Endogenous DHEAS is Causally Linked with Lumbar Spine Bone Mineral Density and Forearm Fractures in Women

Context A recent pooled analysis of four clinical trials demonstrated that treatment with dehydroepiandrosterone (DHEA) increases lumbar spine BMD (LS-BMD) in women. The causal effect of endogenous adrenal-derived DHEA-sulphate (DHEAS) on LS-BMD and fracture risk in women is unknown. Objective To determine whether circulating DHEAS is causally associated with LS-BMD and fracture risk in women. Methods A two-sample mendelian randomization study using genetic predictors of serum DHEAS derived from the largest available female-specific genome wide association study (GWAS) meta-analysis (n=8 565). Genetic associations with DXA-derived BMD (n=22 900) were obtained from female specific GWAS summary statistics available from the GEFOS consortium while individual-level data of 238 565 women of white ancestry from the UK Biobank were used for associations with fractures (11 564 forearm fractures, 2 604 hip fractures) and estimated heel BMD by ultrasound (eBMD). Results A 1 standard deviation (SD) genetically instrumented increase in log serum DHEAS levels was associated with a 0.21 SD increase in LS-BMD (P-value: 0.01) and a 0.08 SD increase in eBMD (P-value: <0.001). Genetically predicted DHEAS decreased forearm fracture risk (odds ratio (OR): 0.70, 95% confidence interval (CI): 0.55-0.88 per SD increase in DHEAS) while no significant causal association with hip fractures was observed. Conclusions Genetically predicted serum DHEAS increases LS-BMD and decreases forearm fracture risk in women. Based on the results of the present study and previous RCTs of DHEA treatment, we propose that both endogenous adrenal-derived DHEA(S) and pharmacological DHEA treatment improve bone health in women.

The Effect of Dehydroepiandrosterone Treatment on Neurogenesis, Astrogliosis and Long-Term Cocaine-Seeking Behavior in a Cocaine Self-Administration Model in Rats

Cocaine addiction is an acquired behavioral state developed in vulnerable individuals after cocaine exposure. It is characterized by compulsive drug-seeking and high vulnerability to relapse even after prolonged abstinence, associated with decreased neurogenesis in the hippocampus. This addictive state is hypothesized to be a form of “memory disease” in which the drug exploits the physiological neuroplasticity mechanisms that mediate regular learning and memory processes. Therefore, a major focus of the field has been to identify the cocaine-induced neuroadaptations occurring in the usurped brain’s reward circuit. The neurosteroid dehydroepiandrosterone (DHEA) affects brain cell morphology, differentiation, neurotransmission, and memory. It also reduces drug-seeking behavior in an animal model of cocaine self-administration. Here, we examined the long-lasting effects of DHEA treatment on the attenuation of cocaine-seeking behavior. We also examined its short- and long-term influence on hippocampal cells architecture (neurons and astrocytes). Using a behavioral examination, immunohistochemical staining, and diffusion tensor imaging, we found an immediate effect on tissue density and activation of astrocytes, which has a continuous beneficial effect on neurogenesis and tissue organization. This research emphasizes the requites concert between astrocytes and neurons in the rehabilitation from addiction behavior. Thus, DHEA may serve as a treatment that corrects brain damage following exposure to and abstinence from cocaine.

Dehydroepiandrosterone Effect on Toxoplasma gondii: Molecular Mechanisms Associated to Parasite Death

Toxoplasmosis is a zoonotic disease caused by the apicomplexa protozoan parasite Toxoplasma gondii. This disease is a health burden, mainly in pregnant women and immunocompromised individuals. Dehydroepiandrosterone (DHEA) has proved to be an important molecule that could drive resistance against a variety of infections, including intracellular parasites such as Plasmodium falciparum and Trypanozoma cruzi, among others. However, to date, the role of DHEA on T. gondii has not been explored. Here, we demonstrated for the first time the toxoplasmicidal effect of DHEA on extracellular tachyzoites. Ultrastructural analysis of treated parasites showed that DHEA alters the cytoskeleton structures, leading to the loss of the organelle structure and organization as well as the loss of the cellular shape. In vitro treatment with DHEA reduces the viability of extracellular tachyzoites and the passive invasion process. Two-dimensional (2D) SDS-PAGE analysis revealed that in the presence of the hormone, a progesterone receptor membrane component (PGRMC) with a cytochrome b5 family heme/steroid binding domain-containing protein was expressed, while the expression of proteins that are essential for motility and virulence was highly reduced. Finally, in vivo DHEA treatment induced a reduction of parasitic load in male, but not in female mice.

Dehydroepiandrosterone Effect on Toxoplasma gondii: Molecular Mechanisms Associated to Parasite Death

Toxoplasmosis is a zoonotic disease caused by the apicomplexa protozoan parasite Toxoplasma gondii. This disease is a health burden, mainly in pregnant women and immunocompromised individuals. Dehydroepiandrosterone (DHEA) has proved to be an important molecule that could drive resistance against a variety of infections, including intracellular parasites such as Plasmodium falciparum and Trypanozoma cruzi, among others. However, to date it has not been explored the role of DHEA on T. gondii. In here, we demonstrated for the first time the toxoplasmicidal effect of DHEA on extracellular tachyzoites. Ultrastructural analysis of treated parasites showed that DHEA alters the cytoskeleton structures, leading to the loss of the organelle structure and organization, as well as the loss of the cellular shape. In vitro treatment with DHEA reduces the viability of extracellular tachyzoites and passive invasion process. 2D SDS-PAGE analysis revealed that in the presence of the hormone a progesterone receptor membrane component (PGRMC) with a cytochrome b5 family heme/steroid binding domain-containing protein was expressed, while the expression of proteins that are essential for motility and virulence was highly reduced. Finally, in vivo DHEA treatment induced a reduction of parasitic load in male, but not in female mice.

Exenatide Improves Endometrial Glands in PCOS Rats through AMPKα-SIRT1

Exenatide can contribute to the therapeutic effect for PCOS patients in restoring menstrual cycles. To exploring endometrial tissue change in PCOS rats and the effects of exenatide on endometrial tissue, we carried out in vivo study of PCOS rat models. Method: PCOS rat models were obtained after DHEA treatment, and the corresponding parameters were measured to confirm the establishment of PCOS models. Hematoxylin-eosin (H&E) staining was performed to observe endometrium morphological change, and western blot and RT-PCR were performed to identify the alteration AMP-activated protein kinase (AMPKα) and SIRT1 proteins and the relative expression of SIRT1 mRNA in endometrial cellular after the intervention of exenatide (EX). Results: The endometrium of PCOS rats appeared to not only the gland number increased but also the gland size enlarged. When the PCOS rats underwent EX treatment, the gland number decreased and the gland size narrowed, the expression of AMPKα and SIRT1 protein increased, and the expression of SIRT1 mRNA level augmented. Conclusion: EX could decrease gland number and narrow gland size in PCOS rat endometrium which may be partly via AMPKα-SIRT1 pathway.

Dehydroepiandrosterone Supplementation May Benefit Women with Asthma Who Have Low Androgen Levels: A Pilot Study

ABSTRACT Introduction Among individuals with severe asthma, FEV1 is low in individuals with low dehydroepiandrosterone (DHEA) sulfate (DHEAS) levels. In the Severe Asthma Research Program (SARP), no women with DHEAS > 200 μg/dL had an FEV1 < 60% predicted. DHEA has benefited patients with COPD and pulmonary hypertension in small trials. Therefore, we hypothesized that DHEA supplementation may improve FEV1 in asthmatic women with low DHEAS. Methods Premenopausal, nonsmoking, otherwise healthy women, 18-50 years old, with mild or moderate asthma and baseline FEV1 > 60% predicted received 100 mg DHEA orally every 12 h for 2 weeks. Spirometry and DHEAS were measured at the initial visit and 2 weeks later, after completion of DHEA treatment. Based on our previous work, the primary outcome variable for this pilot study was post-albuterol spirometry in the low-DHEAS group. Subjects also continued their other routine asthma management. Results Serum DHEAS increased with DHEA treatment in women with starting DHEAS < 200 µg/dL: this increase was from 71 ± 23 to 725 ± 295 µg/dL (n = 10; p = 0.0001). The increase in the high-DHEAS group was smaller. Post-albuterol FEV1 increased by 51 mL, from 3.026 ± 0.5 to 3.077 ± 0.49 L (n = 10; p = 0.034 by paired t test, significant after Bonferroni), in women with low DHEAS. In the high-DHEAS group (baseline DHEAS ≥ 200 µg/dl), post-albuterol FEV1 did not change significantly (n = 3, p = NS). Three subjects were excluded: one had comorbid COPD, one could not perform spirometry, and one did not take the DHEA. There were no adverse effects of DHEA treatment in this trial. Conclusions Endocrine treatments (corticosteroids) are a mainstay of anti-inflammatory management for moderate and severe asthma. Their use has improved asthma outcomes. Androgens also reduce airway inflammation and promote airway smooth muscle relaxation, but are rarely used clinically for asthma treatment. Our results suggest that the over-the-counter steroid DHEA may improve lung function in asthma outcomes among women with DHEAS < 200 ug/dL.

Dehydroepiandrosterone Ameliorates Abnormal Mitochondrial Dynamics and Mitophagy of Cumulus Cells in Poor Ovarian Responders

Mitochondrial dysfunction is related to reproductive decline in humans, with consequences for in vitro fertilization (IVF). We assessed whether dehydroepiandrosterone (DHEA) could regulate mitochondrial homeostasis and mitophagy of cumulus cells (CCs) in poor ovarian responders (PORs). A total of 66 women who underwent IVF treatment at the Reproductive Medicine Center of Kaohsiung Veterans General Hospital were included in this study. Twenty-eight normal ovarian responders (NOR) and 38 PORs were enrolled. PORs were assigned to receive DHEA supplementation (n = 19) or not (n = 19) before IVF cycles. DHEA prevents mitochondrial dysfunction by decreasing the activation of DNM1L and MFF, and increasing MFN1 expression. Downregulation of PINK1 and PRKN occurred after DHEA treatment, along with increased lysosome formation. DHEA not only promoted mitochondrial mass but also improved mitochondrial homeostasis and dynamics in the CCs of POR. We also observed effects of alterations in mRNAs known to regulate mitochondrial dynamics and mitophagy in the CCs of POR. DHEA may prevent mitochondrial dysfunction through regulating mitochondrial homeostasis and mitophagy.

Dehydroepiandrosterone Reduced Lipid Droplet Accumulation via Inhibiting Cell Proliferation and Improving Mitochondrial Function in Primary Chicken Hepatocytes

Dehydroepiandrosterone (DHEA) possesses fat-reducing effect, while little information is available on whether DHEA regulates cell proliferation and mitochondrial function, which would, in turn, affect lipid droplet accumulation in the broiler. In the present study, the lipid droplet accumulation, cell proliferation, cell cycle and mitochondrial membrane potential were analysis in primary chicken hepatocytes after DHEA treated. The results showed that total area and counts of lipid droplets were significantly decreased in hepatocytes treated with DHEA. The cell viability was significantly increased, while cell proliferation was significantly inhibited in a dose dependent manner in primary chicken hepatocytes after DHEA treated. DHEA treatment significantly increased the cell population in S phase and decreased the population in G2/M in primary chicken hepatocytes. Meanwhile, the cyclin A and cyclin-dependent kinases 2 (CDK2) mRNA abundance were significantly decreased in hepatocytes after DHEA treated. No significant differences were observed in the number of mitochondria, while the mitochondrial membrane permeability and succinate dehydrogenase (SDH) activity were significantly increased in hepatocytes after DHEA treated. In conclusion, our results demonstrated that DHEA reduced lipid droplet accumulation by inhibiting hepatocytes proliferation and enhancing mitochondrial function in primary chicken hepatocytes.