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Archives of Endocrinology and Metabolism Mar 2022Adrenal steroid biosynthesis and its related pathology are constant evolving disciplines. In this paper, we review classic and current concepts of adrenal... (Review)
Review
Adrenal steroid biosynthesis and its related pathology are constant evolving disciplines. In this paper, we review classic and current concepts of adrenal steroidogenesis, plus control mechanisms of steroid pathways, distribution of unique enzymes and cofactors, and major steroid families. We highlight the presence of a "mineralocorticoid (MC) pathway of zona fasciculata (ZF)", where most circulating corticosterone and deoxycorticosterone (DOC) originate together with 18OHDOC, under ACTH control, a claim based on functional studies in normal subjects and in patients with 11β-, and 17α-hydroxylase deficiencies. We emphasize key differences between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) and the onset of a hybrid enzyme - CYP11B1/CYP11B2 -, responsible for aldosterone formation in under ACTH control, in "type I familial hyperaldosteronism" (dexamethasone suppressible). In "apparent MC excess syndrome", peripheral conversion of cortisol to cortisone is impaired by lack of 11β-hydroxysteroid dehydrogenase type 2, permitting free cortisol access to MC receptors resulting in severe hypertension. We discuss two novel conditions involving the synthesis of adrenal androgens: the , through which dihydrotestosterone is formed directly from androsterone, being relevant for the fetoplacental setting and sexual differentiation of male fetuses, and the rediscovery of C19 11-oxygenated steroids (11-hydroxyandrostenedione and 11-ketotestosterone), active androgens and important markers of virilization in 21-hydroxylase deficiency and polycystic ovaries syndrome. Finally, we underline two enzyme cofactor deficiencies: cytochrome P450 oxidoreductase which partially affects 21- and 17α-hydroxylation, producing a combined clinical/hormonal picture and causing typical skeletal malformations (Antley-Bixler syndrome), and PAPSS2, coupled to SULT2A1, that promotes sulfation of DHEA to DHEAS, preventing active androgens to accumulate. Its deficiency results in reduced DHEAS and elevated DHEA and androgens with virilization. Future and necessary studies will shed light on remaining issues and questions on adrenal steroidogenesis.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Cytochrome P-450 CYP11B2; Humans; Hyperaldosteronism; Male; Steroids
PubMed: 35263051
DOI: 10.20945/2359-3997000000438 -
Molecules (Basel, Switzerland) Mar 2023Two series of novel steroidal[17,16-]pyrimidines derived from natural epiandrosterone and androsterone were designed and synthesized, and these compounds were screened...
Two series of novel steroidal[17,16-]pyrimidines derived from natural epiandrosterone and androsterone were designed and synthesized, and these compounds were screened for their potential anticancer activities. The preliminary bioassay indicated that some of these prepared compounds exhibited significantly good cytotoxic activities against human gastric cancer (SGC-7901), lung cancer (A549), and hepatocellular liver carcinoma (HepG2) cell lines compared with 5-fluorouracil (5-FU), epiandrosterone, and androsterone. Especially the respective pairs from epiandrosterone and androsterone showed significantly different inhibitory activities, and the possible configuration-activity relationships have also been summarized and discussed based on kinase assay and molecular docking, which indicated that the inhibition activities of these steroidal[17,16-]pyrimidines might obviously be affected by the configuration of the hydroxyl group in the part of the steroidal scaffold.
Topics: Humans; Androsterone; Pyrimidines; Molecular Docking Simulation; Cell Proliferation; Cell Line, Tumor; Antineoplastic Agents; Steroids; Fluorouracil; Carcinoma, Hepatocellular; Drug Screening Assays, Antitumor; Liver Neoplasms; Structure-Activity Relationship
PubMed: 36985662
DOI: 10.3390/molecules28062691 -
EBioMedicine Sep 2023Autonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of...
BACKGROUND
Autonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of endogenous SIOP cannot be explained by cortisol excess alone, and how other steroid metabolites affect bone status is unclear.
METHODS
ACS was diagnosed as serum cortisol ≥1.8 μg/dL after the 1-mg dexamethasone suppression test (DST-cortisol). Using liquid chromatography tandem mass spectrometry, 21 plasma steroid metabolites were measured in 73 patients with ACS and 85 patients with non-functioning adrenal tumors (NFAT). Expression of steroidogenic enzymes and relevant steroid metabolites were analyzed in some of CPA tissues.
FINDINGS
Discriminant and principal component analyses distinguished steroid profiles between the ACS and NFAT groups in premenopausal women. Premenopausal women with ACS exhibited higher levels of a mineralocorticoid metabolite, 11-deoxycorticosterone (11-DOC), and lower levels of androgen metabolites, dehydroepiandrosterone-sulfate, and androsterone-glucuronide. In premenopausal women with ACS, DST-cortisol negatively correlated with trabecular bone score (TBS). Additionally, 11-DOC negatively correlated with lumbar spine-bone mineral density, whereas androsterone-glucuronide positively correlated with TBS. The CPA tissues showed increased 11-DOC levels with increased expression of CYP21A2, essential for 11-DOC synthesis. Adrenal non-tumor tissues were atrophied with reduced expression of CYB5A, required for androgen synthesis.
INTERPRETATION
This study demonstrates that unbalanced production of adrenal steroid metabolites, derived from both adrenal tumor and non-tumor tissues, contributes to the pathogenesis of endogenous SIOP in premenopausal women with ACS.
FUNDING
JSPS KAKENHI, Secom Science and Technology Foundation, Takeda Science Foundation, Japan Foundation for Applied Enzymology, AMED-CREST, JSTA-STEP, JST-Moonshot, and Ono Medical Research Foundation.
Topics: Humans; Female; Adrenal Gland Neoplasms; Hydrocortisone; Androgens; Androsterone; Cushing Syndrome; Glucuronides; Steroids; Osteoporosis; Steroid 21-Hydroxylase
PubMed: 37543511
DOI: 10.1016/j.ebiom.2023.104733 -
Plants (Basel, Switzerland) Dec 2021Although the only known steroid hormones in plants are brassinosteroids, interestingly, mammalian steroid hormones such as androgens or estrogens are also part of the... (Review)
Review
Although the only known steroid hormones in plants are brassinosteroids, interestingly, mammalian steroid hormones such as androgens or estrogens are also part of the plant metabolic profile. This presented review is focused on the progress that has been made in this matter during the last two decades. The presence of testosterone, 17β-estradiol, and other androgens/estrogens in plants (particularly those that can be measured using more advanced techniques) is described. The physiological activity of androgens and estrogens, especially in plants' stress response, are discussed, together with some possible mechanisms of their action. The current knowledge indicates that although androgens and estrogens do not have the status of hormones in plants, they are physiologically active and can serve as regulators that support the activity of classic hormones in (1) regulating the various processes connected with plant growth and development and (2) the interaction of plants with their environment.
PubMed: 34961254
DOI: 10.3390/plants10122783 -
Frontiers in Endocrinology 2020Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been...
Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been continuously searched for. In this context, a group of endogenous or exogenous neurosteroids allosterically positively modulating GABA-A receptors may offer a promising approach. Among endogenous neurosteroids synthesized in the brain, allopregnanolone or allotetrahydrodeoxycorticosterone have been documented to exert anticonvulsant activity in a number of experimental models of seizures-pentylenetetrazol-, bicuculline- pilocarpine-, or 6 Hz-induced convulsions in rodents. Neurosteroids can also inhibit fully kindled seizures and some of them have been reported to counteract maximal electroshock-induced convulsions. An exogenous neurosteroid, alphaxalone, significantly elevated the threshold for maximal electroconvulsions in mice but it did not potentiate the anticonvulsive action of a number of conventional antiepileptic drugs against maximal electroshock-induced seizures. Androsterone not only elevated the threshold but significantly enhanced the protective action of carbamazepine, gabapentin and phenobarbital against maximal electroshock in mice, as well. Ganaxolone (a 3beta-methylated analog of allopregnanolone) needs special consideration for two reasons. First, it performed better than conventional antiepileptic drugs, diazepam or valproate, in suppressing convulsive and lethal effects of pentylenetetrazol in pentylenetetrazol-kindled mice. Second, ganaxolone has been evaluated in the randomized, double-blind, placebo-controlled phase 2 trial in patients with intractable partial seizures, taking maximally 3 antiepileptic drugs. The initial results indicate that add-on therapy with ganaxolone resulted in reduced seizure frequency with adverse effect being mainly mild to moderate. Possibly, ganaxolone may be also considered against catamenial seizures. Some positive effects of ganaxolone as an adjuvant were also observed in children with refractory seizures and its use may also prove efficient for the management of neonatal seizures associated with hypoxic injury. Neurosteroids positively modulating GABA-A receptor complex exert anticonvulsive activity in many experimental models of seizures. Their interactions with antiepileptic drugs seem ambiguous in mice. Initial clinical data indicate that ganaxolone may provide a better seizure control in patients with drug-resistant epilepsy.
Topics: Allosteric Regulation; Animals; Anticonvulsants; Epilepsy; GABA-A Receptor Agonists; Humans; Neurosteroids; Seizures; Treatment Outcome
PubMed: 33117274
DOI: 10.3389/fendo.2020.541802 -
Journal of Human Kinetics Mar 2018The aim of this study was to determine variations in the urinary steroid profile of triathletes following an Ironman event. A total of 10 male participants (age = 36.0...
The aim of this study was to determine variations in the urinary steroid profile of triathletes following an Ironman event. A total of 10 male participants (age = 36.0 ± 1.27 years; body height = 179.29 ± 10.77 cm; body mass = 74.50 ± 1.04 kg) completed an Ironman Championship. Urine samples were collected before, immediately after, and 24 hours following the race. Gas chromatography-mass spectrometry (GC/MS) was used to detect and quantify catabolic and anabolic hormones: Androsterone, Dehydroepiandrosteone (DHEA), Androstenedione and Testosterone (T), Betaestradiol, Estrone, Progesterone, Cortisol (C), Cortisone, Tetrahydrocortisol (THE) and Tetrahydrocortisone (THF). These were measured in their glucuroconjugated and free forms. Androsterone (3297.80 ± 756.83 vs. 2154.26 ± 1375.38), DHEA (47.80 ± 19.21 vs. 32.62 ± 15.96) and Beta-estradiol (59.36 ± 11.7 vs. 41.67 ± 10.59) levels decreased after the event. The significant decrease of DHEA (47.80 ± 19.21 vs. 32.11 ± 14.03) remained at 24 hours. Cortisol (200.38 ± 56.60 vs. 257.10 ± 74.00) and THE (238.65 ± 81.55 vs. 289.62 ± 77.13) increased after exercise and remained elevated 24 hours later (200.38 ± 56.60 vs. 252.48 ± 62.09; 238.65 ± 81.55 vs. 284.20 ± 66.66). The following anabolic/catabolic ratios fell after exercise: T/C (0.85 ± 0.54 vs. 0.54 ± 0.29), T/THE (0.66 ± 0.29 vs. 0.40 ± 0.08), T/THE+THF (0.38 ± 0.17 vs. 0.24 ± 0.06), DHEA/THE (0.22 ± 0.05 vs. 0.12 ± 0.05), DHEA/THF (0.34 ± 0.02 vs. 0.21 ± 0.01) and DHEA/THE+THF (0.12 ± 0.02 vs. 0.08 ± 0.03). The steroid profile showed that athletes were fatigued after finishing the competition and a catabolic state remained 24 hours later.
PubMed: 29599864
DOI: 10.1515/hukin-2017-0130 -
Frontiers in Surgery 2021A 64-year-old female was admitted to our clinic with a 9-cm-sized adrenal mass. The patient's main symptom was hirsutism, which included thinning scalp hair and...
A 64-year-old female was admitted to our clinic with a 9-cm-sized adrenal mass. The patient's main symptom was hirsutism, which included thinning scalp hair and excessive hair growth over her torso and arms. Upon investigation, elevated values of testosterone, androsterone D4, and DHEA-S were found. Contrast-enhanced abdominal CT and MRI scans revealed a heterogenous large mass (diameter 9 × 8.5 cm) with focal calcifications, necrotic areas, and a clear distinction from the adjacent structures. The patient underwent a right adrenalectomy. The histological examination of the tumor revealed a borderline adrenocortical oncocytoma. The patient had an uncomplicated postoperative course and was discharged on postoperative day 8. Similar cases reported in the literature are also being reviewed in this case report.
PubMed: 33829037
DOI: 10.3389/fsurg.2021.646459 -
Biology Mar 2022Glucuronidation, catalyzed by UDP-glucuronosyltransferase UGT2B enzymes, is a major inactivating and elimination pathway for androgen hormones in humans. Whether Ugt2b...
Glucuronidation, catalyzed by UDP-glucuronosyltransferase UGT2B enzymes, is a major inactivating and elimination pathway for androgen hormones in humans. Whether Ugt2b enzymes from mice are also reactive with these hormones have never been investigated. The present study aimed at evaluating the capability of murine tissues and Ugt2b enzymes to glucuronidated androgens. The 7 murine Ugt2b (Ugt2b1, 2b5, 2b34, 2b35, 2b36, 2b37 and 2b38) enzymes were cloned and stably expressed into HEK293 cells. In vitro glucuronidation assays were performed with microsomal proteins or homogenates from mice tissues (liver, kidney, intestine, adipose, testis, prostate, epididymis, bulbo, seminal vesicle, mammary glands, uterus, and ovary) and from Ugt2b-HEK293 cells. Male and female livers, as well as male kidneys, are the major sites for androgen glucuronidation in mice. The male liver is highly efficient at glucuronidation of dihydrotestosterone (DHT) and testosterone and is enriched in Ugt2b1 and 2b5 enzymes. Androsterone and 3α-Diol are conjugated in the male kidney through an Ugt2b37-dependent process. Interestingly, castration partially abolished hepatic Ugt2b1 expression and activity, while Ugt2b37 was totally repressed. DHT injection partially corrected these changes. In conclusion, these observations revealed the substrate- and tissue-specific manner in which murine Ugt2b enzymes conjugate androgens. They also evidence how androgens modulate their own glucuronide conjugation in mice.
PubMed: 35336777
DOI: 10.3390/biology11030403 -
Acta Neurobiologiae Experimentalis 2012The neurosteroids, dehydroepiandrosterone sulfate (DHEAS) and androsterone, are implicated in drug addictions. We examined their influence on locomotor activity and...
The neurosteroids, dehydroepiandrosterone sulfate (DHEAS) and androsterone, are implicated in drug addictions. We examined their influence on locomotor activity and reward in male Wistar rats, and on steroid and monoamine metabolism in the hippocampus and striatum. In the open field test, DHEAS injections (10, 40, 80 mg/kg, i.p.) 30 min prior the test had no significant effect on ambulation, but androsterone (10 mg/kg) increased general locomotion and at doses 1-10 mg/kg, increased central field activity, suggestive of an anxiolytic action. In the conditioned place preference test, both steroids had a biphasic effect: DHEAS was rewarding at doses of 10 and 40 mg/kg, but not at 80 mg/kg, while androsterone was rewarding at doses of 1 and 10 mg/kg, but aversive at 40 mg/kg. Monoamine and steroid concentrations were analyzed in homogenates from the hippocampus and striatum of DHEAS and androsterone injected rats. DHEAS reduced the hippocampal dopamine level, increased striatal homovanilic acid (HVA) and decreased the striatal serotonin concentrations. Androsterone did not affect dopamine levels or turnover, but increased noradrenaline concentration and serotonin turnover in the hippocampus. DHEAS administration augmented concentrations of DHEA, pregnenolone, androstendiol and androstentriol in both brain structures, while androsterone injections increased brain levels of androsterone, epiandrosterone, 5α-dihydrotestosterone, and androstandiol. Present data document that although psychobehavioral and neurochemical effects of DHEAS and androsterone differ in several aspects; both neurosteroids have rewarding properties at certain dose ranges, suggesting their likely involvement in addictions, which entail different mechanisms.
Topics: Androsterone; Animals; Basal Ganglia; Biogenic Amines; Dehydroepiandrosterone Sulfate; Dopamine; Hippocampus; Male; Pregnenolone; Psychomotor Performance; Rats; Rats, Wistar; Reward; Serotonin; Steroids
PubMed: 22508085
DOI: 10.55782/ane-2012-1881