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PubMed1999

Stimulation of specific binding of [3H]-progesterone to bovine luteal cell-surface membranes: specificity of digitonin.

Non-genomic actions of progesterone have been described in the ovary, and luteal membranes of several species have been shown to possess specific binding sites for [3H]-progesterone. However, binding of radiolabelled progesterone to luteal membranes was demonstrable only in the presence of digitonin. Digitonin is a non-ionic detergent which is thought to act by forming one-to-one complexes with certain sterols. It is also a cardiotonic agent, inhibiting (Na+-K+) ATPase activity by interaction with the extracellular (ouabain/K+) binding site. We therefore investigated which properties of digitonin were responsible for its stimulatory actions on progesterone binding to bovine luteal membranes. A range of compounds with detergent, cardiotonic and or cholesterol-complexing activities were tested for their effects on [3H]-progesterone binding to bovine luteal membrane fractions, and on haemolysis of rat erythrocytes. Stimulation of progesterone binding to luteal membranes was highly specific for digitonin, and a number of ionic and non-ionic detergents, cardenolides, saponins and cholesterol-complexing reagents tested failed either to stimulate [3H]-progesterone binding to bovine luteal membranes in the absence of digitonin, or to inhibit binding specifically in the presence of digitonin. When digitonin was first reacted with excess cholesterol or pregnenolone to form the respective digitonides, stimulatory activity was greatly reduced, suggesting that the ability of digitonin to interact with (an) endogenous steroid(s) may be important in its action. High performance liquid chromatography (HPLC)-mass spectrometry of commercially available digitonin preparations indicated the presence of numerous minor impurities in most commercial digitonin preparations. Three major UV-absorbing peaks were isolated and characterised by mass spectrometry: all stimulated progesterone binding to bovine luteal membrane receptors in a dose-dependent manner, though to differing extents. Our data suggest that the unique action of digitonin on luteal membrane progesterone receptors is not related to its detergent or cardiotonic properties, but appears to be related to its ability to complex with membrane sterols.

Animals↗
PubMed2003

Demonstration of progesterone receptor-mediated gonadotrophin suppression in the human male.

OBJECTIVE: Synthetic gestogens in combination with testosterone have potential as a male hormonal contraceptive, predominantly acting by augmenting suppression of gonadotrophin secretion. Little is known, however, of the effects of gestogens in the male. Gestogens have affinity for both androgen and progesterone receptors but the relative contribution of action at these two receptors in gonadotrophin suppression remains unclear. In this study the effects of progesterone, with no significant androgen-receptor affinity are compared to desogestrel, a synthetic gestogen with relatively low affinity for the androgen receptor, on gonadotrophin secretion in normal men. DESIGN: Subjects received either 50 mg progesterone intramuscularly (i.m.) or 300 micro g desogestrel orally daily for 7 days. Frequent blood sampling over 12 h was undertaken before and after drug administration. GnRH [100 micro g intravenously (i.v.)] was administered 2 h before the end of the frequent sampling period. SUBJECTS: Twenty healthy men were randomly allocated to the two treatment groups. RESULTS: Both progesterone and desogestrel administration resulted in decreases in the concentration of both LH and FSH secretion, as well as testosterone. Analysis of the pulsatile nature of LH secretion indicated that both treatments reduced LH pulse amplitude, and that progesterone reduced LH pulse frequency. Progesterone, but not desogestrel, treatment also reduced the increase in LH secretion in response to GnRH. CONCLUSIONS: The effects of progesterone were at least as marked as those of a maximally effective dose of desogestrel. As progesterone has negligible affinity for the androgen receptor, these results are compatible with the suppressive effects of synthetic 19-norgestogens on gonadotrophin secretion in the male being mediated via the progesterone receptor, with its androgenicity contributing minimally to gonadotrophin suppression.

Administration, Oral↗
PubMed2001

Regulation of estrogen receptor alpha and progesterone receptor (isoform A and B) expression in cultured human endometrial cells.

The effects of RU 486 together with estradiol and progesterone on estrogen receptor alpha and progesterone receptor (isoforms A and B) expression were studied in human endometrial long term cultures at the mRNA and protein level. We asked whether ligand induced receptor regulation, found in mammals in vivo, is also found in human cultured endometrial cells with special regard to the progesterone isoforms A and B. Endometrial cultures were maintained for 27 days. Media were supplemented with progesterone and/or estradiol alone or in combination with RU 486. Receptor expression (estrogen receptor alpha and progesterone receptor isoform A and B) was examined at the mRNA level by RT-PCR and at the protein level by western blot analysis. All receptor types examined were expressed in our culture model. Estradiol led to a general increase of receptor expression whereas treatment with estradiol in combination with progesterone down regulated receptor expression. The receptor down regulation was not found when RU 486 was additionally supplemented into the medium. Activation or inhibition of expression due to these treatments was similar for both PR isoforms. Our results (1) show that in our culture system estradiol induced up regulation of estrogen receptor and progesterone receptor A and B and suggest that the estrogen induced up regulation is prevented by progesterone (2) a clear cut antigestagenic effect of RU 486 and (3) suggest that both progesterone isoforms are analogously regulated in our culture model. We conclude that human endometrial cell cultures are suitable for the study of the dynamics of steroid receptor expression.

Blotting, Western↗
PubMed2007

Myometrial progesterone responsiveness.

Progesterone actions in human pregnancy are controlled by the extent of myometrial progesterone responsiveness. Current progress in unraveling the biochemistry for myometrial progesterone responsiveness at the genomic and nongenomic levels have lead to novel hypotheses regarding the role of these pathways in the hormonal control of human pregnancy and parturition. For the genomic pathway, progesterone interacts with the type-B nuclear progesterone receptor (nPR-B), which decreases expression of contraction-associated genes. For the nongenomic pathway, progesterone interacts with membrane-associated PRs (mPRs) to modulate directly intracellular Ca2+ and cyclic adenosine monophosphate (cAMP) levels. During most of human pregnancy the genomic and nongenomic pathway cooperate to maintain myometrial relaxation. However, at parturition the relaxing actions of progesterone are nullified by changes in myometrial progesterone responsiveness. This occurs by (1) increased expression of the nPR variants (e.g., PR-A and/or PR-C) and changes in nPR coregulator levels that together repress the transcriptional activity of PR-B; and (2) increased expression of specific mPRs, especially mPRss, which augments contractility by decreasing intracellular cAMP. Functional progesterone withdrawal may be induced by locally produced prostaglandins that alter myometrial nPR expression. This may be an important physiological link between the control of parturition and the immune/inflammatory process.

Binding Sites↗
PubMed1977

Oestradiol and progesterone: soluble receptor levels and metabolism in the uterus of the ovariectomized ewe.

Ovariectomized ewes received injections designed to mimic to some extent oestradiol and progesterone secretion during early pregnancy (maintenance progesterone), during oestrus (oestrous oestradiol) and during the luteal phase of the previous cycle (priming progesterone). The animals were killed at times equivalent to 1, 4 or 7 days after oestrus in those animals which had received oestrous oestradiol. The level of soluble oestradiol and progesterone receptors in whole uterus, and [3H]oestradiol and [3H]progesterone metabolism by uterus minces were measured. Oestradiol receptor level was highest on day 1 in those animals receiving oestrous oestradiol with no significant effect at any stage of the inclusion or omission of priming or maintenance progesterone. Progesterone receptor level was also high on day 1 in those animals receiving oestrous oestradiol with high levels maintained to day 4. Again, inclusion of priming or maintenance progesterone was without effect. In animals not receiving oestrous oestradiol the level of both receptors was uniformly low. Metabolism of [3H]oestradiol was low and not affected by treatment. [3H]Progesterone metabolism, although more variable, was also low and not affected by treatment.

Animals↗
PubMed1996

Expression of progesterone receptor mRNA in the endometrium during the normal menstrual cycle and in Norplant users.

The expression of endometrial progesterone receptor mRNA during the human menstrual cycle and in Norplant users was studied using digoxigenin-labelled ribonucleic probes for in-situ hybridization on 6 microns paraffin embedded endometrial sections. The staining intensity was scored blind semi-quantitatively. Blood ovarian steroid concentrations were measured in Norplant users. All data were analysed by analysis of variance. Glandular progesterone receptor mRNA concentrations were low during the menstrual-to-early proliferative stage but increased during the early-to-mid to late-proliferative stage then declined non-significantly over the secretory stage. No such variation was observed in stromal cells. Progesterone receptor mRNA concentrations were lower in Norplant than controls during early-to-mid to late-proliferative stages (in glandular epithelium and stroma) and during secretory stage (in stroma only). Norplant subjects with amenorrhoea had higher concentrations of stromal progesterone receptor mRNA but lower plasma oestrogen concentrations than subjects with breakthrough bleeding. The pattern of variation in progesterone receptor mRNA concentrations during the normal menstrual cycle resembles the published pattern for the receptor protein. The results demonstrate: (i) a differential sensitivity of glandular and stromal progesterone receptors to steroid regulation; (ii) in contrast to previous findings of an increase in immunoreactive progesterone receptor protein in Norplant endometrium, progesterone receptor mRNA concentrations in these tissues were reduced; and (iii) there was significantly more progesterone receptor mRNA in subjects with amenorrhoea than in those with breakthrough bleeding.

Contraceptive Agents, Female↗
PubMed2003

Progesterone promotes survival of the rat corpus luteum in the absence of cognate receptors.

Progesterone production by the corpus luteum (CL) is essential for preparation of the endometrium for implantation and for the maintenance of gestation. Progesterone modulates its own production and opposes functional luteal regression induced by exogenous agents, such as prostaglandin F(2alpha). In the present study, we evaluated whether progesterone is also capable of interfering with the process of structural luteal regression, which is characterized by a decrease in weight and size of the gland because of programmed cell death (i.e., apoptosis). We have found that a low number of luteal cells undergo apoptosis throughout gestation. On the day of parturition, but following the initial decline in endogenous progesterone production, a small increase in the number of luteal cells undergoing cell death was observed. This increase in apoptotic cells continued postpartum, reaching dramatic levels by Day 4 postpartum, and was accompanied by a marked decrease in average luteal weight. We have established that the exogenous administration of progesterone significantly reduces the decline in luteal weight observed during structural luteal regression postpartum. This effect was associated with a decrease in the number of cells undergoing apoptosis and with enhanced circulating levels of androstenedione. Furthermore, in vivo administration of progesterone delayed the occurrence of DNA fragmentation in postpartum CL incubated in serum-free conditions. Finally, we have shown that neither the CL of gestation nor the newly formed CL after postpartum ovulation express the classic progesterone-receptor mRNA. In summary, the present results support a protective action of progesterone on the function and survival of the CL through inhibition of apoptosis and stimulation of androstenedione production. Furthermore, this effect is carried out in the absence of classic progesterone receptors.

Androstenedione↗
PubMed1993

High-affinity binding of progesterone to the plasma membrane of Xenopus oocytes: characteristics of binding and hormonal and developmental control.

Progesterone induces maturation of the amphibian oocyte through its action on the plasma membrane. However, whether or not this action requires high-affinity binding to a specific receptor is unclear. In this study, the binding activity of progesterone was characterized in plasma membranes from whole ovaries or defolliculated oocytes of Xenopus laevis. Membrane-bound, radiolabeled progesterone was isolated by filtration of membrane suspensions and quantified by liquid scintillation. The association of progesterone to membrane preparations reached equilibrium within 15 min. Progesterone binding activity was directly proportional to the sample concentration, was significantly reduced by trypsin digestion, and was pH-dependent and temperature-sensitive. Also, binding activity was observed in membrane preparations from whole ovaries and defolliculated oocytes but not in those from somatic cells, indicating that progesterone binding is restricted to the oocyte membrane. Scatchard analysis indicated a single class of high-affinity (average KD, 10(-9) M), low-capacity (average concentration, 10(-12) mol/mg protein) binding sites for progesterone in all oocyte membrane preparations tested. Progesterone binding activity was also detected in preparations from albino frog ovaries, indicating that the binding activity is not an artifact of melanin contamination. Competition studies showed the following order of affinities: progesterone > pregnenolone > 17 alpha, 20 beta, 21-trihydroxy-4-pregnen-3-one > 11-deoxycorticosterone > 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one > 11-deoxycortisol > estradiol > R5020 > corticosterone > aldosterone > cortisol > androstenedione > ouabain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Supplemental progesterone delays heat termination and the loss of progestin receptors from hypothalamic cell nuclei in female guinea pigs.

Previous studies indicate that the retention of hypothalamic nuclear progestin receptors parallels the expression of sexual receptivity in ovariectomized, hormonally treated guinea pigs. In this study, the effect of a supplemental progesterone injection on heat termination and retention of nuclear progestin receptors was examined. Ovariectomized guinea pigs were injected with 50 micrograms progesterone 48 h after receiving 4 micrograms estradiol benzoate and were tested hourly for lordosis. 8 h after progesterone treatment, animals received either 500 micrograms progesterone or the oil vehicle. The supplemental progesterone injection delayed the termination of heat by more than 2 h compared to oil-injected animals. The effect of supplemental progesterone on the retention of nuclear progestin receptors was then determined. Animals were killed 8, 10, or 14 h after the initial injection of progesterone, and cytosol and nuclear progestin receptor concentrations in mediobasal hypothalamus-preoptic area were determined. Supplemental progesterone further increased the level of nuclear progestin receptors measured at 10 h, and at 14 h these levels were still elevated above baseline. In contrast, nuclear progestin receptor levels in animals which received only the initial progesterone injection had returned to baseline by 14 h, a time when similarly treated animals were no longer receptive. These results suggest that the mechanism by which heat termination occurs may involve loss of nuclear progestin receptors.

Animals↗
PubMed1982

Estrogen-insensitive progesterone receptors in a human breast cancer cell line: characterization of receptors and of a ligand exchange assay.

In modified culture conditions, T47D human breast cancer cells synthesize extraordinary amounts of progesterone receptors (PgR), but, unlike other progesterone target cells, the PgR are entirely independent of estrogen controls. In the present studies we characterize some physicochemical properties of the PgR in T47D cells. We also describe an exchange assay for cytoplasmic and nuclear forms of the receptors which has enabled us to demonstrate that after progesterone treatment, translocation is stoichiometric. Despite the anomalous regulation of PgR levels, these receptors are typical of steroid receptors; they sediment at 7-8S on sucrose density gradients, they bind ligands with high affinity (Kd approximately 4 nM for R5020; Kd approximately 2 nM for progesterone), they bind only progestins specifically, and they are thermolabile (t1/2 at 37 C is approximately 15 min). Receptor levels range from 15-40 pmol/mg DNA, or more than 300,000 sites/cell. The ability of ligands to dissociate from and rebind to the receptors was measured and used in an exchange assay for nuclear PgR. The synthetic progestin R5020 dissociates readily from receptors (t1/2 approximately 3 h at 0 C and 1.5 h at 10 C), and the dissociation of progesterone is even faster (t1/2 approximately 30 min at 0 C). To quantify steroid exchange, receptor levels were measured in mixtures of hormone-filled and unfilled cytosols. These studies assess ligand dissociation and subsequent ligand rebinding. At 0 C for 4-18 H or at 10 C for 4 h, unlabeled progesterone dissociates from receptors, and R5020 rebinds all sites, resulting in 100% exchange. In contrast, despite the use of a variety of incubation times and temperatures, no more than 50% of receptors previously filled with R5020 can exchange for [3H]R5020. The progesterone to [3H]R5020 exchange assay was used to measure salt-extracted nuclear progesterone receptors. In cells treated for 5 min with 0.1 microM progesterone, all depleted cytoplasmic sites were quantitatively recovered from nuclei. These cells provide a new model system to study the molecular biology of human PgR.

Breast Neoplasms↗
PubMed1982

Search for a progesterone-binding protein in secretory granules of the ovine corpus luteum.

The hypothesis that electron-dense granules present in the corpus luteum contain progesterone in a protein-bound form was examined using differential and sucrose gradient centrifugation. Ovine luteal tissue was fractionated by differential centrifugation at 1,000 X g (P1 pellet), 10,000 X g (P2), and 82,000 X g (P3; supernatant S3). Samples of P2, P3, and S3 were further fractionated o 20-40% (P2 and P3) or 5-25% (S3) sucrose gradients and examined for progesterone-binding activity by measuring the progesterone content and/or the specific binding of [3H]progesterone of sucrose gradient samples. In addition, saturation binding assays were performed with steroid-free samples of P2 and S3. Saturable binding of progesterone was not found in P2, the fraction containing electron-dense granules. In S3, two progesterone-binding proteins with sedimentation rates of 3.2S and 8.6S and an affinity of 7.1 X 10(5) M-1 for progesterone were detected. The sedimentation behavior of these proteins was distinct from that of ovine plasma transcortin, a 4S protein. The view that a binding protein is released into the interstitial fluid during the exocytosis of granules was examined by measuring the progesterone-binding activity of protein released by slices of corpus luteum in vitro. No binding activity was found. The results of this investigation do not support the hypothesis that putative progesterone-secreting granules observed in luteal tissue contain a binding protein

Alpha-Globulins↗
PubMed1983

Analysis of the effect of progesterone in vivo on estrogen receptor distribution in the rat anterior pituitary and hypothalamus.

An acute injection of estradiol is known to cause a rapid redistribution of estrogen receptors in responsive cells, measurable as depletion of the cytosol receptor content with accompanying accumulation in the nucleus. We have examined the effects of progesterone on this process in the anterior pituitary and hypothalamus using an animal model in which sensitivity to steroidal feedback control of gonadotropin secretion has been defined. Ovariectomized immature rats were administered low dose estrogen replacement for 4 days. On the morning of the fifth day, groups of animals were injected according to one of the following protocols: 1) vehicle alone; 2) 5 or 10 micrograms estradiol; and 3) 0.8 or 3.2 mg progesterone, followed 1 h later by vehicle or 5 or 10 micrograms estradiol. All animals were killed 1 h after estradiol (or vehicle) injection, and levels of cytosol and nuclear estrogen receptors were measured. The only change occasioned by progesterone treatment was a decrease in anterior pituitary nuclear estrogen receptor levels. At the 5-microgram dose of estradiol, 0.8 and 3.2 mg progesterone were equally effective in diminishing nuclear estrogen receptor binding. When 10 micrograms estradiol were used to cause receptor redistribution, only the higher 3.2-mg dose of progesterone significantly depressed nuclear receptor binding. If ovariectomized animals were maintained in the absence of estrogen replacement, progesterone at either the 0.8- or 3.2-mg dosage was completely ineffective in altering the patterns of estradiol-induced cytosol or nuclear estrogen receptor levels. The results demonstrate a tissue-specific inhibitory action of progesterone on estrogen-induced enhancement of nuclear estrogen receptor binding. This inhibition can be partially overcome by increasing the level of estrogen used to effect receptor redistribution. The requirement for maintenance of a background level of estrogen suggests that the inhibitory action of progesterone is mediated through progesterone receptor interactions.

Animals↗
PubMed1984

Progesterone modulation of the luteinizing hormone surge: regulation of hypothalamic and pituitary progestin receptors.

We have investigated the possible role of hypothalamic and pituitary progestin receptors (PR) in modulation of the estradiol-induced LH surge by progesterone in the immature rat. Rats (28 days old) that received Silastic implants containing estradiol in oil at 0900 h had LH surges approximately 32 h later. Progesterone implants were inserted concurrently with estradiol capsules or 24 h later, leading to inhibition or facilitation of the LH surge, respectively. Cytoplasmic and nuclear PR were measured by in vitro exchange assays, using near-saturating concentrations of [3H]R5020 (3H-labeled promegestone; 17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione), 1, 8, 24, and 32 h after insertion of progesterone or blank implants. Kd values of complexes between [3H]R5020 and PR were 0.5-1 nM (cytoplasmic), and 2-3 nM (nuclear). The sedimentation rates of these complexes in sucrose gradients were 7-8S (cytoplasmic) and 3-4S (nuclear). In rats treated concurrently with estradiol and progesterone for 1 or 8 h, cytoplasmic PR were depleted to 40-60%, and this was accompanied by slight increases in nuclear PR. In control rats treated with estradiol and blank implants, there was no induction of either cytoplasmic or nuclear PR in the hypothalamus-preoptic area for up to 48 h; however, in the pituitary and uterus of these animals, PR increased significantly in both compartments (2- to 3-fold at 24 h, 3- to 5-fold at 32 h, and 4- to 7-fold at 48 h). Administration of progesterone either to inhibit or facilitate LH surges almost completely blocked the inductive effect of estradiol on cytoplasmic PR, but the absence of PR from the cytosol could not be accounted for by their presence in the nucleus. In the hypothalamus-preoptic area of estradiol-treated control rats, neither cytoplasmic nor nuclear PR increased significantly for up to 48 h. The low levels of specific [3H]R5020 binding in pituitary and uterine cytosols from progesterone-treated rats appeared to be due mainly to a decrease in the number of binding sites, rather than to an effect on binding affinities. The 7-8S peak of cytoplasmic PR was considerably reduced in rats treated for 48 h with estradiol and 24 h with progesterone. These results are consistent with the notion that hypothalamic and pituitary PR are involved in modulation of the LH surge by progesterone and point primarily to a pituitary site of action for progesterone facilitation.

Animals↗
PubMed1987

Maintenance of progesterone-facilitated sexual behavior in female rats requires continued hypothalamic protein synthesis and nuclear progestin receptor occupation.

The role of ongoing progesterone-directed protein synthesis and hypothalamic cell nuclear progestin receptor occupation in maintaining the duration of the period of sexual receptivity was determined in ovariectomized rats treated with 500 micrograms progesterone 44 h after receiving 2 micrograms estradiol benzoate. Injection of the protein synthesis inhibitor anisomycin (100 mg/kg BW) either 2 or 10 h after progesterone treatment resulted in decreased levels of both receptive and proceptive sexual behavior. Similarly, injection of RU 486, an antiprogestin, 2, 6, or 10 h after progesterone injection resulted in inhibition of sexual behavior within 4-8 h after administration. Using a modified cell nuclear isolation technique for the exchange assay of nuclear-bound progestin receptors, elevated levels of progestin binding in hypothalamic cell nuclear fractions were detected as late as 14 h after progesterone injection. By 18 h after progesterone injection, nuclear progestin receptor levels had returned to baseline, a time when the period of sexual behavior had terminated in similarly treated animals. These data suggest that continued progesterone action in hypothalamic cell nuclei is required for the maintenance of progesterone-facilitated sexual behavior in the female rat. Furthermore, they suggest that progesterone action maintains sexual responsiveness by altering the synthesis of a short-lived protein or set of proteins.

Animals↗
PubMed1991

Divergent effects of antiprogesterone, RU 486, on progesterone, relaxin, and prolactin secretion in pregnant and hysterectomized pigs with aging corpora lutea.

Porcine corpora lutea produce progesterone and relaxin during pregnancy and after hysterectomy. Peak amounts of relaxin are released into peripheral blood in both pregnant and hysterectomized animals on about day 113 (estrus = day 0 and term = 114), and this release coincides with an abrupt decrease in the progesterone concentration. RU 486, a progesterone receptor antagonist, was used to investigate the effects of interruption of progesterone binding to its receptor on luteal function and gonadotropin secretion of pigs with aging corpora lutea. RU 486 was administered orally to hysterectomized gilts (surgery on day 8) once a day (0800 h) on days 111-115 at two dosages (group 1, 2 mg/kg BW; group 2, 4 mg/kg BW). During 5 days of RU 486 treatment, plasma progesterone concentrations in both treated groups were markedly elevated (32 and 37 ng/ml for groups 1 and 2) compared with 22 ng/ml in the controls (group 3; P less than 0.01). PRL concentrations increased in both groups (9 and 13 ng/ml) and differed significantly from those of the controls (3 ng/ml) (P less than 0.04). RU 486 treatment delayed the time of relaxin peak to days 116.1 and 117.0 in groups 1 and 2 compared with day 114.1 in the controls (P less than 0.01). Pregnant gilts received RU 486 orally once a day (0800 h) at 4 mg/kg BW beginning on day 111 until parturition occurred. Parturition was induced on day 112.7 after only two RU 486 treatments compared with day 114.7 in the control group (P less than 0.01). Progesterone decreased abruptly from a pretreatment mean of 11 to less than 0.6 ng/ml during the 2 days that RU 486 was given compared with a shift from 12 to 6 ng/ml during the same period in the controls (P less than 0.01). The time of the relaxin peak was advanced to day 112.1 in RU 486-treated gilts compared with day 113.9 in the controls (P less than 0.01). Results from this study provide strong evidence that the antagonistic effect of RU 486 on progesterone receptor results in an abrupt increase in PRL and progesterone secretion in hysterectomized gilts with aging corpora lutea. In marked contrast with hysterectomized animals, the acute luteolytic effects of RU 486 depend on the presence of the uterus and/or conceptuses in the pig. Disruption of the regulatory loop of progesterone secretion by RU 486 alters the ability of corpora lutea to produce and release peak quantities of relaxin.

Animals↗
PubMed1993

Stimulation of protein tyrosine phosphorylation by a progesterone receptor on the cell surface of human sperm.

Mature human sperm initiate a rapid Ca2+ influx and the acrosomal exocytosis in response to progesterone. Recent evidence indicates that both events can be induced by antibody-mediated cross-linking of a sperm surface progesterone receptor. In many other systems in which signal is generated by receptor cross-linking, protein phosphorylation on tyrosine residues is involved in the signal transduction across the plasma membrane. In this study we examined whether tyrosine phosphorylation is implicated in the function of the sperm surface progesterone receptor, too. The effect of progesterone on the phosphorylation of proteins from a sperm membrane lysate was evaluated by in vitro kinase assay and by phosphoamino acid analysis using [gamma-32P]ATP as precursor. These experiments revealed a selective increase in the tyrosine phosphorylation of a 94-kilodalton phosphoprotein in the presence of progesterone. To decide whether the progesterone-induced increase in protein tyrosine phosphorylation is actually due to the hormone action on the cell surface, living sperm were treated with a cell-impermeant progesterone receptor agonist, and the resulting changes in the cellular level of phosphotyrosine proteins were examined. These experiments showed a clear relationship between the agonist binding and an increase in the phosphotyrosine concentration in the respective cells. This relationship was lost in the presence of genistein, which also efficiently inhibited the phosphorylation of the 94-kilodalton protein and the progesterone-induced acrosomal exocytosis. These results lead to the hypothesis that protein tyrosine phosphorylation is involved in signal transduction through the sperm surface progesterone receptor and may be implicated in nongenomic steroid effects in other cell types.

Adenosine Triphosphate↗
PubMed1989

Acute effects of progesterone and the antiprogestin RU 486 on gonadotropin secretion in the follicular phase of the menstrual cycle.

Considerable controversy still exists concerning the role of progesterone in the initiation of the midcycle gonadotropin surge in humans. We, therefore, carried out a prospective randomized study to determine the potential of progesterone to initiate a gonadotropin surge and the acute effects of a potent progesterone antagonist (RU 486) on follicular phase gonadotropin secretion in normal women. The women underwent frequent blood sampling for 4 in the midfollicular (day 6) or late follicular phase (day 10). They then received either progesterone (10 mg, im) or RU 486 (10 or 100 mg, orally), and blood sampling was continued for an additional 8 h. Four women received each of the drug regimens in the early follicular phase, and four received each regimen in the late follicular phase. Two additional women were studied as control subjects at each stage of the cycle. Progesterone administration in the mid- and late follicular phases resulted in an acute increase in plasma LH and FSH concentrations, and the increases correlated with the base line plasma estradiol concentrations (P less than 0.05). In contrast to progesterone, the women who received RU 486 in the mid- and late follicular phases had a reduction in plasma LH and FSH concentrations after drug administration. The response in the mid-follicular phase was considerably less than that in the late follicular phase, and the extent of the response correlated with the baseline plasma estradiol concentrations (P less than 0.005). The changes were similar in response to both RU 486 doses. We conclude that progesterone can initiate a gonadotropin surge in the late follicular phase of the menstrual cycle. The inhibitory effect of the progesterone antagonist RU 486 suggests that a positive feedback mechanism involving progesterone may be influential some time before the surge onset.

Adult↗
PubMed1986

Cytoplasmic progesterone receptors in uterine tissue of the snapping turtle (Chelydra serpentina).

A high affinity progesterone-binding component was detected in the cytosol of the uterus of the snapping turtle, Chelydra serpentina. Density gradient centrifugation indicated that binding of [3H]progesterone and [3H]promegestone (R5020) was to a fraction with a heavier sedimentation coefficient than bovine serum albumin (BSA) appearing as a broader peak in the 6-7 S region; it was not affected by excess cortisol. Another binding peak, lighter than BSA and appearing with [3H]R5020 and [3H]progesterone near the 4 S region, was affected by excess cortisol. Excess progesterone decreased both the heavier and lighter peaks. Analysis of steroid specificity revealed that, of the natural steroids, progesterone had the highest affinity for the uterine cytosol. This was followed by deoxycorticosterone, 5 alpha-pregnanedione, testosterone, oestradiol-17 beta, corticosterone, 5 alpha-dihydrotestosterone and cortisol. Non-linear regression analysis of saturation data indicated the presence of two classes of high affinity binding sites: progesterone-binding sites (R-sites) with equilibrium association constants (Ka) of 2.9 +/- 0.28 litres/nmol (mean +/- 95% confidence limit) for [3H]R5020 and 0.34 +/- 0.20 litres/nmol for [3H]progesterone, and corticosteroid-binding globulin-like sites (G-sites) with Ka of 4.5 +/- 1.6 litres/nmol for progesterone. The concentration of R-sites was between 0.66 +/- 0.10 and 2.6 +/- 0.55 pmol/mg protein while that of G-sites was between 0.73 +/- 0.05 and 5.0 +/- 0.27 pmol/mg protein. DEAE-cellulose filtration assay also confirmed the presence of R-sites and G-sites in the cytosol. R-sites were detectable without oestrogen priming during the preovulatory and vitellogenic phases (low progesterone, high oestrogen concentrations) when the ovarian follicles are mature (18-22 mm diameter).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗