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At least 19 recordsLinked to original sources
PubMed1992

Evidence that 3 alpha-hydroxy-5 alpha-pregnan-20-one is the metabolite responsible for anesthesia induced by 5 alpha-pregnanedione in the mouse.

Mice were anesthetized with [3H]5 alpha-pregnanedione (5 alpha). Brain levels for 5 alpha and its metabolites were quantitated and compared at time points following injection and at two behavioral endpoints that are characteristic of the anesthetized state. The results support the hypothesis that 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha), a metabolite of 5 alpha, mediates this anesthetic response, and they weigh against the hypothesis that 5 alpha itself is solely responsible for activity. Anesthesia occurred at 3-8 min following injection. During this period, levels of 3 alpha derived from 5 alpha were comparable to those seen when 3 alpha was administered alone. It is estimated that 5 alpha, if active at all, is at least 3-5 times less potent than 3 alpha.

5-alpha-Dihydroprogesterone↗
PubMed1975

[Effects of combination alfaxalone and alfadolone, anesthetic derivatives of pregnanedione, on cerebral hemodynamics in cats].

Intravenous injection of CT 1341 (a mixture of alphaxalone and alphadolone dissolved in cremophor el) induced a decrease in cerebral blood flow (CBF) measured by 133Xe clearance in cats with artificial respiration (the mean reduction in CBF was 2 ml/100 g/mn for 1,2 mg/kg or CT 1341. So, CBF was decreased by 22% when CT 1341 (7,2 mg/kg) was intravenously injected, (mean Pa CO2 equals 30 mm Hg). Changes in CBF following CT 1341 intravenous injection seems to be caused by cerebral vascular constriction evidenced by the direct observation of pial vessels. Following intravenous injection of CT 1341 (from 7, 2 mg/kg to 19,2 mg/kg), the cerebrovascular reactivity to hypercapnia or hypocapnia was not affected, but autoregulation of cerebral blood flow was transiently abolished. In animals with free respiration, CBF was increased in relation with the elevation in Pa CO2 caused by the depression of respiration.

Alfaxalone Alfadolone Mixture↗
PubMed1978

The binding of 5 alpha-pregnane-3,20-dione by cytosol and nuclear preparations of guinea pig uterus.

We compared the binding characteristics of [3H]progesterone and 5 alpha-[3H]pregnanedione in cytosol and nuclear preparations of ovariectomized, estrogen-treated guinea pig uterus. There were similarities as well as differences in binding behavior. [3H]Progesterone and 5 alpha-[3H]pregnanedione were bound in cytosol with approximately the same apparent association constants and concentrations of binding sites. When centrifuged on sucrose gradients in 5 mM phosphate buffer, binding peaks with sedimentation coefficients of 7S were found with both. 5 alpha-[3H]Pregnanedione was bound by uterine nuclei and, like [3H]progesterone, required temperature-activated cytosol of estrogen-stimulated uterus. A series of unlabeled steroids had similar relative abilities to displace both [3H]progesterone and 5 alpha-[3H]pregnanedione from receptor complexes in cytosol or nuclei. When cytosol was incubated with increasing concentrations of [3H]progesterone or 5 alpha-[3H]pregnanedione the amount of 5 alpha-[3H]pregnanedione bound exceeded the amount of [3H]progesterone bound at steroid concentrations above 5 x 10(-9) M. This suggested that 5 alpha-pregnanedione was bound by additional components of the cytosol and the suggestion was strengthened by sucrose gradient analysis. At greater than saturating-steroid concentrations, the partition between 7S and 4 S binding proteins was different. [3H]Progesterone bound to 7S binding proteins in preference to 4S binders, whereas 5 alpha-pregnanedione showed relatively more 4S binding.

Animals↗
PubMed1991

Regulatory effects of 5 beta-reduced steroids.

The first section of this publication summarizes early work according to which 5 beta-pregnanedione is an important metabolite of progesterone in the early stages of the chick embryo's adrenal steroidogenesis, then decreasing gradually as corticosteroidogenesis increases. In the second section a model is described in which adrenal 3 beta-ol hydroxylase-isomerase of the 17-day-old chicken is suppressed pharmacologically, this suppression being correlated with that of the synthesis of aminoevulinic acid (ALA), the first and rate-limiting step of the heme pathway. 5 beta-Pregnanedione (10(-7)-10(-6) M) restored ALA synthesis in this inhibited model to normal values. The effect of 5 beta-pregnanedione was specific since other steroids tested: progesterone; 5 alpha-pregnanedione; corticosterone or estradiol, did not stimulate ALA. Since heme formation by steroidogenic glands contributes to the synthesis of cytochrome P450 rather than hemoglobin, 5 beta-pregnanedione was also assayed as a stimulator of this enzyme system and was found to increase cytochrome P450 in adrenals and testes but not in the liver. In view of these results a hypothesis is advanced according to which 5 beta-reduced progestagens and androgens stimulate cytochrome P450 formation, i.e. the synthesis of progesterone and higher hydroxylated steroids, by steroidogenic glands in the event of an excessive precursor reduction.

Aminolevulinic Acid↗
PubMed1991

In vitro metabolism of progesterone by peripheral blood of rock hyrax (Procavia capensis).

In vitro metabolism of progesterone by hyrax whole blood, erythrocytes, or plasma in the presence or absence of NADPH was investigated. In the presence of NADPH, whole blood metabolized progesterone to 5 alpha-pregnanedione and 5 beta-pregnanedione, but in the absence of NADPH, only 5 beta-pregnanedione was produced. Erythrocytes in the presence and the absence of NADPH produced only 5 beta-pregnanedione. The plasma component of blood metabolized progesterone to give 5 alpha-pregnanedione, but only in the presence of NADPH. These results suggest the presence of two types of steroid reductases found in plasma and erythrocytes. The extent of progesterone metabolism by the blood of animals in different reproductive states is in the order of pregnant females greater than nonpregnant females greater than male.

Animals↗
PubMed1988

Lordosis facilitation in estrogen primed rats by intrabrain injection of pregnanes.

Progesterone (P) and nine of its natural metabolites were bilaterally injected (5 micrograms in 0.5 microliter oil) into either the ventromedial hypothalamus (VMH) or the medial preoptic area (MPOA) of estrogen primed rats to assess their relative potencies for stimulating lordosis. P, 5 alpha-pregnanedione and 5 beta, 3 beta-pregnanolone elicited lordosis when injected at either VMH or MPOA. By contrast, 5 alpha, 3 beta-pregnanolone as well as 20 alpha-OH and 20 beta-OH-pregnenone were much more effective in stimulating lordosis when implanted in the MPOA. Finally, 5 beta-pregnanedione and 5 beta,3 alpha-pregnanolone did not stimulate lordosis at neither VMH nor MPOA. The observation that lordosis was induced in estrogen primed rats both by pregnanes that bind to the P receptor (i.e., P; 5 alpha-pregnanedione; 20 alpha- and 20 beta-OH-pregnenone) and by pregnanes that do not (i.e., 5 alpha, 3 beta-; 5 beta,3 beta- and 5 alpha,3 alpha-pregnanolone) indicates that diverse cellular mechanisms are involved in the facilitation of lordosis by pregnanes.

Animals↗
PubMed1983

Cyclic changes in hormones, carbohydrates and indole metabolism in cervical mucus of normal, fertilizing cows and the relationship with non-fertility.

In the cervical mucus of 'normal' cows the cholesterol content was very low at D--0; at D + 12 it was about fifty times as high; then it decreased to about half its value at D + 17 and then to the low value at D--0. Usually small amounts of oestrogen, testosterone, pregnanedione and progesterone were found at D--0; on D + 12 more pregnanedione was found and less oestrogen, while at D + 17 more oestrogen occurred and less pregnanedione. The fructose and glucose content was very low at D--0; then it increased until D + 12, when glucose was dominant, while at D + 17 it had decreased and rather large amounts of glucuronic acid and of sorbitol occurred. On D + 12 a blue fluorescing indole metabolite was sometimes found. Deviations from these patterns, were found particularly in the winter months, and coincided with lowered fertility. Indole metabolism was stronger in the winter months than in the summer months and occurred more in cows than in heifers.

Animals↗
PubMed1987

Contrasting effects of 5 alpha- and 5 beta-pregnane-3,20-dione on the motor activity of ovariectomized rats.

While progesterone metabolites have long been known to be potent anesthetics in pharmacological doses, there is no available information as to their effects on behaviour at physiological levels. In this study, 5 alpha- and 5 beta-pregnanediones in silastic capsules were implanted in ovariectomized rats. Approximately 4 mg/kg/day was absorbed over a 24-day period. Rats receiving 5 beta-pregnanedione had decreased motor activity (58% control, P less than or equal to 0.001) while those receiving the 5 alpha-isomer had increased activity (143% control, P = 0.01). These studies suggest that these progesterone metabolites may be responsible for some behavioural changes.

5-alpha-Dihydroprogesterone↗
PubMed1989

Intrahypothalamic injection of RU486 antagonizes the lordosis induced by ring A-reduced progestins.

We explored the possibility that ring A-reduced progestins facilitate lordosis in estrogen primed rats through their interaction with an intracellular progestin receptor (PR) by using RU486. This drug binds with high affinity to the PR, thus preventing the action of progesterone (P). Ovariectomized estrogen-primed rats (2 micrograms estradiol benzoate 40 hr earlier) were bilaterally injected into the ventromedial hypothalamic nucleus (VMHN) with 1 microgram of: P, 5 alpha-pregnanedione or 3 beta,5 beta-pregnanolone in 1 microliter oil. All three progestins effectively facilitated lordosis, tested at four and eight hours after intrahypothalamic injections. The ability of RU486 to counteract progestin-induced lordosis was assessed by infusing 10 micrograms of this agent into the VMHN along with any of the progestins. RU486 antagonized the lordosis induced not only by P (67% reduction) but also that induced by 5 alpha-pregnanedione and by 3 beta,5 beta-pregnanolone (47% and 93% reductions, respectively). Results suggest that ring A-reduced progestins may act through the PR mechanism to facilitate lordosis, i.e., in a fashion similar to P.

5-alpha-Dihydroprogesterone↗
PubMed1979

Effects of progestins on the progesterone receptor in guinea pig uterus.

We examined the effects of progesterone and some synthetic progestins and other steroids on the physical properties of the progesterone receptor of guinea pig uterine cytosol and on the binding of the receptor by nuclei. Progestational potency seemed to correlate with the ability to keep the receptor in the 7S form and to prevent dissociation into smaller subunits. The rate of activation prior to nuclear binding was slower with steroids of increasing progestational activity. Therefore activation in vitro may be unrelated to biological activity. Concentration of the cytosol led to a decrease in the equilibrium association constant. The extent of the decrease was less with progesterone than with its metabolite, 5 alpha-pregnanedione. When cytosol and nuclei were incubated in the absence of ligand measureable progesterone receptor was bound by the nuclei. The uncomplexed nuclear receptor bound [3H]-progesterone of [3H]-R5020 rapidly at 0 degrees, but progesterone-receptor complexes exchanged [3H]-progestin slowly at 0 degrees. Progesterone increased the amount of nuclear receptor at concentrations of 10(-9) and 10(-8)M, but decreased binding at higher concentrations. 5 alpha-Pregnanedione had the same effect as progesterone, but other metabolites of progesterone that had little affinity for the 7S progesterone receptor in cytosol had no effect on nuclear binding at any concentration. Glucocorticoids, testosterone and estradiol-17 beta increased the nuclear binding of the progesterone receptor when present at concentration of 10(-8)M and greater.

Animals↗
PubMed1995

Anti-anxiety effects of progesterone and some of its reduced metabolites: an evaluation using the burying behavior test.

In this study, pregnenolone sulfate, progesterone and some of its main reduced metabolites were tested for anxiolytic properties in rats using the burying behavior paradigm. All steroids were subcutaneously injected. Progesterone (0.5, 1.0, 2.0 and 4.0 mg/rat) and its 3 alpha-5 alpha-reduced metabolite (0.125, 0.250, 0.5 and 1.0 mg/rat) produced a clear dose-dependent anxiolytic response, without affecting the spontaneous ambulatory behavior. 5 alpha-Pregnanedione decreased burying behavior only at the highest dose (4.0 mg/rat). Pregnenolone sulfate (1.0, 2.0 and 4.0 mg/rat), 5 beta-pregnanedione and 3 beta- or 5 beta-pregnenolones were devoid of effects. The 3 beta-5 beta-reduced metabolite of progesterone (2.0 and 4.0 mg/rat) decreased motor activity, without altering the burying behavior. These results demonstrate that the 3 alpha-5 alpha metabolite of progesterone shows the highest anxiolytic potency in the burying behavior test, when compared with all steroids evaluated. The data are discussed in terms of the close structure-activity relationship requirements of steroids to stimulate the GABA/benzodiazepine receptor-chloride ionophore complex.

Animals↗
PubMed1983

The in vitro synthesis of final maturational steroids by ovaries of brook trout (Salvelinus fontinalis) and yellow perch (Perca flavescens).

The steroidogenic profile produced by ovaries of brook trout (Salvelinus fontinalis) and yellow perch (Perca flavescens) was examined using radioactive incorporation incubations. The radioactive metabolites produced were identified and were tested for their ability to induce germinal vesicle breakdown (GVBD) in oocytes in in vitro bioassays. Brook trout ovarian tissue converted [14C]progesterone to five metabolites that were effective in inducing GVBD in the bioassays: 5 beta-pregnanedione, 17 alpha-hydroxyprogesterone, deoxycorticosterone, and two more polar metabolites that were not identified. One of these two metabolites comigrated with 11-deoxycortisol and 17 alpha-hydroxy,20 beta-dihydroprogesterone (17 alpha, 20 beta prog) in thin layer chromatography. Androstenedione, testosterone, and estradiol-17 beta were also identified as metabolites of progesterone. Brook trout ovarian tissue did not extensively metabolize [14C]pregnenolone. Dehydroepiandrosterone and 17 alpha-hydroxypregnenolone were tentatively identified as metabolites of pregnenolone. Yellow perch ovarian tissue converted [14C]progesterone or [14C]pregnenolone to six metabolites that were effective in inducing GVBD in the bioassays: 5 alpha-pregnanedione, 17 alpha-hydroxyprogesterone, 20 alpha-dihydroprogesterone, 17 alpha-hydroxy, 20 alpha-dihydroprogesterone (tentatively identified), and two other unidentified metabolites. One of these two metabolites comigrated with 11-deoxycortisol and 17 alpha, 20 beta prog in thin layer chromatography. The only metabolite that induced ovulation of yellow perch oocytes in vitro was the metabolite comigrating with 11-deoxycortisol and 17 alpha, 20 beta prog. Androstenedione and testosterone were also identified as metabolites produced by yellow perch ovarian tissue. The results show that the ovaries of both species produce steroids that are active in the induction of oocyte final maturation.

Animals↗
PubMed1995

Ring A reduced progestins potently stimulate estrous behavior in rats: paradoxical effect through the progesterone receptor.

The effect of ring A reductions at C5 and C3 on the capacity of the progesterone (P) molecule to stimulate estrous behavior was studied in ovariectomized estrogen primed rats (5 micrograms estradiol benzoate, EB, 40 h before progestin administration). Dose-response curves (dose range: 0.75-200 micrograms) for the lordosis quotient (LQ), lordosis score (LS), and proceptivity were constructed for P and all its ring A reduced metabolites: 5 alpha-pregnanedione (alpha DHP), 5 beta-pregnanedione (beta DHP), 3 alpha,5 alpha-pregnanolone (3 alpha,5 alpha-Pgl), 3 alpha,5 beta-pregnanolone (3 alpha,5 beta-Pgl), 3 beta,5 alpha-pregnanolone (3 beta,5 alpha-Pgl), and 3 beta,5 beta-pregnanolone (3 beta,5 beta-Pgl). Progestins were dissolved in propylene glycol and IV injected through an indwelling jugular catheter. Tests for lordosis and proceptivity were made at 5, 30, and 120 min after progestin injection. Weak, though significant lordosis behavior was observed at 5 min following the injection of some of the progestins, particularly the pregnanolones. Maximal responses were obtained at 120 min postinjection for all progestins. Dose response curves of the LQ, LS, and proceptivity were dualistic for alpha DHP and both 3 alpha pregnanolones, smaller responses being observed with high doses. Relative potency analysis revealed that alpha DHP, 3 alpha,5 beta-Pgl, 3 beta,5 alpha-Pgl, and 3 alpha,5 alpha-Pgl were considerably more potent for eliciting lordosis than P (14, 13.7, 9, and 4-fold, respectively). The same order of relative potencies was found for both LS and proceptivity. 3 beta,5 beta-Pgl and beta DHP were only slightly more potent than P (2 and 1.5-fold, respectively). In a second study, the antiprogestin RU486 (5 mg, SC), injected 60 min before one of four selected progestins (alpha DHP, 3 alpha,5 alpha-Pgl, 3 alpha,5 beta-Pgl, and 3 beta,5 beta-Pgl), significantly inhibited their action on estrous behavior (lordosis and proceptivity) when tested at 60 and 120 min postinjection. On the other hand, RU486 failed to inhibit early lordotic responses obtained at 5 and 30 min following 3 alpha,5 alpha-Pgl and 3 alpha,5 beta-Pgl. Similarly RU486 was ineffective in inhibiting lordosis in ovariectomized rats treated only with estradiol (3 micrograms of EB/day for 7 days). Data suggest that: (i) ring A reduction of the P molecule plays an important role in the normal facilitation of estrous behavior in the rat; and (ii) ring A reduced progestins provoke this effect by acting, at least partially, through the progesterone receptor.

Animals↗