Disease relevance of 5-alpha-Dihydroprogesterone

• Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone, pregnenolone sulfate, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnan-20-one [1].
• The role of MAPK in lordosis facilitation by two ring A-reduced metabolites of P, 5alpha-dihydroprogesterone (5alpha-DHP) and 5alpha,3alpha-pregnanolone (5alpha,3alpha-Pgl), was also assessed [2].
• 5alpha-dihydroprogesterone had a low ED50 of 6.2 mg/kg against both the generalized component of the amygdala-kindled seizure and the focal seizure [3].
• Low doses of 5alpha-dihydroprogesterone (0.25 and 0.5 mg/kg body weight, b.w.) prevented the loss of hilar neurones and the appearance of vimentin immunoreactivity in astrocytes [4].
• Tumorous human breast tissue readily converts progesterone to 5alpha-pregnane-3,20-dione (5alphaP), and this metabolite has been shown to stimulate proliferation and to decrease adhesion of MCF-7 breast cancer cells [5].

High impact information on 5-alpha-Dihydroprogesterone

• Here we show that NP-C mouse brain contains substantially less neurosteroid than wild-type brain and has an age-related decrease in the ability to synthesize 5alpha-dihydroprogesterone and allopregnanolone [6].
• Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation [7].
• Variants selected by an initial screening in competition against a large excess of 5beta- or 5alpha-dihydroprogesterone were characterized by a convergent amino acid signature different from that of the wild-type antibody and had lower cross-reactivity [8].
• Allopregnanolone (3alpha,5alpha-TH PROG) and 5alpha-dihydroprogesterone (5alpha-DH PROG), the two most important neuroactive steroids synthesized in the brain, potently modulate neuronal activity by allosterically regulating GABA action at GABA(A) receptors or by changing specific GABA(A) receptor subunit gene expression, respectively [9].
• The ability of the 5 alpha-dihydroprogesterone analog, 4-aza-4-methyl-5 alpha-pregnane-3,20-dione (AMPD), to inhibit the progesterone 5 alpha-reductase and the two 5 alpha-dihydroprogesterone 3 alpha-hydroxysteroid oxidoreductase activities (NADH- and NADPH-linked) from female rat hypothalamus has been studied [10].

Biological context of 5-alpha-Dihydroprogesterone

• From the results of this study, it appears that the concentrations of 5alpha-pregnane-3,20-dione in peripheral blood during the luteal phase are proportional to the availability of progesterone as substrate for the 5alpha-reductase enzyme system [11].
• Progesterone and 5alpha-pregnane-3,20-dione in peripheral blood of normal young women: Daily measurements throughout the menstrual cycle [11].
• The concentrations of progesterone and 5alpha-pregnane-3,20-dione during the follicular phase were 0.11 +/- 0.02 ng/ml (mean +/- SE) and 0.16 +/- 0.01 ng/ml, respectively [11].
• The activity of the nuclear binding protein was specific essentially for progestational steroids; the two most potent progesterone competitors were 5 alpha-pregnane-3,20-dione and medroxyprogesterone (17 alpha-hydroxy-6 alpha-methylprogesterone), while 17 beta-estradiol, testosterone, cortisol, and other related steroids were poor competitors [12].
• This down-regulation appears to be linked to an increase in circulatory 5alpha-pregnane-3,20-dione concentration in the plasma of pregnant animals [13].

Anatomical context of 5-alpha-Dihydroprogesterone

• The binding of 5 alpha-pregnane-3,20-dione by cytosol and nuclear preparations of guinea pig uterus [14].
• The conversion of progesterone into 5 alpha-pregnane-3,20-dione, 3 beta-hydroxy-5 alpha-pregnan-20-one, and its fatty acid esters by preparations of bovine corpora lutea [15].
• The purpose of the present study was to investigate the anticonvulsant actions of progesterone and its primary metabolite 5alpha-dihydroprogesterone in the amygdala kindling model [16].
• During the third cycle, the concentrations of progesterone and of its metabolites 5alpha-dihydroprogesterone and 3alpha-hydroxy-5alpha-pregnan-20-one were measured in the preoptic area (POA) [17].
• The 5alpha-reduced progesterone metabolites such as 5alpha-dihydroprogesterone (5alphaP) promote both mitogenic and metastatic activity in breast cell lines in culture, whereas the 4-pregnene metabolites, 4-pregnen-3alpha-ol-20-one (3alphaHP) and 4-pregnen-20alpha-ol-3-one (20alphaHP) have the opposite (anti-cancer-like) effects [18].

Associations of 5-alpha-Dihydroprogesterone with other chemical compounds

• The modulatory effects of gestational age and circulating concentrations of progesterone, 5alpha-pregnane-3,20-dione, and estradiol-17beta on the uterine sex steroid hormone receptor levels of the African elephant were investigated [13].
• Trilostane inhibited the conversion of pregnenolone to progesterone in vitro (P < 0.001) while mediating an increase (P < 0.05) in concentrations of 5 alpha-pregnane-3,20-dione and 3 beta-hydroxy-5 alpha-pregnan-20-one [19].
• Although 4-ene-5alpha-reductase enzyme(s) is present in the ovary and placenta, significant quantities of the reduced progestin 5alpha-pregnane-3,20-dione are not secreted into the systemic circulation during gestation in the rat [20].
• We compared the effect of 9 and 21 days i.p. administration of paroxetine, a potent SSRI, on the synthesis of THP and its precursor, 5alpha-dihydroprogesterone (DHP), in the mouse cortex, hypothalamus and olfactory bulb [21].
• Besides testosterone and 5alpha-dihydrotestosterone, testes are able to synthesize 5alpha-pregnan-3,20-dione and several 3alpha- and 20alpha-reduced derivatives [22].

Gene context of 5-alpha-Dihydroprogesterone

• Women with steroid 5 alpha-reductase 2 deficiency have normal concentrations of plasma 5 alpha-dihydroprogesterone during the luteal phase [23].
• Previous studies have shown that the progesterone metabolite, 5alpha-pregnane-3,20-dione (5alphaP), exhibits mitogenic and metastatic activity in breast cell lines and that specific, high affinity receptors for 5alphaP are located in the plasma membrane fractions of tumorigenic (ER/PR-positive) MCF-7 cells [24].
• In vitro investigations demonstrated a dose-dependent inhibitory effect of mirtazapine on the activity of the microsomal 3alpha-HSD in the oxidative direction (conversion of 3alpha,5alpha-tetrahydroprogesterone to 5alpha-dihydroprogesterone) [25].
• Tissue radiolabeled P4 and P4 metabolites (5 alpha-pregnane-3,20-dione, DHP; 20 alpha-hydroxy P4; 17 alpha-hydroxy P4, and hydroxylated DHP derivatives) were extracted and separated by thin-layer chromatography (TLC) [26].
• Homogenates of histologically normal human testis from three men were incubated separately with pregnenolone, 16-dehydropregnenolone, 5alpha-pregnane-3,20-dione, 3beta-hydroxy-5alpha-pregnan-20-one and androsta-5,16-dien-3beta-ol (androstadienol) in the presence of NADPH in a study of androst-16-ene and androgen biosynthesis [27].

Analytical, diagnostic and therapeutic context of 5-alpha-Dihydroprogesterone

• The radioactive metabolites, 20alpha-hydroxy-4-pregnen-3-one, 5alpha-pregnane-3,20-dione and 3beta-hydroxy-5alpha-pregnan-20-one, were isolated and identified by derivative formation, a combination of chromatographic techniques, and by crystallization to constant specific activity after addition of authentic standards [28].
• Circulating estradiol-17beta and progesterone concentrations were measured by means of RIAs, while plasma concentrations of 5alpha-pregnane-3,20-dione were determined with an amplified ELISA [13].
• 5beta-pregnane-3,20-dione was not cross-reactive with the radioimmunoassay system and was not detected by gas-liquid chromatography [29].
• For the measurement of 5 alpha-pregnane-3,20-dione (DHP), the predominant ovarian gestagen in both species, an enzyme-immunoassay (EIA) based on commercial reagents was applied [30].

References