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PubMed1986

Germinal vesicle breakdown in oocytes of catfish, Mystus vittatus (Bloch): relative in vitro effectiveness of estradiol-17 beta, androgens, corticosteroids, progesterone, and other pregnene derivatives.

The relative in vitro effectiveness of estradiol-17 beta, androgen, corticosteroids, progesterone, and other pregnene derivatives on germinal vesicle breakdown (GVBD) using folliculated oocytes of an Indian catfish Mystus vittatus was investigated. 17 alpha,20 beta-Dihydroxyprogesterone was found to be the most effective maturation-inducing steroid (MIS). Estradiol-17 beta and testosterone were not effective but androsterone was found to be fairly effective in final oocyte maturation. Deoxycorticosterone (DOC), hydrocortisone, progesterone, and 17 alpha-hydroxyprogesterone were also effective at their higher concentrations. Among 5 beta-reduced pregnenes, all but 5 beta-pregnene-3 alpha-ol-20-one could induce oocyte maturation. The significance of these findings in relation to the progestagens as natural MIS and the present controversial position of another Indian catfish Heteropneustes fossilis is discussed in the light of available literature.

Adrenal Cortex Hormones↗

PubMed1996

Milt and endocrine responses of mature male Atlantic salmon (Salmo salar L.) parr to water-borne testosterone, 17,20 beta-dihydroxy-4-pregnen-3-one 20-sulfate, and the urines from adult female and male salmon.

Mature male Atlantic salmon (Salmo salar L.) parr responded to the urine from ovulated females with significant increases in plasma gonadotropin II, 17,20 beta-dihydroxy-4-pregnen-3-one, testosterone, and 11-ketotestosterone concentrations and volumes of expressible milt. There were also significant increases in biliary free steroid and steroid conjugate concentrations. Urine from mature adult male salmon also affected male parr, which responded with increased plasma gonadotropin II concentrations and expressible milt. However, male urine did not elevate the plasma and bile concentrations of any of the steroids. When two of the three known steroids which are detected by the mature male salmon parr olfactory epithelium were tested for priming activity, results showed that these compounds had little or no activity when added to the water. Only plasma gonadotropin II concentrations increased in mature male parr exposed to 17,20 beta-dihydroxy-4-pregnen-3-one 20-sulfate. Female and mature adult male urines contain at least one priming pheromone and there was no conclusive evidence for this priming pheromone being one of the tested steroids. However, the fact that water-borne 17,20 beta-dihydroxy-4-pregnen-3-one 20-sulfate can have a physiological effect in male parr suggests that it may have a role as one of a mixture of compounds in female urine that males detect and respond to. The lack of a priming-like effect of testosterone supports a previous hypothesis that the major pheromonal role of this steroid is as an attractant for mature male salmon parr.

Animals↗

PubMed1988

Activation of human placental 5-pregnene-3,20-dione isomerase activity by pyridine nucleotides.

Isomerization of 5-pregnene-3,20-dione to progesterone by human placental microsomes was stimulated by NAD and NADH. Concomitant oxidation or reduction of nucleotide was not detected based on absorbance at 340 nm. Concentrations giving half-maximum activity were 0.76 microM for NADH and 24.0 microM for NAD. Vmax values with 9.28 microM 5-pregnene-3,20-dione were 22.0 nmol/min/mg protein with NADH and 65.8 nmol/min/mg protein with NAD. When isomerase was assayed as a function of 5-pregnene-3,20-dione concentration, NAD increased Vmax but had no effect on the Km value for steroid. NADP, NADPH, acetylpyridine NAD and deamino NAD did not activate nor did they compete with NAD. Exposure of microsomes to trypsin, phospholipase A2 or phospholipase C resulted in the loss of isomerase activity. Approximately 30% of the initial activity was recovered after detergent solubilization of microsomes. Hydrogen peroxide did not affect activation by NAD. The data are consistent with nucleotide enhancement of a step in the isomerization reaction other than substrate binding.

Detergents↗

PubMed1996

15 beta-hydroxysteroids (part I). Steroids of the human perinatal period: the synthesis of 3 beta,15 beta, 17 alpha-trihydroxy-5-pregnen-20-one.

15-Hydroxysteroids have long provided information about fetal well-being and fetal steroidogenesis. 3 beta,15 beta,-17 alpha-Trihydroxy-5-pregnen-20-one (1a) is a major 15 beta-hydroxylated metabolite unique to the human perinatal period. The synthesis of 3 beta, 15 beta, 17 alpha-trihydroxy-5-pregnen-20-one (1a) is reported here in the first of a series of publications on the chemical synthesis of 15 beta-hydroxylated steroids for use in the (a) development of new immunoassay techniques for application to newborn screening programs and fetal well-being; (b) development of new anti-androgenic drugs; and (c) study of androgen/estrogen interaction in late pregnancy. To this end, a method for the introduction of the 15 beta-hydroxy group onto the steroid nucleus was developed resulting in a nine-step stereoselective synthesis of 1a with an overall yield of 26%. A high yielding selenation-dehydroselenation procedure was developed for the synthesis of 3 beta-hydroxy-5,15-androstadien-17-one (8) which avoided the previously reported Baeyer-Villiger rearrangement. The introduction of the 15 beta-hydroxy group and the side chain was achieved by the addition of 2-lithio-2-methyl-1,3-dithiane to give 20,20-trimethylenedithio-5,15-pregnadien-3 beta, 17 beta-diol (9a) followed by its acid-catalyzed rearrangement to give 20,20-trimethylenedithio-5, 16-pregnadien-3 beta,15 beta-diol (10a). Acetylation and cleavage of the dithioacetal gave 3 beta,15 beta-diacetoxy-5,16-pregnadien-20-one (11b) which was hydrogenated to give 3 beta,15 beta-diacetoxy-5-pregnen-20-one (12b). Reaction of the ketone (12b) with oxygen and then basic hydrolysis gave the desired product 1a.

17-alpha-Hydroxypregnenolone↗

PubMed1997

Synthesis, metabolism and levels of the neuroactive steroid, 3alpha-hydroxy-4-pregnen-20-one (3alphaHP), in rat pituitaries.

The neuroactive steroid, 3a-hydroxy-4-pregnen-20-one (3alphaHP), is a metabolite of progesterone and a precursor of 3alpha-hydroxy-5alpha-pregnan-20-one (5alphaP3alpha; allopregnanolone). In addition to analgesic and anxiolytic effects by interaction with the GABA(A) receptor complex, 3alphaHP regulates pituitary FSH secretion by rapid non-genomic interaction with the Ca2+-driven cell signaling mechanisms. Since gonadectomy and adrenalectomy do not result in elimination of 3alphaHP, and since there is the possibility of paracrine and/or autocrine regulation of FSH release, the capacity of pituitary cells to regulate levels (by synthesis, metabolism, and storage) of 3alphaHP was examined. Anterior pituitaries from random cycling female rats were incubated, either as fragments or as cultured cells, for 1, 4 or 8 h with 3H- or 14C-labeled progesterone. The steroid metabolites were identified by thin-layer chromatography, autoradiography, high pressure liquid chromatography (HPLC), derivatization and GC/MS. Pituitary cells actively converted progesterone to 3alphaHP along with 5alphaP3alpha, 5alpha-pregnane-3,20-dione, 20alpha-hydroxy-5alpha-pregnan-3-one, 3beta-hydroxy-5alpha-pregnan-20-one, 5alpha-pregnane-3alpha(beta), 20alpha-diols, 20alpha-hydroxy-4-pregnen-3-one, and 4-pregnene-3alpha(beta), 20alpha-diols. The results indicate the presence of the following steroidogenic enzymes in anterior pituitary cells: 3alpha-hydroxysteroid oxidoreductase (3alpha-HSO), 20alpha-HSO, 3beta-HSO, and 5alpha-reductase. The activities of 5alpha-reductase and 3alpha-HSO were approximately equal and greatly exceeded those of the other enzymes. After 8 h of incubation with 100 ng progesterone per pituitary, about 20% of the progesterone was metabolized and 3.18 ng of 3alphaHP had been formed. The accumulation of 3alphaHP increased approximately linearly with the time of incubation. Metabolism studies using [1,2,6,7-(3)H]3alphaHP showed that pituitary cells convert about 29% and 8% of the 3alphaHP to progesterone and 5alphaP3alpha, respectively, in 2 h. Specific radioimmunoassays determined 11.6 and 7.5 ng of 3alphaHP per pituitary, respectively, in 25- and 40-day-old non-cycling female rats; these concentrations of 3alphaHP were about 2-3-fold greater than those of progesterone in the same pituitaries. In older (80-100 days old) cycling rats, the levels of 3alphaHP were about 9.4 and 18.6 ng/pituitary at 13.00 h and 22.00 h, respectively, on the day of proestrus, while the concomitant circulating levels were 13.7 and 5.4 ng/ml. The results indicate a marked capacity of rat pituitary cells to synthesize the neuroactive and FSH regulating steroid, 3alphaHP, from progesterone, and in turn to metabolize 3alphaHP to the neurosteroid, allopregnanolone, and to progesterone. The studies suggest cyclic biosynthetic and metabolic pathways for 3alphaHP and other steroids in the pituitary. They also indicate that the regulation of FSH secretion by 3alphaHP may be (in part, or in whole) via paracrine or autocrine mechanisms.

20-alpha-Dihydroprogesterone↗

PubMed1997

A receptor for the oocyte maturation-inducing hormone 17alpha,20beta,21-trihydroxy-4-pregnen-3-one on ovarian membranes of striped bass.

Previous studies have shown that blood plasma levels of 17alpha, 20beta-dihydroxy-4-pregnen-3-one (DHP) and 17alpha, 20beta, 21-trihydroxy-4-pregnen-3-one (20beta-S) increase in striped bass (Morone saxatilis) undergoing final oocyte maturation (FOM). Both hormones are produced by ovarian fragments undergoing hCG-induced germinal vesicle breakdown (GVBD) in vitro. In the present study, we investigated binding of DHP and 20beta-S to ovarian membranes from striped bass undergoing FOM. Saturable binding sites for DHP were not detected. Saturation of 20beta-S binding sites with 5 nM [3H]20beta-S occurred within 40 min at 0 degrees C (at 3 min, half of the maximum specific binding of steroid was calculated to have occurred), and the binding was pH-dependent. Scatchard analyses revealed the presence of a single class of high-affinity (dissociation constant [Kd] = 1.4 +/- 0.2 nM), limited-capacity (estimated concentration [Bmax] = 2.7 +/- 0.3 pmol/g ovary) 20beta-S binding sites on membranes from striped bass ovaries undergoing FOM. In contrast, only low levels of specific binding (Bmax < 0.04 pmol/g tissue) were detected on membranes from testes, liver, brain, and muscle. Ovarian membranes prepared from vitellogenic females also had low levels (Bmax < 0.1 pmol/g ovary) of specific 20beta-S binding, less than 5% of that found during FOM. Results of competition assays showed that DHP was approximately 250 times less effective than 20beta-S for displacing 20beta-S from ovarian membranes. In contrast, 20beta, 21-dihydroxy-4-pregnen-3-one was a very effective competitor, although it is only a weak inducer of oocyte GVBD in vitro. Of several other steroids tested, only progesterone showed affinity for the 20beta-S binding site within a physiological range of concentrations. Taken together with previous studies of striped bass FOM, these findings indicate that 20beta-S is the oocyte maturation-inducing steroid hormone in striped bass.

Animals↗

PubMed1982

The molecular structure of (20R)-20-phenyl-5-pregnene-3 beta, 20-diol, an inhibitor of cholesterol conversion to pregnenolone.

The crystal and molecular structure of (20R)-20-phenyl-5-pregnene-3 beta, 20-diol hemihydrate has been determined by X-ray analysis in order to establish the configuration and conformation at C(20). Interest in this compound was stimulated by its high affinity inhibitory binding to cytochrome P-450SCC, the enzyme which catalyzes the biosynthesis of pregnenolone (3 beta-hydroxy-5-pregnen-20-one) from cholesterol. The results of the analysis suggest a possible conformation for the cholesterol side chain in the enzyme complex.

Cholesterol↗

PubMed2003

Apparent pregnene hydroxylation deficiency (APHD): seeking the parentage of an orphan metabolome.

This paper collates and reviews a number of clinical cases published over the last 20 years that we believe describe a novel steroid disorder associated with genital ambiguity. The authors of the original papers were unable to diagnose their patients conclusively. Females with the disorder are frequently masculinized and males feminized. The central feature of steroid biosynthesis is overproduction of pregnenolone and progesterone, which results in elevated concentrations of these steroids in plasma and exaggerated response to ACTH. Equivalent urinary data show elevated excretion of 5-pregnene-3beta,20alpha-diol (the major pregnenolone metabolite) and pregnanediol. Another notable feature of the metabolome is the relatively high plasma concentrations of the analytes for 21-hydroxylase deficiency (17-hydroxyprogesterone) and 17-hydroxylase deficiency (corticosterone). Correspondingly, metabolites of these steroids are prominent in urine. Circulating cortisol was generally normal but had blunted response to ACTH. Taken together these features pointed to an apparent relative deficiency of 21- and 17-hydroxylation, but no mutations have been found in the enzymes responsible for these transformations in cases where it has been investigated. The simultaneous presence of mutated genes on two chromosomes is also extremely unlikely. Until more is known of this interesting condition, and the genetic cause (presumed) is known, we propose naming it apparent pregnene hydroxylation deficiency (APHD). The metabolome is similar to that of isolated 17,20-lyase deficiency with which it has been confused. In fact, diminished (but not isolated) lyase activity is probably a significant factor in some patients. We believe that the attenuated steroid hydroxylation could be associated with deficiency of the required co-factors and modulators of hydroxylation such as P450 reductase and cytochrome b5. Post-translational modifications of the hydroxylases such as phosphorylation/dephosphorylation have also been suggested as influential in directionally regulating steroid synthesis. Some patients with the disorder have no dysmorphology apart from genital malformations while others have skeletal abnormalities attributed to Antley-Bixler syndrome. Whether we are looking at different conditions, or a severity continuum is not known. It is possible that the presence of this metabolome may become a required feature for diagnosis of Antley-Bixler syndrome. A combination of intersex phenotype and dysmorphology suggests that an error in a transcription factor may be an alternative to hydroxylation redox partner deficit as causative of the condition.The virilization of female patients with APHD probably results from a transient hyperandrogenism prior to birth.

Adolescent↗

PubMed1985

Biosynthesis of a C21 steroid conjugate in an insect. The conversion of [14C]cholesterol to 5-[14C]pregnen-3 beta,20 beta-diol glucoside in the tobacco hornworm, Manduca sexta.

Following injection into Manduca sexta (L.) female pupae (day 16), [14C]cholesterol was converted to a C21 steroid conjugate, 5-[14C]pregnen-3 beta,20 beta-diol glucoside. The conjugate was isolated from ovaries and eggs and contained three glucose units at least one of which is attached to C-20. The distribution of the other two glucose units remains to be determined. Other than the dealkylation of C-24 alkane or alkene substituents, side-chain cleavage of sterols is uncommon to insects. Here we report the first definitive proof of the biosynthesis of a C21 steroid conjugate from cholesterol in an insect species. The capability of M. sexta to so readily convert cholesterol to a C21 steroid suggests a physiological role for 5-pregnen-3 beta,20 beta-diol in this species.

Animals↗

PubMed1990

Induction of maturation of Atlantic croaker oocytes by 17 alpha,20 beta,21-trihydroxy-4-pregnen-3-one in vitro: consideration of some biological and experimental variables.

We characterized the in vitro control of germinal vesicle breakdown (GVBD) by 17 alpha,20 beta,21-trihydroxy-4-pregnen-3-one (20 beta-S) in intact ovarian follicles of gonadotropin-primed Atlantic croaker. 20 beta-S-induced GVBD was determined in relation to ovarian (oocyte) morphology, duration of incubation, steroid metabolism, and interaction with other steroids. The rate of GVBD in vitro in the absence of exogenous steroid was positively correlated with initial stage of ovarian morphological development. Maximal responsiveness to 20 beta-S was seen in ovaries with oocytes showing the first signs of morphological maturation. Dose-response experiments with 20 beta-S and 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (17 alpha,20 beta-P) over a range of incubation times yielded similar results for both steroids, suggesting that conversion of 17 alpha,20 beta-P to 20 beta-S is not required for 17 alpha,20 beta-P-induced GVBD. The ED50 of these steroids markedly decreased with increasing incubation times. Comparisons between patterns of follicular transformation of various radiolabelled steroids to 20 beta-S and their respective activities (using unlabelled steroids) in the GVBD bioassay suggested that, in addition to 17 alpha,20 beta-P, progesterone has some intrinsic maturational activity. However, the maturational effects of 11-deoxycortisol and pregnenolone may be explained by their conversion to 20 beta-S. For the first time in any vertebrate, we showed that the proposed maturation-inducing steroid (20 beta-S) is not significantly transformed to any extractable, potentially active metabolite by intact, maturing ovarian follicles. These findings strongly suggest that 20 beta-S is the terminal product of the MIS biosynthetic pathway in Atlantic croaker ovaries. Estradiol had no acute effects on 20 beta-S-induced GVBD. However, testosterone decreased and cortisol augmented the maturational activity of 20 beta-S. Excess progesterone reduced the activity of a maximally effective dose of 20 beta-S, but pregnenolone was without effect. The effects of these steroids on 20 beta-S-induced GVBD are discussed in relation to their possible interactions with 20 beta-S at the MIS receptor level.

17-Hydroxycorticosteroids↗

PubMed1994

Purification and characterization of 17 alpha,20 beta-dihydroxy-4-pregnen-3-one binding protein from plasma of rainbow trout, Oncorhynchus mykiss.

A 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (17 alpha,20 beta-DP) (the natural maturation-inducing hormone of salmonid fish) binding protein (DBP) was purified from rainbow trout plasma. It had an apparent molecular weight of 110 kDa on native PAGE and was composed of two subunits with molecular weights of 50 and 55 kDa on SDS-PAGE. Enzymatic digestion of sugar chains converted both subunits to a single peptide with a molecular weight of 42.5 kDa. Scatchard analysis of 17 alpha,20 beta-DP binding to purified DBP showed the presence of a single binding site with a Kd of 21 nM and Bmax of 5 nmol/mg of protein. The affinities of various steroids were estimated by the displacement of [3H]17 alpha,20 beta-DP binding in the decreasing order of 17 alpha,20 beta-DP, testosterone, 17 alpha-hydroxyprogesterone, progesterone, estradiol-17 beta, 17 alpha,20 beta,21-trihydroxy-4-pregnen-3-one, and cortisol. We conclude that DBP is a sex-hormone binding globulin in rainbow trout.

Amino Acids↗

PubMed1995

Sulfated 17,20 beta-dihydroxy-4-pregnen-3-one functions as a potent and specific olfactory stimulant with pheromonal actions in the goldfish.

This study demonstrates that in addition to using the maturational steroid hormone 17,20 beta-dihydroxy-4-pregnen-3-one (17,20 beta-P) as a potent sex pheromone, the goldfish uses its sulfated metabolite 17,20 beta-dihydroxy-4-pregnen-3-one 20-sulfate (17,20 beta-P-20S). As measured by electro-olfactogram recording (EOG), the goldfish olfactory epithelium is extremely sensitive to both free and sulfated 17,20 beta-P (detection thresholds of approximately 10(-12) and 10(-11) M) but not to glucuronidated or phosphated 17,20 beta-P. Furthermore, both structure-activity and cross-adaptation studies using EOG indicated that 17,20 beta-P-20S and 17,20 beta-P are detected by different olfactory receptor sites, suggesting that these cues function as a distinguishable mixture. Finally, although the pheromonal activity of 17,20 beta-P-20S appears to be slightly less than that of 17,20 beta-P, it too stimulates gonadotropin release and sperm production in male goldfish. The precise function of 17,20 beta-P-20S remains somewhat enigmatic, however, because it does not appear to enhance the actions of 17,20 beta-P and is released by a different mechanism. In any case, our findings clearly establish that a fish olfactory system can detect particular conjugated steroidal compounds in a highly specific manner and that naturally released conjugated steroids can function as components of a pheromonal mixture.

Animals↗

PubMed1996

Extragonadal production of 17,20-dihydroxy-4-pregnen-3-ones in vitro in cyprinid fish.

Muscle, heart, eye, testis, blood, and sperm of trout and goldfish have been examined for the presence of 20-hydroxysteroid dehydrogenase by incubation with [3H]17-hydroxyprogesterone in the presence of 0, 0.1, 1, or 10 micrograms/ml of unlabeled substrate. In trout, 17-hydroxyprogesterone was metabolized only by sperm and testis, with 17,20 beta-dihydroxy-4-pregnen-3-one (17,20 beta P) as the major product and traces (< 2%) of 17,20 alpha-dihydroxy-4-pregnen-3-one (17,20 alpha P). In goldfish, maximum conversion of 17-hydroxyprogesterone to 17,20 alpha P was over 30% per 100 mg tissue in eyeball, heart, and testis, 12% per 20 microliters blood, and 18% per 20 microliters sperm, but less than 5% per 100 mg muscle. 17,20 alpha P was the only metabolite of 17-hydroxyprogesterone in all incubations of nongonadal tissue in goldfish. Within the cyprinid eye, there was no significant activity in the lens, the fluids, or the retina. The possible relationship between the teleost 20 alpha- and 20 beta-hydroxysteroid dehydrogenases, the mammalian 20-hydroxysteroid dehydrogenases, and members of the aldo-keto reductase and short-chain dehydrogenase superfamilies is discussed.

17-alpha-Hydroxyprogesterone↗

PubMed1997

Effects of 17alpha,20beta-dihydroxy-4-pregnen-3-one on cortisol production by rainbow trout interrenal tissue in vitro.

Physiological levels of 17alpha,20beta-dihydroxy-4-pregnen-3-one (17, 20-P) stimulated time- and dose-dependent increases in cortisol production by rainbow trout (Oncorhynchus mykiss) interrenal tissue cultured in vitro. Significant stimulation occurred in response to 100, 300, and 1000 ng/ml of 17,20-P. Lower doses were ineffective. Elevated cortisol levels were observed 1 hr after addition of 300 ng/ml 17,20-P. No additive or synergistic interaction was evident between human adrenocorticotropin fragment 1-24 (ACTH1-24) and 17, 20-P in stimulating cortisol secretion, although 300 ng/ml 17,20-P could further enhance cortisol production above levels already stimulated by 300 ng/ml ACTH. 17alpha, 20alpha-dihydroxy-4-pregnen-3-one also stimulated cortisol secretion, but was only half as effective as 17,20-P. Estradiol-17beta, testosterone, and 11-ketotestosterone had no effect on cortisol secretion. Inhibitors of mRNA and protein synthesis had no effect on 17,20-P-stimulated cortisol production. Radiotracer studies demonstrated that the bioconversion of 17,20-P to cortisol could fully account for the cortisol produced by the interrenal in response to 17,20-P and demonstrated that rainbow trout interrenal cells contain an active 20beta-hydroxysteroid dehydrogenase. These data suggest that 17,20-P may be a regulator of cortisol production during the periovulatory period in salmonid fishes.

Animals↗

PubMed1999

Induction of ovulation of mature oocytes by the maturation-inducing steroid 17,20beta,21-trihydroxy-4-pregnen-3-one in the spotted seatrout.

Incubation of mature, hydrated, follicle-enclosed oocytes of the spotted seatrout, Cynoscion nebulosus, with the maturation-inducing steroid (MIS), 17,20beta,21-trihydroxy-4-pregnen-3-one (20beta-S), for 9-12 h resulted in the appearance of ovulated oocytes in the culture media. The ovulation response was concentration-dependent and steroid-specific. The other teleost MIS, 17, 20beta-dihydroxy-4-pregnen-3-one (17,20beta-P), was also a potent inducer of ovulation, whereas progesterone and 11-deoxycorticosterone did not stimulate ovulation above control levels and partially antagonized the action of 20beta-S. The agonist and antagonist activities of these steroids on ovulation are consistent with their relative binding affinities for the ovarian nuclear progestogen receptor previously characterized in this species. Both the RNA synthesis inhibitor actinomycin D and the protein synthesis inhibitor cycloheximide blocked MIS-induced ovulation. This suggests that induction of ovulation by the MIS is through a genomic mechanism of action, and potentially involves the previously characterized nuclear progestogen receptor. Gonadotropin (hCG)-induced ovulation was blocked by addition of the steroid synthesis inhibitor cyanoketone, which was overcome by the addition of 20beta-S, but not pregnenolone. Thus, the most likely mechanism of gonadotropin-induced ovulation is an increase in the synthesis of the MIS. It is concluded that the processes of final oocyte maturation and ovulation are both regulated by the MIS. Whereas final oocyte maturation is mediated by the 20beta-S membrane receptor (P. Thomas and S. Das, 1997, Biol. Reprod. 57, 999-1007), ovulation is regulated by a genomic mechanism and is potentially mediated by the previously characterized nuclear progestogen receptor.

Animals↗

PubMed1997

Acute, nongenomic actions of the neuroactive gonadal steroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), on FSH release in perifused rat anterior pituitary cells.

We have previously shown that the gonadal and neurosteroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), can selectively suppress gonadotrophin-releasing hormone (GnRH) induced follicle-stimulating hormone (FSH) release from static cultures of anterior pituitary cells during a 4-h incubation period. The actions appeared to be at the level of the gonadotroph membrane and the cell signaling pathway involving Ca2+ and protein kinase C (PKC). In order to investigate further if the effects of 3 alpha HP on FSH release are generated by nongenomic mechanisms, we monitored the short-term effects of 3 alpha HP using dispersed anterior pituitary cells in a low dead-volume perifusion system with short (< or = 5 min) exposures to the steroid. Pulses of GnRH (10(-8) or 10(-7) M) lasting 2-5 min resulted in marked peaks of FSH release, and the variation in FSH amounts released from the cells in a particular column were minimal if the interval between successive GnRH pulses was at least 3-4 h. A 5-min pulse of 3 alpha HP (10(-9) M) administered simultaneously with the GnRH pulse suppressed GnRH-induced FSH release. On the other hand, similar treatment with the stereoisomer 3 beta-hydroxy-4-pregnen-20-one (3 beta HP), had no effect, but progesterone and estradiol pulses augmented the GnRH-induced FSH release. Pretreatment of cells with a 5-min pulse of 3 alpha HP, at 120, 60, or 30 min prior to a GnRH pulse suppressed the GnRH-induced FSH release. The suppression of GnRH-induced FSH release by 3 alpha HP was only partial if the start of the 3 alpha HP pulse occurred 0.5 or 1.0 min after the start of the GnRH pulse, and no suppression occurred if the start of the 3 alpha HP pulse was delayed by 2-5 min. The FSH release elicited by 5-min pulses of the Ca2+ ionophore A23187, the Ca2+ agonist BAY K8644, the PKC activator phorbol 12-myristate 13-acetate (PMA), or phospholipase C (PLC) was suppressed by simultaneous pulses of 3 alpha HP. The suppression of FSH release by 3 alpha HP appeared to be stereospecific, since no suppression was observed with 5 alpha-pregnane-3,20-dione (5 alpha P) or 3 alpha-hydroxy-5 alpha-pregnan-20-one (5 alpha P3 alpha). In separate experiments, cells were treated with pulses of BSA conjugates of 3 alpha HP, 3 beta HP, or progesterone; the 3 alpha HP-BSA, but not the 3 beta HP-BSA or the progesterone-BSA, suppressed the GnRH-induced release of FSH. The results of this study provide the first evidence that 3 alpha HP exerts immediate (nongenomic) and direct effects on GnRH-induced FSH release by interacting at the level of the pituitary gonadotroph membrane and the phosphoinositol cell signaling cascade involving Ca2+.

20-alpha-Dihydroprogesterone↗

PubMed1988

Analgesic effects of the putative FSH-suppressing gonadal steroid, 3 alpha-hydroxy-4-pregnen-20-one: possible modes of action.

The effects of intracerebroventricular (i.c.v.) administrations of the putative follicle stimulating hormone (FSH) suppressing gonadal steroid, 3 alpha-hydroxy-4-pregnen-20-one (3A4P) on the nociceptive responses of male mice were examined. This allylic steroid elicited significant, dose-dependent (0.001-1.0 micrograms) analgesic responses for 90-150 min after injection. These analgesic effects of 3A4P were stereospecific, the stereoisomer, 3 beta-hydroxy-4-pregnen-20-one (3B4P) failing to affect the nociceptive responses. The analgesic effects of 3A4P were blocked by peripheral administrations of the GABA antagonists, bicuculline and picrotoxin, and reduced by the benzodiazepine antagonist, Ro 15-1788. The exogenous opiate antagonist, naloxone, and the putative endogenous opioid antagonist, Tyr-MIF-1 (Pro-Leu-Gly-amide), also reduced 3A4P-induced analgesia, while i.c.v. administration of 3A4P (0.001 and 0.01 micrograms) itself attenuated the analgesic effects arising from peripheral administrations of opiate receptor agonist, morphine. In addition, the calcium channel antagonists, nifedipine and verapamil, enhanced 3A4P-induced analgesia but had no evident effects on the actions of 3B4P. These results suggest that the central analgesic effects of the FSH-suppressing steroid, 3A4P, arise via benzodiazepine--GABA--opiate mechanisms and calcium channels. These findings also suggest possible central modes of action whereby 3A4P may elicit selective suppression of FSH.

20-alpha-Dihydroprogesterone↗

PubMed1994

Male preference for the odors of estrous female mice is enhanced by the neurosteroid 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP).

The effects of the centrally produced allylic neurosteroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), on the responses of male mice to the odors of estrous female mice were examined in an odor preference test. Control untreated mice displayed a significant preference for the odors of an estrous female, spending more time in a Y-maze in the vicinity of the odors of an estrous than a non-estrous female. Intracerebroventricular (i.c.v.) administrations of 3 alpha HP enhanced male preference for the odors of estrous females, causing a significant dose-related (0.01-1.0 microgram) increase in the amount of time spent in the proximity of the odors of the estrous female, while having no significant effect on the responses to the non-estrous female odors. These effects of 3 alpha HP were stereospecific, with the stereoisomer, 3 beta-hydroxy-4-pregnen-20-one (3 beta HP), having no significant effects on odor preferences. The analgesic, morphine, also had no significant effects on the responses to female odors suggesting that the enhanced preference for estrous female odors were unlikely to be directly due to any analgesic effects of 3 alpha HP. The effects of 3 alpha HP were significantly reduced by peripheral administrations of the GABAA antagonists, bicuculline and picrotoxin, but were unaffected by either the benzodiazepine antagonist, Ro 15-1788, or the opiate antagonist, naloxone. These results suggest that the neurosteroid 3 alpha HP has facilitatory effects on olfactory mediated male sexual interest or motivation that involve interactions with the GABAA receptor.

20-alpha-Dihydroprogesterone↗