Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “PROGESTERONE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 937 records · Page 52Linked to original sources
PubMed1993

Steroid hormones and receptors of the GABAA supramolecular complex. II. Progesterone and estrogen inhibitory effects on the chloride ion channel receptor in different forebrain areas of the female rat.

The inhibitory effect of female sex steroid hormones on the binding of [35S]t-butylbicyclophosphorothionate [35S]TBPS to the chloride ion channel receptor in different forebrain areas of the female rat proved to be of a differential nature. The in vivo administration of estradiol and estradiol+progesterone were responsible for substantially lower chloride ion channel receptor levels in brain areas that contain elevated steroid receptors, such as the medial preoptic area, the cortico-medial amygdala nucleus, the vertical limb diagonal band-medial septal nucleus and the cortex lamina V. The administration of progesterone alone reduced receptor levels in the oriens-pyramidalis CA1 layer of the hippocampus, caudate putamen, cortex lamina VI (brain areas that contain little if any steroid receptors) and in the lateral and basolateral amygdala nucleus (brain sites that contain noninducible progesterone receptors). On the basis of the progesterone-inhibitory activity on the chloride ion channel receptors, it was important to investigate whether progesterone per se or whether the potent progesterone metabolites 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha, 5 alpha-THP) and 3 beta-hydroxy-5 beta-dihydroprogesterone (3 beta,5 beta-THP) were involved in the binding level changes, and to establish the specific brain sites where these steroid effects occur. In fact, in vitro addition of the 5 alpha-reduced progesterone metabolite produced even greater depressive effects on [35S]TBPS binding not only in the same brain areas as the in vivo progesterone replacement therapy but also in some sites that provided significant receptor level changes following the sequential administration of estradiol+progesterone. However, when the 5 beta-reduced metabolite was tested on the binding of [35S]TBPS to the chloride ion channel receptor, only the basolateral amygdala nucleus, the cortex lamina VI and the dorsolateral septal nucleus exhibited changes. Because the steroid-mediated chloride ion flux is regulated in a GABA-dependent manner, we next checked for the type of GABA effects on the chloride ion channel receptor levels and found that GABA not only intensified the 3 alpha,5 alpha-THP inhibitory effects but, together with this progesterone metabolite, was also involved in binding changes in the vertical limb diagonal band-medial septal nucleus. It is interesting to note that the GABA effects on 5 beta-metabolite-induced receptor changes were not of the enhancing type, but tended, rather, to be inhibitory.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Progesterone suppression of glutamic acid decarboxylase (GAD67) mRNA levels in the preoptic area: correlation to the luteinizing hormone surge.

The progesterone-induced LH surge in the estrogen-primed rat is thought to be mediated through interneurons since LHRH neurons reportedly lack steroid receptors. Along these lines, glutamate and gamma-aminobutyric acid (GABA) neurons are considered to be two of the major interneurons in the hypothalamus involved in the control of LHRH and LH secretion. Glutamate is a major excitatory amino acid neurotransmitter while GABA is a major inhibitory amino acid neurotransmitter in the control of LH secretion. Glutamate is converted in the brain to GABA by the rate-limiting enzyme glutamic acid decarboxylase (GAD). Regulation of GAD by steroid hormones would therefore appear to be a logical mechanism for the control of LHRH and LH secretion based on the changes in glutamate and GABA production which would result from such regulation. Therefore, the purpose of the present study was to determine whether the steroid hormone, progesterone, regulates the GAD enzyme in the hypothalamus at a time when it induces an LH surge. To accomplish this aim, northern and dot blot analysis were used to measure GAD65 and GAD67 mRNA levels in the preoptic area (POA) and medial basal hypothalamus (MBH) in ovariectomized (OVX) immature rats, OVX rats primed with 2 mu g of estradiol (E2) for 2 days, and OVX rats primed with 2 mu g of E2 for 2 days and administered progesterone (1 mg/kg, 09.00 h) to induce an LH surge. The results of the study show that GAD67 mRNA levels were suppressed by progesterone in the POA at 12.00 h (at the start of the surge) (24.4% suppression vs. E2 only; p <0.01) in the first experiment. This suppression was confirmed in a second experiment as progesterone suppressed GAD67 mRNA levels in the POA at 12.00 h (31.8% vs. E2 only; p <0.05) and also at 14.00 h (40% vs. E2 only; p <0.05) which correlates to the peak of the LH surge. The changes in GAD67 by progesterone were restricted to the POA, as GAD67 mRNA levels in the MBH were unaffected by the steroid treatment. Furthermore, the effect of progesterone on POA GAD67 mRNA levels was specific as it was blocked by prior treatment with the antiprogestin, RU486 (400 mu g). In the MBH, both GAD67 and GAD65 mRNA levels were increased by estradiol treatment at 16.00 h and this increase was prevented by progesterone administration in the presence of estrogen priming. In conclusion, these studies demonstrate that the mRNA for the key enzyme responsible for the conversion of the major excitatory amino acid neurotransmitter in the hypothalamus (glutamate) to the major inhibitory amino acid neurotransmitter (GABA), is regulated by the steroid hormone progesterone. Progesterone suppression of GAD67 mRNA levels in the POA, where LHRH neurons reside, and at a time immediately preceding and during the LH surge, could provide a mechanism for greater stimulation of LHRH neurons through enhanced excitatory glutamate production concomitant with deceased inhibitory GABA production in the POA.

Animals↗
PubMed2005

Progesterone antagonizes the vasoprotective effect of estrogen on antioxidant enzyme expression and function.

Oxidative stress plays an important role in the pathogenesis of atherosclerosis and can be effectively influenced by radical scavenging enzymes. Estrogens exert antioxidative effects in the vasculature; however, cotreatment with progesterone may abrogate the vasoprotective effects of estrogen. Therefore, the effects of progesterone on the production of reactive oxygen species (ROS) and expression and function of antioxidant and oxidant enzymes were investigated in cultured vascular smooth muscle cells (VSMCs) and vascular tissue of mice. Progesterone time- and concentration-dependently downregulated extracellular superoxide dismutase (ecSOD) and manganese superoxide dismutase (MnSOD) expression and enzyme activity and reversed 17beta-estradiol-induced overexpression of ecSOD and MnSOD in VSMCs. Nuclear run-on assays revealed that progesterone decreases MnSOD and ecSOD transcription rates. Consequently, progesterone increased ROS release in VSMCs that was prevented by concomitant treatment with 17beta-estradiol. Estrogen deficiency in ovariectomized mice was associated with an increase in vascular superoxide release and NADPH oxidase activity. Estrogen replacement prevented this increase, whereas progesterone substitution enhanced ROS production and NADPH oxidase activity. The modulation of superoxide release coincided with decreased expression of ecSOD and MnSOD and upregulation of the p22phox and p67phox subunits of the NADPH oxidase complex in progesterone-treated animals. Furthermore, administration of progesterone to ovariectomized mice treated with 17beta-estradiol abrogated the antioxidative effects of estrogen. Progesterone antagonizes the vasoprotective effects of estrogen on ecSOD and MnSOD expression and increases NADPH oxidase activity. These findings may in part explain why hormone replacement therapy with estrogen plus progesterone displayed no beneficial effect on cardiovascular event rates in the prospective clinical trials.

Animals↗
PubMed2003

Membrane-bound progesterone receptor expression in human aortic endothelial cells.

Observational studies demonstrate that estradiol and progesterone affect vasoreactivity. In animal studies, progesterone treatment causes immediate relaxation of precontracted arteries with inhibition of calcium influx in vascular endothelial and smooth muscle cells, suggesting a non-genomic mechanism of action. In this study we investigated the presence of novel membrane-bound progesterone receptors in human aortic endothelial cells and correlated the expression with cell-cycle stage. Western blotting analysis with an antibody directed to the hormone-binding domain of the classic progesterone receptors shows predominant bands at 100 and 60 kD, whereas analysis with an antibody to the DNA-binding region shows only the 100-kD band. In contrast, classic nuclear progesterone receptors B and A are identified at 116 and 94 kD in similarly processed T47D cells. Both novel bands localize to the membrane fraction after differential centrifugation. Plasma membrane-bound progesterone receptor was further shown with immunofluorescent antibody and ligand-binding studies in a small percentage of human aortic endothelial cells. Fluorescent activated cell sorting demonstrated that approximately 8% of the human aortic endothelial cells expressed a plasma membrane progesterone receptor and that a greater percentage of the expressing cells were in the G2/M-phase of the cell cycle. Treatment with progesterone conjugated to BSA did not show any significant cell-cycle changes. Plasma membrane-bound progesterone receptor in vascular endothelial cells may regulate the non-genomic actions of progesterone, and expression of the receptor appears to vary with cell cycle stage.

Aorta↗
PubMed1993

Phase I/pharmacokinetic study of high-dose progesterone and doxorubicin.

PURPOSE: We developed a new formulation of progesterone that permits administration of up to 10 g of progesterone as a continuous intravenous infusion over 24 hours and conducted a phase I clinical trial to determine whether progesterone could modulate the in vivo cytotoxicity of the P-glycoprotein substrate doxorubicin. PATIENTS AND METHODS: Thirty-four patients with advanced malignancies were treated with increasing doses of progesterone and a fixed dose of 60 mg/m2 of doxorubicin given as an intravenous bolus 2 hours after starting a 24-hour intravenous infusion of progesterone. RESULTS: Progesterone enhanced doxorubicin-induced myelotoxicity in a dose-dependent fashion without altering the pharmacokinetics of doxorubicin. The steady-state plasma concentration of progesterone at a dose level of 4 g was 4.1 +/- 0.9 mumol/L, which was higher than the minimal concentration required to reverse multidrug resistance (MDR) in vitro. CONCLUSION: Progesterone enhanced the hematologic toxicity of doxorubicin without altering its pharmacokinetics, suggesting that progesterone could modulate P-glycoprotein at the level of pluripotent hematopoietic stem cells. Adequate tissue concentrations of progesterone could be achieved in vivo to modulate doxorubicin toxicity in the bone marrow and thus potentially in tumor tissue as well. Selectivity may potentially be gained by using hematopoietic growth factors to offset the enhanced hematologic toxicity of doxorubicin while leaving the enhancement of toxicity to tumor cells unchanged.

Adult↗
PubMed1981

Acute progesterone and 17 beta-estradiol modulation of luteinizing hormone secretion by pituitaries of cycling rats superfused in vitro.

During the rat estrous cycle there are marked changes in the concentrations of serum 17 beta-estradiol (E2) and progesterone. The objective of the present study was to examine the acute effects of E2 and progesterone on isolated pituitaries obtained at 1230 h at each stage of the 4-day cycle. At time zero, single quartered anterior pituitaries were placed in a chamber and superfused at 0.5 ml/min with medium 199 with or without steroids for 360 min; sequential 10-min effluent samples were collected. LHRH (10 ng/ml) was administered as two successive 10-min pulses at 120 and 240 min. The proestrous and the diestrous-II pituitaries in vitro exhibited the characteristic LHRH self-priming response: an increased LH secretory response to a second pulse of LHRH in both the absence and presence of steroids in the superfusion medium; however, the magnitude of the response to the initial pulse of LHRH was reduced significantly when E2 (50 pg/ml) was present. The presence of progesterone (50 ng/ml) resulted in a marked augmentation of the LH secretory response to the first pulse of LHRH; when both E2 and progesterone were included in the superfusion medium, the stimulatory effect of progesterone was reduced. The progesterone augmentation of LHRH-induced LH secretion was present after 60 min of steroid exposure in vitro but was not demonstrable after only 10 min of exposure. Cycloheximide inhibited the progesterone augmentation and the LHRH self-priming without affecting the LH secretory response to the initial LHRH pulse in the absence of steroid. Progesterone augmentation was not observed on estrus and diestrous-I. The presence of E2 in the medium, however, resulted in a significant decrease in the response to the first pulse of LHRH for pituitaries from either estrus or diestrous-I. These data 1) demonstrate that E2 by itself suppresses LHRH-induced LH secretion by the proestrous pituitary and 2) provide proof for a direct stimulatory action of progesterone, in the absence of E2, on the proestrous pituitary and suggest a positive feedback role for progesterone during the preovulatory LH surge. (Endocrinology 108: 413, 1981)

Animals↗
PubMed1983

Sensory mechanisms involved in the induction of pseudopregnancy by progesterone: increased sensitivity to stimulation of the pudendal sensory field.

The sensory mechanisms that participate in the induction of pseudopregnancy after a single injection of progesterone were investigated. Unless otherwise indicated, rats were kept in group cages and vaginal smears were taken daily. Progesterone evoked pseudopregnancy in a dose-dependent manner when administered to proestrous or estrous rats that received no cervicovaginal stimulation. The probability of pseudopregnancy after progesterone was higher on estrus. Cervicovaginal stimulation of proestrous rats that received 5 mg progesterone 10 h before was performed with a rod with a sliding stop attached to regulate its intravaginal penetration. Progesterone facilitated responsiveness to this stimulus, although the amount injected was not significantly effective in increasing the incidence of pseudopregnancy in nonstimulated rats. However, the mere application of the stop of the stimulator on the perineal skin was followed by a significantly higher incidence of pseudopregnancy in progesterone-injected rats than in their vehicle-injected controls, which suggested an action of the steroid on perineal sensitivity. Accordingly, the pseudopregnancy-evoking effect of progesterone was clearly inhibited by refraining from taking vaginal smears for 5 days after steroid injection on estrus. No further inhibition was observed after isolating the animals in single rat cages. However, daily finger stimulation of the perineal skin of nonsmeared rats restored to a normal level response to progesterone. Furthermore, this response was severely impaired by transecting the pudendal nerves before the injection. It is concluded that pseudopregnancy is induced in progesterone-treated rats through sensory stimulation of the pudendal receptive field and it is suggested that the pudendal nerve may subserve as a secondary afferent system to elicit the pseudopregnancy response. The possibility progesterone also acts on other afferent systems including the main afferent system constituted by the pelvic nerve is discussed.

Animals↗
PubMed1986

Modulation of the estradiol-induced luteinizing hormone surge by progesterone or antiestrogens: effects on pituitary gonadotropin-releasing hormone receptors.

The present study examined the question of whether modulation of estradiol-induced LH surges by progesterone or antiestrogens in the immature rat might be related to changes in the concentration of pituitary GnRH receptors (GnRH-R). Rats (28 days old) that received estradiol implants at 0900 h had LH surges approximately 32 h later. Administration of progesterone or nafoxidine (U-11,100 A; 1-(2-[P-(3,4-dihydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]pyrrolidine hydrochloride) concomitantly with estradiol led to blockade of these LH surges (progesterone or nafoxidine inhibition), while progesterone treatment 24 h after estradiol brought about premature and enhanced LH release (progesterone facilitation). GnRH-R-binding capacity was determined by saturation analysis in homogenates of single pituitaries from immature rats treated with estradiol and progesterone or nafoxidine and controls treated only with estradiol using [125I]iodo-(D-Ala6,Des-Gly10)GnRh ethylamide. The affinity of GnRH-R for this analog ranged from 8.2-15.1 X 10(9) M-1 and was not affected by in vivo steroid or antiestrogen treatment. The number of GnRH-R in gonadotrophs from untreated 28-day-old rats (57.2 +/- 2.6 fmol/pituitary or 177 +/- 11 fmol/mg protein) was comparable to values previously reported for 30 day-old females. GnRH-R levels were first measured 1, 8, 24, 32, and 48 h after estradiol treatment. The pituitary content of GnRH-R paralleled changes in total pituitary protein (nadir at 24 h, rebound at 32 h, continued increase at 48 h), while their concentration (femtomoles per mg protein) was highest at 8 h. Next, GnRH-R levels were examined at 1200 h and at hourly intervals (1400-1800 h) on the afternoon of the LH surge. While GnRH-R concentrations were significantly lower at 1400 and 1700 h than at 1200 or 1800 h in animals treated with estradiol in the progesterone facilitation model, they did not change over time in the other two paradigms. There was no significant difference in pituitary content or concentration of GnRH-R at any time between immature rats treated with estradiol and progesterone or nafoxidine and their respective estradiol-treated controls. These results suggest that changes in GnRH-R levels in pituitary gonadotrophs do not play a major role in enhancement of LH surges by progesterone or in their suppression by progesterone or nafoxidine in the immature rat; therefore, these compounds may affect the pituitary at a site distal to the GnRH receptor.

Animals↗
PubMed1986

RU486 antagonizes the inhibitory action of progesterone on prostacyclin and thromboxane A2 synthesis in cultured rat myometrial explants.

A myometrial explant culture system was developed to investigate the effect of progesterone and the antiprogestagen RU486 on prostacyclin (PGI2) and thromboxane A2 (TXA2) synthesis by the rat myometrium. After culture, eicosanoid synthesis was stimulated with arachidonic acid (AA) and the calcium ionophore A23187 (A23187). Spontaneous release of eicosanoids was also studied. Progesterone inhibited the spontaneous release of PGI2 and TXA2 release by myometrial explants in a concentration- and time-dependent manner. Adequate inhibition of myometrial eicosanoid synthesis by physiological concentrations was achieved at 18 h of culture: all subsequent studies were carried out after an 18-h culture of explants. A23187- and AA-stimulated PGI2 and TXA2 synthesis were inhibited equipotently by progesterone. 17 beta-Estradiol alone was without effect on spontaneous AA- or A23187-stimulated PGI2 or TXA2 synthesis and was without effect on progesterone-elicited inhibition of eicosanoid synthesis in the myometrial explants. The protein synthesis inhibitors, actinomycin D and cycloheximide, did not block the inhibitory action of progesterone on A23187- or AA-stimulated eicosanoid synthesis by the myometrial explants and alone mimicked the inhibitory action of progesterone. The inhibitory action of progesterone on AA- and A23187-stimulated PGI2 and TXA2 synthesis was antagonized in a concentration-dependent manner by RU486. These data indicate that within this ex vivo system, progesterone probably inhibits myometrial cycloxygenase, that progesterone may exert this action through inhibition of a modulating or permissive protein, and that the antiprogestagen RU486 is an effective in vitro antagonist or progesterone.

Animals↗
PubMed1991

Prostaglandin F2 alpha-induced calcium transient in ovine large luteal cells: II. Modulation of the transient and resting cytosolic free calcium alters progesterone secretion.

A previous study demonstrated that prostaglandin F2 alpha (PGF2 alpha) stimulates a transient increase in cytosolic free Ca2+ levels [( Ca2+]i) in ovine large luteal cells. In the present study, the magnitude of the PGF2 alpha (0.5 microM)-induced calcium transient in Hanks' medium (87 +/- 2 nM increase above resting levels) was reduced (P less than 0.05) but not completely eliminated in fura-2 loaded large luteal cells incubated in Ca2(+)-free or phosphate- and carbonate-free medium (10 +/- 1 nM, 32 +/- 6 nM, above resting levels; respectively). Preincubation for 2 min with 1 mM LaCl3 (calcium antagonist) eliminated the PGF2 alpha-induced calcium transient. The inhibitory effect of PGF2 alpha on secretion of progesterone was reduced in Ca2(+)-free medium or medium plus LaCl3. Resting [Ca2+]i levels and basal secretion of progesterone were both reduced (P less than 0.05) in large cells incubated in Ca2(+)-free medium (27 +/- 4 nM; 70 +/- 6% control, respectively) or with 5 microM 5,5'-dimethyl bis-(O-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid (40 +/- 2 nM; 49 +/- 1% control; respectively). In addition, secretion of progesterone was inhibited (P less than 0.05) by conditions that increased (P less than 0.05) [Ca2+]i; that is LaCl3 ([Ca2+]i, 120 +/- 17 nM; progesterone, 82 +/- 8% control) and PGF2 alpha ([Ca2+]i, 102 +/- 10 nM; progesterone, 82 +/- 3% control). In small luteal cells, resting [Ca2+]i levels and secretion of progesterone were reduced by incubation in Ca2(+)-free Hanks ([Ca2+]i, 28 +/- 2 nM; progesterone, 71 +/- 6% control), however, neither LaCl3 nor PGF2 alpha increased [Ca2+]i levels or inhibited secretion of progesterone. The findings presented here provide evidence that extracellular as well as intracellular calcium contribute to the PGF2 alpha-induced [Ca2+]i transient in large cells. Furthermore, whereas an adequate level of [Ca2+]i is required to support progesterone production in both small and large cells, optimal progesterone production in large cells depends upon an appropriate window of [Ca2+]i.

Animals↗
PubMed1991

The timing of progesterone-induced ribonucleic acid and protein synthesis for augmentation of luteinizing hormone secretion.

Progesterone addition to pituitary cells pretreated with estradiol leads within 45 min to an unambiguous augmentation of pulsatile GnRH-stimulated LH secretion. To investigate this rapid action, we established the kinetics of early events through manipulation of RNA synthesis, protein synthesis, and progesterone-receptor binding. Female rat pituitary cells cultured in medium containing charcoal-treated serum plus 0.2 nM estradiol were changed to 0.1% BSA-medium +/- 200 nM progesterone at time 0; at 90 and 150 min the cells were challenged with 1 nM GnRH 15-min pulses. The 3-fold augmentation of GnRH-stimulated LH secretion induced by progesterone was inhibited completely by simultaneous addition of 1 microM actinomycin D or emetine as was GnRH self-priming. In another series, the ability of cycloheximide to completely block progesterone augmentation was gradually diminished with delay of addition, but even 90 min after progesterone (30 min before GnRH pulse) cycloheximide resulted in 50% blockade of augmentation. In contrast, inhibition of RNA synthesis 60-90 min after progesterone introduction had little or no effect on progesterone augmentation. The temporal profile of inhibition by the progesterone antagonist RU486 was indistinguishable from that resulting from blockade of RNA synthesis and suggests that continual activation of the receptor is required for continued RNA synthesis. In summary: 1) both RNA and protein synthesis are required for GnRH self-priming; and 2) progesterone augmentation of GnRH-stimulated LH secretion requires RNA synthesis and synthesis of protein(s) which appear to be turning over rapidly, accumulating slowly, or both.

Animals↗
PubMed1975

The control of progesterone secretion during the estrous cycle and early pseudopregnancy in the rat: prolactin, gonadotropin and steroid levels associated with rescue of the corpus luteum of pseudopregnancy.

The hormonal factors associated with converting a corpus luteum of estrous cycle into a corpus luteum of pseudopregnancy were studied by measuring LH and FSH prolactin, estradiol and progesterone levels in decapitated rats during the 4-day estrous cycle and a comparable time of pseudopregnancy (lights on 0600-0800 hr.). During the estrous cycle, prolactin, LH and FSH remained low and unchanging except on the afternoon of proestrus, when typical proestrous surges were observed. In contrast, estradiol levels began to increase on D-1, from baseline values of 7 pg/ml to approximately 15-20 pg/ml. These levels were maintained until the afternoon of D-2 when estradiol further increased to reach peak levels of 40-50 pg/ml by 0900 hr on proestrus. Estradiol then declined in relation to the increase in LH secreation and had returned to baseline by estrus. Progesterone secretion by the corpora lutea of the cycle also increased on the afternoon of D-1 and reached a maximum value of 25-30 ng/ml early on the morning of D-2. At this time, a precipitious fall in progesterone occurred, returning to baseline values of 5-1- ng/ml by 0700 on D-2 signifying the regression of the corpora lutea of the cycle. Progesterone remained low thereafter until the afternoon of proestrus when levels increased in response to the proestrus when levels increased in response to the proestrous surge of LH. Following cervical stimulation at 1900 hr on proestrus, no differences were noted, with respect to the estrous cycle, in LH, FSH or estradiol secreation through the afternoon of D-2. Surprisingly, progesterone levels did not differ in the cycle and pseudopregnancy until the early morning of D-29 instead of progesterone levels falling to baseline as they had during the cycle, the corpora lutea of pseudopregnancy were rescused, progesterone increasing dramatically to reach levels of 45-50 ng/ml by 1700 hr on that same day. The only difference in hormone secretion that was noted which could account for this marked divergence in progesterone secretion was the pattern of prolactin secretion following cervical stimulation. In contrast to the low levels seen during the estrous cycle, biphasio surges of prolactin secretion occured each day, one being nocturnal (0100-0900 hr) and the other diurnal (1500-2100 hr). The rescue of the corpus luteum occured in association with the nocturnal surge on D-2. These results suggest that nocturnal surge on D-2, PROLACTIN IS THE MAJOR Luteotropic stimulus which transforms and estrous cycle into pseudopregnancy by prolonging progesterone secretion from the corpus luteum. Moreover, if LH is important for progesterone secretion, no changes were observed in the pattern of LH secretion which can account for the rescue of the corpus luteum.

Animals↗
PubMed1976

Uptake of (3H)progesterone and (3H)5alpha-dihydroprogesterone by rat tissues in vivo and analysis of accumulated radioactivity: accumulation of 5alpha-dihydroprogesterone by pituitary and hypothalamic tissues.

These in vivo studies explored the possibility that the metabolism of progesterone to 5alpha-dihydroprogesterone (5alpha-DHP) and 3alpha-hydroxy-5alpha-pregnan-20-one in hypothalamus and pituitary may influence gonadotropin release. [3H]progesterone or [3H]5alpha-DHP was injected iv into ovariectomized or ovariectomized-adrenalectomized rats for 10 0r 30 min. 3H content was determined for plasma, anterior pituitary, medial basal hypothalamus (MBH), cerebral cortex, muscle and uterus. Isotopic dilution analyses of the accumulated 3H were made for progesterone, 5alpha-DHP, 3alpha-hydroxy-5alpha-pregnan-20-one, 20alpha-dihydroprogesterone, 20alpha-hydroxy-5alpha-pregnan-3-one, and 5alpha-pregnane-3alpha, 20alpha-diol on samples from the 10 min groups. With progesterone injections, most of the tissue 3H was distributed among progesterone, 5alpha-DHP, and 3alpha-hydroxy-5alpha-pregnan-20-one. Progesterone was the predominant 3H-steroid in uterus, MBH, cerebral cortex and muscle. [3H]5alpha-DHP was the other major 3H-steroid in MBH and the predominant one in pituitary. In terms of tissue/plasma concentration comparisons, no tissue concentration of [3H]progesterone was greater than that in plasma except for MBH in the ovariectomized-adrenalectomized group. In contrast, [3H]5alpha-DHP levels in pituitary, MBH and cerebral cortex were many fold greater than those in plasma and muscle. MBH and pituitary levels were significantly greater than that in cerebral cortex. With 5alpha-DHP injections, most tissue 3H was associated with 5alpha-DHP and/or 3alpha-hydroxy-5alpha-pregnan-20-one. No [3H]progesterone was detected. [3H]5alpha-DHP predominated in pituitary and MBH, while 3alpha-hydroxy-5alpha-pregnan-20-one predominated in the others. In terms of tissue and plasma concentration comparisons, MBH, pituitary and cerebral cortical concentrations of [3H]5alpha-DHP were markedly higher than plasma, muscle, and uterine levels. Pituitary and MBH concentrations were also greater than that in cerebral cortex. Tissue levels of [3H]3alpha-hydroxy-5alpha-pregnan-20-one were not significantly greater than that in plasma. Thus, 10 min after injection of either [3H]progesterone or [3H]5alpha-DHP, high and significant amounts of 5alpha-DHP are accumulated in pituitary and hypothalamus, but not in uterus, which suggests that its presence may be functionally important in governing progesterone-sensitive processes in these feedback tissues.

20-alpha-Dihydroprogesterone↗
PubMed1995

Ferritin heavy chain is a progesterone-inducible marker in the uterus during pregnancy.

The female sex steroid, progesterone, plays a central role in mammalian pregnancy by regulating crucial events in the uterus such as transformation of endometrium for implantation and maintenance of pregnancy. The hormone acts through its specific nuclear receptor and modulates the functions of target cells by controlling the synthesis of specific proteins. The identity of genes that are regulated by progesterone in the uterus during various phases of pregnancy, however, remains largely unknown. In this study, we employed a differential gene-screening method to identify the gene encoding ferritin heavy chain (FHC), a component of the multisubunit iron-binding protein ferritin, as being regulated by progesterone in the uterus. We observed that uterine expression of the FHC messenger RNAs (mRNAs) rose dramatically at the onset of pregnancy, coincident with the surge of progesterone. FHC expression continued at this elevated level throughout gestation when the progesterone concentration remained high. At term, FHC expression declined sharply as the progesterone concentration dropped. We localized FHC proteins exclusively in uterine stromal cells, a major site of action of progesterone during pregnancy. Administration of mifepristone, an antiprogestin, during the early stages of pregnancy abolished both FHC mRNA and protein expression, clearly suggesting a primary role of progesterone in the regulation of this gene. Consistent with this scenario, administration of progesterone to ovariectomized animals after a brief estrogen priming led to a marked (25-fold) induction of FHC mRNA in the uterus, whereas estrogen, dexamethasone, or dihydrotestosterone had no effect. Based on these results, we propose that FHC is a novel and useful marker to study progesterone-regulated events in the uterus during pregnancy.

Animals↗
PubMed1997

Progesterone regulates osteopontin expression in human trophoblasts: a model of paracrine control in the placenta?

Osteopontin (OPN), a matrix glycosylated phosphoprotein, has been proposed to play a role(s) in basic cellular processes, such as neovascularization and tissue remodeling, which are essential to placental morphogenesis and embryo implantation. We have shown OPN to be expressed by cytotrophoblasts of the chorionic villus, and a putative progesterone regulatory element in the OPN promoter suggests hormonal regulatory control. This led us to test the hypothesis that progesterone regulates OPN expression in human cytotrophoblasts. Cytotrophoblasts isolated from human placentas were treated with combinations of progesterone, RU486, and/or aminoglutethimide, and their expression of OPN was assessed by Northern hybridization and immunocytochemistry. The expression of OPN messenger RNA (mRNA) declined as trophoblasts aggregated, but rebounded at later times when syncytia and mononuclear cytotrophoblasts coexisted in culture. Progesterone increased OPN mRNA expression by aggregating mononuclear cytotrophoblasts. Aminoglutethimide suppression of endogenous steroidogenesis by syncytiotrophoblasts inhibited OPN expression, whereas the addition of exogenous progesterone to cells treated with aminoglutethimide reversed this inhibitory effect. These observations were confirmed at the protein level by immunocytochemistry. Treatment of cytotrophoblasts with both progesterone and RU486 inhibited the up-regulatory effect on OPN mRNA associated with exposure to progesterone alone, further confirming a direct effect of progesterone. We conclude that progesterone up-regulates OPN expression in human cytotrophoblasts, and we propose that in vivo, progesterone secretion by syncytiotrophoblasts regulates the expression of OPN by the underlying cytotrophoblasts. As the receptors for OPN, alpha(v) integrins, are expressed by syncytiotrophoblasts, we postulate that these paracrine regulatory mechanisms contribute to the adhesive and/or signaling events between the two trophoblast cell types of the chorionic villus.

Aminoglutethimide↗
PubMed1997

Regulation of prostaglandin endoperoxide H synthase 1 and 2 by estradiol and progesterone in nonpregnant ovine myometrium and endometrium in vivo.

PG endoperoxide H synthase-2 (PGHS-2) messenger RNA (mRNA) and protein levels are increased dramatically in ovine myometrium and endometrium during both glucocorticoid-induced premature labor and spontaneous term labor. In this study, we examined estradiol and progesterone regulation in vivo of PGHS-1 and PGHS-2 expression at both mRNA and protein levels using a nonpregnant ovariectomized sheep model. We determined the differential distribution of PGHS-2 and PGHS-1 in ovine myometrium and endometrium with immunocytochemistry. Twenty ovariectomized ewes were treated with saline (n = 5) or estradiol infused i.v. for 2 days (50 microg/day; n = 5) or an intravaginal progesterone sponge for 10 days (containing 0.3 g progesterone; n = 5) or an intravaginal progesterone sponge for 10 days with estradiol (50 microg/day) administered on days 9 and 10 with the progesterone sponge still in place (EP; n = 5). PGHS-1 and -2 mRNA and protein were measured by Northern and Western blot analyses, respectively. PGHS-2 mRNA and protein abundance increased significantly in myometrium after estradiol treatment (P < 0.01). In contrast, progesterone was a more potent stimulator than estradiol of PGHS-2 protein abundance in endometrium (P < 0.01). PGHS-1 concentration did not change after estradiol and/or progesterone administration (P > 0.05). PGHS-2 was immunolocalized in myometrial cells and endometrial glandular epithelial cells, whereas immunoreactive PGHS-1 was located in the myometrial cells, endothelial and smooth muscle cells of blood vessels, as well as epithelial cells of glands and stromal cells in endometrium. Estradiol-dependent activation of PGHS-2 gene expression resulted in increased PGHS-2 levels in sheep myometrium in vivo. Progesterone did not have any effect on PGHS-2 gene expression in the myometrium. In contrast, progesterone was a more potent stimulator of endometrial PGHS-2 abundance than estradiol. Estradiol and progesterone did not regulate PGHS-1 expression in either endometrium or myometrium. The distribution and differential regulation of PGHS-1 and -2 in myometrium and endometrium are consistent with the differential functions of both enzymes.

Animals↗
PubMed1999

Progesterone can block transmission of the estradiol-induced signal for luteinizing hormone surge generation during a specific period of time immediately after activation of the gonadotropin-releasing hormone surge-generating system.

The preovulatory GnRH/LH surge in the ewe is stimulated by a rise in the circulating estradiol concentration that occurs in conjunction with preovulatory ovarian follicle development. In the presence of high levels of progesterone, such as during the luteal phase of the estrous/menstrual cycle, the stimulatory effects of elevated estradiol on GnRH/LH secretion are blocked. Recent work in the ewe has shown that a relatively short period of estradiol exposure can stimulate a GnRH/LH surge that begins after estrogenic support has been removed. This result suggests that surge generation is characterized by an estradiol-dependent period (during which the signal is read) and an estradiol-independent period (during which a cascade of neuronal events transmits the stimulatory signal to the GnRH neurosecretory system, which releases a surge of GnRH). In this series of studies, we addressed the hypothesis that progesterone can block transmission of the stimulatory estradiol signal after it has been read. Nine ovariectomized ewes were run through repeated artificial estrous cycles by sequential addition and removal of exogenous steroids. In study one, ewes received three treatments in a randomized cross-over design. Exposure to a follicular phase estradiol concentration for 10 h (positive control treatment) stimulated an LH surge in all ewes, as determined in hourly jugular blood samples. Maintenance of luteal phase progesterone concentrations throughout the artificial follicular phase (2 x CIDR-G devices, negative control) blocked the stimulatory effects of a 10-h estradiol signal, and no ewes that received this treatment expressed an LH surge. In the experimental group, exposure to luteal phase levels of progesterone, during the period after the surge generating system had been activated by estradiol, blocked the LH surge in six of nine ewes. This result demonstrates that progesterone can block the surge, even when applied after the surge-generating system has been activated and, therefore, that it inhibits either the transmission of the estradiol signal and/or the release of the GnRH/LH surge. In study 2, we assessed whether sensitivity to the inhibitory effects of progesterone was confined to a specific stage of the transmission of the estradiol signal. Eight ewes were exposed to four treatments, over successive artificial estrous cycles. Positive and negative controls were similar to those described in Study 1, except the duration of the stimulatory estradiol signal was reduced to 8 h. The two experimental groups consisted of an EARLY P (progesterone) treatment, in which progesterone was given from hours 8-13 after estradiol insertion (immediately after estradiol removal), and a LATE P treatment, in which progesterone was given from hours 13-18 (immediately before LH surge secretion). As expected, LH surges were stimulated and blocked, in response to the positive and negative controls, respectively. Whereas the EARLY P treatment blocked the LH surge in seven of eight ewes, the LATE P treatment was only successful in inhibiting a surge in one of eight animals. This result demonstrates that progesterone can block the estradiol-induced surge-generating signal soon after the onset of signal transmission (immediately after estradiol removal) but not during the later stages of signal transmission (at the time of GnRH/LH surge onset).

Animals↗
PubMed1976

Levels of free and protein-bound progesterone in plasma during late pregnancy.

Using a filter method, levels of free (unbound) and protein-bound progesterone in blood samples were measured serially from the 23rd week of pregnancy until delivery in 16 healthy women. In addition, total estrogen and progesterone concentrations were determined by radioimmunoassay. The levels of both free and total progesterone increased steadily until the end of pregnancy. Free progesterone increased with advancing pregnancy more in proportion to the total progesterone, as it rose from 6% (of total) at week 24 to 13% at week 40. Both free and total progesterone decreased markedly very soon (2 h) after delivery. However, the corresponding decrease in the level of free progesterone was considerably less, with the result that it rose to 19% of the total, the greatest proportion of free progesterone observed at any time. The levels of both total estrogen and progesterone in plasma increased with advancing pregnancy, and at no time, prior to delivery, was there a significant fall in progesterone or an abrupt rise in estrogen.

Blood Proteins↗