrine disrupting chemicals (EDCs). Exposure in people is typically a result of contamination of the food chain, inhalation of contaminated house dust or occupational exposure. EDCs include pesticides and herbicides (such as dichlorodiphenyl trichloroethane or its metabolites), methoxychlor, biocides, heat stabilisers and chemical catalysts (such as tributyltin), plastic contaminants (e.g. bisphenol A), pharmaceuticals (i.e. diethylstilbestrol; 17α-ethinylestradiol) or dietary components (such as phytoestrogens). The goal of this review is to address the sources, effects and actions of EDCs, with an emphasis on topics discussed at the International Congress on Steroids and the Nervous System. EDCs may alter reproductively-relevant or nonreproductive, sexually-dimorphic behaviours. In addition, EDCs may have significant effects on neurodevelopmental processes, influencing the morphology of sexually-dimorphic cerebral circuits. Exposure to EDCs is more dangerous if it occurs during specific 'critical periods' of life, such as intrauterine, perinatal, juvenile or puberty periods, when organisms are more sensitive to hormonal disruption, compared to other periods. However, exposure to EDCs in adulthood can also alter physiology. Several EDCs are xenoestrogens, which can alter serum lipid concentrations or metabolism enzymes that are necessary for converting cholesterol to steroid hormones. This can ultimately alter the production of oestradiol and/or other steroids. Finally, many EDCs may have actions via (or independent of) classic actions at cognate steroid receptors. EDCs may have effects through numerous other substrates, such as the aryl hydrocarbon receptor, the peroxisome proliferator-activated receptor and the retinoid X receptor, signal transduction pathways, calcium influx and/or neurotransmitter receptors. Thus, EDCs, from varied sources, may have organisational effects during development and/or activational effects in adulthood that influence sexually-dimorphic, reproductively-relevant processes or other functions, by mimicking, antagonising or altering steroidal actions., (© 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.)

Developments in behavioral assessment, autonomic and/or baseline reactivity, psychopharmacology, and genetics, have contributed significantly to the assessment of performance-enhancing drugs in animal models. Particular classes of steroid hormones: androgenic steroids are of interest. Anecdotally, the performance enhancing effects of androgens are attributed to anabolic events. However, there is a discrepancy between anecdotal evidence and investigative data. While some androgen steroids may promote muscle growth (myogenesis), effects of androgens on performance enhancement are not always seen. Indeed, some effects of androgens on performance may be attributable to their psychological and cardiovascular effects. As such, we consider androgen effects in terms of their behavioral, autonomic, and neuroendocrine components. Techniques are discussed in this chapter, some of which are well established, while others have been more recently developed to study androgen action. Androgens may be considered for their positive impact, negative consequence, or psychotropic properties. Thus, this review aims to elucidate some of the effects and/or mechanisms of androgens on behavioral, autonomic, and/or neuroendocrine assessment that may underlie their controversial performance enhancing effects.

Psychological, physical and/or immune stressors during pregnancy are associated with negative birth outcomes, such as preterm birth and developmental abnormalities. In rodents, prenatal stressors can alter the expression of 5α-reductase enzymes in the brain and may influence cognitive function and anxiety-type behaviour in the offspring. Progesterone plays a critical role in maintaining gestation. In the present study, it was hypothesised that 5α-reduced progesterone metabolites influence birth outcomes and/or the cognitive and neuroendocrine function of the offspring. 5α-Reduced steroids were manipulated in pregnant Long-Evans rats via the administration of vehicle, the 5α-reduced, neuroactive metabolite of progesterone, 5α-pregnan-3α-ol-20-one (3α,5α-THP, allopregnanolone; 10 mg/kg/ml, s.c.), or the 5α-reductase inhibitor, finasteride (50 mg/kg/ml, s.c.), daily from gestational days 17-21. Compared to vehicle or 3α,5α-THP treatment, finasteride, significantly reduced the length of gestation and the number of pups per litter found in the dams' nests after parturition. The behaviour of the offspring in hippocampus-dependent tasks (i.e. object recognition, open field) was examined on post-natal days 28-30. Compared to vehicle-exposed controls, prenatal 3α,5α-THP treatment significantly increased motor behaviour in females compared to males, decreased progesterone content in the medial prefrontal cortex (mPFC) and diencephalon, increased 3α,5α-THP and 17β-oestradiol content in the hippocampus, mPFC and diencephalon, and significantly increased serum corticosterone concentrations in males and females. Prenatal finasteride treatment significantly reduced object recognition, decreased hippocampal 3α,5α-THP content, increased progesterone concentration in the mPFC and diencephalon, and increased serum corticosterone concentration in female (but not male) juvenile offspring, compared to vehicle-exposed controls. Thus, inhibiting the formation of 5α-reduced steroids during late gestation in rats reduces gestational length, the number of viable pups per litter, and impairs cognitive and neuroendocrine function in the juvenile offspring., (© 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.)

Immune challenge during pregnancy is associated with preterm birth and poor perinatal development. The mechanisms of these effects are not known. 5α-Pregnan-3α-ol-20-one (3α,5α-THP), the neuroactive metabolite of progesterone, is critical for neurodevelopment and stress responses, and can influence cognition and affective behaviours. To develop an immune challenge model of preterm birth, pregnant Long-Evans rat dams were administered lipopolysaccharide [LPS; 30 μg/kg/ml, intraperitoneal (IP)], interleukin-1β (IL-1β; 1 μg/rat, IP) or vehicle (0.9% saline, IP) daily on gestational days 17-21. Compared to control treatment, prenatal LPS or IL-1β reduced gestational length and the number of viable pups born. At 28-30 days of age, male and female offspring of mothers exposed to prenatal IL-1β had reduced cognitive performance in the object recognition task compared to controls. In females, but not males, prenatal IL-1β reduced anxiety-like behaviour, indicated by entries to the centre of an open field. In the hippocampus, progesterone turnover to its 5α-reduced metabolites was lower in prenatally exposed IL-1β female, but not in male offspring. IL-1β-exposed males and females had reduced oestradiol content in hippocampus, medial prefrontal cortex and diencephalon compared to controls. Thus, immune stress during late pregnancy reduced gestational length and negatively impacted birth outcomes, hippocampal function and central neurosteroid formation in the offspring.

Steroid hormones, such as progesterone, are typically considered to be primarily secreted by the gonads (albeit adrenals can also be a source) and to exert their actions through cognate intracellular progestin receptors (PRs). Through its actions in the midbrain ventral tegmental Area (VTA), progesterone mediates appetitive (exploratory, anxiety, social approach) and consummatory (social, sexual) aspects of rodents' mating behaviour. However, progesterone and its natural metabolites ('progestogens') are produced in the midbrain VTA independent of peripheral sources and midbrain VTA of adult rodents is devoid of intracellular PRs. One approach that we have used to understand the effects of progesterone and mechanisms in the VTA for mating is to manipulate the actions of progesterone in the VTA and to examine effects on lordosis (the posture female rodents assume for mating to occur). This review focuses on the effects and mechanisms of progestogens to influence reproduction and related processes. The actions of progesterone and its 5α-reduced metabolite and neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP; allopregnanolone) in the midbrain VTA to facilitate mating are described. The findings that 3α,5α-THP biosynthesis in the midbrain occurs with mating are discussed. Evidence for the actions of 3α,5α-THP in the midbrain VTA via nontraditional steroid targets is summarised. The broader relevance of these actions of 3α,5α-THP for aspects of reproduction, beyond lordosis, is summarised. Finally, the potential role of the pregnane xenobiotic receptor in mediating 3α,5α-THP biosynthesis in the midbrain is introduced., (© 2011 The Author. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.)

Maternal-offspring interactions begin prior to birth. Experiences of the mother during gestation play a powerful role in determining the developmental programming of the central nervous system. In particular, stress during gestation alters developmental programming of the offspring resulting in susceptibility to sex-typical and stress-sensitive neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. However, neither these effects, nor the underlying mechanisms, are well understood. Our hypothesis is that allopregnanolone, during gestation, plays a particularly vital role in mitigating effects of stress on the developing fetus and may mediate, in part, alterations apparent throughout the lifespan. Specifically, altered balance between glucocorticoids and progestogens during critical periods of development (stemming from psychological, immunological, and/or endocrinological stressors during gestation) may permanently influence behavior, brain morphology, and/or neuroendocrine-sensitive processes. 5α-reduced progestogens are integral in the developmental programming of sex-typical, stress-sensitive, and/or disorder-relevant phenotypes. Prenatal stress (PNS) may alter these responses and dysregulate allopregnanolone and its normative effects on stress axis function. As an example of a neurodevelopmental, neuropsychiatric, and/or neurodegenerative process, this review focuses on responsiveness to drugs of abuse, which is sensitive to PNS and progestogen milieu. This review explores the notion that allopregnanolone may effect, or be influenced by, PNS, with consequences for neurodevelopmental-, neuropsychiatric-, and/or neurodegenerative- relevant processes, such as addiction.

Progesterone may have actions independent of intracellular progestin receptors (PRs) to influence depressive behavior. To investigate this, we examined effects of progesterone (P; 10mg/kg, SC) on the depressive behavior of mice in the forced swim test (FST). In Experiment 1, subjects were 4 to 6 months old, intact or ovariectomized (OVX) female and intact or gonadectomized (GDX) male, C57/BL6 mice. Progesterone reduced depressive behavior of young diestrous and OVX mice but male mice were impervious to effects of P. In Experiment 2, subjects were intact aged (20-28 months old) C57/BL6 female and male mice. Progesterone reduced depressive behavior of aged female and male C57/BL6 mice, albeit effects were greater among males. In Experiment 3, effects of P were examined in 4 to 6 months old, gonadally-intact, female and male mice that were wildtype or PR knockouts (PRKOs). Progesterone decreased depressive behavior of young adult, wildtype and PRKO mice, which showed greater immobility than did their wildtype counterparts. In Experiment 4, subjects were 18-24 months old wildtype or PRKO mice (Exp 4). Progesterone decreased immobility among wildtype and PRKO mice (which were not different in terms of their baseline depressive behavior). Together these data demonstrate that P decreases depressive behavior of young and older adult C57/BL6, wildtype and PRKO mice, which suggest that acute anti-depressant effects of P may occur independent of actions at "classic" PRs., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Among women and female rodents, progesterone (P) influences social affiliation and affect. These effects may be partly due to formation of its 5α-reduced, 3α- hydroxylated metabolite, 5α-pregnan-3α-ol-20-one (3α,5α- THP)., Aim: To elucidate whether actions of 3α,5α-THP in the midbrain ventral tegmental area (VTA) are both necessary and sufficient to enhance non-sexual and sexual social behaviors, affect, and central 3α,5α-THP metabolism., Materials and Methods: P and 3α,5α-THP formation were unperturbed or blocked in VTA via infusions of vehicle, PK11195 (400 ng), and/or indomethacin (10 μg). Rats then received subsequent infusions of vehicle or 3α,5α-THP (100 ng) and were assessed in a battery of tasks that included open field (exploration), elevated plus maze (anxiety behavior), social interaction (social affiliation), and paced mating (sexual behavior) or were not tested. Metabolic turnover of P to its 5α-reduced metabolites was assessed in plasma, midbrain, hippocampus, frontal cortex, diencephalon, and remaining subcortical tissues (control interbrain)., Results: Infusions of any combination of inhibitors significantly reduced social and affective behavior in all tasks compared to vehicle, concomitant with reduced turnover of P to its 5α-reduced metabolites, in midbrain only. Subsequent infusions of 3α,5α-THP significantly reinstated/enhanced anti- anxiety behavior, lordosis, and P turnover to its 5α-reduced metabolites in midbrain, as well as hippocampus, cortex, and diencephalon (but not plasma or interbrain)., Conclusions: These data are the first to provide direct evidence that actions of 3α,5α-THP in the VTA are both necessary and sufficient for social and affective behavior, as well as initiation of central 5α-reduction.

Cognitive decline can occur with aging; however, some individuals experience less cognitive decline than do others. Secretion of ovarian hormones is reduced post-menopause and may contribute to cognitive function. The extent to which hormonal effects may be parsed out from other age-related factors to influence cognition is of interest. Middle-aged (12-month-old) female rats that were retired breeders were categorized as maintaining or declining reproductive function based upon their estrous cyclicity (regular 4-5 day cycles), fertility (> 60 % successful pregnancy), and fecundity (>10 pups/litter). Performance in object recognition, Y-maze, water maze, inhibitory avoidance, and contextual-cued fear conditioning was evaluated. Estradiol, progesterone (P(4)), dihydroprogesterone, and 5α-pregnan-3α-ol-20-one (3α,5α-THP) were assessed in medial prefrontal cortex (mPFC) and hippocampus; corticosterone was assessed in plasma. Rats maintaining reproductive function performed significantly better on the object recognition, Y-maze, water maze, inhibitory avoidance, and cued fear conditioning tasks than did rats with declining reproductive function. Steroid concentrations varied greatly within groups. Higher levels of P(4) in mPFC and hippocampus were associated with better Y-maze performance. In mPFC, higher levels of P(4) were associated with poorer inhibitory avoidance performance; greater levels of 3α,5α-THP were associated with better object memory. Neither estradiol nor corticosterone levels significantly contributed to cognitive performance. Thus, the capacity for cortico-limbic P(4) utilization may influence cognitive performance in aging., (Copyright © 2010 Elsevier B.V. All rights reserved.)