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Medicine Dec 2017Spironolactone, a nonselective mineralocorticoid receptor antagonist (MRA), may have a deleterious effect on glycemia. The objective of this review was to assess current... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Spironolactone, a nonselective mineralocorticoid receptor antagonist (MRA), may have a deleterious effect on glycemia. The objective of this review was to assess current knowledge on MRAs' influence (spironolactone, eplerenone, and canrenone) on glucose homeostasis and the risk of diabetes.
METHOD
A systematic review was conducted using the Medline database on articles published from 1946 to January 2017 that studied the effects of MRAs on any glucose-related endpoints, without any restrictions regarding the participants' characteristics.Study design, patient population, dose and duration of intervention, and the quantitative results on glycemic markers were extracted, interpreted for result synthesis, and evaluated for sources of bias. From the articles included in the qualitative analysis, a select number were used in a meta-analysis on studies having measured glycated hemoglobin (HbA1c) or risk of diabetes.
RESULTS
Seventy-two articles were selected from the Medline database and references of articles. Results on spironolactone were heterogeneous, but seemed to be disease-specific. A potential negative effect on glucose regulation was mainly observed in heart failure and diabetes trials, while a neutral or positive effect was detected in diseases characterized by hyperandrogenism, and inconclusive for hypertension. Interpretation of data from heart failure trials was limited by the small number of studies. From a meta-analysis of 12 randomized controlled studies evaluating spironolactone's impact on HbA1c in diabetic patients, spironolactone had a nonsignificant effect in parallel-group studies (mean difference 0.03 [-0.20;0.26]), but significantly increased HbA1c in crossover studies (mean difference 0.24 [0.18;0.31]). Finally, eplerenone did not seem to influence glycemia, while limited data indicated that canrenone may exert a neutral or beneficial effect.The studies had important limitations regarding study design, sample size, duration of follow-up, and choice of glycemic markers.
CONCLUSION
Spironolactone may induce disease-specific and modest alterations on glycemia. It is uncertain whether these effects are transient or not. Data from the most extensively studied population, individuals with diabetes, do not support a long-term glycemic impact in these patients. Further prospective studies are necessary to establish spironolactone's true biological effects and their clinical implications.
Topics: Blood Glucose; Canrenone; Eplerenone; Glycated Hemoglobin; Homeostasis; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone
PubMed: 29310346
DOI: 10.1097/MD.0000000000008719 -
Journal of Asian Natural Products... Dec 2023Two new pregnane glycosides ( and ), together with four known ones (- ), were isolated from the roots of Royle ex Wight (Asclepiadaceae). On the basis of detailed...
Two new pregnane glycosides ( and ), together with four known ones (- ), were isolated from the roots of Royle ex Wight (Asclepiadaceae). On the basis of detailed spectroscopic analysis and chemical method, the structures of new compounds were characterized to be metaplexigenin 3---D-cymaropyranosyl- (1→4)--L-diginopyranosyl-(1→4)--D-cymaropyranoside (), metaplexigenin 3---L-diginopyranosyl-(1→4)--D-cymaropyranoside (). All the isolated compounds (-) were tested for their inhibitory activity against the growth of human colon cancer cell lines HCT-116. Compounds and showed significant cytoxicities with IC values of 43.58 µM and 52.21 µM.
Topics: Humans; Cynanchum; Plant Roots; Pregnanes; Glycosides; Molecular Structure
PubMed: 37178131
DOI: 10.1080/10286020.2023.2211550 -
Domestic Animal Endocrinology Jan 2023Sepsis is a major cause of morbidity and mortality in neonatal foals. Relative adrenal insufficiency (RAI), defined as an inadequate cortisol response to stress, has...
Sepsis is a major cause of morbidity and mortality in neonatal foals. Relative adrenal insufficiency (RAI), defined as an inadequate cortisol response to stress, has been associated with sepsis, prematurity, and poor outcome in newborn foals. In addition to cortisol, the adrenal gland synthesizes several biologically important steroids and steroid precursors, including aldosterone, androgens, and progestogens. However, concentration of these hormones during hospitalization and their association with the severity of disease and mortality in critically ill foals have not been completely evaluated. We hypothesized, that in addition to cortisol and aldosterone, concentration of steroid precursors (progestogens and androgens) will be altered in critically ill foals. We also proposed that septic foals will have higher concentrations of steroid precursors than healthy foals, and steroid concentrations will be persistently increased during hospitalization in non-surviving septic and premature foals. Foals <4 days of age were categorized as healthy, septic, sick non-septic, and premature based on physical exam, medical history, and laboratory data. Blood samples were collected on admission (0 h), 24 h, and 72 h after admission. Concentrations of steroids and ACTH were measured by immunoassays. The area under the curve over 72 h (AUC0-72h) of hospitalization was calculated for each hormone. Serum cortisol, aldosterone, progesterone, pregnenolone, dehydroepiandrosterone sulfate (DHEAS), and 17 α-hydroxyprogesterone concentrations were higher in septic and premature foals compared to healthy foals at 0 h and throughout 72 h of hospitalization (P < 0.05). Plasma ACTH concentrations were higher in septic and premature foals on admission compared to healthy controls (P < 0.05). The progesterone (AUC0-72h) cut-off value above which non-survival could be reliably predicted in hospitalized foals was 1,085 ng/mL/h, with 82% sensitivity and 77% specificity. Critically ill neonatal foals had an appropriate response to stress characterized by increased concentrations of cortisol and steroid precursors on admission. A rapid decline in steroid concentration was observed in healthy foals. However, persistently elevated progestogen and androgen concentrations were associated with a lack of improvement in the course of disease and poor outcome.
Topics: Horses; Animals; Hydrocortisone; Adrenocorticotropic Hormone; Critical Illness; Animals, Newborn; Horse Diseases; Progesterone; Aldosterone; Progestins; Steroids; Sepsis; Hospitalization
PubMed: 36162341
DOI: 10.1016/j.domaniend.2022.106764 -
Journal of Veterinary Internal Medicine Sep 2021The frequency with which multiple corticosteroid abnormalities occur in cats with aldosterone secreting adrenocortical tumors is unknown.
BACKGROUND
The frequency with which multiple corticosteroid abnormalities occur in cats with aldosterone secreting adrenocortical tumors is unknown.
OBJECTIVES
To evaluate adrenal-derived corticosteroids in cats in which blood samples were submitted for measure of aldosterone.
ANIMALS
Two hundred ninety-seven cats.
METHODS
Retrospective study. Analysis of a convenience sample of previously submitted serum or plasma. Progesterone, corticosterone, and cortisol were measured in feline serum or plasma samples submitted to an endocrinology laboratory for aldosterone measurements. Demographics and clinical history were retrieved from submittal forms when provided. Statistical testing was performed to investigate associations among the adrenal corticosteroids.
RESULTS
Progesterone and corticosterone concentrations were strongly correlated (ρ = 0.74; P < .001). Progesterone (median, 5 nmol/L; interquartile range, 3-10 nmol/L) and corticosterone (113 nmol/L, 38-250 nmol/L) in cats with markedly increased aldosterone concentrations (≥3000 pmol/L) were higher than progesterone (1 nmol/L, 1-2 nmol/L) and corticosterone (12 nmol/L, 3-25 nmol/L) in cats with normal aldosterone concentrations (P < .001 for both comparisons). Progesterone concentrations ≥10 nmol/L (normal, ≤2 nmol//L) occurred in 24 of 76 (32%) cats with aldosterone concentrations ≥3000 pmol/L. Cortisol was lower in cats with aldosterone concentrations ≥3000 pmol/L as compared to those with aldosterone concentrations <500 pmol/L (59 nmol/L, 27-103 nmol/L vs 103 nmol/L, 49-182 nmol/L; P = .002).
CONCLUSIONS AND CLINICAL IMPORTANCE
Multiple corticosteroid abnormalities occur in a subset of cats with hyperaldosteronism. The magnitude of increases in progesterone and corticosterone in some cats with hyperaldosteronism is likely to be clinically relevant.
Topics: Adrenocorticotropic Hormone; Aldosterone; Animals; Cat Diseases; Cats; Corticosterone; Hydrocortisone; Hyperaldosteronism; Retrospective Studies
PubMed: 34331479
DOI: 10.1111/jvim.16224 -
Comparative Biochemistry and... Jul 2023Herein we review our work involving dispersed adrenocortical cells from several lizard species: the Eastern Fence Lizard (Sceloporus undulatus), Yarrow's Spiny Lizard... (Review)
Review
Herein we review our work involving dispersed adrenocortical cells from several lizard species: the Eastern Fence Lizard (Sceloporus undulatus), Yarrow's Spiny Lizard (Sceloporus jarrovii), Striped Plateau Lizard (Sceloporus virgatus) and the Yucatán Banded Gecko (Coleonyx elegans). Early work demonstrated changes in steroidogenic function of adrenocortical cells derived from adult S. undulatus associated with seasonal interactions with sex. However, new information suggests that both sexes operate within the same steroidogenic budget over season. The observed sex effect was further explored in orchiectomized and ovariectomized lizards, some supported with exogenous testosterone. Overall, a suppressive effect of testosterone was evident, especially in cells from C. elegans. Life stage added to this complex picture of adrenal steroidogenic function. This was evident when sexually mature and immature Sceloporus lizards were subjected to a nutritional stressor, cricket restriction/deprivation. There were divergent patterns of corticosterone, aldosterone, and progesterone responses and associated sensitivities of each to corticotropin (ACTH). Finally, we provide strong evidence that there are multiple, labile subpopulations of adrenocortical cells. We conclude that the rapid (days) remodeling of adrenocortical steroidogenic function through fluctuating cell subpopulations drives the circulating corticosteroid profile of Sceloporus lizard species. Interestingly, progesterone and aldosterone may be more important with corticosterone serving as essential supportive background. In the wild, the flux in adrenocortical cell subpopulations may be adversely susceptible to climate-change related disruptions in food sources and to xenobiotic/endocrine-disrupting chemicals. We urge further studies using native lizard species as bioindicators of local pollutants and as models to examine the broader eco-exposome.
Topics: Male; Female; Animals; Corticosterone; Aldosterone; Progesterone; Caenorhabditis elegans; Lizards; Adrenocorticotropic Hormone; Birds; Testosterone
PubMed: 37080352
DOI: 10.1016/j.cbpa.2023.111424 -
The Journal of Clinical Endocrinology... Dec 2023
Topics: Humans; Hydrocortisone; Cortisone; Dexamethasone; Saliva; Adrenal Gland Neoplasms
PubMed: 37290037
DOI: 10.1210/clinem/dgad348 -
Molecular Medicine Reports Apr 2019Fibroblast growth factor 15 (FGF15) was previously identified to be highly expressed in the ileum and functions as an endocrine factor to regulate bile acid synthesis in...
Fibroblast growth factor 15 (FGF15) was previously identified to be highly expressed in the ileum and functions as an endocrine factor to regulate bile acid synthesis in the liver. FGF15 targets its receptor fibroblast growth factor receptor 4 in the liver and serves important roles in energy metabolism, including bile acid homeostasis, glucose metabolism and protein synthesis. The expression of FGF15 is known to be regulated by the transcription factor farnesoid X receptor (FXR). In the present study, reverse transcription‑quantitative polymerase chain reaction was used for measuring Fgf15 expression from the animal and tissue culture experiments, and it was identified that dexamethasone, a drug widely used in anti‑inflammation therapy, and a classical inducer of glucocorticoid receptor (GR)‑ and pregnane X receptor (PXR)‑target genes, may downregulate Fgf15 expression in the ileum. GR was identified to be highly expressed in the ileum by western blot analysis. Furthermore, it was demonstrated that the downregulation of Fgf15 by dexamethasone is due to the repression of ileal FXR activity via GR; however, not PXR, in the ileum. The present results provide insight for a better understanding of the adverse effects associated with dexamethasone therapy.
Topics: Animals; Dexamethasone; Fibroblast Growth Factors; Gene Expression Regulation; Ileum; Intestinal Mucosa; Male; Mice; Pregnane X Receptor; Receptors, Glucocorticoid
PubMed: 30720089
DOI: 10.3892/mmr.2019.9915 -
Epilepsia Oct 2018Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog, ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic...
Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog, ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic γ-aminobutyric acid (GABA) receptors that exhibit antiseizure activity in diverse animal seizure models, including models of status epilepticus (SE). The 2 neuroactive steroids are being investigated as treatments for SE, including as a treatment for SE induced by chemical threat agents. Intramuscular injection is the preferred route of administration in the prehospital treatment of SE. The objective of this study was to assess the efficacy of intramuscular allopregnanolone and ganaxolone in the treatment of SE induced by the chemical threat agent tetramethylenedisulfotetramine (TETS). The test agents were administered 40 minutes after the onset of SE when mice are refractory to treatment. Allopregnanolone and ganaxolone (each at 3 mg/kg) terminated SE in, respectively, 92% and 75% of animals, and prevented mortality in 85% and 50% of animals; the mean times to termination of behavioral seizures were, respectively, 172 ± 16 and 447 ± 52 seconds. In a separate series of experiments, mice were dosed with the neuroactive steroids by intramuscular injection, and plasma and brain levels were sampled at various time points following injection to estimate pharmacokinetic parameters. Plasma C (maximum concentration) values for allopregnanolone and ganaxolone were 645 and 550 ng/mL, respectively. Brain exposure of both steroids was approximately 3-fold the plasma exposure. Two-compartment pharmacokinetic analysis revealed that the central compartment V (volume of distribution), CL (clearance), t (terminal half-life), and F (intramuscular bioavailability) values for allopregnanolone and ganaxolone were, respectively, 4.95 L/kg 12.88 L/kg/h,16 minutes, 97%, and 5.07 L/kg, 8.35 L/kg/h, 25 minutes, 95%. Allopregnanolone and ganaxolone are effective in the treatment of TETS-induced SE when administered by the intramuscular route. Allopregnanolone is more rapidly acting and modestly more effective, possibly because it has greater potency on GABA receptors.
Topics: Animals; Anticonvulsants; Brain; Bridged-Ring Compounds; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intramuscular; Longitudinal Studies; Male; Mice; Pregnanolone; Status Epilepticus; Time Factors
PubMed: 29453777
DOI: 10.1111/epi.13999 -
BMJ Open Respiratory Research Jan 2024Randomised controlled trials (RCTs) have demonstrated conflicting results regarding the effects of corticosteroids on the treatment of severe community-acquired... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Randomised controlled trials (RCTs) have demonstrated conflicting results regarding the effects of corticosteroids on the treatment of severe community-acquired pneumonia (CAP). We aimed to investigate the efficacy and safety of different corticosteroids on patients who were hospitalised for severe CAP.
METHODS
We performed a systematic search through PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus from inception to May 2023. The primary outcome was all-cause mortality. Data analysis was performed using a random-effects model.
RESULTS
A total of 10 RCTs comprising 1962 patients were included. Corticosteroids were associated with a lower rate of all-cause mortality (risk ratio (RR), 0.70 (95% CI 0.54 to 0.90); I=0.00%). When stratified into different corticosteroid types, hydrocortisone was associated with an approximately 50% lower mortality risk (RR, 0.48 (95% CI 0.32 to 0.72); I=0.00%). However, dexamethasone, methylprednisolone or prednisolone were not associated with an improvement in mortality. Furthermore, hydrocortisone was associated with a reduction in the rate of mechanical ventilation, acute respiratory distress syndrome, shock and duration of intensive care unit stay. These trends were not observed for dexamethasone, methylprednisolone or prednisolone. Corticosteroids were not associated with an increased risk of adverse events including gastrointestinal bleeding, secondary infection or hyperglycaemia.
CONCLUSIONS
The use of hydrocortisone, but not other types of corticosteroids, was associated with a reduction in mortality and improvement in pneumonia outcomes among patients hospitalised with severe CAP.PROSPERO registration numberCRD42023431360.
Topics: Humans; Hydrocortisone; Adrenal Cortex Hormones; Methylprednisolone; Community-Acquired Infections; Pneumonia; Dexamethasone
PubMed: 38262670
DOI: 10.1136/bmjresp-2023-002141 -
Seizure Dec 2018The anti-seizure effects of progesterone family compounds have long been known. Over the years, however, most studies have focused on progesterone and on its secondary... (Review)
Review
The anti-seizure effects of progesterone family compounds have long been known. Over the years, however, most studies have focused on progesterone and on its secondary metabolite allopregnanolone (ALLO), with less attention being paid to its primary metabolite 5a-dihydroprogesterone (DHP). Here we review animal and clinical studies related to the anti-seizure effects of progesterone and its 5a neuroactive metabolites, including DHP and ALLO. Progesterone and its reduced metabolites all have demonstrated seizure-suppression effects in animal models - except in models of absence seizures - with the common side effects of sedation and ataxia. Progesterone and ALLO have also shown anti-seizure effects in clinical trials. A large Phase III trial has revealed that female patients with premenstrual exacerbations of seizures benefit most from progesterone therapy. A liquid suspension of ALLO has also been tested in patients with supra-refractory status epilepticus with some success in a small phase II trial. ALLO's C3 methyl analog ganaxolone is under development as an anti-seizure drug. Progesterone's anti-seizure effects are mostly independent of its genomic receptors and are, in large part, due to its active metabolites. ALLO is a potent allosteric modulator of GABA receptors. Other membrane receptors are thought to be involved in the DHP's anti-seizure actions, but their exact nature is not yet known. Potential drawbacks to the development of progesterone family compounds as anti-seizure drug are their endocrine effects. These compounds might form a basis for the future development of novel anti-seizure drugs, however, with hormonal side effects being mitigated through rational drug design.
Topics: 20-alpha-Dihydroprogesterone; Animals; Anticonvulsants; Humans; Pregnanolone; Progesterone; Seizures
PubMed: 30391663
DOI: 10.1016/j.seizure.2018.10.012