China
Africa
Explore chapters and articles related to this topic
Clinical Endocrinology of Pregnant Mares
Published in Juan Carlos Gardón, Katy Satué, Biotechnologies Applied to Animal Reproduction, 2020
Progestins can be classified in pregnenes and 5α-pregnenes. The first group includes P5, P4 and 5-pregnene-3β,20β-diol (P5ββ), while second group includes 5α-pregnane-3,20-dione (5αDHP), 3β-hydroxy-5α-pregnan-3-one (3β5P), 20α-hydroxy-5α-pregnan-3-one (20α5P), 5α-pregnane-3β,20β-diol (ββ-diol), and 5α-pregnane-3β,20α-diol (βα-diol). Of them, the most important ones in maternal plasma during this period are 5α-dihydroprogesterone (5αDHP) and its derivatives, 20α-hydroxy-5α-pregnan-3-one (20α5P) and 5α-pregnano-3β,20α-diol (βα-diol). The origin of all of them is found in P5, synthesized mainly in the fetal adrenal gland, with a production rate exceeding 10 μmol/min. In the placenta, P5 is converted to P4 and this is transformed into 5αDHP in the endometrium (Hamon et al., 1991; Han et al., 1995). Maternal plasma concentrations of 5αDHP progressively increase from 1.5 ng/mL in the first week of gestation to 38 ng/mL at term. Although at the beginning of gestation the pattern of secretion runs parallel to that of P4 around 90 days of gestation. Subsequently, the onset of P4 decline gives way to fetoplacental synthesis of the different progestogens whose concentrations continue to increase during the second half of gestation. Thus, 20α5P, which is initially at 5 ng/mL, reaches 69 ng/mL at 200 days of gestation and 300 ng/mL at term. On the other hand, the concentrations of βα-diol increase to 484 ng/mL (Legacki et al., 2016), while 3β5P, P5ββ, and ββ-diol reach values of 100, 10, and 100 ng/mL, respectively toward the end of gestation (326–350 days) (Ousey et al., 2005).
Steroid Metabolism in the Brain: Role in Sexual Differentiation
Published in Akira Matsumoto, Sexual Differentiation of the Brain, 2017
Paola Negri-Cesi, Angelo Poletti, Luciano Martini, Flavio Piva
An important aspect, which has emerged in the last 30 years, is that the brain in general, and some specialized CNS structures in particular, may metabolize hormonal steroids. Several enzymatic systems have been described, and some of them have been fully characterized. Among these, some have the peculiarity of totally changing the molecular behavior of the substrate (e.g., the aromatization of testosterone to estradiol), while others have the property of enhancing its activity (e.g., the 5α-reductase, 5α-R, which converts testosterone to the more androgenic compound 5α-DHT); finally, some enzymes (e.g., the 3α-hydroxy steroid dehydrogenase, 3α-HSD) may modify steroids so that the resulting metabolites may eventually interact with receptors other than the classical intracellular steroid receptors (e.g., the 3α-hydroxylated derivatives of 5α-dihydroprogesterone, 5α-DHP, and 5α-deoxycorticosterone, 5α-DOC, which bind and activate the GABAA receptor,25,26 see below).
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
We tested that hypothesis using cloned cDNAs encoding rat 3a HSD and human type III 3a HSD, the enzyme that can convert 5α-dihydroprogesterone to allopregnanolone.107 Our data indicated that three SSRIs, Prozac, Paxil, and Zoloft, all increased allopregnanolone production by increasing the efficiency of conversion of 5α-dihydroprogesterone to allopregnanolone. As 3a HSD catalyzes a reversible reaction, we also tested the hypothesis that these SSRIs increased allopregnanolone concentrations by inhibiting the oxidation of allopregnanolone to 5α-dihydroprogesterone. Our data suggested that Prozac, but not Paxil or Zoloft, increased the oxidation of allopregnanolone as well, but that the overall effect (reductive and oxidative reactions) was to increase allopregnanolone.
GABA(A) receptor-targeted drug development -New perspectives in perioperative anesthesia
Published in Expert Opinion on Drug Discovery, 2019
Bernd Antkowiak, Gerhard Rammes
Etifoxine (Stresam™) has been developed by Hoechst in the 1960s and has anxiolytic and anticonvulsant properties [234]. In hypothalamic neurons, etifoxine enhanced the tonic inhibition mediated by extrasynaptic GABAA receptor, an effect that was partly blocked by the 5α-reductase inhibitor finasteride [235]. Consistent with this observation, etifoxine caused an elevation of plasma and brain levels of pregnenolone, progesterone, 5α-dihydroprogesterone and 3α,5α-THPROG. Interestingly, etifoxine binds with lower affinity but it turned out to be a more potent enhancer of neurosteroidogenesis as XBD173 [236] hence demonstrating that efficacy is not simple predictable from binding affinity to TSPO. The increase in neurosteroid levels was independent from peripheral sources, indicating a brain-specific release of neurosteroids. These data suggest that activation of brain neurosteroidogenesis partially contributes to the anxiolytic-like effects of etifoxine [237]. Moreover, the reduction of chemotherapy-induced neuropathic pain by etifoxine is mediated by 3α,5α-THPROG [238]. Etifoxine is structurally distinct and does not bind to the benzodiazepine receptor [239]. It is more effective than lorazepam as an anxiolytic, and, unlike benzodiazepines does not induce sedation and ataxia. Presently, etifoxine is approved and marketed in France for the treatment of anxiety disorders, and studies are underway to promote neurosteroid-induced peripheral nerve healing and to treat axonal neuropathies [240].
The history of natural progesterone, the never-ending story
Published in Climacteric, 2018
In the early 1940s too, it was shown by Hans Seyle that high doses of progesterone can very rapidly modulate brain excitability by inducing anesthesia in rats23. In the 1970s, Karavolas and collaborators showed that progesterone was converted to 5α-dihydroprogesterone and allopregnanolone within the rat hypothalamus and pituitary gland24; in 1986 came the demonstration that both allopregnanolone (3α,5α-tetrahydroprogesterone) and 3α,5α-tetrahydrodeoxycorticosterone are natural positive modulators of neuronal GABAA receptors, providing a mechanistic insight into the rapid psychopharmacological actions of progesterone and its metabolites, including anxiolytic, antidepressant, anesthetic, anticonvulsant, and analgesic effects25.
Ziram inhibits rat neurosteroidogenic 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase
Published in Toxicology Mechanisms and Methods, 2018
Ying Su, Huitao Li, Xiaomin Chen, Yiyan Wang, Xiaoheng Li, Jianliang Sun, Ren-Shan Ge
In the nerve system, there are several steroids, such as allopregnanolone (ALLO) and 5α-androstane-3α, 17β-diol (DIOL), which exert nervous activity. They bind to GABAA receptors potently as the agonists to regulate nervous functions (Murono and Derk 2004). The synthesis of ALLO and DIOL in rat nerve system requires two important enzymes: steroid 5α-reductase 1 (SRD5A1) and 3α-Hydroxysteroid dehydrogenase (AKR1C14). SRD5A1 uses either progesterone or testosterone to convert them into 5α-dihydroprogesterone or dihydrotestosterone (DHT), respectively (Scheme 2) (Fry et al. 2014). SRD5A1 is a microsomal enzyme, which catalyzes the reduction at the five-position of steroids and requires NADPH as the cofactor. AKR1C14 then converts the above steroid intermediates into either ALLO or DIOL (Scheme 2) (Murono and Derk 2004). AKR1C14 is a cytosolic enzyme, which catalyzes the reduction at the 3α-position of the steroids (Hung and Penning 1999) and requires NADPH as the cofactor (Karavolas and Hodges 1990; Mellon and Vaudry 2001; Fry et al. 2014). The brain levels of ALLO and DIOL are regulated not only by these neurosteroid synthetic enzymes but also by the metabolizing enzyme, retinol dehydrogenase 2 (RDH2). RDH2, a brain steroidogenic enzyme, exerts the oppositely catalytic direction of AKR1C14, eliminating ALLO and DIOL (Scheme 2). RDH2 is an NAD+-dependent microsomal enzyme, which regulates not only the retinol biosynthesis but also the ALLO and DIOL metabolism. RDH2 belongs to the short-chain dehydrogenase/reductase family and removes a hydrogen from 3α-position of many steroids (Hardy et al. 2000). In the present study, we performed experiments to demonstrate that ziram inhibited SRD5A1 and AKR1C14 without affecting RDH2 in rats.