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PubMed1983

Additional conformational data for the mapping of the progestin binding site: crystal structures of 21-(phenylseleno)progesterone and 17 alpha-(phenylseleno)progesterone.

The crystal structures of 21-(phenylseleno)progesterone (1), which binds with moderate affinity to the progestin receptor, and 17 alpha-(phenylseleno)progesterone (2), which binds hardly at all, have been studied in an attempt to explain these differences in affinity and to obtain further information on the location of the progestin receptor binding site with respect to the progesterone molecule. The crystal structures were refined by isotropic thermal approximation to R values of 0.082 for 1 and 0.084 for 2. The unusual 17 beta side-chain orientation of 2 with a C16-C17-C20-O20 torsion angle of +13 degrees compared to -7 degrees for progesterone would seem to preclude hydrogen bonding with the progestin receptor binding site and provides strong supporting evidence for the contention that this site is located above the beta face of the molecule. Any rotation of the C21 methyl group into a more appropriate position is furthermore impeded by the presence of the 17 alpha-phenylseleno substituent. On the other hand, some hydrogen bonding can occur in the case of 1 (C16-C17-C20-O20 = 31 degrees) despite the fact that the difference in torsion angle (24 degrees) with respect to progesterone is, in absolute values, greater than that for 2 (20 degrees). This is because the orientation of the 17 beta-acetyl side chain of 1 is directed above the beta face closer to the progestin binding site, as previously defined on the basis of data on a large number of molecules, and because the 21-phenylseleno substituent constitutes only limited steric hindrance to binding. Thus, the difference in affinity of these two compounds is entirely consistent with observations that the H-bond donor is located toward O20 in the beta region of C16.

Crystallization↗

PubMed1970

Effects of oestradiol-17-beta and progesterone on total and nuclear-protein synthesis in epithelial and stromal tissues of the mouse uterus, and of progesterone on the ability of these tissues to bind oestradiol-17-beta.

1. A method is described for separating uterine epithelium that is 80% pure and connective-tissue stroma that is 60% pure. This was used to study the effects of steroid hormones on total and nuclear-protein synthesis in these tissues. 2. Oestradiol-17beta given alone produces mitoses in the epithelium but not in the stroma. It stimulated incorporation in vitro of [(14)C]lysine into total protein, histones and acidic nuclear proteins to a greater extent in epithelium than stroma. Incorporation into acidic nuclear proteins was most markedly stimulated, reaching four to six times the normal value 4h after treatment, and then declining rapidly. This peak was only seen in epithelial preparations. 3. After pretreatment with progesterone, oestradiol-17beta has the reverse effect, producing mitoses only in stroma. Progesterone alone had no effect on the amounts or rates of incorporation of [(14)C]lysine into stromal nuclear proteins, but changes after oestradiol-17beta treatment were similar to those seen in epithelium with oestradiol-17beta alone. In the epithelium, progesterone alone depressed incorporation into histones and acidic nuclear proteins, but did not abolish the subsequent response to oestradiol-17beta. With this treatment there was a rapid, large and transient increase in incorporation into epithelial total protein not seen with oestradiol-17beta alone. 4. Progesterone had no qualitative effect on the distribution of specific oestrogen-binding proteins, as judged by sucrose-density-gradient centrifugation. However, progesterone treatment increased the uptake in vivo of [6,7-(3)H]oestradiol-17beta by stroma, and it is possible that this is important although the differences were not apparent after labelling in vitro.

Animals↗

PubMed1969

Interaction of estrogen and progesterone in chick oviduct development. I. Antagonistic effect of progesterone on estrogen-induced proliferation and differentiation of tubular gland cells.

Daily administration of estrogen to immature female chicks results in marked oviduct growth and appearance of characteristic tubular gland cells which contain lysozyme. Although a rapid increase in total DNA and RNA content begins within 24 hr, cell specific protein, lysozyme, is first detectable after 3 days of estrogen. Progesterone administered concomitantly with estrogen antagonizes the estrogen-induced tissue growth as well as appearance of tubular gland cells and their specific products, lysozyme and ovalbumin. When the initiation of progesterone administration is delayed for progressively longer periods (days) during estrogen treatment, proportionally greater growth occurs with more lysozyme and tubular gland cells after 5 days of total treatment. Progesterone does not inhibit the estrogen-stimulated increase in uptake of alpha-aminoisobutyric acid and water by oviduct occurring within 24 hr or the estrogen-induced increase in total lipid, phospholipid, and phosphoprotein content of serum. The above results of progesterone antagonism can best be explained by the hypothesis that progesterone inhibits the initial proliferation of cells which become tubular gland cells but does not antagonize the subsequent cytodifferentiation leading to the synthesis of lysozyme and ovalbumin once such cell proliferation has occurred.

Aminoisobutyric Acids↗

PubMed2000

Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination.

Some steroids are synthesized within the central and peripheral nervous system, mostly by glial cells. These are known as neurosteroids. In the brain, certain neurosteroids have been shown to act directly on the function of membrane receptors for neurotransmitters. For example, progesterone inhibits the neuronal nicotinic acetylcholine receptor, whereas its 3alpha,5alpha-reduced metabolite 3alpha,5alpha-tetrahydroprogesterone (allopregnanolone) activates the gamma-aminobutyric acid receptor complex A (GABA-R(A)). Besides these effects, neurosteroids also regulate important glial functions such as the synthesis of myelin proteins. Thus, in cultures of glial cells prepared from neonatal rat brain, progesterone increases the number of oligodendrocytes expressing the myelin basic protein (MBP) and the 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase). An important role for neurosteroids in myelin repair has been demonstrated in the rodent sciatic nerve, where progesterone and its direct precursor pregnenolone are synthesized by Schwann cells. After cryolesion of the male mouse sciatic nerve, blocking the local synthesis or action of progesterone impairs remyelination of the regenerating axons, whereas administration of progesterone to the lesion site promotes the formation of new myelin sheaths.

Animals↗

PubMed1986

Changes in plasma progesterone, estradiol, follicle-stimulating hormone and luteinizing hormone during diestrus and ovulation in rats with 5-day estrous cycles: effect of antibody against progesterone.

Progesterone secretion remained significantly higher during diestrus in the 5-day cyclic rat than in the 4-day cyclic animal. Injection of a sufficient amount of antiprogesterone serum (APS) at 2300 h on metestrus in a 5-day cycle advances ovulation and completion of the cycle by 1 day in the majority of animals (75 and 80%, respectively). Progesterone (250 micrograms) administered with APS eliminated the effect of the antiserum. Within 2 h after administration of APS, levels of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) elevated significantly, while a significant elevation of plasma estradiol above the control value followed as late as 36 h after the treatment. None of the 5-day cyclic rats treated with APS showed ovulatory increases of FSH and LH at 1700 h on the second day of diestrus, although 3 of the 4 animals receiving the same treatment ovulated by 1100 h on the following day. The onset of ovulatory release of gonadotropins might have been delayed for several hours in these animals. These results indicate that recurrence of the 5-day cycle is due to an elevated progesterone secretion on the morning of diestrus, and suggest that a prolongation of luteal progesterone secretion in an estrous cycle suppresses gonadotropin secretion. Rather than directly blocking the estrogen triggering of ovulatory LH surge, the prolonged secretion of luteal progesterone may delay the estrogen secretion itself, which decreases the threshold of the neural and/or hypophyseal structures for ovulatory LH release.

Animals↗

PubMed1982

Antibodies against progesterone receptor from chick oviduct. Cross-reactivity with mammalian progesterone receptors.

The highly purified, molybdate-stabilized '8-9-S' form of the chick oviduct progesterone receptor complexed with [3H]progesterone (Specific activity approximately equal to 10-12 nmol bound steroid/mg protein) was prepared according to the three-step method [Renoir et al. (1982) Eur. J. Biochem. 127,71-79] and 50-90 micrograms samples were injected into a goat and a rabbit. Specific antibodies were observed as early as 2 weeks following the first booster injection and increased considerably 12 weeks later after further booster injections. Results were similar in the two animals, with higher titers observed in the goat. Antibodies cross-reacted with the 'transformed' 4-S form of the chick oviduct progesterone receptor. They also cross-reacted with molybdate-stabilized 8-9-S progesterone receptors of mammalian species (obtained from MCF-7 human breast cancer cells and from rabbit and mouse uteri), suggesting some evolutionary conservation of steroid hormone receptors. No cross-reaction was observed with chick oviduct oestradiol receptor and with chick plasma transcortin (a non-receptor progesterone-binding protein).

Animals↗

PubMed1977

The effects of progesterone and oestrogen treatment in heifers on oestrous cycle control and plasma progesterone levels.

Data are presented on the effects of a short-term progesterone treatment for oestrous cycle control in cattle. Progesterone was administered by intravaginal sponge pessaries inserted for a 10-day period. Progesterone pessaries alone did not affect oestrous cycle length or corpus luteum function at either early (day 2) or midluteal (day 12) cycle stages. However, when progesterone (250 mg) and oestradiol benzoate (7-5 mg) were given intramuscularly on the day of pessary insertion corpus luteum development was inhibited in animals treated at day 2 and was regressed in animals at day 12. This combined oestrogen-progesterone treatment efficiently controlled oestrous cycle length.

Animals↗

PubMed1991

Tokishakuyakusan stimulates progesterone and estradiol-17 beta production by rat granulosa cells and progesterone, testosterone and estradiol-17 beta by the residual portion of the follicle in vitro.

To examine the possible effects of Tokishakuyakusan (TS) on steroidogenesis by preovulatory follicles at the cell level, the expressed granulosa cells and remaining portion of follicles from pregnant mare's serum gonadotropin (PMS)-treated immature rats were incubated in vitro with increasing concentrations of TS for 3 h. TS significantly stimulated progesterone and estradiol-17 b production, with a predominant stimulation of progesterone, by the expressed granulosa cells, while testosterone production was not stimulated. In the remaining portion of the follicle, TS also significantly stimulated progesterone, testosterone and estradiol-17 b production. Similar to the effect produced by granulosa cells, the stimulatory effect of TS was stronger on progesterone than on testosterone and estradiol-17 b production. These results suggest that TS has a potent, direct stimulatory effect on steroidogenesis, especially progesterone production, by constituent tissue compartments of rat preovulatory follicles in vitro.

Animals↗

PubMed1977

A new concept for control of the estrous cycle of the ewe based on the temporal relationships between luteinizing hormone, estradiol and progesterone in peripheral serum and evidence that progesterone inhibits tonic LH secretion.

The temporal relationships between LH, estradiol and progesterone in peripheral serum of the ewe were characterized throughout the estrous cycle. Between successive preovulatory LH sruges, serum concentrations of LH fluctuated markedly in a manner indicative of pulsatile discharges. Mean serum LH and progesterone concentrations were inversely related, LH being highest during the early and late luteal phases of the estrous cycle and lowest in the mid-luteal phase. A progressive, 5-fold increase in serum LH concentrations occurred between the onset of the precipitous fall in circulating progesterone attendant to luteolysis and the initiation of the preovulatory LH surge. Two major increments in circulating estradiol were observed in each cycle, both occurring when serum LH concentrations were relatively high. One estradiol increment occurred during the early luteal phase, the other during the 2-3 days prior to onset of the preovulatory LH surge. The latter estradiol increment thus accompanied the progressive, 5-fold increase in circulating LH which precedes the LH surge. The observations are inconsistent with the view that tonic LH secretion in the ewe is solely a function of a negative feedback action of estradiol. Rather, the temporal relationships between circulating hormones, in conjunction with recent findings that progesterone can inhibit tonic LH secretion in the ewe, lead to the conclusion that progesterone plays a major role in the regulation of tonic LH secretion during the estrous cycle of sheep.

Animals↗

PubMed1986

Use of progesterone 11-glucuronide-alkaline phosphatase conjugate in a sensitive microtitre-plate enzymeimmunoassay of progesterone in milk and its application to pregnancy testing in dairy cattle.

A simple direct-addition microtitre plate enzymeimmunoassay (EIA) for progesterone in whole milk is described. The assay used antiserum raised against 11 alpha-hydroxyprogesterone 11-hemisuccinate (progesterone 11-hemisuccinate) and a heterologous label prepared by conjugation of 11 alpha-hydroxyprogesterone 11-glucuronide (progesterone 11-glucuronide) with alkaline phosphatase using an active ester procedure. The sensitivity, analytical recovery, linearity of response and precision of the assay compared favourably with radioimmunoassay (RIA). Results from EIA of milk samples were compared with determinations made after isolation of progesterone by HPLC (r = 0.910). Milk samples (200) were assayed by RIA at both the Milk Marketing Board and the Cattle Breeding Centre and the results were correlated with EIA performed at the Cattle Breeding Centre (r = 0.890 and r = 0.833 respectively). Calving data were obtained from a further 110 cows for which the milk progesterone EIA had provided a pregnancy test 24 days after AI; 46 cows were correctly identified as non-pregnant and 58 as pregnant and there were 4 false positive and 2 inconclusive results.

Alkaline Phosphatase↗

PubMed1993

Effects of induction of low plasma progesterone concentrations with a progesterone-releasing intravaginal device on follicular turnover and fertility in cattle.

The effects of concentration of progesterone in plasma on development and fertility of the first wave dominant follicle were studied in cattle. To identify a source of exogenous progesterone that would permit extension of the first wave dominant follicle, nonlactating Holstein cows (n = 6) received on day 8 of two successive oestrous cycles an injection of PGF2 alpha (25 mg) and a new (1.9 g of progesterone (Period 1)) or used (approximately 1.2 g of progesterone (Period 2)) CIDR-B device that was removed on day 17. Control cows (n = 6) received a new CIDR-B device on day 8 that was removed on day 17 and a PGF2 alpha injection (25 mg) on day 17. Ultrasonography and collection of blood samples were performed on alternate days throughout the experiment. Plasma concentrations of progesterone and oestradiol were different between treatments (P < 0.0001 and P < 0.05, respectively). The dominant follicle was maintained until day 17 and ovulated upon removal of the intravaginal device in 1 of 6, 6 of 6 and 0 of 6 in new CIDR-B, used CIDR-B and control groups, respectively (P < 0.01). The preovulatory dominant follicles were 14.2 +/- 1.6 mm, 20 +/- 1.3 mm and 10 +/- 1.3 mm, respectively (P < 0.001) on day 17. There were fewer 5-9 mm follicles in cows having a persistent dominant follicle (P < 0.01). The interval to onset of oestrus was negatively correlated with size of the dominant follicle on day 17 (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intravaginal↗

PubMed2005

Miscarriage in the first trimester according to the presence or absence of the progesterone-induced blocking factor at three to five weeks from conception in progesterone supplemented women.

PURPOSE: To determine if the failure to detect the immonomodulatory protein progesterone induced blocking factor (PIBF) at three to five weeks of seemingly normal pregnancies in women supplemented by extra progesterone is associated with a higher miscarriage rate. METHODS: Progesterone-induced blocking factor expression by lymphocytes was measured by an immunocytochemistry technique. The serum beta human chorionic gonadotropin (hCG) and/or ultrasound were also deemed appropriate so that by these criteria there was no evidence of a poor pregnancy. The minimum progesterone dosage was 200 mg twice daily vaginal suppositories. RESULTS: Progesterone-induced blocking factor was detected in 17/39 (43.5%) of pregnant patients at this early time. There were three miscarriages by 12 weeks in this group (17.6%). The miscarriage rate was 6/21 (28.5%) in those where it was not detected. CONCLUSIONS: There was insufficient power to show significance. However there seems to be a trend for higher rates of miscarriage when PIBF is absent so these preliminary data encourage continuation of the study.

Abortion, Spontaneous↗

PubMed1989

[Catalytic activity of conjugates of peroxidase with progesterone in aqueous and micellar media in the presence of antibodies against progesterone].

At 22 and 41 degrees C the horseradish peroxidase (HRP) conjugates with progesterone, HRP-PROG-1 and HRP-PROG-2, were obtained by HRP reaction with N-hydroxysuccinimide ester of 3-O-carboxymethyloxime of progesterone. The interaction of these conjugates and unmodified enzyme with antibodies against progesterone was studied in phosphate-citrate buffer pH 3.6 and in the reversed micelles of Aerosol OT and Triton X-45 in heptane. Catalytic function of conjugates in buffered solutions and in reversed micelles increases as result of the conjugates' interaction with antibodies. The free progesterone in reversed micelles competes with HRP-PROG-1 for antibody binding, which may be the basis for homogeneous enzyme-immunoassay of progesterone, depending on the micelle composition, the antibody concentration and temperature.

Antibodies↗

PubMed1988

Progesterone receptor distribution in the human endometrium. Analysis using monoclonal antibodies to the human progesterone receptor.

Two monoclonal antibodies to the human progesterone receptor (PR), JZB39 and KD68, were used in determining the immunohistochemical distribution of PR in the human endometrium throughout the menstrual cycle and after menopause. These antibodies recognized PR, as demonstrated by a downfield shift in the radiolabeled progestin binding peak when KD68 or JZB39 was added to high salt sucrose density gradients. The specificity of both antibodies for PR was confirmed with Western immunoblots and competition studies performed with purified receptor. Progesterone receptor was identified with these antibodies and the peroxidase-antiperoxidase technique in the nuclei of epithelial cells, stromal cells, and myometrial smooth muscle cells. The receptor content of endometrial epithelium and stroma varied with the menstrual cycle. The variation was most marked in the epithelium, which demonstrated very strong PR immunostaining during the proliferative phase and postovulation Days 1-3 of the early secretory phase, but PR immunostaining decreased sharply at postovulation Day 4 and remained relatively weak or absent during the mid and late secretory phase. In contrast, stromal cell nuclei were moderately to strongly immunostained even during the secretory phase. Progesterone receptor was not localized in vascular smooth muscle cells or endothelial cells. Specific cytoplasmic staining for PR was not identified in any of these cases, even prior to ovulation, when circulating levels of progesterone are low, indicating that both the steroid-occupied and -unoccupied forms of human progesterone receptor, like rabbit and guinea pig PR, and estrogen receptor, is a nuclear protein.

Antibodies, Monoclonal↗

PubMed1994

[Effects of gossypol acetate, danazol, progesterone and GnRH-A on estrogen and progesterone receptors of human endometrial cells].

In order to evaluate the drugs in treating endometriosis, the direct effects of gossypol acetate, danazol, progesterone, and gonadotropin releasing hormone-agonist (GnRH-A) on the isolated human endometrial cells were determined by DCC assay. The binding capacity of cytosolic estradiol receptor (E2R) and progesterone receptor (PR) in groups treated with gossypol acetate or progesterone decreased. In danazol-treated group, the binding capacity of PR decreased but not that of E2R. GnRH-A showed no significant effect on the binding capacity of E2R and PR. There was a significant linear correlation between the inhibitory rates of PR binding capacity of progesterone and danazol. The results suggested that gossypol acetate, danazol and progesterone might have peripheral effects mediated by steroid receptors, while GnRH-A work clinically through the central path way only.

Adult↗

PubMedDate not supplied

[Luteal phase support after vaginal progesterone: comparative study with micronized oral progesterone].

Two progesterone presentations, a vaginal application of 90 mg progesterone per day (Crinone) or 300 mg progesterone orally administered (Utrogestan) were compared for luteal phase support of patients undergoing an in vitro fertilisation (IVF) procedure. 283 patients were randomly allocated to either treatment. The treatment started within 24 hours after the embryo transfer procedure and continued until day 30 in cases of implantation. Efficacy was assessed using the pregnancy and delivery rates. Safety was assessed through specific symptoms and usual safety monitoring. The pregnancy rate per transfer was not significantly different in the Crinone and Utrogestan groups at day 12 (Crinone: 35.3%, Utrogestan: 29.9%, p = 0.55), at day 30 (Crinone: 28.8%, Utrogestan: 25%, p = 0.61), at day 90 (Crinone: 25.9%, Utrogestan: 22.9%, p = 0.69). No difference in spontaneous abortion rates were seen thereafter. The delivery rate was not significantly different (proportion delivery per patients included, Crinone: 23.0%, Utrogestan: 22.2%, p = 1), as well as the ratio new-born per transferred embryo (Crinone: 11.7%; Utrogestan: 11.1%, p = 0.91). Safety parameters were similar in both groups except for drowsiness, which was more significantly frequent in the oral P group than in the Crinone group at all time points. No serious adverse events were recorded in this study. The fact that Crinone matches the efficacy of the larger doses of progesterone used orally reflects an advantage of the transvaginal route of administration which avoids metabolic inactivation of progesterone during its first liver pass.

Administration, Intravaginal↗

PubMed1983

Regulation of uteroglobin synthesis and conservation of progesterone and estrogen receptors in immature rabbit uterus during prolonged progesterone treatment.

Daily progesterone administration (1.33 mg/kg body weight) to immature rabbits brought about an initial increase in the uterine content of uteroglobin which, however, subsided when progesterone treatment was continued for 10 days. During this treatment period progesterone did not lose its own uterine receptors nor did it lose its inhibitory effect on the accumulation of occupied nuclear estrogen receptors. Since immature rabbits were used, the decrease of uteroglobin concentration cannot be explained by inhibitory effects of endogenous estrogens. The results suggest that termination of uteroglobin secretion may be a selective and inherent effect of progesterone itself.

Animals↗

PubMed2006

The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle.

Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. Progestin activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. Progestin induction of the cyclin D1 gene, which lacks a progesterone response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional progesterone response element was unaffected by mutations that interfere with PR activation of Src. Progestin induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression.

Animals↗