Hormonal Treatments and Vaginal Moisturizers for Genitourinary Syndrome of Menopause : A Systematic Review.

BACKGROUND: Postmenopausal women commonly experience vulvovaginal, urinary, and sexual symptoms associated with genitourinary syndrome of menopause (GSM). PURPOSE: To evaluate effectiveness and harms of vaginal estrogen, nonestrogen hormone therapies, and vaginal moisturizers for treatment of GSM symptoms. DATA SOURCES: Medline, Embase, and CINAHL through 11 December 2023. STUDY SELECTION: Randomized controlled trials (RCTs) of at least 8 weeks' duration enrolling postmenopausal women with at least 1 GSM symptom and reporting effectiveness or harms of hormonal interventions or vaginal moisturizers. DATA EXTRACTION: Risk of bias and data extraction were performed by one reviewer and verified by a second reviewer. Certainty of evidence (COE) was assessed by one reviewer and verified by consensus. DATA SYNTHESIS: From 11 993 citations, 46 RCTs evaluating vaginal estrogen (k = 22), nonestrogen hormones (k = 16), vaginal moisturizers (k = 4), or multiple interventions (k = 4) were identified. Variation in populations, interventions, comparators, and outcomes precluded meta-analysis. Compared with placebo or no treatment, vaginal estrogen may improve vulvovaginal dryness, dyspareunia, most bothersome symptom, and treatment satisfaction. Compared with placebo, vaginal dehydroepiandrosterone (DHEA) may improve dryness, dyspareunia, and distress, bother, or interference from genitourinary symptoms; oral ospemifene may improve dryness, dyspareunia, and treatment satisfaction; and vaginal moisturizers may improve dryness (all low COE). Vaginal testosterone, systemic DHEA, vaginal oxytocin, and oral raloxifene or bazedoxifene may provide no benefit (low COE) or had uncertain effects (very low COE). Although studies did not report frequent serious harms, reporting was limited by short-duration studies that were insufficiently powered to evaluate infrequent serious harms. LIMITATIONS: Most studies were 12 weeks or less in duration and used heterogeneous GSM diagnostic criteria and outcome measures. Few studies enrolled women with a history of cancer. CONCLUSION: Vaginal estrogen, vaginal DHEA, oral ospemifene, and vaginal moisturizers may improve some GSM symptoms in the short term. Few long-term data exist on efficacy, comparative effectiveness, tolerability, and safety of GSM treatments. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality and Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42023400684).

The beneficial role of the synthetic microneurotrophin BNN20 in a focal demyelination model.

BNN20, a C17-spiroepoxy derivative of the neurosteroid dehydroepiandrosterone, has been shown to exhibit strong neuroprotective properties but its role in glial populations has not been assessed. Our aim was to investigate the effect of BNN20 on glial populations by using in vitro and in vivo approaches, taking advantage of the well-established lysophosphatidylcholine (LPC)-induced focal demyelination mouse model. Our in vivo studies, performed in male mice, showed that BNN20 treatment leads to an increased number of mature oligodendrocytes (OLs) in this model. It diminishes astrocytic accumulation during the demyelination phase leading to a faster remyelination process, while it does not affect oligodendrocyte precursor cell recruitment or microglia/macrophage accumulation. Additionally, our in vitro studies showed that BNN20 acts directly to OLs and enhances their maturation even after they were treated with LPC. This beneficial effect of BNN20 is mediated, primarily, through the neurotrophin receptor TrkA. In addition, BNN20 reduces microglial activation and their transition to their pro-inflammatory state upon lipopolysaccharides stimulation in vitro. Taken together our results suggest that BNN20 could serve as an important molecule to develop blood-brain barrier-permeable synthetic agonists of neurotrophin receptors that could reduce inflammation, protect and increase the number of functional OLs by promoting their differentiation/maturation.

Management of postmenopausal vulvovaginal atrophy: recommendations of the International Society for the Study of Vulvovaginal Disease.

OBJECTIVE: To develop a best practice document for the management of postmenopausal vulvovaginal atrophy (VVA). METHOD: Literature review carried out using clinical terms, treatments or interventions and comorbidity related to VVA. RESULTS: There is a wide variety of interventions that may produce temporal benefits for VVA. However, there are significant limitations in scientific publications concerning VVA and related issues, including variable outcome evaluations, variability in population age range, and small, often underpowered sample sizes. Therapeutic management of VVA should follow a sequential order, considering women's age, symptoms, general health as well as treatment preference. Beneficial options include lubricants, moisturizers, vaginal estrogens (estradiol, estriol, promestriene, conjugated estrogens), androgens, prasterone, and laser application. In women with general menopausal symptoms who are candidates for systemic hormone therapy, the lowest effective dose should be used. Oral ospemifene is an effective selective estrogen receptor modulator to treat VVA. Systemic androgens have a limited role. Although laser procedures are commonly used, at this moment the International Society for the Study of Vulvovaginal Disease does not endorse its use out of the setting of clinical trials. Pelvic floor muscle training improves blood flow and elasticity of the vulvovaginal tissue. In breast cancer survivors, moisturizers and lubricants are first line therapy. However, limited absorption of low/ultra-low doses of estrogens suggests safety, especially in women under treatment with aromatase inhibitors. As clinical practice and available preparations vary between countries this text should be adapted to local circumstances. CONCLUSIONS: There is a wide range of therapeutic options to individualize VVA treatments.

Premature ovarian insufficiency - novel hormonal approaches in optimizing fertility.

Premature ovarian insufficiency (POI) is a delicate medical problem in young women. This condition is not unchangeable and permanent but is associated with intermittent and unpredictable ovarian activity, resulting in low conception rate. Over the period of 8 years, the evaluation of secondary amenorrhea was conducted in 90 patients below the age of 40 who wished to restore fertility. Having confirmed the diagnosis and investigated the etiology of POI, hormone replacement therapy was applied (sequential administration of estradiol and norethisterone acetate) in the first 30 patients (group A). Estrogen-progestogen therapy with daily supplementation of 25 mg of micronized oral dehydroepiandrosterone (DHEA) was conducted in 44 patients (group B), whereas a combined regime (estrogen-progestogen therapy, DHEA supplementation in daily dose of 25 mg, and melatonin supplementation in daily dose of 3 mg) was conducted in 16 patients (group C). In the course of our study, 16 pregnancies were realized (18% of all cases: 17% in group A; 18% in group B; 19% in group C) 6 to 20 months after the initiation of hormone therapy, and there have been 13 completed term pregnancies so far with normal fetal growth and development. We concluded that estrogen-progestogen therapy combined with DHEA and melatonin could optimize fertility and lead to successful pregnancy in POI patients.

Does Dehydroepiandrosterone (DHEA) improve in vitro fertilisation (IVF) outcomes in poor responders?

BACKGROUND: In reproductive medicine poor ovarian response (POR) among women undergoing in vitro fertilisation (IVF) is of great concern. Meta-analysis showed that Dehydroepiandrosterone (DHEA) administration resulted in a significant increase in the number of oocytes retrieved in women with POR. The aim of this study was to assess the effectiveness of DHEA supplementation on IVF outcomes among poor responders undergoing IVF. METHODS: Sixteen patients who were diagnosed with POR scheduled to undergo their second cycle of Intracytoplasmic sperm injection (ICSI)/embryo transfer cycle were enrolled. All enrolled patients had earlier undergone their first ICSI/embryo transfer cycle at least four months prior to this study. All subjects were given DHEA supplementation of 25mg three times daily for at least three months prior to their second ICSI/embryo transfer cycle. Statistical analysis of various ovarian response and ICSI outcomes parameter were compared pre and post DHEA. RESULTS: Sixteen women with the mean age of 35 years were enrolled in the study. The comparative analysis of results showed a significant increase in the number of good quality of embryos obtained (p<0.05). After the treatment with DHEA, there was an improvement in the number of oocytes retrieved, Metaphase II (MII) oocyte (mature) oocytes obtained, fertilised and transferrable embryos and the pregnancy rate. There was no significant effect of DHEA treatment on the number of days of stimulation and cumulative dose of gonadotrophins used. CONCLUSION: Our results is able to show that DHEA supplementation may help to enhance IVF-ICSI outcomes in women with POR especially in those age 35 years and below.

Phase II Study of Dehydroepiandrosterone in Androgen Receptor-Positive Metastatic Breast Cancer.

LESSONS LEARNED: The androgen receptor (AR) is present in most breast cancers (BC), but its exploitation as a therapeutic target has been limited.This study explored the activity of dehydroepiandrosterone (DHEA), a precursor being transformed into androgens within BC cells, in combination with an aromatase inhibitor (to block DHEA conversion into estrogens), in a two-stage phase II study in patients with AR-positive/estrogen receptor-positive/human epidermal growth receptor 2-negative metastatic BC.Although well tolerated, only 1 of 12 patients obtained a prolonged clinical benefit, and the study was closed after its first stage for poor activity. BACKGROUND: Androgen receptors (AR) are expressed in most breast cancers, and AR-agonists have some activity in these neoplasms. We investigated the safety and activity of the androgen precursor dehydroepiandrosterone (DHEA) in combination with an aromatase inhibitor (AI) in patients with AR-positive metastatic breast cancer (MBC). METHODS: A two-stage phase II study was conducted in two patient cohorts, one with estrogen receptor (ER)-positive (resistant to AIs) and the other with triple-negative MBC. DHEA 100 mg/day was administered orally. The combination with an AI aimed to prevent the conversion of DHEA into estrogens. The main endpoint was the clinical benefit rate. The triple-negative cohort was closed early. RESULTS: Twelve patients with ER-positive MBC were enrolled. DHEA-related adverse events, reported in four patients, included grade 2 fatigue, erythema, and transaminitis, and grade 1 drowsiness and musculoskeletal pain. Clinical benefit was observed in one patient with ER-positive disease whose tumor had AR gene amplification. There was wide inter- and intra-patient variation in serum levels of DHEA and its metabolites. CONCLUSION: DHEA showed excellent safety but poor activity in MBC. Although dose and patient selection could be improved, high serum level variability may hamper further DHEA development in this setting.

Effect of topical administration of the microneurotrophin BNN27 in the diabetic rat retina.

PURPOSE: Diabetic retinopathy (DR) is a complex eye disease associated with diabetes mellitus. It is characterized by three pathophysiological components, namely microangiopathy, neurodegeneration, and inflammation. We recently reported that intraperitoneal administration of BNN27, a novel neurosteroidal microneurotrophin, reversed the diabetes-induced neurodegeneration and inflammation in rats treated with streptozotocin (STZ), by activating the NGF TrkA and p75 receptors. The aim of the present study was to investigate the efficacy of BNN27 to protect retinal neurons when applied topically as eye drops in the same model. METHODS: The STZ rat model of DR was employed. BNN27 was administered as eye drops to diabetic Sprague-Dawley rats for 7 days, 4 weeks post-STZ (70 mg/kg) injection. Immunohistochemistry and western blot analyses were employed to examine the viability of retinal neurons in control, diabetic, and diabetic-treated animals and the involvement of the TrkA receptor and its downstream signaling ERK1/2 kinases, respectively. RESULTS: BNN27 reversed the STZ-induced attenuation of the immunoreactive brain nitric oxide synthetase (bNOS)- and tyrosine hydroxylase (TH)-expressing amacrine cells and neurofilament (NFL)-expressing ganglion cell axons in a dose-dependent manner. In addition, BNN27 activated/phosphorylated the TrkA receptor and its downstream prosurvival signaling pathway, ERK1/2 kinases. CONCLUSIONS: The results of this study provide solid evidence regarding the efficacy of BNN27 as a neuroprotectant to the diabetic retina when administered topically, and suggest that its pharmacodynamic and pharmacokinetic profiles render it a putative therapeutic for diabetic retinopathy.

Inulin and metformin ameliorate polycystic ovary syndrome via anti-inflammation and modulating gut microbiota in mice.

Polycystic ovary syndrome (PCOS) represents an endocrine disorder, which is closely related with gut microbiota. Inulin, a kind of probiotics, has been proven to alleviate gut microbiota dysbiosis. Metformin, a biguanide agent, shows beneficial effects on chronic metabolic diseases. Our objective was to assess the effects and associated mechanisms of inulin and metforin on attenuation of PCOS in mice. Mice were divided into 4 groups: control group (CON), model group (MOD), inulin group (INU), metformin group (MET). The last three groups were fed 6 mg of dehydroepiandrosterone (DHEA) per 100 g body weight and 60% high-fat diet to generate mice model. After 21 days of intervention, mice were euthanized and associated indications were investigated. Body weight (BW) and testosterone (T) levels were significantly decreased, but estradiol (E2) levels were increased in INU or MET group, respectively. Ovary HE staining demonstrated that inulin or metformin ameliorated PCOS morphology. Inflammatory indicators from plasma and ovary including TNF-α, IL-6, and IL-17A were decreased in INU or MET group. Moreover, IL-10 in ovary of INU or MET group was increased. Sequencing and analysis of gut microbiota showed that compared to MOD group, Bifidobacterium was increased, but Proteobacteria, Helicobacter and Parasutterella were decreased in INU group. Helicobacter was decreased in MET group. Correlation analysis showed that gut microbiota was correlated with inflammatory factors. Our results revealed that inulin and metformin alleviated PCOS via anti-inflammation and modulating gut microbiota, which may contribute to potential clinical therapy for the disease.

Oral dehydroepiandrosterone restores ß-endorphin response to OGTT in early and late postmenopause.

ß-endorphin is a neuropeptide involved in several brain functions: its plasma levels are higher in obese women and its release increases after oral glucose tolerance test (OGTT) in normal or obese women. The study included 46 healthy women and evaluated the effect of oral dehydroepiandrosterone [DHEA] (50 mg/day) in early postmenopausal women (50-55 years) both of normal weight (group A, n = 12, BMI = 22.1 ± 0.5) and overweight (group B, n = 12, BMI = 28.2 ± 0.5), and late postmenopausal women (60-65 years) both normal weight (group C, n = 11, BMI = 22.5 ± 0.6) and overweight (group D, n = 11, BMI = 27.9 ± 0.4) undergone OGTT, in order to investigate if DHEA could restore/modify the control of insulin and glucose secretion and ß-endorphin release in response to glucose load. The area under the curve (AUC) of OGTT evaluated plasma levels of different molecules. DHEA, DHEAS, and ß-endorphin plasma levels were lower in baseline conditions in older women than younger women. Considering the AUC of ß-endorphin response to OGTT, all groups showed a progressive significant increase after 3 and also after 6 months of treatment in comparison to baseline and 3 months of treatment.

ERß-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid.

Multiple sclerosis (MS), an autoimmune disease of the CNS, is mediated by autoreactive Th cells. A previous study showed that the neurosteroid dehydroepiandrosterone (DHEA), when administered preclinically, could suppress progression of relapsing-remitting experimental autoimmune encephalomyelitis (EAE). However, the effects of DHEA on human or murine pathogenic immune cells, such as Th17, were unknown. In addition, effects of this neurosteroid on symptomatic disease, as well as the receptors involved, had not been investigated. In this study, we show that DHEA suppressed peripheral responses from patients with MS and reversed established paralysis and CNS inflammation in four different EAE models, including the 2D2 TCR-transgenic mouse model. DHEA directly inhibited human and murine Th17 cells, inducing IL-10-producing regulatory T cells. Administration of DHEA in symptomatic mice induced regulatory CD4(+) T cells that were suppressive in an IL-10-dependent manner. Expression of the estrogen receptor ß by CD4(+) T cells was necessary for DHEA-mediated EAE amelioration, as well as for direct downregulation of Th17 responses. TGF-ß1 as well as aryl hydrocarbon receptor activation was necessary for the expansion of IL-10-producing T cells by DHEA. Thus, our studies demonstrate that compounds that inhibit pathogenic Th17 responses and expand functional regulatory cells could serve as therapeutic agents for autoimmune diseases, such as MS.

Systemic and local effects of vaginal dehydroepiandrosterone (DHEA): NCCTG N10C1 (Alliance).

BACKGROUND: Dehydroepiandrosterone (DHEA) is helpful for treating vaginal symptoms. This secondary analysis evaluated the impact of vaginal DHEA on hormone concentrations, bone turnover, and vaginal cytology in women with a cancer history. METHODS: Postmenopausal women, diagnosed with breast or gynecologic cancer, were eligible if they reported at least moderate vaginal symptoms. Participants could be on tamoxifen or aromatase inhibitors (AIs). Women were randomized to 3.25 versus 6.5 mg/day of DHEA versus a plain moisturizer (PM) control. Sex steroid hormone levels, biomarkers of bone formation, vaginal pH, and maturation index were collected at baseline and 12 weeks. Analysis included independent t tests and Wilcoxon rank tests, comparing each DHEA arm with the control. RESULTS: Three hundred forty-five women contributed evaluable blood and 46 contributed evaluable cytology and pH values. Circulating DHEA-S and testosterone levels were significantly increased in those on vaginal DHEA in a dose-dependent manner compared to PM. Estradiol was significantly increased in those on 6.5 mg/day DHEA but not in those on 3.25 mg/day DHEA (p < 0.05 and p = 0.05, respectively), and not in those on AIs. Biomarkers of bone formation were unchanged in all arms. Maturation of vaginal cells was 100% (3.25 mg/day), 86% (6.5 mg/day), and 64% (PM); pH decreased more in DHEA arms. CONCLUSION: DHEA resulted in increased hormone concentrations, though still in the lowest half or quartile of the postmenopausal range, and provided more favorable effects on vaginal cytology, compared to PM. Estrogen concentrations in women on AIs were not changed. Further research on the benefit of vaginal DHEA is warranted in hormone-dependent cancers.

Dehydroepiandrosterone supplementation combined with Weight-Loading Whole-Body Vibration Training (WWBV) affects exercise performance and muscle glycogen storage in middle-aged C57BL/6 mice.

Background: Adequate nutritional intake and an optimal training program are important elements of any strategy to preserve or increase muscle mass and strength during aging. Purpose: In the current study, we investigate the effects of Dehydroepiandrosterone (DHEA), one of the most abundant circulating steroids in humans and a precursor hormone, supplementation combined with a weight-loading whole-body vibration (WWBV) on exercise performance, physical fatigue-related biochemical responses and testosterone content in middle-aged 9 months old C57BL/6 mice. Methods: Male middle-aged C57BL/6 mice were divided into 3 groups (n = 8 per group) and treated for 4 weeks with the following: 1) Sedentary control (SC) with vehicle 2) DHEA supplementation (DHEA, 10.2 mg/kg) and 3) DHEA supplementation with WWBV training (DHEA: 10.2 mg/kg; WBV: 5.6 Hz, 2 mm, 0.13 g). Exercise performance was evaluated by forelimb grip strength and time to exhaustion, as well as changes in body composition and anti-fatigue levels after a 15-min swimming exercise. Fatigue-related biochemical responses of serum lactate, ammonia, glucose, creatine kinase (CK), and blood urea nitrogen (BUN) were measured following the swimming exercise. In addition, the biochemical parameters and the testosterone levels were measured at the end of the experiment. Results: DHEA supplementation combined with WWBV training for 4 weeks significantly decreased the amount of white adipose tissue and increased the food and water intake. Additionally, WWBV+DHEA supplementation improved exercise performance, testosterone levels and glycogen contents of both liver and muscle. WWBV+DHEA supplementation also decreased serum lactate, ammonia and BUN levels, while increasing glucose levels following the 15-min swim test. Conclusion: Taken together, our results suggest that combining the WWBV training program with DHEA supplementation could provide an anti-fatigue pharmacological effect for elderly populations.

Female rats are more susceptible to metabolic effects of dehydroepiandrosterone treatment.

Dehydroepiandrosterone (DHEA) is a steroid hormone that presents several effects on metabolism; however, most of the studies have been performed on male animals, while few authors have investigated possible sex differences regarding the metabolic effects of DHEA. Therefore, the aim of this study was to evaluate the effect of different doses of DHEA on metabolic parameters of male and ovariectomized female Wistar rats. Sex differences were found in the metabolism of distinct substrates and in relation to the effect of DHEA. In respect to the glucose metabolism in the liver, the conversion of glucose to CO2 and the synthesis of lipids from glucose were 53% and 33% higher, respectively, in males. Also, DHEA decreased hepatic lipogenesis only in females. Regarding the hepatic glycogen synthesis pathway, females presented 73% higher synthesis than males, and the effect of DHEA was observed only in females, where it decreased this parameter. In the adipose tissue, glucose uptake was 208% higher in females and DHEA decreased this parameter. In the muscle, glucose uptake was 168% higher in females and no DHEA effect was observed. In summary, males and females present a different metabolic profile, with females being more susceptible to the metabolic effects of DHEA.

Efficacy of dehydroepiandrosterone (DHEA) supplementation for in vitro fertilization and embryo transfer cycles: a systematic review and meta-analysis.

Dehydroepiandrosterone (DHEA) supplementation might hold some promise in vitro fertilization and embryo transfer cycles. However, the results remain controversial. We conducted a systematic review and meta-analysis to evaluate the efficacy of DHEA in patients for in vitro fertilization. PubMed, EMbase, Web of science, EBSCO and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of DHEA versus placebo on in vitro fertilization were included. Two investigators independently searched articles, extracted data and assessed the quality of included studies. The primary outcomes were clinical pregnancy and live birth rate. Meta-analysis was performed using random-effect model. Six RCTs involving 745 patients were included in the meta-analysis. Overall, compared with placebo, DHEA supplementation was associated with the significant increase in clinical pregnancy (OR = 1.45; 95% CI = 1.04-2.03; p = .03), live birth rate (OR = 2.70; 95% CI = 1.24-5.85; p = .01) and endometrial thickness (Std. mean difference = 0.67; 95% CI = 0.02-1.32; p = .04) but showed no influence on E2 on hCG day (Std. mean difference = 0.69; 95% CI = -0.46 to 1.85; p = .24), embryos transferred (Std. mean difference = 0.42; 95% CI = -0.04 to 0.88; p = .07) and miscarriage rate (OR = 0.43; 95% CI = 0.03-6.66; p = .55). DHEA supplementation could significantly improve clinical pregnancy, live birth rate, endometrial thickness and retrieved oocytes but failed to alter E2 on hCG day, embryos transferred and miscarriage rate.

Genitourinary Syndrome of Menopause.

Genitourinary syndrome of menopause (GSM) describes a collection of exam findings and bothersome symptoms associated with estrogen deficiency involving changes to the labia, introitus, clitoris, vagina, urethra, and bladder. Vulvovaginal atrophy is a component of GSM. GSM is a highly prevalent medical condition with adverse effects on the health and quality of life of midlife women. There are many effective treatment options, including nonhormonal lubricants and moisturizers, physical therapy, low-dose vaginal estrogen therapy, vaginal dehydroepiandrosterone, and oral ospemifene. Despite the availability of safe and effective therapies, GSM often remains unrecognized and untreated.

Short-term Dehydroepiandrosterone Intake and Supramaximal Exercise in Young Recreationally-trained Women.

WADA has banned dehydroepiandrosterone (DHEA) but its ergogenic effect in female athletes has never been investigated. The aim of this study was to determine whether short-term DHEA intake would improve performance during a supramaximal field exercise in healthy young recreationally trained women. Its impact on body composition, metabolic responses was also measured. Eleven young female volunteers completed four running-based anaerobic sprint tests: just before and after treatment with either oral placebo or DHEA (100 mg/day/28days), following a double-blind and randomized protocol. Bioelectrical impedance assessed body composition. At rest and after passive recovery, blood samples were collected for lactate measurement and saliva samples for DHEA, testosterone and cortisol analysis. There was no significant difference in body composition or performance parameters after DHEA administration, despite a tendency toward increased peak power and decreased fat mass. However, DHEA treatment induced a very marked increase in saliva DHEA and testosterone concentrations (p<0.001), with no change in cortisol or lactate levels. In conclusion, short-term DHEA administration did not improve performance or have an anabolic effect in young female recreationally trained athletes, despite the increase in androgenic hormones. Further studies are needed to determine whether a higher daily dose would generate an ergogenic effect during anaerobic exercise.

Neurosteroid dehydroepiandrosterone enhances activity and trafficking of astrocytic GLT-1 via σ1 receptor-mediated PKC activation in the hippocampal dentate gyrus of rats.

Neurosteroid dehydroepiandrosterone (DHEA) has been reported to exert a potent neuroprotective effect against glutamate-induced excitotoxicity. However, the underlying mechanism remains to be elucidated. One of the possible mechanisms may be an involvement of astrocytic glutamate transporter subtype-1 (GLT-1) that can quickly clear spilled glutamate at the synapse to prevent excitotoxicity. To examine the effect of DHEA on GLT-1 activity, we measured synaptically induced glial depolarization (SIGD) in the dentate gyrus (DG) of adult rats by applying an optical recording technique to the hippocampal slices stained with voltage-sensitive dye RH155. Bath-application of DHEA for 10 min dose-dependently increased SIGD without changing presynaptic glutamate releases, which was sensitive to the GLT-1 blocker DHK. Patch-clamp recordings in astrocytes showed that an application of 50 µM DHEA increased glutamate-evoked inward currents (Iglu) by approximately 1.5-fold, which was dependent on the GLT-1 activity. In addition, the level of biotinylated GLT-1 protein in the surface of astrocytes was significantly elevated by DHEA. The DHEA-increased SIGD, Iglu, and GLT-1 translocation to the cell surface were blocked by the σ1 R antagonist NE100 and mimicked by the σ1 R agonist PRE084. DHEA elevated the phosphorylation level of PKC in a σ1 R-dependent manner. Furthermore, the PKC inhibitor chelerythrine could prevent the DHEA-increased SIGD, Iglu, and GLT-1 translocation. Collectively, present results suggest that DHEA enhances the activity and translocation to cell surface of astrocytic GLT-1 mainly via σ1 R-mediated PKC cascade.

The Application of Dehydroepiandrosterone on Improving Mitochondrial Function and Reducing Apoptosis of Cumulus Cells in Poor Ovarian Responders.

Poor ovarian responders (PORs) pose a great challenge for in vitro fertilization (IVF). Previous studies have suggested that dehydroepiandrosterone (DHEA) may improve IVF outcomes in PORs. The current study attempted to investigate the clinical benefits of DHEA in PORs and the possible mechanisms of DHEA on cumulus cells (CCs). This was a prospective study performed at one tertiary center from January 2015 to March 2016. A total of 131 women who underwent IVF treatment participated, including 59 normal ovarian responders (NORs) and 72 PORs. PORs were assigned to receive DHEA supplementation or not before the IVF cycle. For all patients, CCs were obtained after oocyte retrieval. In the CCs, mRNA expression of apoptosis-related genes and mitochondrial transcription factor A (TFAM) gene, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, mitochondrial dehydrogenase activity and mitochondrial mass were measured. The results indicated that PORs with DHEA supplementation produces a great number of top-quality embryos at day 3 and increased the number of transferred embryos and fertilization rate compared with those without DHEA supplementation. Additionally, supplementation with DHEA in PORs decreased DNA damage and apoptosis in CCs while enhancing the mitochondrial mass, mitochondrial dehydrogenase activity and TFAM expression in CCs. In conclusion, our results showed that the benefits of DHEA supplementation on IVF outcomes in PORs were significant, and the effects may be partially mediated by improving mitochondrial function and reducing apoptosis in CCs.

Protection of cumulus cells following dehydroepiandrosterone supplementation.

BACKGROUND: Growing studies have demonstrated that dehydroepiandrosterone (DHEA) may improve fertility outcomes in poor ovarian responders (PORs). The aim of this study was to compare clinical outcomes and cumulus cell (CC) expression before and after DHEA treatment in PORs undergoing in vitro fertilization (IVF) cycles. METHODS: Six patients with poor ovarian response were enrolled in the study according to Bologna criteria. DHEA was supplied at least 2 months before patients entered into the next IVF cycle. Expression of apoptosis-related genes in CCs was determined by quantitative real-time PCR. Mitochondrial dehydrogenase activity of CCs was assessed by cell counting kit-8 assay. RESULTS: Metaphase II oocytes, maturation rate, embryos at Day 3, and fertilization rate significantly increased following DHEA treatment. Expression of cytochrome c, caspase 9, and caspase 3 genes in CCs were significantly reduced after DHEA therapy. Additionally, increased mitochondrial activity of CCs was observed following DHEA supplementation. CONCLUSIONS: DHEA supplementation may protect CCs via improved mitochondrial activity and decreased apoptosis, leading to better clinical outcomes in PORs.

Mood disturbances during combined oral contraceptive use and the effect of androgen supplementation. Results of a double-blind, placebo-controlled, single-case alternation design pilot study.

OBJECTIVES: To evaluate the effect of androgen supplementation in healthy combined oral contraceptive (COC) users who experience mood disturbances during COC-use only. METHODS: Six women with mood disturbances during COC-use only, received COC with co-treatment of 50 mg dehydroepiandrosterone (DHEA) during three cycles and placebo during another three cycles in an individualized random order. Daily mood rating was measured by a single item: 'In what kind of mood have you been in the past 24 h?' The results were analysed using a randomisation test for single-case experimental designs. RESULTS: The p values for the alternation design randomisation tests on the raw data of the six healthy individuals varied between 0.21 and 1, indicating that the average daily mood ratings of the active treatment DHEA are not statistically significantly larger than the average daily mood ratings of placebo. The combined p value of the subjects using a DRSP-containing pill was 0.97, and of the subjects using an LNG-containing pill was 0.65, indicating no statistically significant treatment effect for any of the pill types. CONCLUSIONS: In this single-case alternation design study, concomitant treatment with DHEA for intermittent periods of 4 weeks did not result in improvement of mood disturbances related to COC-use, but had also no side-effects.