Steroid-tacrolimus drug-drug interaction and the effect of CYP3A genotypes.

AIMS: Tacrolimus, metabolized by CYP3A4 and CYP3A5 enzymes, is susceptible to drug-drug interactions (DDI). Steroids induce CYP3A genes to increase tacrolimus clearance, but the effect is variable. We hypothesized that the extent of the steroid-tacrolimus DDI differs by CYP3A4/5 genotypes. METHODS: Kidney transplant recipients (n = 2462) were classified by the number of loss of function alleles (LOF) (CYP3A5*3, *6 and *7 and CYP3A4*22) and steroid use at each tacrolimus trough in the first 6 months post-transplant. A population pharmacokinetic analysis was performed by nonlinear mixed-effect modelling (NONMEM) and stepwise covariate modelling to define significant covariates affecting tacrolimus clearance. A stochastic simulation was performed and translated into a Shiny application with the mrgsolve and Shiny packages in R. RESULTS: Steroids were associated with modestly higher (3%-11.8%) tacrolimus clearance. Patients with 0-LOF alleles receiving steroids showed the greatest increase (11.8%) in clearance compared to no steroids, whereas those with 2-LOFs had a negligible increase (2.6%) in the presence of steroids. Steroid use increased tacrolimus clearance by 5% and 10.3% in patients with 1-LOF and 3/4-LOFs, respectively. CONCLUSIONS: Steroids increase the clearance of tacrolimus but vary slightly by CYP3A genotype. This is important in individuals of African ancestry who are more likely to carry no LOF alleles, may more commonly receive steroid treatment, and will need higher tacrolimus doses.

Effect of Chronic Steroid Use on Postoperative Wound Complications in Patients Undergoing Arterial Bypass Surgery for Lower Extremity Peripheral Arterial Disease.

OBJECTIVE: While existing literature reports adverse effects of chronic steroid use on surgical wound outcomes, there remains lack of data exploring the effect of steroids on postoperative outcomes following lower extremity arterial bypass surgery. This study aims to explore the effect of chronic steroid use on surgical outcomes in patients undergoing open revascularization for lower extremity arterial occlusive disease. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) files between 2005 and 2020, all patients receiving aortoiliac or infrainguinal arterial bypass for peripheral arterial disease (PAD) were identified by Current Procedural Terminology (CPT) codes. Patient characteristics and 30-day outcomes were compared using χ2 test and independent t-test, and association of chronic steroid use with wound complications was studied using multivariable logistic regression analysis. RESULTS: A total of 44,675 patients undergoing open lower extremity revascularization were identified, of which 1,807 patients were on chronic steroids and 42,868 patients were not on chronic steroids. On multivariable logistic regression analysis, being on chronic steroids was associated with higher rates of deep SSI (OR 1.37, 95% CI 1.03-1.83), any SSI (OR 1.22, 95% CI 1.04-1.43) and wound dehiscence (OR 1.42, 95% CI 1.03-1.96). Chronic steroid users also had significantly increased odds of developing sepsis (OR 1.56, 95% CI 1.19-2.04), pneumonia (OR 1.44, 95% CI 1.08-1.91), UTI (OR 1.54, 95% CI 11.13-2.09), DVT (OR 1.60, 95% CI 1.01-2.53), and 30-day readmission (OR 1.30, 95% CI 1.12-1.50), reoperation (OR 1.17, 95% CI 1.01-1.37) and mortality (OR 1.33, 95% CI 1.01-1.76) compared to non-chronic steroid users. CONCLUSION: This study confirms that chronic corticosteroid use is associated with higher risk of surgical site infections (SSIs) in patients undergoing lower extremity arterial bypass surgery. These patients typically have various underlying health issues, emphasizing the need for personalized treatment and management to reduce steroid-related postoperative complications and improve survival.

Presentation and Management of Granulomatous Mastitis in the United States: Results of an American Society of Breast Surgeons Registry Study.

BACKGROUND: Granulomatous mastitis (GM) is a benign, chronic, inflammatory disease lacking clear treatment guidelines. The purpose of this American Society of Breast Surgeons (ASBrS) prospective, multisite registry was to characterize the presentation of GM and identify treatment strategies associated with symptom resolution and optimal cosmesis. METHODS: ASBrS members entered data into a registry on patient demographics, treatment, symptoms, and cosmesis over a 1-year period. Initial symptoms were graded as mild, moderate, or severe. The Chi-square test and logistic regression were used to identify factors related to symptom improvement and cosmesis. RESULTS: Overall, 112 patients with a mean age of 36 years were included. More patients were Hispanic (49.1%) and from the Southwest (41.1%), and management included observation (4.5%), medical (70.5%), surgical (5.4%), or combination treatment (19.6%). Immunosuppression was used in 83 patients (74.1%), including 43 patients who received intralesional steroid injections. Patients with severe symptoms were more likely to undergo surgical intervention compared with those with mild or moderate symptoms (21.4% vs. 0% and 7.5%, respectively; p = 0.004). Within 1 year, 85 patients (75.9%) experienced symptom improvement and/or resolution at a median of 3 months. Receipt of immunosuppressive therapy was predictive of improvement or resolution at 1 month (odds ratio 4.22; p = 0.045). One-year physician-assessed cosmesis was excellent or good for 20/35 patients (57.1%) and was not associated with type of treatment or symptom severity. CONCLUSION: Although GM can have a protracted course, the majority of patients in this registry resolved within 1 year, with good cosmetic result. Treatment with immunosuppression appears to be most beneficial, and a symptom-based algorithm may be helpful to guide treatment.

Guillain-Barre Syndrome as an Atypical Early Presentation of Adult-Onset Still's Disease: A Case Report.

Adult-onset Still's disease (AOSD) is a rare auto-inflammatory disorder with unknown pathophysiology. Although having a heterogeneous clinical spectrum, the major features of AOSD include fever, rash, and arthritis or arthralgia. Neurological involvement is rare in AOSD with aseptic meningitis being the most common presentation. Guillain-Barre syndrome (GBS) has never been reported as an early presentation of AOSD. Herein, we describe the case of a patient presenting with GBS and fever of unknown origin who was soon diagnosed with AOSD and improved with corticosteroid therapy.

Does the use of double hormone replacement therapy for trauma patient organ donors improve organ recovery for transplant.

BACKGROUND: With an ongoing demand for transplantable organs, optimization of donor management protocols, specifically in trauma populations, is important for obtaining a high yield of viable organs per patient. Endocrine management of brain-dead potential organ donors (BPODs) is controversial, leading to heterogeneous clinical management approaches. Previous studies have shown that when levothyroxine was combined with other treatments, including steroids, vasopressin, and insulin, BPODs had better organ recovery and survival outcomes were increased for transplant recipients. AIM: To determine if levothyroxine use in combination with steroids in BPODs increased the number of organs donated in trauma patients. METHODS: A retrospective review of adult BPODs from a single level 1 trauma center over ten years was performed. Exclusion criteria included patients who were not solid organ donors, patients who were not declared brain dead (donation after circulatory death), and patients who did not receive steroids in their hospital course. Levothyroxine and steroid administration, the number of organs donated, the types of organs donated, and demographic information were recorded. Univariate analyses were performed with P < 0.05 considered to be statistically significant. RESULTS: A total of 88 patients met inclusion criteria, 69 (78%) of whom received levothyroxine and steroids (ST/LT group) vs 19 (22%) receiving steroids without levothyroxine (ST group). No differences were observed between the groups for gender, race, pertinent injury factors, age, or other hormone therapies used (P > 0.05). In the ST/LT group, 68.1% (n = 47) donated a high yield (3-5) of organ types per donor compared to 42.1% (n = 8) in the ST group (P = 0.038). There was no difference in the total number of organ types donated between the groups (P = 0.068). CONCLUSION: This study suggests that combining levothyroxine and steroid administration increases high-yield organ donation per donor in BPODs in the trauma patient population. Limitations to this study include the retrospective design and the relatively small number of organ donors who met inclusion criteria. This study is unique in that it mitigates steroid administration as a confounding variable and focuses specifically on the adjunctive use of levothyroxine.

A practical approach to supported liquid extraction and measurement of 18 steroids in plasma and serum by targeted liquid chromatography tandem mass spectrometry.

Chromatography combined with mass spectrometry is a gold standard technique for steroid measurement, however the type of sample preparation, the dynamic range and reliability of the calibration curve, the chromatographic separation and mass spectrometry settings ultimately determine the success of the method. The steroid biosynthetic pathway is conserved in higher mammals and literature demonstrates that the concentration ranges of different steroid groups are relatively comparable across species. We sought to develop a robust and reliable multi steroid targeted analysis method for blood that would have wide application across higher mammals. The method was developed following bioanalytical method validation guidelines to standards typically applied to human clinical studies, including isotopically labelled internal standards where at all possible. Here we describe the practical approach to a 96-well supported liquid extraction (SLE) method of extraction from plasma (200 µL) using an Extrahera liquid handling robot (Biotage, Sweden), including quality control samples, followed by a comprehensive separation and targeted LC-MS/MS analysis of 18 steroids in plasma (pregnenolone, progesterone, 17α-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, 11-dehydrocorticosterone, aldosterone, 11-deoxycortisol, 21-deoxycortisol, cortisol, cortisone, androstenedione, testosterone, 5α-dihydrotestosterone, dehydroepiandrosterone, estrone, 17ß-estradiol and estriol). •SLE in a 96-well format of up to 74 biological plasma samples, enriched with multiple isotopically labelled internal standards, a 12-point aqueous calibration curve, and 6 serum quality controls, designed to monitor long-term performance of the method•Chromatographic separation of multiple steroids along the gradient, with ammonium fluoride mobile phase additive to improve sensitivity, followed by electrospray ionisation and constant polarity switching•Aqueous calibration standards that cover physiologically relevant ranges - high nanomolar glucocorticoids, low nanomolar androgens and picomolar ranges for estrogens and steroid intermediates.

Hypothalamus-pituitary-adrenal axis (HPA axis) suppression with inappropriate use of steroids in recalcitrant dermatophytosis - A cross-sectional study.

Background: Improper use of over-the-counter (OTC) steroid medication has been linked to recalcitrant dermatophytosis. There is proven evidence of HPA axis suppression by the use of long-term oral steroids. This study aims to determine the prevalence and pattern of inappropriate OTC steroid use and its effects on the hypothalamus-pituitary-adrenal (HPA) axis in adults with recalcitrant dermatophytosis. Materials and Methods: This cross-sectional study of 2 months was conducted in a hospital setting and included patients of recalcitrant dermatophytosis with a history of OTC steroid use. Clinico-demographic details and basal serum cortisol levels were recorded in all and analyzed. Result: Of a total of 103 patients, 59.22% (n = 61/103) were males, and the mean duration of steroid abuse was 17.78 months. About 48.54% (n = 50/103), 3.88% (n = 4/103), and 47.57% (n = 49/103) patients reported the use of topical steroids, oral steroids, and both oral and topical steroids, respectively. Among all the topical steroid users (n = 99), clobetasol propionate 48.48% (n = 48/99), while among oral steroid users (n = 53), prednisolone 45.28% (n = 24/53) were the most commonly used agents, respectively. The morning serum cortisol levels (8-9 AM) were found to be decreased in 42.7% (n = 44/103), with a mean value of 44.28 ± 17.34 µg/dL. Conclusion: Improper OTC steroid use in recalcitrant dermatophytosis leads to HPA axis suppression. This highlights the need for intervention from apex health officials.

How international guidelines recommend treating children who have severe COVID-19 or risk disease progression.

AIM: This study reviewed the current knowledge and guidelines on managing COVID-19 in children and proposed a practical approach to drug treatment. METHODS: We analysed international guidelines from four prominent scientific bodies on treating COVID-19 in children. These were the UK National Institute for Health and Care Excellence, the American National Institutes of Health, the Infectious Diseases Society of America and the Australian National Clinical Evidence Taskforce COVID-19. RESULTS: Most paediatric patients with COVID-19 only require symptomatic treatment. There was limited evidence on treatment recommendations for children with severe COVID-19 or at risk of disease progression. However, several drugs are available for children and we have summarised the guidelines, in order to provide a concise, practical format for clinicians. All the guidelines agree that nirmatrelvir plus ritonavir or remdesivir can be used as prophylaxis for severe COVID-19 in high-risk patients. Remdesivir can also be used for severe COVID-19 cases. Glucocorticosteroids are recommended, particularly in patients requiring oxygen therapy. Tocilizumab or baricitinib should be reserved for patients with progressive disease and/or signs of systemic inflammation. CONCLUSION: The guidelines provide useful advice and a degree of consensus on specific drug treatment for children with severe COVID-19 or at risk of progression.

Cranial hypertrophic pachymeningitis with myelodysplastic syndrome.

Hypertrophic pachymeningitis (HP) is a rare inflammatory disease characterized by thickening of the dura mater. HP develops with several inflammatory diseases. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and IgG4 related disease are reported as 2 major causes. With hematologic diseases, only 3 cases have been reported. We report the case of myelodysplastic syndrome (MDS) developing HP. Our case provides a thought-provoking hypothesis regarding the potential relationship between MDS and HP.

Is endocrine surveillance important in the care of Duchenne Muscular Dystrophy? Results from a national survey to patients and families on endocrine complications.

Glucocorticoids are standard of care for patients with Duchenne muscular dystrophy (DMD). Although prolonged exposure is associated with multiple endocrine side effects, current guidelines related to monitoring and management of endocrinopathies are suboptimal. We aim to explore community perceptions of endocrine related complications in patients with DMD, assess current level of understanding, and desire for further education. A 31-item online survey was sent through Parent Project to Muscular Dystrophy (PPMD) to Duchenne Registry members to be completed by patients or their caretakers. Response rate was 55% (n = 75). Steroids were taken by 93%, but only 50% were followed by endocrinology and 21% report never been seen by endocrinology. Bone health was discussed with 87% of patients and 60% were diagnosed with osteoporosis. Delayed puberty was discussed with 41% of patients with 23% receiving testosterone therapy. About half the patients reported a diagnosis of slowed growth. Only 51% of the participants recalled discussing adrenal insufficiency. Obesity was discussed with 59% of participants. Families felt education about steroid-induced endocrinopathies to be very or extremely important and prefer to discuss about this at the beginning of their steroid therapy. This demonstrates significant gaps in education and access to endocrine care in patients with DMD.

Illegal Use of Testosterone and Other Anabolic-Androgenic Steroids in the Population of Amateur Athletes in Wroclaw, Poland-An Unfavorable Lifestyle Trend in the Population of Men of Reproductive Age.

Background: One factor that may negatively impact male reproductive health is the illegal use of testosterone and anabolic-androgenic steroids. This study aimed to evaluate the prevalence of testosterone use in recreational athletes, as well as factors associated with its use, and to determine the profile of a person using testosterone. Methods: A cross-sectional analysis of data from an anonymous, online questionnaire of men recruited from gyms, randomly selected in Wroclaw, Poland, has been performed. The minimal sample size was evaluated with the univariate logistic regression model. The association between testosterone use and other factors was also evaluated with the univariate logistic regression model. Results: A total of 35% of respondents used testosterone. The main purposes of testosterone use were the improvement of training effects and the improvement of body shape. The respondents most likely to use testosterone and other anabolic-androgenic steroids were men aged 26-35, whose earnings were at the level of the middle class or higher, who were married, had children, had training experience of at least 6 months, exercised at least once a week, took part in weightlifting competitions, were managers in a corporation or enterprise, or were self-employed. Most of the people using testosterone had self-treated side effects. Conclusions: The profile of the person most likely to use testosterone corresponds to the characteristics of men in optimal socio-demographic conditions for reproduction. These results indicate that this is a significant social problem that may impact male reproductive health.

Association between Disgust Sensitivity during Pregnancy and Endogenous Steroids: A Longitudinal Study.

The emotion of disgust protects individuals against pathogens, and it has been found to be elevated during pregnancy. Physiological mechanisms discussed in relation to these changes include immune markers and progesterone levels. This study aimed to assess the association between steroids and disgust sensitivity in pregnancy. Using a prospective longitudinal design, we analyzed blood serum steroid concentrations and measured disgust sensitivity via text-based questionnaires in a sample of 179 pregnant women during their first and third trimesters. We found positive correlations between disgust sensitivity and the levels of C19 steroids (including testosterone) and its precursors in the Δ5 pathway (androstenediol, DHEA, and their sulfates) and the Δ4 pathway (androstenedione). Additionally, positive correlations were observed with 5α/ß-reduced C19 steroid metabolites in both trimesters. In the first trimester, disgust sensitivity was positively associated with 17-hydroxypregnanolone and with some estrogens. In the third trimester, positive associations were observed with cortisol and immunoprotective Δ5 C19 7α/ß-hydroxy-steroids. Our findings show that disgust sensitivity is positively correlated with immunomodulatory steroids, and in the third trimester, with steroids which may be related to potential maternal-anxiety-related symptoms. This study highlights the complex relationship between hormonal changes and disgust sensitivity during pregnancy.

Baricitinib and Pulse Steroids Combination Treatment in Hyperinflammatory COVID-19: A Rheumatological Approach in the Intensive Care Unit.

Hyperinflammatory Coronavirus disease 2019 (COVID-19) and rapidly-progressive interstitial lung diseases (RP-ILD) secondary to inflammatory myopathies (IIM) present important similarities. These data support the use of anti-rheumatic drugs for the treatment of COVID-19. The aim of this study was to compare the efficacy of combining baricitinib and pulse steroids with the Standard of Care (SoC) for the treatment of critically ill COVID-19 patients. We retrospectively enrolled consecutive patients admitted to the Intensive Care Unit (ICU) with COVID-19-pneumonia. Patients treated with SoC (dexamethasone plus remdesivir) were compared to patients treated with baricitinib plus 6-methylprednisolone pulses (Rheuma-group). We enrolled 246 patients: 104/246 in the SoC and 142/246 in the Rheuma-group. All patients presented laboratory findings suggestive of hyperinflammatory response. Sixty-four patients (26.1%) died during ICU hospitalization. The mortality rate in the Rheuma-group was significantly lower than in the SoC-group (15.5 vs. 40.4%, p < 0.001). Compared to the SoC-group, patients in the Rheuma-group presented significantly lower inflammatory biomarker levels after one week of treatment. Higher ferritin levels after one week of treatment were strongly associated with mortality (p < 0.001). In this large real-life COVID-19 cohort, baricitinib and pulse steroids led to a significant reduction in mortality, paralleled by a prompt reduction in inflammatory biomarkers. Our experience supports the similarities between hyperinflammatory COVID-19 and the IIM-associated RP-ILD.

Assessing the prevalence and knowledge of anabolic steroid use in male athletes in Al Madina Al Munawara, Saudi Arabia.

OBJECTIVES: To assess the prevalence of anabolic steroid use and the level of knowledge on anabolic steroids among the male athletes in Al Madina Al Munawara, Saudi Arabia. METHODS: A cross-sectional study was conducted on male athletes randomly selected from the private athletic centers in Al Madina Al Munawara over 5 months. Data were collected from all participants using a self-administered anonymous questionnaire with 33 questions. The questionnaire covered the socio-demographic characteristics of the participants, and their knowledge, attitudes, and use of anabolic steroids. RESULTS: Of the 150 male athletes surveyed, 121 completed the questionnaire (response rate: 80.6%). Over half were aged between 18 and 23 years (56.2%) and were single (79.3%). Thirty-two percent reported using anabolic steroids, mainly to increase muscle mass, following coaches' advice (46.1%). Key sources included the internet (30.7%), coaches (30%), and friends (27.9%), and non-healthcare professionals. The top motivations were price, coach's/physician's advice, and availability. The perceived benefits included increased muscle mass, strength, and endurance, while the perceived adverse effects included kidney/liver damage and sexual problems. CONCLUSION: One-third of the male athletes surveyed used anabolic steroids, influenced by accessibility and social contact, rather than healthcare guidance. This highlights the need for greater awareness of the long-term health risks, ideally through education provided by sports medicine specialists.

Insights into adjunctive corticosteroid therapy in fulminant herpes simplex virus encephalitis: case analysis with contrasting outcomes.

Herpes simplex virus (HSV) encephalitis, predominantly caused by HSV-1, presents with significant morbidity and mortality challenges. This research investigates the particular role of adjunctive corticosteroid therapy in fulminant HSV encephalitis through in-depth analyses of two contrasting cases. Corticosteroids show potential benefits to improve an exaggerated immune response and limit viral dissemination within the brain. Daily assessments and frequent neuroimaging, particularly using magnetic resonance imaging, aid in the management of fulminant cases. Although existing evidence relies on limited case series and retrospective comparisons, the results of the present study emphasize the necessity for large-scale controlled trials to establish definitive guidelines. The discretion of the treating neurologist governs the decision to implement corticosteroids, emphasizing the imperative need for continued research and evidence-based strategies for this challenging neurological condition.

Recurrent Oral Ulcers: Are They Horses or Zebras?

Oral ulcers are one of the most common complaints seen by general practitioners in their offices. Recurrent aphthous stomatitis affects roughly 20% of the general population. When ulcers persist despite conventional treatment, it is crucial to consider systemic diseases such as Behçet's disease to prevent delays in care. Early recognition and appropriate management of underlying conditions are essential for improving patient outcomes and quality of life. We present a case of a 41-year-old Scottish male who came in with complaints of recurrent oral ulcers and oral thrush. Initial treatment by an infectious disease specialist resolved the oral thrush but not the ulcers. Despite further treatment attempts for three years, including biopsy and antiviral therapy, ulcers persisted. Finally, referral to rheumatology led to comprehensive autoimmune testing, revealing positive HLA B51 and a diagnosis of Behçet's disease. Treatment with topical steroids and colchicine yielded significant improvement.

Rhegmatogenous Retinal Detachment in Anterior Scleritis With Ulcerative Colitis.

Rhegmatogenous retinal detachment (RRD) is an ocular emergency as it is sight-threatening and requires urgent surgical intervention. Ulcerative colitis (UC) is an immune-mediated inflammatory bowel disease that can present with ocular manifestations. The objective of this case report is to share the rare presentation of RRD associated with UC leading to diagnosis and management dilemmas. A 35-year-old man with active UC presented with a right chronic red eye for two months. The best corrected visual acuity (BCVA) was 6/6 in both eyes (OU). On examination, sectoral inferotemporal anterior scleritis (AS) with subclinical inferior RRD with peripheral holes in the lattice at the 6 o'clock position was noted. There was no posterior vitreous detachment. Optical coherence tomography (OCT) delineated the RRD objectively and was non-progressive for nine months. Barricade laser was given, in addition to intravenous methylprednisolone (IVMP), followed by a tapering dose of oral prednisolone and topical dexamethasone 0.1% over three months. Over a year, the scleritis resolved. However, six months later, while still on immunomodulating agents, the inferior RRD progressed on OCT. Segmental scleral buckle, indirect laser retinopexy, and subtenon triamcinolone injection were performed. IVMP 1 g per day was given for three days prior to surgery. Two months later, his BCVA was 6/6, with signs of fluid resorption and normal intraocular pressure. No recurrent AS was seen. Treatment of non-progressive, subclinical RRD patients with UC and active AS can be delayed with regular follow-up. When RRD progressed and there was no AS activity, it was the window of opportunity for the success of scleral buckle and perioperative steroids.

Direct measurements of neurosteroid binding to specific sites on GABAA receptors.

BACKGROUND AND PURPOSE: Neurosteroids are allosteric modulators of GABAA currents, acting through several functional binding sites although their affinity and specificity for each site are unknown. The goal of this study was to measure steady-state binding affinities of various neurosteroids for specific sites on the GABAA receptor. EXPERIMENTAL APPROACH: Two methods were developed to measure neurosteroid binding affinity: (1) quenching of specific tryptophan residues in neurosteroid binding sites by the neurosteroid 17-methylketone group, and (2) FRET between MQ290 (an intrinsically fluorescent neurosteroid) and tryptophan residues in the binding sites. The assays were developed using ELIC-α1GABAAR, a chimeric receptor containing transmembrane domains of the α1-GABAA receptor. Tryptophan mutagenesis was used to identify specific interactions. KEY RESULTS: Allopregnanolone (3α-OH neurosteroid) was shown to bind at intersubunit and intrasubunit sites with equal affinity, whereas epi-allopregnanolone (3ß-OH neurosteroid) binds at the intrasubunit site. MQ290 formed a strong FRET pair with W246, acting as a site-specific probe for the intersubunit site. The affinity and site-specificity of several neurosteroid agonists and inverse agonists was measured using the MQ290 binding assay. The FRET assay distinguishes between competitive and allosteric inhibition of MQ290 binding and demonstrated an allosteric interaction between the two neurosteroid binding sites. CONCLUSIONS AND IMPLICATIONS: The affinity and specificity of neurosteroid binding to two sites in the ELIC-α1GABAAR were directly measured and an allosteric interaction between the sites was revealed. Adaptation of the MQ290 FRET assay to a plate-reader format will enable screening for high affinity agonists and antagonists for neurosteroid binding sites.

Reproductive function and behaviors: an update on the role of neural estrogen receptors alpha and beta.

Infertility is becoming a major public health problem, with increasing frequency due to medical, environmental and societal causes. The increasingly late age of childbearing, growing exposure to endocrine disruptors and other reprotoxic products, and increasing number of medical reproductive dysfunctions (endometriosis, polycystic ovary syndrome, etc.) are among the most common causes. Fertility relies on fine-tuned control of both neuroendocrine function and reproductive behaviors, those are critically regulated by sex steroid hormones. Testosterone and estradiol exert organizational and activational effects throughout life to establish and activate the neural circuits underlying reproductive function. This regulation is mediated through estrogen receptors (ERs) and androgen receptor (AR). Estradiol acts mainly via nuclear estrogen receptors ERα and ERß. The aim of this review is to summarize the genetic studies that have been undertaken to comprehend the specific contribution of ERα and ERß in the neural circuits underlying the regulation of the hypothalamic-pituitary-gonadal axis and the expression of reproductive behaviors, including sexual and parental behavior. Particular emphasis will be placed on the neural role of these receptors and the underlying sex differences.