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PubMed1979

Regulation and function of estrogen and progesterone receptor systems.

We have developed and validated assay methods which are appropriate for studying the subcellular distribution of estrogen receptor (Re) and progesterone receptor (Rp) in hamster uterus during the estrous cycle and pregnancy. Cytosol receptors were monitored by conventional procedures, and nuclear receptors were extracted from nuclei at 2 C using 0.5 M KCl in buffer containing glycerol and measured by ligand exchange during incubation with [3H] progesterone (P) at 2 C for 24 h or [3H] estradiol-17 beta (E2) at 30 C for 1 h. The nuclear exchange assay described herein measures total receptor and also permits estimation of unlabeled steroid in the nuclear KCl extract. Nuclear Rp translocation was shown to be target-tissue specific, hormone specific, and dependent on P dosage under in vivo conditions. The duration of nuclear Rp retention was about 6 h following exogenous P treatment. During the estrous cycle, Re and Rp levels in uterine cytosol and nuclei varied in response to the changing pattern of E2 and P secretion. Our results document a positive relationship between serum E2, nuclear Re and cytosol Rp levels during the follicular phase of the cycle. Nuclear Rp remained low on cycle days 1--3, and increased abruptly on day 4 coincident with preovulatory P secretion and cytosol Rp depletion. Nuclear Rp translocation during the preovulatory period on cycle day 4 was associated with a marked decline in nuclear Re, and the latter was demonstrated to be a rapid (2--4 h) response to P action rather than serum E2 withdrawal. The negative effect of P on nuclear Re levels may represent a fundamental mechanism for P antagonism of E action. Cytosol and nuclear Rp levels in deciduomal and myometrial tissue were responsive to experimental alteration of serum P, indicating that nuclear Rp is maintained by a continuous process of P-induced Rp translocation. Of interest was the finding in pregnant animals that Re levels declined dramatically in deciduoma as compared to myometrium. The loss of cytosol and nuclear Re from deciduomal cells cannot be attributed to changes in serum E2 or P. Thus, the intracellular regulation of Re numbers may change during differentiation of certain target cells such as those found in the deciduoma.

Animals↗
PubMed1978

Uterine progesterone receptors in the aged golden hamster.

Uterine capacity to form cytoplasmic progesterone receptor was compared in ovariectomized golden hamsters at three months and 15-17 months of age. A dose-response test with 17beta-estradiol(E2) showed that the uterine content of progesterone receptor (pmole/uterus) was equal in young and old at all dose levels. However, heavier old uteri had less receptor per gm tissue. Old and young hamsters were mated, ovariectomized on day 7 post coitum and after two weeks, all were given the same dose of E2. Endometrium was separated from myometrium before analysis of progesterone receptor. Myometrium was analyzed for both estrogen and progesterone receptors. Myometrium of both groups had comparable levels of both receptors. The mean concentration of progresterone receptor (pmole/gm tissue) was higher in old endometrium. Some old animals with liver, kidney and adrenal disease had more endometrial reaction after E2 treatment. A few with low endometrial receptor levels had normal livers but at least one sterile uterine horn. There was, however, no general decline with age in intrinsic uterine capacity to form progesterone receptors.

Aging↗
PubMed2025

Progesterone receptor isoform modulation via enhancer activation regulates progesterone signaling in endometrial stromal cells.

OBJECTIVE: To investigate enhancer-mediated regulation of progesterone receptor (PGR) isoforms, PGR-A and PGR-B, in human endometrial stromal cells, and to determine how isoform modulation shapes the progesterone-responsive transcriptome and cistrome relevant to endometrial function. DESIGN: A clustered regularly interspaced short palindromic repeats-based functional genomic screen was used to identify distal enhancers in telomerase-immortalized human endometrial stromal cells. Subsequent clustered regularly interspaced short palindromic repeats targeting of identified enhancers and the PGR promoter was used to modulate PGR isoform balance and assess functional consequences. SUBJECTS: None. EXPOSURE: Engineered endometrial stromal cells were treated with medroxyprogesterone acetate or vehicle. MAIN OUTCOME MEASURES: PGR isoform expression was assessed by western blot, the progesterone-responsive transcriptome was characterized by bulk ribonucleic acid sequencing, and the PGR cistrome was characterized by Cut&Run. RESULTS: Two distal PGR enhancers were identified in endometrial stromal cells located approximately 60 and 220 kb upstream of the PGR transcription start site. Clustered regularly interspaced short palindromic repeats-based activation of these enhancers upregulated both PGR-A and PGR-B, whereas promoter activation primarily upregulated PGR-B. Bulk ribonucleic acid sequencing revealed that shifting the PGR isoform balance altered the progesterone-regulated transcriptome: PGR-A/B-equivalent cells exhibited proinflammatory gene signatures, whereas PGR-B-dominant cells demonstrated suppression of inflammatory signaling and altered cell cycle programs. The PGR Cut&Run profiling revealed distinct genomic binding patterns associated with each isoform profile. Integration of the PGR cistrome with chromatin interaction maps suggested that these isoforms directly regulate distinct gene subsets involved in inflammation and fibrosis. Mechanistically, estrogen receptor alpha (ESR1) indirectly activated PGR-A expression, potentially through recruitment of Forkhead box protein O1 (FOXO1) at the distal enhancer, suggesting a noncanonical, enhancer-mediated mechanism of PGR regulation. CONCLUSIONS: Distal enhancers regulate the PGR isoform balance and shape the progesterone-responsive transcriptome in human endometrial stromal cells. This enhancer-mediated mechanism expands current models of PGR regulation beyond promoter-level control and may offer potential therapeutic targets to restore normal progesterone responsiveness in conditions marked by PGR isoform imbalance.

Humans↗
PubMed1978

[The influence of endogenous hormones on the oestrogen and progesterone receptor determination in tissue of mammary carcinoma (author's transl)].

Oestrogen and progesterone receptors were determined in 48 primary tumors of invasive mammary carcinoma. 86% showed a positive oestrogen receptor binding, 53% were progesterone receptor positive. The binding capacity for oestradiol was 5-211 pmoles/g tissue protein, for progestin (R 5020) 7-146 pmoles. The question of the investigation was whether the content of determined receptors depends on endogenous oestradiol and progesterone concentrations. A clear dependence did not exist between the hormone level in the plasma, collected just before the excision of the tumor, and the amount of identifiable receptors in the tumor. On the contrary, in considering the quantities of endogenous hormones in the tissues, based on the plasma content of the tissue and the plasma hormone level, a correlation could be found. The content of identifiable receptors decreased with increasing amounts of endogenous hormones in the cytosol. It is postulated that rather the amount of endogenous hormones in the tissue than the plasma hormone level characterizes the degree of saturation of existing receptors by endogenous hormones. Apparently, the determined receptor concentrations at endogenous hormone values under 2 pmoles/g tissue protein reflect rather the true receptor content, whereas at higher values too low or false negative results should be reckoned with.

Breast Neoplasms↗
PubMed1979

Search for progesterone receptors in testes from various animal species.

Using [3H]R5020 as binding probe, we have looked for the presence of progesterone receptors in testis cytosol from a few vertebrate species ranging from the turtles to the humans. In addition, we have tested in the rat several experimental conditions potentially susceptible to induce progesterone receptors. With the exception of chicken, tfm patients and possibly the frogs, progesterone receptors could not be conclusively demonstrated in any of the other animal species tested nor could they be induced in the rat. Surprisingly, they were not present in Stanley-Grumbeck pseudohermaphrodite rats. In chicken testes, the levels of progesterone receptor were variable (3--45 fmol per mg prot.) in the adults and high (87 fmol per mg prot.) in one-day-old animals. The presence of progesterone receptor, a marker of estradiol action in many estrogen-target tissues, seems to be parallel to the capacity of chicken testes for sex reversal under the influence of estrogens. In human tfm, the presence of these receptors could also indicate that the gonads are estrogen-sensitive or that they were so during embryonic life although the nature of estrogenic action is not known.

Animals↗
PubMed1978

Measurement of the corticosteroid-binding globulin, progesterone, and progesterone "receptor" content in human endometrium.

The corticosteroid-binding globulin (CBG) content has been determined in cytosols prepared from human endometrium taken at different phases of the menstrual cycle, at 8-10 weeks gestation, and during treatment with an oral contraceptive. The data were compared to the progesterone "receptor" and the progesterone concentration in the same tissue extracts. The plasma contamination was estimated by the serum albumin content. It was observed that CBG is a constant contaminant of the endometrial cytosols. All of the CBG content can be considered to be of plasma origin. The cytoplasmic progesterone "receptor" content is between 21-33% of the CBG concentration during the menstrual cycle and is only 1% during pregnancy. The cytosol progesterone concentration is much higher in endometrium than would be expected from the plasma contamination and the level of the progesterone "receptor".

Cell Nucleus↗
PubMed1978

[The effect of enzymes on progesterone-receptor binding and chromatin binding of the complex in the estrogen-primed rabbit uterus (author's transl)].

The present study was designed to determine the characteristics of the progesterone receptor and chromatin binding site ("acceptor") of the progesterone-receptor complex in the rabbit uterus. The uterus was obtained from an estrogen-primed immature female rabbit. The binding of progesterone to the uterine receptor was examined in vitro. The progesterone-receptor binding was reduced only by proteases, and phosphorus moiety may not be related for progesterone-receptor binding. The effects of enzymes on the acceptor of the chromatin were investigated. The progesterone-receptor complex was bound to the dehistonized chromatin. The dehistonized chromatins, which were pretreated with enzymes at 4 degrees C or 37 degrees C for 30 minutes, were incubated with 3H-progesterone prelabeled uterine cytosol at 4 degrees C for 30 minutes, and the radioactivity in the chromatin pellet was counted. Proteases effectively decreased the receptor binding capacity to the dehistonized chromatin in the following order: pronase greater than trypsin greater than papain greater alpha-chymotrypsin. DNAse moderately and phospholipase A slightly decreased its binding capacity. The results may indicate that the acceptor site of the progesterone receptor is nonhistone protein over DNA of chromatin and may contain phosphorus moiety.

Animals↗
PubMed1978

Progesterone receptors of chick oviduct.

The chick oviduct progesterone receptor has been purified to homogeneity by affinity chromatography and its molecular action studied in vitro. The native receptor is a 200,000 MW dimer of two dissimilar 4S subunits with different intranuclear function. The receptors directly regulate RNA chain initiation sites in oviduct chromatin by interactions involving target tissue nuclear acceptor sites. There is a 1:1 correspondence between receptor "acceptor" sites and RNA sites. Only the dimer form of the receptor is active in vitro on chromatin templates. The study suggests a novel model for hormone action which can be tested directly in this system.

Animals↗
PubMed1977

Changes in progesterone receptor levels during deciduomata development in the pseudopregnant rat.

A specific cytoplasmic progesterone receptor has been identified and quantified in the deciduomata of the pseudopregnant rat. The receptor had a sedimentation coefficient of 6-7S on sucrose density gradients and was inactivated by proteolytic enzymes, sulfhydryl blocking agents and elevated temperature. The equilibrium association constant for the binding of progesterone by the deciduomal receptor was determined to be approximately 10(9)M-1. The concentrations of progesterone receptor sites in cytosols prepared from deciduomata on day 3 and 5 of decidualization were 3.4 +/- 0.3 X 10(-10)M and 3.6 +/- 0.4 X 10(10)M, respectively, when normalized to a protein concentration of 1 mg/ml. These concentrations of progesterone receptor sites were similar to that measured in the uterine cytosol of estrous rats or in the contralateral untreated uterine horn of rats undergoing decidualization. Following day 5 of decidualization the concentrations of progesterone receptor sites decreased linearly so that by day 7 the concentration was approximately one-half that at days 3 and 5. The physiological significance of the progesterone receptor and the decrease in its concentration with time are discussed with regard to their influence on the decidualization reaction.

Animals↗
PubMed1978

Stoichiometric translocation of the rat uterine progesterone receptor.

In several previous studies nuclear accumulation of the progesterone receptor was significantly lower than the quantity depleted from the cytosol one h after progesterone injection. The results presented herein indicate that this apparent lack of stoichiometry is due to loss of detectable receptor from the nucleus during the nuclear washes and after the assay incubation. This decrease in measured receptor results both from solubilization of the receptor-progesterone complex into the supernatant and from dissociation of [3H] ligand from the receptor. Conversely, no significant quantities of receptor were detected in the mitochondrial/microsomal fraction, preincubation nuclear washes, second ethanol extraction of the nuclear pellet, and soluene digest of the extracted pellet. Thin layer chromatography of the radioactive ligand bound to the nuclear receptor after in vitro exchange confirmed that virtually all the specific binding was due to [3H] progesterone, in spite of a 30% conversion to other metabolites in the incubation fluid.

Animals↗
PubMed1979

Progesterone receptors and RNA polymerase activity in the rat uterus during the oestrous cycle.

The concentrations of progesterone receptors in uterine cytoplasm and nuclei were measured during the oestrous cycle of the rat. The concentration of cytoplasmic progesterone receptors was highest at pro-oestrus and declined at oestrus to reach lowest levels at metoestrus before rising at dioestrus. Similar changes were observed in the concentration of nuclear progesterone receptors, the highest levels being present at pro-oestrus and dioestrus. In addition, both activities A and B of RNA polymerase mirrored these alterations in nuclear receptor levels.

Animals↗
PubMed1977

Progesterone receptors in the chick oviduct. Determination of the total concentration of binding sites in the cytosol and nuclear fraction and effect of progesterone on their distribution.

1. Exchange techniques were developed for measurement of total progesterone receptor binding sites concentration in the cytosol and nuclei of chicken oviduct. 2. The level of progesterone receptor in the cytosol was under both oestrogen and progesterone control. Primary stimulation by oestradiol benzoate increased the receptor concentration from approximately 10 000 sites/cell to approximately 40 000 sites/cell in the magnum cytosol; subsequent withdrawal from oestrogen treatment led to a decrease to approximately 14 000 sites/cell after 6 weeks. After progesterone administration (3 mg/kg) to oestrogen-stimulated, withdrawn chicken, the receptor concentration decreased to approximately 40% of the initial level within the first 4 h; afterwards the receptor level rose again and by 40 h exceeded slightly the initial one. 3. The nuclear levels of the receptor reached a maximum at 1 h after the progesterone injection; however, the gain of the binding sites by the nuclei (approximately 900/nucleus) did not account for their loss from the cytosol. The maximum nuclear receptor level was not influenced by the dose of progesterone within range of 1-10 mg/kg. 4. The extractibility of the nuclear progesterone receptor by 0.5 M NaCl was strongly influenced by preincubation of the nuclei at 30 degrees C; irrespective of this preincubation, approximately 12% of the nuclear receptor resisted extraction with 2 M NaCl/5 M urea.

Animals↗
PubMed1979

Progesterone receptor in the rat ovary: further characterization and localization in the granulosa cell.

We have recently described a progesterone receptor in the cytosol of ovaries of hypophysectomized, estrogen-primed, immature rats. This progesterone receptor was shown to be a thermolabile, saturable protein, which is specific for progestins (R5020 and progesterone), and elutes at the void volume of a Sephadex G-200 column. In the present study, we performed a more detailed analysis of the biochemical properties of this receptor and examined its cellular localization within the ovary. Treatment of the ovary cytosol with protamine sulfate and N-ethyl maleimide abolishes the specific binding of 3H-R5020, indicating that the receptor is an acidic protein containing cysteine residues necessary for binding. Gel exclusion chromatography shows the progesterone receptor to have a mean Stokes radius of 86 A and a molecular weight of approximately 300,000 daltons. Kinetic analysis indicates that the receptor--R5020 complex dissociates very rapidly, with a t1/2 of 10 minutes. The cytosol of isolated granulosa cells bind 3H-R5020 specifically, demonstrating that the ovarian progesterone receptor is present in the granulosa cell.

Animals↗
PubMed1979

Oestrogen and progesterone receptor concentrations in human endometrium during gestation.

The concentrations of endometrial oestrogen and progesterone receptors, both in cytosol and in nuclei, have been studied at 8--10 weeks and at 38--40 weeks of gestation. At these two periods the concentration of oestrogen receptors is comparable with the concentration observed during the late secretory phase of the menstrual cycle. At 8--10 weeks of gestation, concentration of progesterone receptors is also comparable with the concentration observed during the secretory phase of the menstrual cycle, but at term there is a significant increase (P less than 0.05) and the concentration is then comparable with the concentration observed in the pre-ovulatory period of the menstrual cycle. The receptor binding sites are always predominantly found in nuclei and the increase in progesterone nuclear receptor at term suggests that in man the progesterone withdrawal is not a necessary step in the mechanism of uterine activation during parturition as it is in other species.

Cell Nucleus↗
PubMed1977

Interaction of progesterone receptor with immobilized adenosine triphosphate.

Affinity chromatography has been used to study the binding of ATP to cyto-plasmic progesterone receptors of hen oviduct. A resin which selectively binds the receptor protein was prepared by linking ATP covalently to Sepharose 4B through a 6-carbon bridge of adipic acid dihydrazide. Receptor bound to the affinity resin was recovered in a single peak upon gradient elution with KCl (0.2-1 M) or ATP (0-0.1 M). While affinity chromatography was normally accomplished using the [3H]progesterone receptor complex, the hormone was not necessary for ATP binding under the conditions employed. The chromatography of crude receptor preparations allowed up to 100-fold purification with greater than 80% recovery of the receptor. The semipurified receptor appeared intact when analysed by sucrose gradient centrifugation, polyacrylamide gel electrophoresis, and DEAE-cellulose chromatography. The latter procedure separated the receptor into two components, A and B, both of which were capable of binding ATP. Although a specific biochemical role of ATP in hormone receptor action has not been demonstrated, the present studies support this possibility and, in addition, offer a convenient and reliable step for the purification of progesterone receptors.

Adenosine Triphosphate↗
PubMed1975

Specific progesterone receptors in human breast cancer.

We have identified a specific progesterone receptor in 11 of 33 human breast cancer cytosols. Since progesterone itself binds to glucocorticoid receptor, to corticosteroid binding globulin (CBG), and to nonspecific components as well as to its own receptor, we have used a synthetic progestin, R5020 (17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione), whose binding specificity is restricted to progesterone receptor. Bound R5020 sediments at 8 S in sucrose gradients; binding is competed by excess unlabeled R5020 or progesterone. The receptor is distinct from glucocorticoid receptor and CBG as determined by competition studies using dexamethasone and hydrocortisone. The dissociation constant for R5020 obtained by Scatchard analysis of dextran-coated charcoal assays is approximately 2 times 10- minus 9 M.

Binding Sites↗