Importance Of Progesterone Research Articles

The importance of progesterone in pregnancy establishment in cattle

Progesterone (P4) plays a key role in reproductive events associated with the establishment and maintenance of pregnancy through its effects on oocyte quality and its action on the uterine endometrium. Reduced P4 concentrations during growth of the ovulatory follicle are associated with lower fertility, while low concentrations of circulating P4 after ovulation have been associated with a reduction in conceptus growth and elongation, a decrease in interferon-tau production and lower pregnancy rates in cattle. In contrast, elevated concentrations of circulating P4 in the immediate post-conception period have been associated with an advancement of conceptus elongation, an increase in interferon-tau production and, in some cases, higher pregnancy rates in cattle. Despite the potential beneficial effects of exogenous P4 supplementation on fertility, results of supplementation studies have been inconsistent. This article highlights some of the recent findings in relation to embryo maternal interaction during bovine pregnancy establishment and the role of P4 in in uterine biology and embryo development.

Enhanced progesterone support during stimulated cycles of transvaginal follicular aspiration improves bovine in vitro embryo production

The in vitro production (IVP) of cattle embryos requires that germinal-vesicle stage oocytes undergo a period of maturation in vitro prior to fertilization and culture to the blastocyst stage. Success of IVP in taurine cattle is enhanced following ovarian stimulation prior to oocyte retrieval (OPU), particularly if preceded by a short period of FSH withdrawal (‘coasting’). However, evidence regarding the importance of progesterone (P4) support during OPU-IVP is equivocal. The current study, therefore, determined the effects of increased peripheral P4 concentrations during FSH-stimulated (‘coasted’) cycles of OPU. Progesterone support was provided by either an active corpus luteum (CL) and/or one of two intravaginal P4 releasing devices (i.e., CIDR® [1.38 g P4] or PRID® Delta [1.55 g P4]). Expt. 1 established an initial estrus prior to OPU, allowing CL formation (single luteal phase) spanning the first two of five cycles of OPU; the remaining three cycles were supported by either a CIDR® or PRID® Delta. Expt. 2 commenced with two cycles of dominant follicle removal (including prostaglandin F2α) undertaken seven days apart prior to six cycles of OPU. The absence of a CL meant that these cycles were supported only by a CIDR® or PRID® Delta. As each experiment involved several sequential cycles of OPU, the cumulative effects of device use on vaginal discharges were also assessed. Each experiment involved 10 sexually mature Holstein heifers. In the absence of a CL, peak plasma P4 concentrations were greater (P = 0.002) for the PRID® Delta (4.3 ± 0.22) than for the CIDR® (2.9 ± 0.22). In Expt. 1 there was an interaction (P < 0.05) between CL presence at OPU and P4 device on Day 8 blastocyst yields, indicating an effect of P4 device only when the CL was absent. The percentage hatching/hatched blastocysts of matured oocytes for the CIDR® and PRID® Delta was 44.3 ± 5.04 and 41.0 ± 5.40 in the presence, and 17.1 ± 3.48 and 42.2 ± 3.76 in the absence, of a CL (P = 0.018). Combined analyses of data from Expt. 1 and 2, when no CL was present, confirmed that Day 8 blastocyst yields were greater (P = 0.022) for the PRID® Delta than the CIDR®. Vaginal discharge scores were higher (P < 0.001) for the PRID® Delta than the CIDR® in Expt. 1 but not in Expt 2; however scores were low, did not increase with repeated use, and thus were deemed of no clinical or welfare concern. In conclusion, enhanced P4 support during FSH-stimulated cycles of OPU-IVP can improve in vitro embryo development.

Characterisation of serum progesterone and progesterone-induced blocking factor (PIBF) levels across trimesters in healthy pregnant women

Progesterone-induced blocking factor (PIBF), which plays an important role in maintaining healthy pregnancies, has shown great promise as a prognostic biomarker for threatened miscarriage. To better characterise the physiological trends of progesterone and PIBF, we analysed serum progesterone and PIBF concentrations in healthy non-pregnant and pregnant women across trimesters. We saw increasing concentrations of progesterone and PIBF in pregnant women with advancing trimesters. The serum progesterone and PIBF percentiles across gestational age in healthy pregnancies can be used as a guide for the formulation of reference ranges. We also demonstrated a significant positive correlation between progesterone and PIBF levels. This study demonstrates increasing progesterone and PIBF concentrations in later trimesters and underscores the importance of progesterone and PIBF in healthy pregnancies. Characterisation of progesterone and PIBF across gestational age in healthy pregnant women may help to prognosticate pregnancy viability and support further research into the importance of progesterone and PIBF in the maintenance of healthy pregnancies.

The Association Between Elevated Progesterone Level on Day of hCG Trigger and Live Birth Rates in ART Cycles: A Single Centre Observational Study.

Background:The advent of ovarian stimulation within an in vitro fertilization (IVF) cycle has resulted in modifying the physiology of stimulated cycles and has helped optimize pregnancy outcomes. In this regard, the importance of progesterone (P4) elevation at time of human chorionic gonadotrophin (hCG) administration within an IVF cycle has been studied over several decades. Our study aimed to evaluate the association of P4 levels at time of hCG trigger with live birth rate (LBR), clinical pregnancy rate (CPR) and miscarriage rate (MR) in fresh IVF or IVF-ICSI cycles.Methods:This was a retrospective cohort study (n=170) involving patients attending the Centre for Reproductive and Genetic Health (CRGH) in London. The study cohort consisted of women undergoing controlled ovarian stimulation using GnRH antagonist or GnRH agonist protocols. Univariate and multiple logistic regression analyses were used to evaluate the association of clinical outcomes. Differences were considered statistically significant if p≤0.05.Results:As serum progesterone increased, a decrease in LBR was observed. Following multivariate logistical analyses, LBR significantly decreased with P4 thresholds of 4.0 ng/ml (OR 0.42, 95% CI:0.17–1.0) and 4.5 ng/ml (OR 0.35, 95% CI:0.12–0.96).Conclusion:P4 levels are important in specific groups and the findings were statistically significant with a P4 threshold value between 4.0–4.5 ng/ml. Therefore, it seems logical to selectively measure serum P4 levels for patients who have ovarian dysfunction or an ovulatory cycles and accordingly prepare the individualized management packages for such patients.

Milk progesterone on day 5 following insemination in the dairy cow: associated metabolic variables and reproductive consequences

Despite the importance of progesterone on the fertility of lactating dairy cows, the factors that affect post ovulatory progesterone concentration are still unclear. Thus, the aim of the present study was to identify factors associated with the post ovulatory progesterone rise following 1 st insemination in lactating dairy cows. Data collected across a number of complimentary studies were compiled to produce a single database of 168 lactating Holstein Friesian dairy cows maintained under commercial conditions. In all animals a number of variables were measured during the insemination period and related to milk progesterone measured on day 5 following 1 st artificial insemination (AI). Overall, 44% of cows conceived to 1 st AI and while mean day 5 progesterone was not significantly higher in these cows, there was a significant quadratic relationship between milk progesterone concentration and conception rate. While a number of variables showed some association with progesterone concentration, the only variable showing a strong and repeatable relationship was plasma leptin concentration. We conclude that adequate but not excessive progesterone levels on day 5 bring about a better fertility, and plasma leptin concentration may be a much better indicator of metabolic status in lactating dairy cows. Keywords: Conception rate, dairy cow, leptin, metabolic variables, milk progesterone

Selective progesterone receptor modulators (SPRMs) for uterine fibroids.

Selective progesterone receptor modulators (SPRMs) for uterine fibroids.

168 INHIBITION OF BOVINE OOCYTE CUMULUS CELL PROGESTERONE SYNTHESIS DURING IN VITRO MATURATION AFFECTS CHROMOSOME ALIGNMENT AND SPINDLE INTEGRITY IN FERTILIZED EGGS AND EARLY EMBRYOS

We have previously demonstrated the importance of progesterone (P4) synthesis by cumulus cells during oocyte maturation in vitro (IVM) for bovine oocyte acquisition of developmental competence and subsequent embryo development (Aparicio et al. 2011 Biol. Reprod. 84). The aim of this study was to identify key processes that may be deregulated by the inhibition of P4 signalling in the cumulus–oocyte complex (COC) during IVM. To this end, good quality immature COC were placed in IVM medium [TCM-199 supplemented with 10% (vol/vol) FCS and 10 ng mL–1 epidermal growth factor] and cultured at 39°C for 22 h in a humidified atmosphere containing 5% CO2, in the presence or absence of 10 μM trilostane (which blocks P4 synthesis by inhibiting 3 β-hydroxysteroid dehydrogenase; Stegram Pharmaceuticals Ltd., Surrey, UK). Matured COC were washed and placed in 250 μL of fertilization medium (25 mM bicarbonate, 22 mM Na-lactate, 1 mM Na-pyruvate, 6 mg mL–1 fatty acid-free BSA, and 10 mg mL–1 heparin). In vitro fertilization (IVF) was performed with 250 μL of frozen–thawed semen at a final concentration of 1 × 106 spermatozoa mL–1 at 39°C under 5% CO2 during 20 h. Presumptive zygotes were denuded, washed, and transferred to 25-μL culture droplets (SOF + 5% FCS) at 39°C under 5% CO2, 90% of N2, and 5% O2 atmosphere with maximum humidity. Subsets of presumptive fertilized eggs and developing embryos were recovered at 6, 72, 120, and 192 h postinsemination (hpi) and processed for confocal whole-mount immunocytochemistry. The meiotic and mitotic spindles and chromosomes were visualised by immunofluorescent labelling of α-tubulin and 4′,6-diamindino-2-phenylindole (DAPI), respectively, and classified as normal if the chromosomes were correctly aligned or appropriately segregated, or abnormal if lagging chromosomes or abnormal chromosome segregation were observed. Samples were collected from 5 replicates (n = 50 zygotes/embryos per treatment, per timepoint) and a total of 157 spindles were observed. Logistic regression analysis was conducted to determine the probability of abnormal spindle formation. The incidence of spindle abnormality was regressed on time, treatment, and treatment by time. For all time points, there was significant reduction in the odds of abnormal spindle formation in control samples versus trilostane-treated samples (P &lt; 0.001). In conclusion, our data imply a role for P4 signalling in maintaining spindle integrity during oocyte meiotic maturation and progression through the initial mitotic divisions of early embryo development in cattle.

Abstract 449: Progesterone-induced immunosuppression thwarts immunosurveillance to tumors and promotes lung metastasis in a breast cancer model.

Abstract Exposure to sexual hormones is one of the strongest risk factors for breast cancer. Increased risk is entwined with a greater number of reproductive cycles and the use of progestin-containing hormone replacement therapy. In addition, the importance of progesterone in dampening immune response was illustrated in several models of infection and pregnancy. Based on the tolerogenic properties of progesterone (Pg) and its promoting role in breast cancer, in this work we investigated whether progesterone may thwart immunosurveillance and promote tumor metastasis by fostering an immunosuppressive microenvironment in breast cancer. Exogenously added Pg: (10−8M) or its synthetic analogue medroxiprogesterone acetate (MPA: 10−8M) induced the expression of the immunosuppressive protein galectin-1 (Gal1) in the hormone-dependent human breast cancer cell lines T47D and MCF-7 and in the mouse mammary adenocarcinoma C4HD. This effect was abrogated by pre-treatment with RU486 (10−7M) indicating that the progesterone receptor (PR) was involved. Interestingly, in vitro MPA treatment of human PBMC or mouse splenocytes controlled the expansion of regulatory T cells (Tregs) (CD4+CD25+Foxp3+) and skewed the balance toward a Th2-type cytokine profile. Furthermore, differentiation from naive T-cells to Tregs cells was enhanced in the presence of MPA, IL-2 and suboptimal concentrations of TGF-β. In addition, in vivo treatment with MPA (15mg 30-day release depot) of C4HD tumor-bearing mice increased both the expression of Gal1 and the frequency of Treg cells in tumor-draining lymph nodes and the tumor microenvironment. While the increase in Treg cell frequency was associated with an effect on Treg cell SMAD4 expression that potentiates TGF-β signalling, homing of Treg cells to tumor sites was supported through the induction of tumor-derived CCL22. Finally, we used a PR negative breast tumor model (4T1) to evaluate the effect of MPA on the tumor microenvironment and the consequences of this effect on tumor progression. In vivo treatment with MPA promoted lung metastasis by inducing an invasive phenotype in breast cancer cells. Co-culture of Treg cells differentiated in vivo in the presence of MPA with 4T1 cells promoted its invasive activity and modulate several genes associated with EMT, including SNAIL. In summary, these results demonstrate that progesterone hierarchically fosters an immunosuppressive tumor microenvironment that promotes metastasis by co-ordinately regulating Gal1 expression, stimulating the TGF-β pathway and augmenting the frequency of Treg cells. Our findings provide new insights into the role of progesterone in breast cancer as a crucial promoter of tumor-immune escape. Citation Format: Mariana Salatino, Tomás Dalotto, Diego O. Croci, Santiago P. Mendez Huergo, Sebastian L. Dergan Dylon, Juan P. Cerliani, Marta A. Toscano, Gabriel A. Rabinovich. Progesterone-induced immunosuppression thwarts immunosurveillance to tumors and promotes lung metastasis in a breast cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 449. doi:10.1158/1538-7445.AM2013-449

Expression and Function of Myometrial PSF Suggest a Role in Progesterone Withdrawal and the Initiation of Labor

Progesterone (P4), acting through its receptor (PR), is essential for the maintenance of pregnancy. P4 acts by suppressing uterine contractility and the expression of contraction-associated proteins (CAP) such as connexin 43 (Cx43). P4 levels must be reduced or its actions blocked to allow the increased expression of CAP genes and the initiation of labor. Although the importance of progesterone in pregnancy has been known for about 80 yr, the fundamental mechanisms by which P4/PR maintains myometrial quiescence and by which this signaling is blocked at term labor remain to be determined. In this manuscript, we demonstrate that ligand-bound PR interacts with the Cx43 gene promoter through activator protein-1 transcription factors. We show that the ability of PR to repress Cx43 transcription is conferred through the recruitment of the PR coregulator, polypyrimidine tract binding protein-associated splicing factor (PSF), and the further recruitment of the yeast switch independent 3 homolog A/histone deacetylase corepressor complex. PSF expression is elevated during pregnancy but falls toward term as a result of increased mechanical stretch of the myometrium and a rise in the concentrations of circulating estrogen. These data together indicate that PSF is a critical regulator of P4/PR signaling and labor. We suggest that decreased PSF at term may result in a de-repression of PR transcriptional control of CAP genes and thereby contributes to a functional withdrawal of progesterone at term labor.

258 ROLE OF PROGESTERONE AND ITS RECEPTORS ON DEVELOPMENTAL COMPETENCE OF OOCYTES IN CATTLE

Several studies have demonstrated the importance of progesterone (P4) through its receptors (PR) in the regulation of the ovulatory cycle, but its participation in oocyte maturation in mammals has not yet been clarified. Previous results in our group showed changes in the protein expression of genomic (nPR-A/B) and nongenomic (mPRα/β) PR in bovine cumulus–oocyte complexes (COC) during in vitro maturation (IVM), indicating a possible function for these receptors on bovine oocyte maturation. Therefore, we aimed to study the role of P4 and PR in oocyte developmental competence. Good-quality immature COC were placed in maturation medium [TCM-199 supplemented with 10% (vol/vol) FCS and 10 ng mL–1 of epidermal growth factor] and cultured at 39°C for 22 h in a humidified atmosphere containing 5% CO2, in the presence or absence of trilostane (0.001, 0.1, and 10 μM), P4 (50 and 100 ng mL–1), promegestone (50 and 100 ng mL–1), RU 486 (0.1, 1, and 10 μM), or antibodies against mPRα or mPRβ. Matured COC were washed and placed in wells containing 250 μL of fertilization medium (25 mM bicarbonate, 22 mM Na-lactate, 1 mM Na-pyruvate, 6 mg mL–1 fatty acid-free BSA, and 10 mg mL–1 heparin). In vitro fertilization was performed with 250 μL of frozen–thawed semen at a final concentration of 1 × 106 spermatozoa mL–1 at 39°C under 5% CO2 during 20 h. Presumptive zygotes were denuded, washed, and transferred to 25-μL culture droplets (SOF + 5% FCS) at 39°C under 5% CO2, 90% of N2, and 5% O2 atmosphere with maximum humidity. Number of embryos was recorded at day 2, 3, 7, and 8 (Day 0 = day of IVF). Data were analysed using ANOVA analysis using SPSS v. 15.0 software package. Inhibition of P4 production by 10 μM of trilostane during IVM reduced progesterone production in the media, cumulus cells expansion, but had no effect on meiotic resumption in Day 2 and Day 3 embryos; however, there was a significant decrease in the percentage of blastocysts at Day 7 (12 ± 3.5) and Day 8 (14 ± 3.3) compared with the control (30 ± 4.5 and 42 ± 2.5). This reduction on embryo development was overcome by the addition of 50 or 100 ng mL–1 of P4 at Day 8 (33 ± 5.7 and 32 ± 4.1). The same results were obtained with nonmetabolizable P4, where the reduction on blastocysts with trilostane at Day 8 (20 ± 2.0) was completely overcome by 50 or 100 ng mL–1 of promegestone (41 ± 5.1 and 40 ± 6.7). Specific inhibition nPR-A/B with 10 μM of RU 486 produced a significant reduction on blastocysts at Day 7 (24 ± 4.3) and Day 8 (29 ± 5.5) compared with the control (44 ± 2.6 and 47 ± 3.0). Inhibition of mPRα reduced cleavage rate and Day 3 embryos, whereas the inhibition of mPRβ had no effect on meiotic resumption or embryo development. In conclusion, the intracellular signaling of P4 on developmental competence of oocytes in cattle seems to be mainly mediated by nPR-A/B receptors and could be associated with cytoplasmic maturation.

Conventional progesterone receptors (PR) B and PRA are expressed in human spermatozoa and may be involved in the pathophysiology of varicocoele: a role for progesterone in metabolism

The physiological roles of intracellular progesterone (PRG) receptors (PRs) have been studied intensively in female mammals, while their functions in male are scarce. Conventional PRs were evidenced in our study by Western blotting, concomitantly in healthy spermatozoa and in oligoasthenoteratozoospermic samples without and with varicocoele. Transmission electron microscopy revealed the presence of the PRs on the membrane as well as in the nucleus, mitochondria and flagellum. A reduced expression of the PRs was observed only in varicocoele spermatozoa. Responses to PRG treatment on cholesterol efflux, tyrosine phosphorylation, src and Akt activities, acrosin activity and acrosome reaction in varicocoele spermatozoa were reduced or absent. To further investigate PRG significance in human male gamete, we focused its action on lipid and glucose metabolism. The evaluation of the triglycerides content, lipase and acyl-CoA dehydrogenase activities suggests that PRG through the PRs exerts a lipolytic effect on human spermatozoa. An increase in glucose-6-phosphate dehydrogenase activity was also obtained, evidencing a role for PRG on glucose metabolism. In 'varicocoele' spermatozoa, the PRG did not induce energy consumption. The action of PRs on sperm metabolism is a novel finding that renews the importance of PRG in male fertility. Our results showed that varicocoele may lead to male factor infertility by a mechanism involving a decreased PR expression in human spermatozoa that evidences a detrimental effect on spermatozoa at the molecular level, going beyond the abnormal sperm morphology described to date.

Prevention of spontaneous preterm birth: the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment

Prevention of spontaneous preterm birth: the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment

Evaluation of the Effect of Muscular Injection of Progesterone on Days 2-5 Following Insemination on Pregnancy Rate in Dairy Cows

It was hypothesized that suboptimal progesterone concentrations during the late embryo and early fetal period may act to compromise conceptus development in dairy cattle. The importance of progesterone during early pregnancy in cows is well established. Adequate secretion of progesterone is clearly the major requirement for success of early pregnancy. The aim of this study was to evaluate the efficacy of exogenous progesterone injection from day 2 to 5 following AI on conception rate in dairy cattle. At 48 h after the AI the cows were alternately assigned to treatment group (n = 40), received 4 consecutive day, from Day 2 to 5, i.m. injection of 100 mg progesterone (Vetagesterone, Aburaihan, Iran, Each mL contains: 2.5 mg progesterone) and control group (n = 68), received no treatment. The study population was stratified by parity, milk yield production, number of AI and days in milk. Pregnancy proportion in treatment and control groups were 30.88 and 35%, respectively. The results demonstrated that there was no significant differences between two groups (p < 0.05).

Progesterone enhances motor, anxiolytic, analgesic, and antidepressive behavior of wild-type mice, but not those deficient in type 1 5α-reductase

The importance of progesterone's (P 4) metabolism by the 5α-reductase type I enzyme was examined in homozygous and heterozygous 5α-reductase type I knockout mice and their wild-type siblings. P 4 (1.0 mg) or vehicle was administered and effects on motor, anxiety, nociceptive, and depression behavior were observed. After testing, whole-brain progesterone and 5α-pregnan-3α-ol-20-one (3α,5α-THP) levels were determined by radioimmunoassay. Motor behavior in the horizontal crossing and open field tasks of 5α-reductase-deficient mice administered P 4 was similar to vehicle control mice and significantly reduced compared to wild-type mice administered P 4. In the open field, 5α-reductase-deficient mice administered P 4 had a similar number of central entries as did vehicle control mice, both were lower than central entries of P 4-administered wild-type mice. However, in the plus maze, P 4 to 5α-reductase-deficient or wild-type mice significantly increased open arm activity compared to vehicle-administered control mice. P 4 to wild-type, but not 5α-reductase-deficient mice, significantly increased latencies to lick front and back paws in response to radiant heat stimuli compared to vehicle administration to control mice. In the forced swim test, 5α-reductase-deficient mice administered P 4 were similar to vehicle control mice and the latency to immobility was significantly decreased, and the duration of immobility was significantly increased, compared to wild-type mice administered P 4. Thus, these data suggest metabolism by the 5α-reductase type I enzyme may mitigate P 4's effects on some tasks of motor, anxiety, nociception, and depression behavior.

Role of progesterone antagonists and new selective progesterone receptor modulators in reproductive health.

Given the importance of progesterone in female reproductive health, it was inevitable that analogues of this molecule would be developed to treat a variety of gynecologic maladies. Such medications, termed progesterone antagonists, act to counteract the effect of progesterone. A newer class of molecules, the selective progesterone receptor modulators (SPRMs), have both agonist and antagonist activities depending upon the site of action. These compounds have been studied for their effect on endometrial growth, endometrial vascular development, the hypothalmic-pituitary-ovarian axis and cervical integrity. Such research has led to a number of potential clinical applications. Progesterone antagonists are well established in their use for termination of pregnancy, although SPRMs seem to have a diminished capacity for induction of abortion. Similarly, antagonists work well to soften and dilate the cervix before surgery, but such efficacy by SPRMs is unlikely. Other applications for progesterone antagonists include induction of labor, the treatment of endometriosis, fibroids and contraception; SPRMs also may prove useful in the treatment of endometriosis and fibroids, as well as for postmenopausal hormone replacement therapy and the treatment of dysfunctional uterine bleeding. Finally, these compounds may aid investigators in unraveling many of the nuances of the role of progesterone in reproductive function. Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to describe the receptor action and selective modulation of progesterone, explain the effects of progesterone receptor modulators, and list the potential clinical applications of progesterone antagonists and selective progesterone receptor modulators.

The Effect of Feeding Calcium Soaps of Fatty Acids on the Reproductive Physiology of Lactating Dairy Cows

Although it is not a substantial constituent of dairy cattle feed, there has been much work on the effects of feeding supplemental fat on reproductive performance. Supplemental fat increases the energy concentration of the diet and may lessen the effects of the negative energy balance post calving. Adding fat has been reported to positively influence reproduction in a number of ways, for instance increasing plasma progesterone concentration and increasing the life span of the corpus luteum (for a review Staples et al., 1998). A number of studies have demonstrated the importance of progesterone in early pregnancy and in particular the timing and strength of the post ovulatory progesterone rise. The aim of this study was to establish the effect of a dietary supplement of fat, in the form of calcium soaps of fatty acids, on reproductive function and in particular on post ovulatory progesterone levels in lactating dairy cows.

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

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. 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. 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. 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.

Progesterone and testicular function

Defined by most encyclopedias and textbooks as a female hormone, the importance of progesterone in male reproduction has remained in the shadow. Testicular progesterone has been regarded as a by-product of steroidogenesis, which is not converted into testosterone. In many conditions, including aging, the testicular progesterone/androgen ratio increases and absolute progesterone concentrations can reach high levels. Only during the past few years has the role of progesterone as a modulator of male reproductive function become evident. Progesterone has been shown to act through binding to a protein at the cell membrane in sperm as well as in interstitial Leydig cells. The current review elaborates on the importance of progesterone in testicular physiology.

Induction of Progestin Receptors by Estradiol in the Forebrain of Estrogen Receptor-α Gene-Disrupted Mice

Mice, rats, and humans have two types of estrogen receptors, estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta). Estrogen receptor-alpha gene-disrupted (ERalpha-disrupted) mice bear two nonfunctional copies of the ERalpha gene. This mutation blocks the synthesis of full-length ERalpha, renders the animals infertile, and inhibits the induction of female sexual behaviors by estradiol and progesterone. It is likely that many of the processes contributing to the regulation of sexual receptivity by estradiol and progesterone are compromised in ERalpha-disrupted mice. However, given the importance of progesterone in the regulation of sexual receptivity and given the importance of progestin receptors (PRs) in mediating the responses of females to progesterone, we investigated the effects of ERalpha disruption on the induction of PRs by estradiol in the forebrain. We hypothesized that estradiol would induce PRs in wild-type mice but not in ERalpha-disrupted mice. Ovariectomized wild-type and ERalpha-disrupted mice were implanted with either estradiol-filled capsules or empty capsules for 5 d, after which their brains were processed for the immunocytochemical detection of PR. Estradiol increased the number of PR-immunoreactive cells in both wild-type and ERalpha-disrupted mice. The residual responsiveness of ERalpha-disrupted mice to estradiol could be accounted for by an ERbeta-dependent mechanism or another as yet unidentified estrogen receptor; however, because ERalpha-immunoreactivity and PCR product representing the 3' end of ERalpha mRNA were found in at least one PR-containing region of the ERalpha-disrupted mice, an ERalpha splice variant may also mediate the induction of PR-immunoreactivity in ERalpha-disrupted mice.

Regulation of uterine immune function by progesterone—lessons from the sheep

Survival of the fetal allograft results from orchestrated adjustments in activity of maternal lymphoid cells as well as in trophoblast gene expression. One molecule that regulates uterine immune responsiveness is progesterone. In fact, uterine skin graft survival and susceptibility to bacterial infections are increased by progesterone. This review focuses on the role of progesterone in regulation of uterine immune function in the sheep. While the importance of progesterone as a regulator of immune function likely varies between species, concepts derived from the sheep model may prove pertinent to other species also. The actions of progesterone on uterine immune function in the ewe change during pregnancy. Before day 50 of gestation, i.e. when the uterus is still dependent upon the corpus luteum as a source of progesterone, concentrations of progesterone are probably not high enough at the maternal–fetal interface to inhibit lymphocyte activation. During this early period of pregnancy, progesterone inhibits uterine immune function by inducing endometrial secretion of a protein called uterine milk protein (UTMP) that itself is inhibitory to lymphocyte function. After day 50 of pregnancy, it is likely that the placenta produces sufficient amounts of progesterone to directly inhibit lymphocyte proliferation. Additional inhibition is achieved because of sustained synthesis of UTMP. Accordingly, progesterone acts to regulate uterine immune function in ways that allows for inhibition of immune responses at the utero–placental interface without systemic immunosuppression.