The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains

Pregnanolone glutamate (PA-G) is a neuroactive steroid that has been previously demonstrated to be a potent neuroprotective compound in several biological models in vivo. Our in vitro experiments identified PA-G as an inhibitor of N-methyl-D-aspartate receptors and a potentiator of γ-aminobutyric acid receptors (GABAARs). In this study, we addressed the hypothesis that combined GABAAR potentiation and NMDAR antagonism could afford a potent anticonvulsant effect. Our results demonstrated the strong age-related anticonvulsive effect of PA-G in a model of pentylenetetrazol-induced seizures. PA-G significantly decreased seizure severity in 12-day-old animals, but only after the highest dose in 25-day-old animals. Interestingly, the anticonvulsant effect of PA-G differed both qualitatively and quantitatively from that of zuranolone, an investigational neurosteroid acting as a potent positive allosteric modulator of GABAARs. Next, we identified 17-hydroxy-pregnanolone (17-OH-PA) as a major metabolite of PA-G in 12-day-old animals. Finally, the administration of PA-G demonstrated direct modulation of unexpected neurosteroid levels, namely pregnenolone and dehydroepiandrosterone sulfate. These results suggest that compound PA-G might be a pro-drug of 17-OH-PA, a neurosteroid with a promising neuroprotective effect with an unknown mechanism of action that may represent an attractive target for studying perinatal neural diseases.

The Utilization of Dehydroepiandrosterone as a Sexual Hormone Precursor in Premenopausal and Postmenopausal Women: An Overview

Dehydroepiandrosterone (DHEA), and its metabolite, dehydroepiandrosterone sulfate ester (DHEAS), are the most abundant circulating steroid hormones, and are synthesized in the zona reticularis of the adrenal cortex, in the gonads, and in the brain. The precise physiological role of DHEA and DHEAS is not yet fully understood, but these steroid hormones can act as androgens, estrogens, and neurosteroids, and perform many roles in the human body. Since both levels decline with age, use of DHEA supplements have gained more attention due to being advertised as an antidote to aging in postmenopausal women, who may have concerns on age-related diseases and overall well-being. However, current research has not reached an overall consensus on the effects of DHEA on postmenopausal women. This overview is a summary of the current literature, addressing the metabolic pathway for DHEA synthesis and utilization, as well as the effects of DHEA on premenopausal and postmenopausal women with disease states and other factors. As for the therapeutic effects on menopausal syndrome and other age-related diseases, several studies have found that DHEA supplementations can alleviate vasomotor symptoms, preserve the integrity of the immune system, reduce bone loss, and increase muscle mass. Intravaginal DHEA has shown significant beneficial effects in menopausal women with severe vulvovaginal symptoms. On the other hand, DHEA supplements have not shown definitive effects in cardiovascular disease, adrenal insufficiency, insulin sensitivity, and cognition. Due to inadequate sample sizes and treatment durations of current studies, it is difficult to assess the safety and efficacy of DHEA and draw reliable conclusions for the physiological role, the optimal dosage, and the effects on premenopausal and postmenopausal women; therefore, the study of DHEA warrants future investigation. Further research into the roles of these steroid hormones may bring us closer to a therapeutic option in the future.

Novel Opipramol-Baclofen Combination Alleviates Depression and Craving and Facilitates Recovery From Substance Use Disorder—An Animal Model and a Human Study

Substance use disorders (SUDs) are associated with depression and anxiety, with the latter being one of the major factors in substance-seeking and relapse. Due to dose-dependent sedative side effects there is limited efficacy of baclofen treatment for SUDs. Here we suggest the use of a novel combination of opipramol and baclofen (O/B) which is known to attenuate anxiety and depression, for the facilitation of recovery from SUDs. Since both opipramol and baclofen have a common downstream signal transduction, their individual doses could be reduced while still maintaining the benefits of the combination. We tested the O/B combination in both animals and patients. Rats treated with O/B showed significant attenuation in craving behavior and in relapse rate during withdrawal from cocaine. In a double-blind, placebo-controlled pilot study, conducted in a residential detoxification center, 14 males and 3 females, aged 28–60 years were assigned to a study (n = 6) and a placebo (n = 11) group (placebo group: 40 ± 10.5 years; O/B group 40 ± 10.8 years). The participants completed scales measuring depression, anxiety and craving symptoms and provided saliva samples for stress hormone examination [cortisol and dehydroepiandrosterone-sulfate (DHEA-S)]. Participants with polysubstance use disorder (PsUD) treated with O/B showed a reduction in cravings and depression and an increase in DHEA-S and in the DHEA-S/cortisol ratio. Our findings indicate a beneficial effect of O/B treatment. This study suggests a novel candidate for pharmacological treatment of patients with SUD and comorbid mood/anxiety disorders that may facilitate their rehabilitation.

Inter-individual differences in pain anticipation and pain perception in migraine: Neural correlates of migraine frequency and cortisol-to-dehydroepiandrosterone sulfate (DHEA-S) ratio

Previous studies targeting inter-individual differences in pain processing in migraine mainly focused on the perception of pain. Our main aim was to disentangle pain anticipation and perception using a classical fear conditioning task, and investigate how migraine frequency and pre-scan cortisol-to-dehydroepiandrosterone sulfate (DHEA-S) ratio as an index of neurobiological stress response would relate to neural activation in these two phases. Functional Magnetic Resonance Imaging (fMRI) data of 23 participants (18 females; mean age: 27.61± 5.36) with episodic migraine without aura were analysed. We found that migraine frequency was significantly associated with pain anticipation in brain regions comprising the midcingulate and caudate, whereas pre-scan cortisol-to DHEA-S ratio was related to pain perception in the pre-supplementary motor area (pre-SMA). Both results suggest exaggerated preparatory responses to pain or more general to stressors, which may contribute to the allostatic load caused by stressors and migraine attacks on the brain.

“The Competitive Season and Off-Season”: Preliminary Research concerning the Sport-Specific Performance, Stress, and Sleep in Elite Male Adolescent Basketball Athletes

Background: Through scholastic sports programs, adolescent athletes compete to represent their communities. However, few studies investigate the changes in physiological and mental profiles during varied sport periodization among this population. Therefore, the purpose of this study was to compare the changes in sports performance and stress-related biomarkers between the competitive season (CS) and off-season (OS) in elite adolescent basketball players. Method: Nine elite Division I male basketball players (age: 15–18 years. old) participated in this study. Basketball-specific performance, salivary dehydroepiandrosterone sulfate (DHEA-S)/cortisol levels, mood state, and sleep quality were all accessed during the CS and OS periods. Results: The training load during OS was 26.0% lower than CS (p = 0.001). Muscle mass, aerobic capacity, 10 m sprint, and Abalakov jump (AJ) power during OS were greater than that during CS (+2.2–9.8%, p < 0.05), but planned agility was greater during CS (p = 0.003). The salivary DHEA-S/cortisol was greater during CS than during OS (p = 0.039). The overall mood state and sleep quality did not differ between periods, but the POMS-tension was higher during CS (p = 0.005). Conclusion: The present study demonstrates that muscle mass, aerobic capacity, peak AJ power, and 10 m sprint performance, but not planned agility, were greater during OS compared to CS among elite adolescent basketball players. Furthermore, the stress-related responses reflected by the D/C ratio and mood tension were relatively lower during the OS in these athletes. Thus, this study suggests that coaches and sport science professionals should closely monitor athletes’ training states across varied training/competition periods to better react to modifying training or recovery plans.

Commentary to the article “Multiple hormonal and metabolic deficiency syndrome predicts outcome in heart failure: the T.O.S.CA. Registry”, Antonio Cittadini et al. Eur J Prev Cardiol. 2021

: Chronic heart failure represents a relevant concern for public health. The endocrine system is heavily involved in the induction and progression of chronic heart failure. Among endocrine dysfunction, the most relevant alterations are related to the growth hormone-insulin like growth factor 1 axis, serum testosterone, dehydroepiandrosterone sulfate, triiodothyronine levels, insulin resistance, and type 2 diabetes mellitus. It is currently debated whether these changes might be simple adaptive mechanisms or, instead, they may deteriorate myocardial pump function over time. Medical management of patients exhibiting one or more hormonal deficiencies or metabolic disorders, including insulin resistance and diabetes mellitus, may have a therapeutic role.

An infant with 49XXXXY syndrome: a case report

Background 49XXXXY syndrome is the rarest X chromosome aneuploidy, with approximate incidence of 1:85,000–100,000 male births. Worldwide, around 100 cases have been reported. In this report, we describe one such case seen in Sri Lanka. Case presentation A 10-day-old Sri Lankan neonate born in a tertiary care center was referred to the pediatric endocrinology unit of Lady Ridgeway Hospital due to detection of ambiguous genitalia at birth. He was the first child born to nonconsanguineous healthy parents following an uncomplicated antenatal period. He was born at term via normal vaginal delivery, with a birth weight of 2.385 kg. The baby was active, and there was no documented hypoglycemia or alteration in basic biochemical investigations. On examination, the child had hypertelorism, upslanting palpebral fissures, flat occiput, and mild webbing of the neck. System examination was normal. Genitalia examination revealed bifid scrotum, perineal urethra, 2 cm phallus, and bilateral testis in situ. Hormonal analysis, including dehydroepiandrosterone sulfate, testosterone, and 17-OH progesterone levels, was normal except for an elevated level of follicle-stimulating hormone, indicating gonadal dysgenesis. Ultrasound of the abdomen detected testis located at bilateral inguinal canal, and no Müllerian structures were visible. Echocardiography showed a small patent foramen ovale with otherwise normal heart. Chromosome analysis revealed 49XXXXY syndrome. Conclusion 49XXXXY syndrome should be entertained as a rare possibility for ambiguous genitalia, and karyotyping is an essential investigation for evaluation of such patients.

Feasibility of In-home Saliva Collection of Cortisol and DHEA-S as a Biomarker of Stress in Dementia Care Dyads

Dementia afflicts affected individuals and their family caregivers worldwide. Although a non-pharmacological intervention has been recommended as a first-line approach to minimize adverse outcomes (e.g., stress) in dementia care dyads (persons with dementia [PWD] and their family caregivers), most evaluations of such interventions have relied on subjective (e.g., self- or proxy-report) rather than objective (e.g., biomarkers) measures. We aimed to explore the feasibility of saliva collection of cortisol and dehydroepiandrosterone sulfate (DHEA-S) as a non-intrusive method in dementia care dyads. Dementia care dyads living at home were recruited from the memory center in Sweden. Prior to the saliva collection, participants received a one-hour education session with a hands-on demonstration led by a trained study coordinator. Participants were instructed to collect saliva three times (two for morning, one for evening)/day, five days/week for eight consecutive weeks. Out of 32 care dyads (32 PWD and 32 family caregivers), 24 (75.0%) completed the saliva collection. On average, 105.5 (87.92%) and 105.9 (88.25%) samples were collected from PWD and family caregivers during eight weeks. There were no statistically significant differences (p&gt;0.05) in the average number of saliva samples (i.e., total samples, morning or evening samples) between PWD and family caregivers. The findings of this pilot study showed that saliva collection of cortisol and DHEA-S as a stress measurement was feasible in dementia care dyads living at home. Robust and person-centered procedures, tailored educational materials, and effective communication with dementia care dyads should be considered in future biomarker research on stress in dementia care dyads.

Correlation assessment of gender and thyroid hormones in patients with primary oligomenorhea in anamnesis

Objective. To determine the concentration of pituitary, ovarian and thyroid hormones in the blood and the correlation between them in women with a history of primary oligomenorrhea. Material and methods. The study involved 56 women of reproductive age with primary oligomenorrhea. Control 50 women of fertile age with an undisturbed rhythm of menstruation. An ultrasound of the uterus, ovaries and thyroid gland was performed. Concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, estradiol, testosterone dehydroepiandrosterone sulfate (DHEA-S), triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH) were determined by ELISA. Results. The average age of women in the main and control groups was 30.0 1.34 and 30.52 5.92 years (p 0.05), respectively. The average age of menarche in women of the main group was 13.27 0.80 years; duration of menstruation 3.4 0.40 days and 5.2 0.82 days (p = 0.051), respectively; duration of the menstrual cycle was 33.90 0.70 days (p = 0.001). Length and width of the uterus 3.99 0.19 cm (p = 0.055) and 4.51 0.11 cm, respectively; endometrial thickness 9.78 1.20 mm. The sizes of thyroid lobes did not differ between the groups. The LH level and the LH / FSH ratio were higher than the control values by 50.79 % (p = 0.052) and 52.66 % (p = 0.045), respectively. Testosterone and TSH concentrations were 38.33 and 34.36 % higher, respectively. The estradiol level was reduced by 56.67 % (p = 0.113). A weak correlation was revealed between sex and thyroid hormones. Conclusions. In women with a history of primary oligomenorrhea, the concentration of luteini-zing hormone and the LH / FSH ratio in the blood serum are significantly higher (p 0.05). In women with primary oligomenorrhea, there was a weak correlation between sex and thyroid hormones. The results will provide insight into the relationship between the thyroid function and the menstrual cycle.