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PubMed1996

Regulation of oxytocin, oestradiol and progesterone receptor concentrations in different uterine regions by oestradiol, progesterone and oxytocin in ovariectomized ewes.

The regulation of oxytocin, oestradiol and progesterone receptors in different uterine cell types was studied in ovariectomized ewes. Animals were pretreated with a progestogen sponge for 10 days followed by 2 days of high-dose oestradiol to simulate oestrus. They then received either low-dose oestradiol (Group E), low-dose oestradiol plus progesterone (Group P) or low-dose oestradiol, progesterone and oxytocin (via osmotic minipump; Group OT). Animals (three to six per time-point) were killed following ovariectomy (Group OVX), at oestrus (Group O) or following 8, 10, 12 or 14 days of E, P or OT treatment. In a final group, oxytocin was withdrawn on day 12 and ewes were killed on day 14 (Group OTW). Oxytocin receptor concentrations and localization in the endometrium and myometrium were measured by radioreceptor assay, in situ hybridization and autoradiography with the iodinated oxytocin receptor antagonist d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)]-vasotocin. Oestradiol and progesterone receptors were localized by immunocytochemistry. Oxytocin receptors were present in the luminal epithelium and superficial glands of ovariectomized ewes. In Group O, endometrial oxytocin receptor concentrations were high (1346 +/- 379 fmol [3H]oxytocin bound mg protein-1) and receptors were also located in the deep glands and caruncular stroma in a pattern resembling that found at natural oestrus. Continuing low-dose oestradiol was unable to sustain high endometrial oxytocin receptor concentrations with values decreasing significantly to 140 +/- 20 fmol mg protein-1 (P < 0.01), localized to the luminal epithelium and caruncular stroma but not the glands. Progesterone treatment initially abolished all oxytocin receptors with none present on days 8 or 10. They reappeared in the luminal epithelium only between days 12 and 14 to give an overall concentration of 306 +/- 50 fmol mg protein-1. Oxytocin treatment caused a small increase in oxytocin receptor concentration in the luminal epithelium on days 8 and 10 (20 +/- 4 in Group P and 107 +/- 35 fmol mg protein-1 in Group OT, P < 0.01) but the rise on day 14 was not affected (267 +/- 82 in Group OT and 411 +/- 120 fmol mg protein-1 in Group OTW). In contrast, oestradiol treatment was able to sustain myometrial oxytocin receptors (635 +/- 277 fmol mg protein-1 in Group O and 255 +/- 36 in Group E) and there was no increase over time in Groups P, OT and OTW with values of 61 +/- 18, 88 +/- 53 and 114 +/- 76 fmol mg protein-1 respectively (combined values for days 8-14). Oestradiol receptor concentrations were high in all uterine regions in Group O. This pattern and concentration was maintained in Group E. In all progesterone-treated ewes, oestradiol receptor concentrations were lower in all regions at all time-points. The only time-related change occurred in the luminal epithelium in which oestradiol receptors were undetectable on day 8 but developed by day 10 of progesterone treatment. Progesterone receptors were present at moderate concentrations in the deep glands, caruncular stroma, deep stroma and myometrium in Group O. Oestradiol increased progesterone receptors in the luminal epithelium, superficial glands, deep stroma and myometrium. Progesterone caused the loss of its own receptor from the luminal epithelium and superficial glands and decreased its receptor concentration in the deep stroma and myometrium at all time-points. There was a time-related loss of progesterone receptors from the deep glands of progesterone-treated ewes between days 8 and 14. These results show differences in the regulation of receptors between uterine regions. In particular loss of the negative inhibition by progesterone on the oxytocin receptor by day 14 occurred only in the luminal epithelium, but is unlikely to be a direct effect of progesterone as no progesterone receptors were present on luminal epithelial cells between days 8 and 14.

Animals↗
PubMed1982

Silastic implants of progesterone produce high circulating levels of both progesterone and 20 alpha-hydroxyprogesterone in ovariectomized, adrenalectomized rats.

Previous studies indicated that circulating 20 alpha-hydroxyprogesterone (20 alpha-OH-P) in cyclic female rats derived from enzymatic conversion of progesterone in corpus luteum tissue (Hashimoto and Wiest, 1969). A possibility of extraovarian conversion of progesterone to 20 alpha-OH-P also was revealed by our recent finding that placement of Silastic implants of progesterone produced not only high plasma progesterone but also 20 alpha-OH-P in ovariectomized (OVX), previously pseudo-pregnant, rats (Gilman et al., 1981). This study was performed to measure the amounts of serum 20 alpha-OH-P and progesterone in intact or adrenalectomized (ADX), cyclic female rats and in OVX, ADX or OVX-ADX animals with or without progesterone implants. Twenty-four-hour patterns of serum progestins revealed that OVX rats exhibited low progesterone secretion (3-6 ng/ml) and undetectable levels of 20 alpha-OH-P in the absence of ovaries. In intact, cyclic females, circulating concentrations of 20 alpha-OH-P were 4- to 6-fold greater than those or progesterone. ADX resulted in a partial reduction of progesterone but not 20 alpha-OH-P in the circulation. Placement of 4 cm Silastic implants of progesterone produced high serum concentrations of both progesterone (29 +/- 4 ng/ml, mean +/- SEM) and 20 alpha-OH-P (27 +/- 1 ng/ml) in OVX and OVX-ADX rats. These findings demonstrate that placement of progesterone implants into female rats produces high circulating concentrations of both progesterone and 20 alpha-OH-P, and indicate that an extraovarian and extra-adrenal system(s) for progestin conversion is functioning under persistently high circulating progesterone conditions. By this system, large amounts of circulating progesterone are transformed into a less potent progestational compound, 20 alpha-OH-P.

Adrenalectomy↗
PubMed2001

Demonstration of mixed properties of RU486 in progesterone receptor (PR)-transfected MDA-MB-231 cells: a model for studying the functions of progesterone analogues.

Progesterone antagonist RU486 (mifepristone) has been implicated for many anti-neoplastic and obstetrical applications. But the compound has demonstrated undesired agonist-like effect depending on cell, tissue and species studied. Using PR-transfected breast cancer cells MDA-MB-231, this report describes the similarities and differences between progesterone- and RU486-mediated effects on cell growth, cell differentiation and, at the molecular level, on the activation of p44/p42 MAP kinases (MAPK). Like progesterone, RU486 inhibited cells growth by arresting the cells in G0/G1 phase of the cell cycle. In contrast to progesterone that induced cell spreading, RU486 induced a multipolar, stellate morphology. RU486-treated cells showed no increase of stress fibers, nor was there any increase of focal adhesions as progesterone-treated cells did. Furthermore, despite of the fact that both compounds inhibited cell growth, RU486 significantly stimulated the activation of p44/p42 MAP kinases whereas progesterone markedly inhibited the activation. Nonetheless, the effects of RU486 were PR-mediated and RU486 was able to antagonize the effect of progesterone on cell growth and focal adhesion. In conclusion, RU486 can act not only as a progesterone antagonist, a progesterone agonist but also induced morphological and molecular changes that were distinct from progesterone-mediated effects in PR-transfected MDA-MB-231 cells. The non-progesterone-like effect of RU486 may be mediated through a pathway that is different from the progesterone-mediated pathway, or it is the result of a blockade of certain critical step(s) in the progesterone-mediated pathway. In any case, undesired side effects of antiprogestin may create clinical complications. PR-transfected MDA-MB-231 breast cancer cells provide a model for studying the functions of progesterone analogues.

Breast Neoplasms↗
PubMed2004

Anticonvulsant activity of progesterone and neurosteroids in progesterone receptor knockout mice.

Many of the biological actions of progesterone are mediated through the progesterone receptor (PR), a nuclear transcription factor. Progesterone is well recognized to protect against seizures in animal models. Although this activity has been attributed to the progesterone metabolite allopregnanolone, a GABAA receptor-modulating neurosteroid with anticonvulsant properties, PRs could also play a role. Here, we used PR knockout (PRKO(-/-)) mice bearing a targeted deletion of the PR gene that eliminates both isoforms of the PR to investigate the contribution of the PR to the anticonvulsant activity of progesterone. The protective activity of progesterone was examined in female and male homozygous PRKO mice and isogenic wild-type controls in the pentylenetetrazol (PTZ), maximal electroshock, and amygdala-kindling seizure models. In all three models, the anticonvulsant potency of progesterone was undiminished in PRKO mice compared with control mice. On the contrary, there was a substantial increase in the anticonvulsant potency of progesterone in the PTZ and kindling models. The antiseizure activity of progesterone in PRKO mice was reversed by pretreatment with finasteride, a 5alpha-reductase inhibitor that blocks the metabolism of progesterone to allopregnanolone. Unlike progesterone, the neurosteroids allopregnanolone and allotetrahydrodeoxycorticosterone exhibited comparable anticonvulsant potency in PRKO and wild-type mice. The basis for the heightened progesterone responsiveness of PRKO mice is not attributable to pharmacokinetic factors, because the plasma allopregnanolone levels achieved after progesterone administration were not greater in the PRKO mice. These studies provide strong evidence that the PR is not required for the antiseizure effects of progesterone, which mainly occurs through its conversion to the neurosteroid allopregnanolone.

Animals↗
PubMed2006

TReP-132 is a novel progesterone receptor coactivator required for the inhibition of breast cancer cell growth and enhancement of differentiation by progesterone.

The sex steroid progesterone is essential for the proliferation and differentiation of the mammary gland epithelium during pregnancy. In relation to this, in vitro studies using breast carcinoma T47D cells have demonstrated a biphasic progesterone response, consisting of an initial proliferative burst followed by a sustained growth arrest. However, the transcriptional factors acting with the progesterone receptor (PR) to mediate the progesterone effects on mammary cell growth and differentiation remain to be determined. Recently, it has been demonstrated that the transcriptional regulating protein of 132 kDa (TReP-132), initially identified as a regulator of steroidogenesis, is also a cell growth suppressor. Similar to progesterone-bound PR, TReP-132 acts by inducing the gene expression of the G1 cyclin-dependent kinase inhibitors p21WAF1/Cip1 (p21) and p27Kip1 (p27). The putative interaction between TReP-132 and progesterone pathways in mammary cells was therefore analyzed in the present study. Our results show that TReP-132 interacts in vitro and in T47D cells with progesterone-activated PR. TReP-132 synergizes with progesterone-bound PR to trans activate the p21 and p27 gene promoters at proximal Sp1-binding sites. Moreover, TReP-132 overexpression and knockdown, respectively, increased or prevented the induction of p21 and p27 gene expression by progesterone. As a consequence, TReP-132 knockdown also resulted in the loss of the inhibitory effects of progesterone on pRB phosphorylation, G1/S cell cycle progression, and cell proliferation. Furthermore, the knockdown of TReP-132 expression also prevented the induction of both early and terminal markers of breast cell differentiation which had been previously identified as progesterone target genes. As well, the progesterone-induced accumulation of lipid vacuoles was inhibited in the TReP-132-depleted cells. Finally, TReP-132 gene expression levels increased following progesterone treatment, indicating the existence of a positive auto-regulatory loop between PR and TReP-132. Taken together, these data identify TReP-132 as a coactivator of PR mediating the growth-inhibitory and differentiation effects of progesterone on breast cancer cells.

Binding Sites↗
PubMed1989

Nuclear progesterone-binding protein in the guinea pig adrenal cortex: distinction from the classical progesterone receptor.

Nuclei purified from the guinea pig adrenal cortex contain a specific progesterone-binding activity which, based on enzyme degradation studies, appears to be proteinaceous. Saturation analysis revealed a Kd of about 15 nM and a binding capacity of about 33 pmol/mg DNA. The activity of the nuclear binding protein was specific essentially for progestational steroids; the two most potent progesterone competitors were 5 alpha-pregnane-3,20-dione and medroxyprogesterone (17 alpha-hydroxy-6 alpha-methylprogesterone), while 17 beta-estradiol, testosterone, cortisol, and other related steroids were poor competitors. The adrenocortical nuclear progesterone-binding protein was present to an equal extent in both male and female guinea pigs. The adrenocortical nuclear progesterone-binding protein differed from the classical progesterone receptor in that 1) the affinity of the adrenocortical binding protein for progesterone is an order of magnitude lower; 2) the potent synthetic progestin R5020 binds less tightly to the adrenocortical progesterone-binding protein; 3) the adrenocortical progesterone-binding protein is not modulated by estrogenic activity; 4) the adrenocortical progesterone-binding protein is more stable at 37 C; 5) the adrenocortical nuclear progesterone-binding protein is not salt extractable; and 6) Western blot analysis has revealed that an antiprogesterone receptor monoclonal antibody, which recognizes the guinea pig uterine classical nuclear progesterone receptor, does not recognize the adrenocortical nuclear progesterone-binding protein. Thus, the guinea pig adrenocortical nucleus contains a type of progesterone-binding protein that appears to be clearly different from the classical progesterone receptor.

Adrenal Cortex↗
PubMed1997

Performance of the fully automated progesterone assays on the Abbott AxSYM and the Technicon Immuno 1 analyser compared with the radioimmunoassay Progesterone MAIA.

OBJECTIVE: Test performance of two automated progesterone assays available on the immunoassay analysers Abbott AxSYM and Technicon immuno 1, respectively, was evaluated in comparison with the radioimmunoassay Progesterone MAIA. METHODS: For assessment of test performance imprecision, functional sensitivity and linearity of dilution was examined. Correlation with the manual radioimmunoassay was assessed using 122 serum samples over the range 0-110 nmol/L. RESULTS: Imprecision studies revealed for the AxSYM Progesterone within-run CV's of 1.8-6.4% and day-to-day CV's of 3.5-9.7% (concentration range 2.3-75 nmol/L); Immuno 1 Progesterone: within-run CV's 1.0-7.3%, day-to-day CV's 2.3-7.7% (concentration range 1.2-60 nmol/L). The functional sensitivity was < 1.7 nmol/L for the AxSYM Progesterone and < 1.1 nmol/L for the Immuno 1 Progesterone. With the AxSYM Progesterone the mean recovery after dilution from five samples was 102% (89-107%), from one sample only 69-80% was recovered; with the Immuno 1 Progesterone the mean recovery was 95% (80-105%). Despite of a quite good overall correlation (coefficients 0.972 and 0.981) the relationship of both assays to the Progesterone MAIA significantly deviate from linearity with a considerably higher slope within the lower concentration range. The relationship between the automated assays was linear over the entire concentration range (Immuno = 1.207 * AxSYM + 1; r = 0.986). The time to first result was 20 min for the AxSYM Progesterone, 45 min for the Immuno 1 Progesterone and 90 min for the Progesterone MAIA. CONCLUSION: The evaluated progesterone assays both exhibit an excellent precision and a high degree of sensitivity. They offer a rapid and flexible method for progesterone determination which may be especially useful for the monitoring of ovarian stimulation during in-vitro fertilization.

Automation↗
PubMed2000

Salivary, but not serum or urinary levels of progesterone are elevated after topical application of progesterone cream to pre-and postmenopausal women.

OBJECTIVE: The use of topically applied micronised ('natural') progesterone as a substitute for synthetic oestrogens and progestogen preparations is controversial. The aim of this study was to examine the changes in blood and salivary concentrations of progesterone following a single topical application of a progesterone cream. PATIENTS AND MEASUREMENTS: We investigated six premenopausal women in the luteal phase and six postmenopausal women to determine the short-term changes in serum, urinary and salivary progesterone concentrations following a single 64 mg topical application of micronised progesterone. RESULTS: Serum progesterone concentrations did not increase during the first 3 hours after application of progesterone cream, however, salivary values rose significantly in both premenopausal and postmenopausal women, consistent with the view that progesterone is absorbed and transported through the body. Salivary progesterone concentrations were significantly elevated above basal levels by 30-60 minutes and reached peak levels at 1-4 h, with mean levels approximately fivefold higher in premenopausal, than in menopausal women. CONCLUSIONS: Salivary progesterone measurements confirm that topically applied progesterone is absorbed, despite the lack of change in serum progesterone concentrations. However, at the dose administered, serum progesterone levels do not reach those observed after oral or vaginally delivered progesterone preparations. Higher doses may be required to induce biological responses within the endometrium.

Absorption↗
PubMed1999

Evidence of a progesterone receptor in the liver of the green frog Rana esculenta and its down-regulation by 17 beta estradiol and progesterone.

Progesterone is a versatile hormone showing an ample variety of effects. One of the numerous functions attributed to progesterone is the modulation of vitellogenesis in oviparous vertebrates. As a prerequisite for the possible involvement of progesterone in vitellogenesis modulation, we investigated the presence of a progesterone receptor (PR) in the liver of the female green frog Rana esculenta. 3H-Progesterone (3H-P) binding activity was found in both cytosol and nuclear extract of the liver of Rana esculenta. The progesterone-binding moiety showed the typical characteristics of a true receptor, such as high affinity, low capacity, and specificity for progesterone. It also bound to DNA-cellulose and was eluted with a linear salt gradient at a concentration of 0.05 M of NaCl. The progesterone-binding moiety was down regulated by steroid hormones, in that ovariectomy resulted in a significant increase, in both cytosol and nuclear extract, of 3H-P binding activity with respect to intact females. On the contrary, 3H-P binding activity was almost undetectable after estradiol and/or progesterone treatment. The progesterone binding moiety of Rana esculenta was analyzed by Western blotting with the aid of a monoclonal antibody raised against the subunits A and B of the chicken PR. An immunoreactive band of about 67 kDa was observed in the liver of both intact and treated females. The 67 kDa band showed an increased intensity in ovariectomized animals, while it was faint following treatment with estradiol and/or progesterone. This is the first report on the presence of a progesterone receptor (PR) in the liver of an amphibian. PR of Rana esculenta is down regulated by estradiol and/or progesterone and shows peculiar immunological and biochemical characteristics, which make it rather different from the PR of other vertebrates.

Animals↗
PubMed1991

Progesterone downregulates progesterone receptor, but not estrogen receptor, in the estrogen-primed oviduct of a turtle (Trachemys scripta).

Progesterone downregulates nuclear progesterone receptor (Rp) and estrogen receptor (Re) in the estrogen-primed mammalian uterus and chick oviduct. We sought to determine if this downregulation mechanism is operative in the turtle oviduct. Female turtles were primed for 4 days with 17-beta-estradiol, after which progesterone (5 mg) was administered by injection every 24 h. Re and Rp levels in progesterone-treated and control turtle oviducts were measured by [3H]steroid-binding assays (pyridoxal 5' phosphate method) at 12, 24, 48 and 72 hr after initial progesterone treatment. Serum progesterone levels of progesterone-treated turtles increased only slightly from 0 hr (0.3 ng/ml) to 12 hr (0.6 ng/ml) after progesterone administration, increased considerably by 24 hr (5.3 ng/ml), and remained elevated (6-8 ng/ml) through 72 hr. Cytosol and nuclear Rp levels of estrogen-primed turtle oviducts showed distinct seasonal variation, with Rp levels higher in spring and summer months than in winter months. There was no seasonal variation in Re levels. Both cytosol and nuclear Rp responded to progesterone treatment. Cytosol Rp levels of progesterone-treated oviducts were significantly reduced below control levels by 12 hr after progesterone administration and remained low through 72 hr. Nuclear Rp levels of progesterone-treated oviducts showed no change at 12 hr, increased at 24 hr and then dropped at 48 and 72 hr. However, progesterone did not downregulate Re in the turtle oviduct.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Effect of systemic progesterone concentration on the expression of progesterone-responsive genes in the bovine endometrium during the early luteal phase.

Increasing evidence indicates an association between the concentration of systemic progesterone during the early luteal phase of the oestrous cycle and embryo survival rate in cattle. We examined the relationship between the concentration of systemic progesterone on Days 4 to 8 post-ovulation and expression of progesterone receptor (PGR), oestrogen receptor +/- (ESR1) and retinol-binding protein (RBP) mRNA in the bovine endometrium. Heifers were blood sampled from the day of ovulation (Day 0) to Day 8 post-ovulation. On Day 4, animals were divided into low progesterone control (LC) and high progesterone control (HC) groups based on their plasma progesterone concentrations. Half of each group was supplemented with exogenous progesterone resulting in two further groups, low progesterone supplemented (LS) and high progesterone supplemented (HS). Endometrial tissues were recovered from all groups on Day 6 or Day 8 and gene expression was analysed following Northern blotting. Increasing progesterone concentrations were associated with decreased PGR and ESR1 expression. Duration-dependent effects of progesterone supplementation on ESR1 were evident and there was an effect of systemic progesterone concentrations between Day 0 and Day 4 on the expression of RBP at Days 6 and 8. Such progesterone-responsive changes in uterine gene expression are likely to affect embryo development.

Animals↗
PubMed1983

Subcellular compartmentalization of the progesterone receptor in cat uteri following the acute administration of progesterone.

Cytosol and nuclear progesterone receptors in the cat uterus were measured by Scatchard analysis to determine the relationships between dose of progesterone administered and the time following administration with the content of receptor in these two cellular compartments. Cats were ovariectomized, treated for 7 days with estradiol and then injected via the saphenous vein with progesterone. One uterine horn was removed prior to, and the other uterine horn after the injection of progesterone. The amount of cytosol receptor translocated was found to be dose-dependent over the range of 0-200 micrograms of progesterone. A maximum of 40% of the cytosol receptor was depleted even when the amount of progesterone injected was increased. In non-estradiol-primed animals it was also found that approximately 40% of the cytosol receptor was depleted following a progesterone injection. Within 3 h of the injection of 300 micrograms of progesterone, the cytosol and nuclear receptor levels had returned to preinjection values. A second administration of progesterone at 1 or 3 h after the first injection of progesterone caused a partial depletion of the cytosol receptor and an increase in nuclear progesterone receptor concentration. These data suggest that the translocation of cytosol receptor and the appearance of nuclear receptor is dose-dependent until approximately 40% of the cytosol receptor is depleted following a single injection of progesterone, that the retention of nuclear receptor after an acute injection of progesterone is of short duration (less than 1 h), and that the replenishment of cytosol receptor is complete within 3 h.

Animals↗
PubMed1995

Progesterone and oestrogen receptors in the decidualized mouse uterus and effects of different types of anti-progesterone treatment.

Pseudopregnant mice were treated systemically with monoclonal anti-progesterone antibody (DB3) (model 1), or progesterone receptor antagonists RU486 or ZK98,299 (ZK299) (model 2) on day 3 post coitum. On day 4, sesame oil was administered intraluminally into one uterine horn to induce decidualization. On day 7, the average mass of the oil-injected horn was 335.2 +/- 52.4 mg, eight times greater than that of the non-injected horn (40.8 +/- 5.3 mg; P < 0.001). After treatment with DB3, RU486 or ZK299, the masses of the injected horns did not differ significantly from those of non-injected horns. In the control group, concentrations of progesterone receptors (ligand-binding assay) increased twofold in the decidualized (52.2 +/- 7.4 fmol mg-1) compared with the non-injected horn (26.0 +/- 7.6 fmol mg-1; P < 0.05), whereas oestrogen receptor content (ligand-exchange assay) decreased by 53% (104.9 +/- 18.2 versus 224.3 +/- 18.1 fmol mg-1; P < 0.001). In model 1, antibody-treated animals showed a tenfold increase in the concentration of progesterone receptors (261.7 +/- 81.1 fmol mg-1; P < 0.001), but there was no differential distribution of progesterone or oestrogen receptors in the oil-injected versus non-injected uterine horns. In model 2, uterine progesterone and oestrogen receptors again showed no differential response between injected and non-injected horns regardless of the route of administration (systemic or intraluminal). Concentrations of progesterone receptors in RU486-treated (35.8 +/- 9.4 fmol mg-1) and ZK299-treated (32.0 +/- 10.2 fmol mg-1) mice were comparable to those in non-injected horns (35.3 +/- 6.3 and 34.2 +/- 5.1 fmol mg-1, respectively) and were not significantly different from the control group (26.0 +/- 7.6 fmol mg-1). The results show that oil-induced decidualization is accompanied by increased concentrations of progesterone receptors and decreased concentrations of oestrogen receptors. When decidualization is blocked by anti-progesterone treatment (antibody against progesterone or progesterone receptor antagonist), there are differing effects on receptor responses with an increase in progesterone receptors and decrease in oestrogen receptors after passive immunization, and no change in progesterone receptors and a reduction in oestrogen receptors after anti-progestins. The anti-decidualization effect in the two models was therefore achieved via dissimilar uterine receptor responses.

Animals↗
PubMed2000

Progesterone exacerbates striatal stroke injury in progesterone-deficient female animals.

BACKGROUND AND PURPOSE: We have previously shown that female animals experience substantial protection from brain injury after reversible middle cerebral artery occlusion (MCAO) compared with their male or ovariectomized female counterparts. The reproductive steroid estrogen has been shown to provide neuroprotection from a variety of experimental insults, but the importance of progesterone as an anti-ischemic treatment has not been well explored. We evaluated histological outcomes after MCAO in ovariectomized female rats with or without acute or chronic progesterone replacement therapy. METHODS: Age-matched, adult female Wistar rats were ovariectomized and treated with 0, 30, or 60 mg/kg progesterone IP 30 minutes before ischemia (n=12 to 14 per group) or with 30 mg/kg progesterone IP daily for 7 to 10 days before ischemia (n=16). Each animal subsequently underwent 2 hours of MCAO with the intraluminal filament technique, followed by 22 hours of reperfusion. Ipsilateral parietal cortex perfusion was monitored with laser Doppler flowmetry throughout ischemia. Cortical, caudate-putamen, and hemispheric infarction volumes were determined with 2,3,5-triphenyltetrazolium chloride staining and digital image analysis. RESULTS: Intraischemic plasma progesterone levels were 5+/-3, 102+/-20,* 181+/-28,* and 133+/-25* ng/mL in the 0, 30, and 60 mg/kg acute progesterone group and the 30 mg/kg chronic progesterone group, respectively (*P<0.05 compared with 0 mg/kg). Caudate-putamen infarction volume (percent contralateral structure) was significantly increased by chronic progesterone treatment: 45.6+/-5.1%* in the 30 mg/kg chronic progesterone group and 29.2+/-5.3%, 35.8+/-5.1%, and 42.0+/-5.0% in the 0, 30, and 60 mg/kg acute progesterone groups, respectively (*P<0.05 compared with 0 mg/kg). Cortical and total hemispheric infarction volumes (percent contralateral structure) were unchanged by progesterone treatment. CONCLUSIONS: Exogenous progesterone therapy does not ameliorate histological injury after MCAO in previously ovariectomized, adult female rats. Furthermore, chronic progesterone administration can exacerbate infarction in subcortical regions.

Animals↗
PubMed1976

Experimental studies on the positive feedback effect of progesterone, 17 alpha-hydroxyprogesterone and 20 alpha-dihydroprogesterone on the pituitary release of LH and FSH in the human female. The estrogen priming of the progesterone feedback on pituitary gonadotropins in the eugonadal woman.

Administration of progesterone eugonadal women during the midfollicular phase of the menstrual cycle failed to induce a positive feedback effect on the serum concentrations of LH and FSH. The levels of estradiol in serum decreased following the injection of progesterone without a parallel change in LH and FSH concentrations indicating a direct ovarian effect of the exogenous progesterone. In the late follicular phase of the cycle, when preovulatory levels of estradiol were present in serum, or under a ethinyl estradiol treatment progesterone was able to induce an LH discharge indicating the requirement of an estradiol priming of the positive feedback of progesterone in eugonadal women. In order to establish the time required for a sufficient estrogen priming with preovulatory levels of estradiol in serum 3 mg of estradiol-benzoate were administered i.m. 1, 12 and 24 h prior to the administration of 30 mg of microcristalline progesterone in the midfollicular phase of the menstrual cycle, when progesterone alone did not cause an LH surge. Only when estradiol-benzoate was injected 24 h prior to the progesterone administration an LH surge reproducible in time course and magnitude occurred. Administration of estradiol-benzoate alone under these conditions did not cause an LH surge within the elapse of time after the injection when the progesterone induced LH surge occurred. Thus, these experiments demonstrate that a defined estrogen priming is required for the positive feedback effect of progesterone on the gonadotropin release in eugonadal women. Furthermore, progesterone levels in serum of about only 1--2 ng/ml were required for the induction of an LH surge indicating that under physiological conditions progesterone may have an supplementory effect on the primarily estradiol induced LH midcycle peak. 17-hydroxyprogesterone administered during the mid follicular phase of the menstrual cycle and under pretreatment with ethinyl estradiol failed to induce a positive feedback effect on the serum concentrations of LH and FSH, indicating that this steroid does not play a regulatory role on the midcycle LH release in women. 20alpha-dihydroprogesterone administered under the same experimental conditions as 17-hydroxyprogesterone seems to be able to induce an LH surge in serum provided there is an adequate estrogen priming.

20-alpha-Dihydroprogesterone↗
PubMed1983

Characterization and assay of progesterone-binding components in DMBA-induced rat mammary carcinoma tissue after progesterone administration.

Nuclear and cytoplasmic progesterone-binding components were characterized and measured in DMBA-induced rat mammary carcinoma tissue, before and after progesterone administration. Rats, bearing growing tumors, were ovariectomized and then primed for two days with estradiol. Biopsy specimens were taken prior to or following administration of progesterone. Nuclear binding was assayed in the 0.4 M KCl extract of the nuclear fraction using [3H]R5020 as ligand. The receptor character of the binding was demonstrated by: (1) high affinity (Kd approximately 2 nM); (2) specificity: competition by R5020 and progesterone, minimal competition by 17 alpha-hydroxyprogesterone, corticosterone, testosterone and estradiol; (3) sedimentation constant at about 3S in a sucrose density gradient. Similar characteristics displayed the cytoplasmic receptor before and after progesterone administration. Progesterone receptor distribution in the nuclear extract and cytosol were determined in 36 tumors. The levels of total receptors (cytoplasmic plus nuclear) before and after progesterone administration varied widely, however the average values found after progesterone administration were significantly lower, 1.59 +/- 0.20 pmol/mg DNA compared to 2.58 +/- 0.32 pmol/mg DNA. Before progesterone administration only cytoplasmic receptors were found. One hour after progesterone administration a variable amount of the receptor (0-40%) was found in the nucleus of the tumorous tissue. In uteri of the same rats a uniform distribution of receptors (about 40% in the nucleus) was found after progesterone administration. A defect in the translocation process might be considered in the tumors with low receptors level, which suggests that DMBA-tumors may not respond uniformly to progesterone administration.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Tissue specific effects of progesterone on progesterone and estrogen receptors in the female urogenital tract.

The effect of progesterone administration on progesterone and estrogen receptors in the uterus, vagina and urethra of rabbits was studied. After 24 h of progesterone treatment the concentration of cytosolic progesterone receptors decreased to about 25% of the control value in the uterus, whereas no significant change in receptor concentration was observed in the vagina or the urethra. The concentration of the nuclear progesterone receptor did not change in any of the three tissues studied. The apparent dissociation constant (Kd) of nuclear progesterone receptor increased after progesterone treatment in all three tissues. Although the Kd of the cytosolic progesterone receptor also increased in all tissues, the difference was significant for only the vagina and urethra. The concentration of cytosolic estrogen receptors in the uterus decreased significantly (P less than 0.001) after progesterone treatment whereas the Kd value increased slightly (P less than 0.05). In vagina or the urethra, there was no change in either estrogen receptor concentration or Kd values after progesterone treatment. These data clearly showed that the reduction by progesterone of progesterone and estrogen receptor concentrations occurs only in the uterus and not in the vagina or the urethra.

Animals↗
PubMed2002

Expression of the progesterone receptor and progesterone- metabolising enzymes in the female and male human kidney.

Due to high binding affinity of progesterone to the human mineralocorticoid receptor (hMR), progesterone competes with the natural ligand aldosterone. In order to analyse how homeostasis can be maintained by mineralocorticoid function of aldosterone at the MR, especially in the presence of elevated progesterone concentrations during the luteal phase and pregnancy, we investigated protective mechanisms such as the decrease of free progesterone by additional binding sites and progesterone metabolism in renal cells. As a prerequisite for sequestration of progesterone by binding to the human progesterone receptor (hPR) we demonstrated the existence of hPR expression in female and male kidney cortex and medulla at the level of transcription and translation. We identified hPR RNA by sequencing the RT-PCR product and characterised the receptor by ligand binding and scatchard plot analysis. The localisation of renal hPR was shown predominantly in individual epithelial cells of distal tubules by immunohistology, and the isoform hPR-B was detected by Western blot analysis. As a precondition for renal progesterone metabolism, we investigated the expression of steroid-metabolising enzymes for conversion of progesterone to metabolites with lower affinity to the hMR. We identified the enzyme 17alpha-hydroxylase for renal 17alpha-hydroxylation of progesterone. For 20alpha-reduction, different hydroxysteroid dehydrogenases (HSDs) such as 20alpha-HSD, 17beta-HSD type 5 (3alpha-HSD type 2) and 3alpha-HSD type 3 were found. Further, we detected the expression of 3beta-HSD type 2 for 3beta-reduction, 5alpha-reductase (Red) type 1 for 5alpha-reduction, and 5beta-Red for 5beta-reduction of progesterone in the human kidney. Therefore metabolism of progesterone and/or binding to hPR could reduce competition with aldosterone at the MR and enable the mineralocorticoid function.

20-Hydroxysteroid Dehydrogenases↗