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PubMed1986

Regulation of estradiol and progesterone receptor concentrations in cat uteri following chronic progesterone administration.

The purpose of this study was to determine the early effect of progesterone (P) on the estradiol (E2) and P receptor systems in cat uteri. Ovariectomized animals were treated with E2 for 7 days. Animals were then treated for up to 48 h with E2 and P, treated with P while being E2 withdrawn, or just E2 withdrawn. P treatment resulted in a significant decrease in P cytosol receptor (PcR) and a significant increase in P nuclear receptor (PnR) at all times included in this study when compared to levels measured in the E2-treated animal. E2 cytosol receptor (EcR) and E2 nuclear receptor (EnR) levels were significantly lower after 12 h of P treatment and remained so for the duration of this study. When EcR and EnR levels were compared after 48 h of P treatment in the presence or absence of E2, or after 48 h of E2 withdrawal, the loss of EnR following P treatment appeared to be independent of any changes in EcR levels or serum E2 levels, and only dependent on the presence of P. These results clearly illustrate that the chronic administration of P decreases the uterine concentration of its own receptor, and suggests that P decreases the E2 receptor system by a selective action within the nucleus which diminishes their ability to retain EnR.

Animals↗
PubMed1986

Differential suppression of progesterone receptors by progesterone in the reproductive tract of female macaques.

Ovariectomized cynomolgus macaques were treated with implants of estradiol (E2) for 14 days. Some animals then received an additional implant of progesterone (P) for 7-14 more days. After treatment with either E2 alone or with E2 plus P we removed the reproductive tracts and measured nuclear and cytosolic P receptors by exchange assay. In addition we used steroid radioimmunoassays(RIA) to measure levels of E2 and P in parallel aliquots of the nuclear and cytosolic fractions. P treatment reduced the concentrations of E2 in nuclear and cytosolic fractions in the cervix, endometrium, myometrium and oviduct compared to the amounts present after 14 days of E2; these data are consistent with many reports that P treatment significantly lowers the amount of nuclear and cytosolic estrogen receptors in all of these tissues. In the oviduct, myometrium and cervix both cytosolic and nuclear P receptor levels were lowered during P action. In the endometrium, however, P treatment reduced the amount of P receptor only in the cytosolic but not the nuclear fraction. RIA determinations of the amount of P retained in nuclear fractions of the P-treated animals indicate that P levels were significantly elevated only in the nuclei obtained from endometrium. This specific increase in the retention of P by endometrial nuclei during P action is consistent with the specific retention of P receptor by endometrial nuclei. These results lead to the unexpected conclusion that the stimulatory effects of P as expressed in the maintenance of the progestational state in the primate endometrium may require higher levels of occupied nuclear P receptor than do the suppressive effects of P as expressed in oviductal atrophy, diminished cervical secretion and myometrial quieting.

Animals↗
PubMed1999

Recognition of a human sperm surface protein involved in the progesterone-initiated acrosome reaction by antisera against an endomembrane progesterone binding protein from porcine liver.

Antisera against a porcine liver endomembrane progesterone (P4)-binding protein inhibited the P4-initiated acrosome reaction (AR) but not the ionomycin-initiated AR of human sperm. Indirect immunofluorescence studies detected antigen in the sperm head that moved during capacitation from a posterior head region to a midhead region. Moreover, the antisera detected a 44.6 kDa protein in western blots of sperm digitonin extracts. These results suggest that a sperm protein with at least partial homology to the liver endomembrane P4-binding protein, is a putative P4-receptor on the sperm plasma membrane involved in the P4-initiated AR.

Acrosome Reaction↗
PubMed1980

Progesterone-binding components of chick oviduct: partial purification and characterization of a calcium-activated protease which hydrolyzes the progesterone receptor.

A calcium (Ca2+)-activated protease has been purified from laying hen oviducts. This enzyme can catalyze the limited proteolysis of the native chick oviduct progesterone receptor subunits, A and B, to smaller hormone-binding fragments. The protocol used has resulted in a 2000-fold purification of the enzyme in 40% yield from hen oviduct postmitochondrial supernatant fractions. This resulted in an active, purified protease preparation which can be used as an analytical tool for studying receptor protein structure. Characterization of the purified enzyme has shown that it is activated by Ca2+ (0.5-1 mM), has a molecular weight of 113 000, and has a sedimentation value of 6 S. No effect of calmodulin (Ca2+-dependent regulator) could be shown on the enzymatic activity of the protease. The enzyme has a Km of 1.04 x 10(-8) M for the receptor protein substrate. The protease is inactivated by sulfhydryl attacking reagents and thus can be classified as a sulfhydryl protease. This protease exhibits remarkable similarities to the "receptor transforming factor (RTF)", a Ca2+-activated protease which performs a limited proteolysis on the calf uterine estrogen receptor [Puca, G. A., Nola, E., Sica, V., & Bresciani, F. (1977) J. Biol. Chem. 252, 1358].

Animals↗
PubMed1998

The negative feedback actions of progesterone on gonadotropin-releasing hormone secretion are transduced by the classical progesterone receptor.

Progesterone (P) powerfully inhibits gonadotropin-releasing hormone (GnRH) secretion in ewes, as in other species, but the neural mechanisms underlying this effect remain poorly understood. Using an estrogen (E)-free ovine model, we investigated the immediate GnRH and luteinizing hormone (LH) response to acute manipulations of circulating P concentrations and whether this response was mediated by the nuclear P receptor. Simultaneous hypophyseal portal and jugular blood samples were collected over 36 hr: 0-12 hr, in the presence of exogenous P (P treatment begun 8 days earlier); 12-24 hr, P implant removed; 24-36 hr, P implant reinserted. P removal caused a significant rapid increase in the GnRH pulse frequency, which was detectable within two pulses (175 min). P insertion suppressed the GnRH pulse frequency even faster: the effect detectable within one pulse (49 min). LH pulsatility was modulated identically. The next two experiments demonstrated that these effects of P are mediated by the nuclear P receptor since intracerebroventricularly infused P suppressed LH release but 3alpha-hydroxy-5alpha-pregnan-20-one, which operates through the type A gamma-aminobutyric acid receptor, was without effect and pretreatment with the P-receptor antagonist RU486 blocked the ability of P to inhibit LH. Our final study showed that P exerts its acute suppression of GnRH through an E-dependent system because the effects of P on LH secretion, lost after long-term E deprivation, are restored after 2 weeks of E treatment. Thus we demonstrate that P acutely inhibits GnRH through an E-dependent nuclear P-receptor system.

Animals↗
PubMed2000

A membrane-associated progesterone-binding protein, 25-Dx, is regulated by progesterone in brain regions involved in female reproductive behaviors.

The ventromedial hypothalamus (VMH) plays a central role in the regulation of the female reproductive behavior lordosis, a behavior dependent upon the sequential activation of receptors for the ovarian steroid hormones estradiol (E) and progesterone (P). These receptors function as transcription factors to alter the expression of target genes. To discover behaviorally relevant genes targeted by E and P in the VMH, we used the differential display PCR to identify messenger RNAs that are differentially expressed in the hypothalamus of ovariectomized (ovx) rats treated with E alone compared with ovariectomized rats treated with E and P. We show here that one interesting mRNA within the hypothalamus that is repressed by P after E priming encodes the protein 25-Dx, the rat homolog of the human membrane-associated P-binding protein Hpr6.6. Neurons in the brain containing the highest levels of 25-Dx are located in several nuclei of the basal forebrain, including the VMH. 25-Dx expression is also higher in the hypothalamus of female P receptor "knockout" mice than in their wild-type littermates. These findings suggest a mechanism in which the activation of nuclear P receptor represses expression of a membrane P receptor, 25-Dx, during lordosis facilitation.

Animals↗
PubMed1998

Regulation of the progesterone receptor and estrogen receptor in decidua basalis by progesterone and estradiol during pregnancy.

In this study we examined the roles of progesterone (P4) and estradiol-17beta (E2) in regulation of the P4 receptor (PR) and estrogen receptor (ER) in the decidua basalis (DB) during stromal cell proliferation and regression (Days 10 and 14 of pregnancy, respectively). Pregnant rats were ovariectomized (Ovx) on Day 8 or 12 and killed on Day 10 or 14, respectively, following treatment with P4, E2, or both. In some experiments, rats received pellets of the anti-progestin RU-486 on Day 9 and were killed 3, 6, 12, and 24 h later. Immunolocalization of PR and ER showed that both receptors decreased from Day 10 to Day 14. Histologic integrity of the placenta and DB were maintained only when P4 was present. Control and hormone-treated groups expressed established isoforms of PR and ER: PR-B, 110 kDa; PR-A, 80-90 kDa; PR-C, 64-60 kDa; ER-66, 66 kDa; and ER-49, 49 kDa. On Day 10, expression of PR-A, PR-B, and ER-66 decreased 50-99% (p < 0.05) after Ovx or RU-486 treatment but was restored to control levels after Ovx by exogenous P4. On Day 14, PR-B and ER-66 declined 66-75% (p < 0.05) after Ovx and could not be restored by P4 treatment. Estrogen could not substitute for P4, and co-administration of E2 with P4 did not enhance the response over P4 alone. In contrast, PR-C was abundantly expressed on Days 10 and 14 in all treatment groups after Ovx and RU-486. P4 maintained PR mRNA and ER mRNA after Ovx. Thus, regression of the DB may be initiated via changes in relative expression of PR isoforms, which result in impaired stromal cell response to P4 action.

Animals↗
PubMed2000

Effects of progesterone receptor blockers on human granulosa-luteal cell culture secretion of progesterone, estradiol, and relaxin.

We have developed culture methods for human luteinizing granulosa cells (GLC) that support the timely and dynamic secretion of estrogen (estradiol-17beta; E(2)), progesterone (P(4)), and relaxin (Rlx) in patterns that mimic serum hormone concentrations during the luteal phase of the menstrual cycle. Additional hCG, to simulate rescue of the corpus luteum, prevented the normal decline in GLC hormone production. To test the importance of the P(4) receptor in P(4) production, GLC were treated in vitro with two P(4) receptor antagonists. Human GLC received one of two hCG support protocols: a Baseline group simulating the normal luteal phase or a Rescue group simulating early pregnancy. Baseline and Rescue groups were treated with either RU-486 or HRP2000 either early or late in the cell culture period. The effects of treatments or control on ovarian steroid and peptide hormone production were determined (significant difference was P < 0.05). In the Rescue group, late treatment resulted in an immediate and dramatic decline in E(2), P(4), and Rlx secretion to nearly nondetectable levels within 1 day after treatment, and hormones remained depressed for the remaining 10 days of culture. In contrast, early treatment resulted in a decline in steroid hormone secretion that returned to control levels within 5 days of cessation of treatment, and Rlx secretion was delayed for approximately 5 days more than in controls. The data support the hypothesis that P(4) may be a required autocrine factor, not only for its own production but also for the maintenance of full endocrine function of the corpus luteum.

Cells, Cultured↗
PubMed1986

Progesterone receptor replenishment during sustained progesterone treatment in the hamster uterus.

Previous studies have demonstrated that uterine progesterone (P) receptor is under dual hormonal control; estradiol (E2) induces the synthesis of cytosolic P receptor, and P induces the loss of its own receptor and antagonizes E2-induced P receptor replenishment. The objective of this study was to examine the contributions of E2 and P in the replenishment of uterine P receptor during sustained P exposure. Silastic implants of varying length (0.4, 0.8, 1.5, 2.5, and 5.0 cm) were packed with crystalline P and placed sc in the flank region of ovariectomized adult female hamsters. The serum P levels obtained with these implants (2-22 ng/ml) were within the physiological range observed previously during the estrous cycle, pregnancy, and lactation in the Syrian hamster. Control animals received a blank implant (1.5 cm). Three, 5, and 7 days after placement of the implants, uterine cytosolic and nuclear P receptor levels were decreased as serum P level was increased by the P implants. Total cellular P receptor level was inversely correlated with serum P level at 3 days (r = -0.996), 5 days (r = -0.98), and 7 days (r = -0.99). To distinguish the effect of E2 and P, ovariectomized animals were maintained on Silastic implants of P (1.5 cm) or P plus E2 (1.0 cm). After 3 days, cytosolic P receptor was determined 0, 8, 16, 24, and 48 h after removal of P implants. No difference was observed in cytosolic P receptor between P and P plus E2 groups before P withdrawal. E2-maintained animals showed a significant rise of cytosolic P receptor at all time points after P withdrawal. Although P withdrawal in the absence of E2 showed no significant change in P receptor at 8 or 16 h, a significant increase in P receptor (equivalent to that of ovariectomized control animals) was observed at 24 and 48 h. Treatment of ovariectomized animals with cycloheximide significantly reduced uterine cytosolic P receptor levels 8, 18, and 24 h after treatment. These results suggest that 1) an active receptor replenishment process occurs in the absence of E2; 2) this replenishment process does not appear to be P dependent, but, rather, constitutively expressed; and 3) the rate of constitutive P receptor replenishment is slower and of lower magnitude than that promoted by E2. Because P antagonizes E2-induced P receptor, a constitutive P receptor replenishment mechanism may play an important role in the maintenance of P action during sustained P exposure, such as in pregnancy.

Animals↗
PubMed1998

Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis.

The role of epithelial and stromal progesterone (P) receptors (PR) in the regulation of uterine epithelial DNA synthesis by P was investigated by analyzing the four types of tissue recombinants prepared with uterine stroma (S) and epithelium (E) from wild-type (wt) and PR knockout (PRKO) mice: wt-S + wt-E, PRKO-S + PRKO-E, wt-S + PRKO-E, and PRKO-S + wt-E. 17-Beta estradiol (E2) stimulated DNA synthesis in all four types of tissue recombinants. On the other hand, P inhibited E2-induced DNA synthesis only in tissue recombinants prepared with wild-type (PR-positive) stroma (wt-S + wt-E or wt-S + PRKO-E) but not knockout (PR-negative) stroma (PRKO-S + wt-E or PRKO-S + PRKO-E). These results clearly demonstrate that the inhibitory effect of P on uterine epithelial DNA synthesis is mediated by stromal PR. Epithelial PR is neither necessary nor sufficient for P inhibition of E2-induced epithelial DNA synthesis.

Animals↗
PubMed2006

Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term.

Progestin withdrawal is a crucial event for the onset of labor in many mammalian species. However, in humans the mechanism of a functional progestin withdrawal is unclear, because progestin concentrations do not drop in maternal plasma preceding labor. We report the presence of two novel functional membrane progestin receptors (mPRs), mPRalpha and mPRbeta, in human myometrium that are differentially modulated during labor and by steroids in vitro. The mPRs are coupled to inhibitory G proteins, resulting in a decline in cAMP levels and increased phosphorylation of myosin light chain, both of which facilitate myometrial contraction. Activation of mPRs leads to transactivation of PR-B, the first evidence for cross-talk between membrane and nuclear PRs. Progesterone activation of the mPRs leads also to a decrease of the steroid receptor coactivator 2. Our data indicate the presence of a novel signaling pathway mediated by mPRs that may result in a functional progestin withdrawal, shifting the balance from a quiescent state to one of contraction.

Acetyltransferases↗
PubMed1993

Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function.

Two distinct isoforms of the human progesterone receptor (hPR-A and hPR-B) have been identified previously. They differ only in that hPR-B contains an additional 164 amino acids at the amino terminus. Among various species these two forms arise as a result of either alternate initiation of translation from the same mRNA or by transcription from alternate promoters within the same gene. In order to understand the reason for their existence, we studied the transcriptional capacity of these individual receptors and observed that their activity was influenced strongly by cell and promoter context. More surprising was the observation that in promoter and cell contexts where hPR-A was inactive, it acted as a potent trans-dominant repressor of hPR-B-mediated transcription. This event occurred at substoichiometric concentrations of hPR-A and was hormone dependent. Human PR-A was not a general repressor of ligand-mediated transcription, as it had no effect on vitamin D receptor function. Interestingly, hPR-A but not hPR-B was capable of a similar inhibition of glucocorticoid, androgen, and mineralocorticoid receptor-mediated gene transcription. This suggests a specific role for the hPR-A isoform in this regulatory process. The trans-dominant effects of hPR-A were induced also by the antiprogestins ZK112993 and ZK98299 and a DNA binding defective hPR-A mutant, suggesting that the inhibitory function of hPR-A does not require DNA binding. The dual role of hPR-A as an activator or repressor of transcription defines a potential mechanism by which cells can generate dissimilar responses to a single hormone and provides a molecular explanation for the existence of two distinct forms of the hPR.

Animals↗
PubMed1981

Most cystosarcoma phyllodes and fibroadenomas have progesterone receptor but lack estrogen receptor: stromal localization of progesterone receptor.

Biochemical study of fibroepithelial tumors of the female breast showed presence of progesterone receptor (PgR) in all five cystosarcoma phyllodes (two malignant, three benign), and in 11 of 13 fibroadenomas tested. Estrogen receptor (ER) was detected in only one of five cystosarcomas and 2 of 13 fibroadenomas. The relative volumes occupied by epithelium and stroma in each tumor were measured from histologic sections. The results were consistent with presence of PgR in the stroma and ER in the epithelium. Different types of cystosarcoma (benign and malignant) and different types of fibroadenomas (intracanalicular, pericanalicular, and mixed) did not differ significantly in content of PgR, and mean levels of PgR in cystosarcoma were comparable with those in fibroadenomas. The presence of PgR in cystosarcomas suggests that progestational therapy, and possibly other forms of hormonal therapy, should be tested in the treatment of advanced, malignant cystosarcoma phyllodes.

Adenofibroma↗
PubMed1991

The value of estrogen and progesterone receptor determinations in advanced breast cancer. Estrogen receptor level but not progesterone receptor level correlates with response to tamoxifen.

Four hundred fifteen patients with metastatic breast cancer with known hormone receptor status received primary treatment with tamoxifen. Measured values for the estrogen receptor (ER, i.e., with estrogen binding) followed a continuous distribution (range, 3 to 1000 fmol/mg of protein). These values correlated positively with age. The response to treatment with tamoxifen correlated with the ER level, with response rates of approximately 80% when the ER level was greater than 30.1 fmol/mg of protein. Two hundred eighteen (218 of 415, 52%) patients had progesterone receptor (PR) values greater than 10 fmol/mg. The PR positivity correlated with the ER level. Patients with PR levels greater than 10 fmol/mg of protein (124 of 226, 55%) had a significantly higher response rate than those with values less than 10 fmol/mg of protein (45 of 189, 24%). However, in a multivariate analysis including both receptor levels, age, site, and number of metastases, only the ER level was significant in predicting the response to treatment with tamoxifen. A quantitative estimation of the ER level thus is the best predictor of response to hormonal treatment with tamoxifen for advanced breast cancer.

Adult↗
PubMedDate not supplied

Progesterone receptor availability in mouse spermatozoa during epididymal transit and capacitation: ligand blot detection of progesterone-binding protein.

The goals of the present study were to determine the availability of progesterone (P4) receptor (P4r) in mouse sperm during maturation and capacitation and to make the first steps toward a characterization of P4r. It has been proposed that P4 is able to induce an acrosomal reaction (AR) by using a membrane P4r. This induction was verified in sperm isolated from the cauda epididymis (fully mature) when incubated in specific conditions that capacitate sperm. First, we set up the conditions in our laboratory to induce an AR in mature and capacitated sperm triggered by P4 that was detected by a chlortetracycline (CTC) assay. Then, we examined sperm isolated from the caput epididymis (immature) incubated under conditions that support cauda sperm capacitation and found that the AR could not be detected. Moreover, P4 was unable to induce the AR when it was applied to sperm isolated from either region and incubated under conditions that did not support capacitation. These results can be explained by changes in P4r availability. A suitable marker for P4r is the gold (Au)-P4 complex. This marker shows a binding capacity that can be visualized directly by electron microscopy (EM) and indirectly by silver-enhanced methods with light microscopy. The Au-P4 complex was localized in capacitated cauda sperm at the dorsal edge of the head. Using these techniques, we observed a significant decrease in both noncapacitated cauda sperm and caput sperm (whether incubated in capacitating media or not). Genomic P4r could be responsible for the signal detected, but antibodies against the P4 nuclear receptor did not recognize any sites in the sperm by immunostaining methodology. Instead, a 44-kd protein band was detected in the sperm by a ligand blot assay. In conclusion, P4 promotes the AR in capacitated cauda sperm but is unable to do so in noncapacitated or immature sperm because the availability of P4r increases during epididymal transit and after capacitation. The P4r responsible for this behavior is different from a classical nuclear receptor-on the basis of the immunostaining results-and is probably a protein close to 44 kd-on the basis of the ligand assay results.

Acrosome Reaction↗
PubMed1985

Progesterone-mediated suppression of estradiol receptors in cynomolgus macaque cervix, endometrium and oviduct during sequential estradiol-progesterone treatment.

We used sequential treatment with implants of estradiol (E2) and progesterone (P) to create varied hormonal states in a group of spayed cynomolgus macaques. The reproductive tracts were removed, and nuclear and cytosolic estrogen receptors were analyzed in the cervical mucosa, endometrium, and oviducts. Nuclear receptor quantities were greater in tissues of E2-treated monkeys than in tissues of spayed animals. Sequential P treatment, even in the presence of continuous E2, decreased the amounts of nuclear and cytosolic E2 receptors. In the oviduct and endometrium, the P-mediated suppression of receptors occurred within 1 or 2 days. In the cervix, suppression occurred only if the serum P:E2 ratio was elevated to twice the amount (approximately 100:1) usually found during the luteal phase of the menstrual cycle (approximately 50:1) in this species. Of these three reproductive tract tissues, the cervix had the highest threshold for suppression by P of E2 receptors in the presence of E2.

Animals↗
PubMed1986

Induction of progesterone receptor in an estrogen, progesterone receptor-negative breast cancer cell line.

In MCF-7 cell culture, some sera endow estradiol-17 beta with strong growth promoting properties ("active" sera) while other fail to display this property ("inactive" sera). Passage from "inactive" to "active" sera are shown here to induce the appearance of a progestin binding capacity in the receptor negative line Evsa-T. Competition with various unlabeled steroids established the specificity of this binding reaction. The induction of progesterone receptor required neither estrogens, nor ER and failed to confer major growth sensitivity to hormonal steroids: only medroxyprogesterone acetate was slightly inhibitory at high concentration. These observations disclose the influence of seric factors independent of estrogens and of ER-related mechanisms on PgR induction.

Breast Neoplasms↗
PubMed1987

Radioimmunoassay of plasma progesterone after oral administration of micronized progesterone.

A 200 mg dose of micronized progesterone (P) was administered orally to six healthy volunteers. Serial blood samples were collected and plasma P was assayed according to three methods of different specificity. The results were compared to those obtained with a reference technique based on gas chromatography-mass spectrometry. The interference of P metabolites particularly 5 alpha- and 5 beta-dihydroprogesterone was shown to be important when no or inadequate chromatography was included in the method. Radioimmunoassay after chromatography on a Celite column yielded results similar to those of the reference method. After oral administration, plasma P reached a peak at 3.00 +/- 0.44 h (mean +/- SEM; range: 1-4 h). The mean peak level 4.70 +/- 1.15 ng/ml (mean +/- SEM; range: 2.40-10.10 ng/ml) was at the lower limit of the range defined for a normal functional corpus luteum. The levels returned to initial values by 24 h after the single oral dose. The separation of P from its metabolites by an adequate chromatographic system appears mandatory after oral administration of micronized P.

Administration, Oral↗