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Physiological Research 2006Apart from thyroid hormones, as the main hormonal regulators of obligatory thermogenesis, and catecholamines, as major hormonal regulators of facultative thermogenesis,... (Review)
Review
Apart from thyroid hormones, as the main hormonal regulators of obligatory thermogenesis, and catecholamines, as major hormonal regulators of facultative thermogenesis, production of heat in homeotherms can also be influenced by steroids. Generally, hormones can influence heat production by regulating the activity of various enzymes of oxidative metabolism, by modulating membrane protein carriers and other membrane or nuclear protein factors. Proton carriers in the inner mitochondrial membrane, known as uncoupling proteins, play the key role in heat dissipation to the detriment of the formation of energy-rich phosphates. In this minireview we have focused on the effects of steroids and thyroid hormones on heat production in brown adipose tissues and in skeletal muscles, with particular respect to their effect on uncoupling protein expression. Apart from hormonal steroids, dehydroepiandrosterone, an important precursor in the metabolic pathway leading to hormonal steroids which possess many, mostly beneficial effects on human health, modulates metabolic pathways which may lead to increased heat production. Recent studies demonstrate that 7-oxo-dehydroepiandrosterone, one of its 7-oxygenated metabolites, is even more effective than dehydroepiandrosterone. Recent findings of various actions of these steroids support the view that they may also participate in modulating thermogenic effects.
Topics: Adrenal Cortex Hormones; Animals; Carrier Proteins; Dehydroepiandrosterone; Etiocholanolone; Gonadal Steroid Hormones; Humans; Ion Channels; Membrane Proteins; Mitochondrial Proteins; Steroids; Thermogenesis; Thyroid Hormones; Uncoupling Protein 1
PubMed: 15910167
DOI: 10.33549/physiolres.930758 -
Journal of Clinical Pathology.... 1974
Review
Topics: Adrenalectomy; Animals; Breast Neoplasms; Calcium; Castration; Cell Transformation, Neoplastic; Diethylstilbestrol; Estrogens; Etiocholanolone; Female; Humans; Hypophysectomy; Mammary Neoplasms, Experimental; Mice; Models, Biological; Progesterone; Prolactin; Rats; Receptors, Cell Surface
PubMed: 4364584
DOI: 10.1136/jcp.s3-7.1.65 -
Cell Reports Oct 2022The pyrin inflammasome acts as a guard of RhoA GTPases and is central to immune defenses against RhoA-manipulating pathogens. Pyrin activation proceeds in two steps....
The pyrin inflammasome acts as a guard of RhoA GTPases and is central to immune defenses against RhoA-manipulating pathogens. Pyrin activation proceeds in two steps. Yet, the second step is still poorly understood. Using cells constitutively activated for the pyrin step 1, a chemical screen identifies etiocholanolone and pregnanolone, two catabolites of testosterone and progesterone, acting at low concentrations as specific step 2 activators. High concentrations of these metabolites fully and rapidly activate pyrin, in a human specific, B30.2 domain-dependent manner and without inhibiting RhoA. Mutations in MEFV, encoding pyrin, cause two distinct autoinflammatory diseases pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) and familial Mediterranean fever (FMF). Monocytes from PAAND patients, and to a lower extent from FMF patients, display increased responses to these metabolites. This study identifies an unconventional pyrin activation mechanism, indicates that endogenous steroid catabolites can drive autoinflammation, through the pyrin inflammasome, and explains the "steroid fever" described in the late 1950s upon steroid injection in humans.
Topics: Etiocholanolone; Familial Mediterranean Fever; Humans; Inflammasomes; Mutation; Pregnanolone; Progesterone; Pyrin; Testosterone
PubMed: 36223753
DOI: 10.1016/j.celrep.2022.111472 -
Journal of the Endocrine Society Jul 2018To investigate the excretion and conjugation profile of testosterone (T), Epitestosterone (EpiT), and other androgen metabolites in different phases of pregnancy and...
OBJECTIVE
To investigate the excretion and conjugation profile of testosterone (T), Epitestosterone (EpiT), and other androgen metabolites in different phases of pregnancy and postpregnancy as a reflection of the "androgenic exposure."
DESIGN
Consecutive recruitment of pregnant women.
SETTING
Maternity outpatient low-risk pregnancy clinic.
PATIENTS
Seventy-seven pregnant women.
INTERVENTIONS
Collection of urine for analyses of sulfate (S) and glucuronide (G) conjugates and metabolic ratios of androgens and androgen metabolites using liquid chromatography-tandem mass spectrometry.
MAIN OUTCOME MEASURES
Excretion profiles and metabolic ratios of G and S conjugates of T, EpiT, dehydroepiandrosterone (DHEA), androsterone (A), etiocholanolone (Etio), and dihydrotestosterone in relation to trimester and postpartum, body mass index, fetal sex, and ethnicity.
RESULTS
T-S excretion increased significantly between the second and third trimester, whereas excretion of T-G did not change. In contrast, both conjugates of EpiT increased markedly, more so for the -(17-fold) than the G-conjugate (1.6-fold). The preference for S over G conjugation was conspicuous for EpiT and DHEA (S/G ratio 2.1 and 4.7, respectively, in the third trimester), whereas the reverse was true for T, A, and Etio (S/G 0.6, 0.13, and 0.11, respectively).
CONCLUSIONS
Pregnancy influences the androgen excretion profile, with the most profound change being an increase in EpiT excretion throughout the trimesters. EpiT may modulate the effect of T, but its exact role during pregnancy is not known. There were marked differences in the S/G conjugate ratios between androgens upstream and downstream from T in the metabolic network. These results are interesting to compare with the androgen disposition in women with endocrine disorders or abuse of steroids.
PubMed: 29942924
DOI: 10.1210/js.2018-00064 -
Progress in Brain Research 2010This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and their therapeutic potentials. Neurosteroids are synthesized... (Review)
Review
This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and their therapeutic potentials. Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. They are classified as pregnane neurosteroids, such as allopregnanolone and allotetrahydrodeoxycorticosterone, androstane neurosteroids, such as androstanediol and etiocholanolone, and sulfated neurosteroids such as pregnenolone sulfate. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful anti-seizure activity in diverse animal models. Neurosteroids increase both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety, and stress. Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-A receptor modulators, are memory-enhancing agents. Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy, and other brain disorders. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of epilepsy have been encouraging. Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.
Topics: Androstane-3,17-diol; Anesthetics; Anxiety; Brain; Depression; Female; Humans; Male; Neurotransmitter Agents; Pregnanolone; Premenstrual Syndrome; Receptors, GABA-A; Seizures; Sex Characteristics; Stress, Physiological
PubMed: 21094889
DOI: 10.1016/B978-0-444-53630-3.00008-7 -
European Journal of Heart Failure Oct 2022We examined the effects of istaroxime in patients hospitalized for acute heart failure (AHF) related Society for Cardiovascular Angiography and Interventions (SCAI)... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of istaroxime in patients with acute heart failure-related pre-cardiogenic shock - a multicentre, randomized, double-blind, placebo-controlled, parallel group study (SEISMiC).
AIMS
We examined the effects of istaroxime in patients hospitalized for acute heart failure (AHF) related Society for Cardiovascular Angiography and Interventions (SCAI) stage B pre-cardiogenic shock (CS).
METHODS AND RESULTS
Sixty patients with AHF without acute myocardial infarction with pre-CS, defined as systolic blood pressure (SBP) <90 mmHg without hypoperfusion, venous lactate ≥2 mmol/L and/or mechanical or inotropic support, were randomized to istaroxime 1.0-1.5 μg/kg/min or placebo for 24 h. The primary endpoint, the adjusted area under the curve (AUC) change in SBP from time of treatment to 6 h, was 53.1 (standard error [SE] 6.88) mmHg × hour versus 30.9 (SE 6.76) mmHg × hour with istaroxime versus placebo (p = 0.017). Adjusted SBP AUC at 24 h was 291.2 (SE 27.5) versus 208.7 (SE 27.0) mmHg × hour (p = 0.025). At 24 h, some echocardiographic measurements improved with istaroxime versus placebo including cardiac index (+0.21 L/min/m ; p = 0.016), left atrial area (-1.8 cm ; p = 0.008), and left ventricular end-systolic volume (-12.0 ml; p = 0.034). There were no significant differences in pulse pressure, laboratory measurements, serious adverse events or adverse events between the treatment groups except for more nausea, vomiting and infusion site pain in the istaroxime-treated patients. In a post-hoc analysis, patients receiving ≤1.0 μg/kg/min versus 1.5 μg/kg/min had similar increase in blood pressure, but a trend towards less adverse events.
CONCLUSION
In a phase 2a study of patients with AHF related pre-CS, istaroxime improved blood pressure and some echocardiography measures related to heart failure and was well tolerated.
Topics: Humans; Heart Failure; Shock, Cardiogenic; Cardiotonic Agents; Etiocholanolone; Double-Blind Method
PubMed: 35867804
DOI: 10.1002/ejhf.2629 -
Clinica Chimica Acta; International... Mar 2023Preoperative identification of malignant adrenal tumors is challenging. 24-h urinary steroid profiling by LC-MS/MS and machine learning has demonstrated high diagnostic...
OBJECTIVES
Preoperative identification of malignant adrenal tumors is challenging. 24-h urinary steroid profiling by LC-MS/MS and machine learning has demonstrated high diagnostic power, but the unavailability of bioinformatic models for public use has limited its routine application. We here aimed to increase usability with a novel classification model for the differentiation of adrenocortical adenoma (ACA) and adrenocortical carcinoma (ACC).
METHODS
Eleven steroids (5-pregnenetriol, dehydroepiandrosterone, cortisone, cortisol, α-cortolone, tetrahydro-11-deoxycortisol, etiocholanolone, pregnenolone, pregnanetriol, pregnanediol, and 5-pregnenediol) were quantified by LC-MS/MS in 24-h urine samples from 352 patients with adrenal tumor (281 ACA, 71 ACC). Random forest modelling and decision tree algorithms were applied in training (n = 188) and test sets (n = 80) and independently validated in 84 patients with paired 24-h and spot urine.
RESULTS
After examining different models, a decision tree using excretions of only 5-pregnenetriol and tetrahydro-11-deoxycortisol classified three groups with low, intermediate, and high risk for malignancy. 148/217 ACA were classified as being at low, 67 intermediate, and 2 high risk of malignancy. Conversely, none of the ACC demonstrated a low-risk profile leading to a negative predictive value of 100% for malignancy. In the independent validation cohort, the negative predictive value was again 100% in both 24-h urine and spot urine with a positive predictive value of 87.5% and 86.7%, respectively.
CONCLUSIONS
This simplified LC-MS/MS-based classification model using 24-h-urine provided excellent results for exclusion of ACC and can help to avoid unnecessary surgeries. Analysis of spot urine led to similarly satisfactory results suggesting that cumbersome 24-h urine collection might be dispensable after future validation.
Topics: Humans; Chromatography, Liquid; Tandem Mass Spectrometry; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adrenocortical Adenoma; Adrenal Gland Neoplasms; Steroids
PubMed: 36948238
DOI: 10.1016/j.cca.2023.117301 -
Experimental and Therapeutic Medicine Dec 2018Osteoporosis is liable to affect patients with gonadal hormone deficiency, and a supplement of androgens may be used to increase bone density of patients with...
Osteoporosis is liable to affect patients with gonadal hormone deficiency, and a supplement of androgens may be used to increase bone density of patients with osteoporosis. Since the androgens currently used may cause severe side effects, it is useful to investigate the effect of other androgens and progestin on bone improvement. The aim of the current study was to investigate the effects of pregnenolone (Preg), androstenedione (AD), etiocholanolone (Etio), androsterone (An), nandrolone (NA) and testosterone (T) on the proliferation and differentiation of osteoblasts for potential clinical applications. Human osteoblasts were cultured and treated with androgens and progestin, including Preg, AD, Etio, An, NA, and T, at concentrations of 0, 10, 10, 10 and 10 mol/l. The levels of cell proliferation, alkaline phosphatase (ALP) activity and osteocalcin content were measured and assessed. Preg, AD, Etio, An, and T at concentrations of 10 and/or 10 mol/l significantly improved osteoblast proliferation. NA at concentrations of 10, 10, 10 and 10 mol/l also significantly improved osteoblast proliferation. Preg, AD, Etio, An, NA, and T significantly increased ALP activity and osteocalcin content. The present study demonstrated, for the first time, that Preg, AD, Etio, An, and NA could improve the proliferation and differentiation of osteoblasts .
PubMed: 30542427
DOI: 10.3892/etm.2018.6772 -
Journal of Investigative Medicine : the... Feb 2012The survival and progression of prostate cancer are generally dependent on expression of the androgen receptor (AR), as well as the availability of endogenous AR... (Review)
Review
The survival and progression of prostate cancer are generally dependent on expression of the androgen receptor (AR), as well as the availability of endogenous AR agonists. Originating from the gonads, testosterone is released into circulation and is converted by steroid-5α-reductase in prostate cancer to 5α-dihydrotestosterone (DHT), potently activating AR and driving tumor progression. Advanced prostate cancer is initially treated with gonadal testosterone depletion, which suppresses this cascade of events and typically leads to a treatment response. Eventually, resistance to testosterone deprivation occurs with "castration-resistant" prostate cancer (CRPC) and is driven by the intratumoral synthesis of DHT. The generation of DHT occurs in large part from adrenal 19-carbon precursor steroids, which are dependent on expression of CYP17A1. Although the path from adrenal precursor steroids to DHT was generally thought to require 5α-reduction of testosterone, recent data suggest that it instead involves conversion from Δ-androstenedione by steroid-5α-reductase isoenzyme-1 to 5α-androstanedione, followed by subsequent conversion to DHT. The 5α-androstanedione pathway to DHT therefore bypasses testosterone entirely. Abiraterone acetate effectively inhibits CYP17A1, blocks the synthesis of androgens, and extends the survival of men with CRPC. Further progress in the hormonal treatment of CRPC is dependent on an understanding of the mechanisms that underlie CRPC and resistance to abiraterone acetate.
Topics: Abiraterone Acetate; Androstadienes; Biosynthetic Pathways; Dihydrotestosterone; Etiocholanolone; Humans; Male; Orchiectomy; Prostatic Neoplasms
PubMed: 22064602
DOI: 10.2310/JIM.0b013e31823874a4 -
Frontiers in Endocrinology 2021Alterations in glucocorticoid metabolism may contribute to the development of obesity and insulin resistance (IR). Obesity in turn affects the androgen balance. The...
Alterations in glucocorticoid metabolism may contribute to the development of obesity and insulin resistance (IR). Obesity in turn affects the androgen balance. The peripheral metabolism of steroids is equally an important determinant of their bioavailability and activity. The aim of this study was to evaluate steroid metabolism in obese children and to define which enzyme alterations are associated with IR. Clinical characteristics and anthropometric measurements were determined in 122 obese children and adolescents (72 girls, 50 boys) aged 8 - 18 years. 26 of them (21.3%) were diagnosed with IR (13 boys, 13 girls). Routine laboratory tests were performed and 24h urinary steroid excretion profiles were analyzed by gas chromatography/mass spectrometry. Positive relationship between 5α-reductase (SRD5A) activity and IR was found. According to the androsterone to etiocholanolone (An/Et) ratio the activity of SRD5A was significantly increased in obese children with IR, but the difference remained insignificant once the 5α-dihydrotestosterone to testosterone (5αDHT/T) ratio was considered. Furthermore, this relationship persisted in boys but was not observed in girls. The activity of 20α-hydroxysteroid dehydrogenase (20αHSD) and 20β-hydroxysteroid dehydrogenase (20βHSD) was reduced only in obese girls with IR. Conclude, in the context of obese children and adolescents with IR, we surmise that increased SRD5A represents a compensatory mechanism to reduce local glucocorticoid availability. This phenomenon is probably different in the liver (restriction) and in the adipose tissue (expected increase in activity). We show significant changes in 20αHSD and 20βHSD activity in obese girls with IR, but it is difficult to clearly determine whether the activity of these enzymes is an indicator of the function in their ovaries or adrenal glands.
Topics: 20-alpha-Hydroxysteroid Dehydrogenase; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Adolescent; Case-Control Studies; Child; Cortisone Reductase; Female; Humans; Insulin Resistance; Male; Membrane Proteins; Pediatric Obesity; Steroids
PubMed: 34764940
DOI: 10.3389/fendo.2021.759971