Progesterone Response Research Articles

The effect of progesterone level prior to oocyte retrieval on the numbers of oocytes retrieved and embryo quality in IVF treatment cycles: an analysis of 2,978 cycles.

The study was designed to evaluate the relationship between serum progesterone (P4) response after hCG administration and the number of oocytes retrieved and the embryo quality in fresh IVF cycles. We conducted a retrospective cohort study of women aged 24-43 years who underwent first fresh IVF cycle from 2011 to 2013 at a single practice. We compared the post-hCG serum P4 level with values on the day of hCG trigger. Patients were analyzed in long and short protocols independently. In addition, patients were stratified by post-hCG P4 response. Number of oocytes retrieved and embryo quality were the primary outcomes of interest. Ordinary least square regression models and logistic regression analysis models were created to identify predictive factors associated with embryological outcomes while adjusting for potential confounders. Among the 2,978 IVF cycles, 2,484 patients were in long protocols, and 494 patients were in short protocols. After adjusting for patient age, rFSH duration, and basal FSH levels, the associations between P4 response after hCG administration and number of oocytes retrieved (P < 0.001) remained statistically significant in both long and short protocols. Additionally, mature oocyte rate, fertilization rate, good quality embryo rate, pregnancy rate and implantation rate were not significantly associated with the P4 increase when adjusting for the same factors. However, pregnancy rate and implantation rate from frozen-thawed cycles increased gradually across the seven groups. Post-hCG P4 levels were positively associated with the number of oocytes retrieved, but did not affect oocyte or embryo quality. Our study suggests that the change in the post-hCG P4 level is another parameter that can be used by clinicians to assess the number of oocytes retrieved, and may further to estimate the pregnancy rate and live birth rate indirectly.

Sex differences in neurosteroid and hormonal responses to metyrapone in posttraumatic stress disorder.

Mechanisms contributing to sex differences in the regulation of acute stress responsivity and their effect on the increased incidence of posttraumatic stress disorder (PTSD) in women are poorly understood. The reproductive hormone, progesterone, through conversion to allopregnanolone (ALLO), suppresses the hypothalamic pituitary adrenal (HPA) axis and has potent anxiolytic effects. The potential that progesterone and allopregnanolone reactivity modulate HPA axis responses and account for sex differences in PTSD has not been previously examined. The present study examined the effects of sex and PTSD on adrenocorticotropic hormone (ACTH), progesterone, and allopregnanolone responses to metyrapone and whether progesterone and allopregnanolone reactivity could affect the ACTH response in PTSD. Healthy medication-free male and premenopausal follicular phase female participants with chronic PTSD (n = 43; 49 % female) and controls (n = 42; 50 % female) completed an overnight metyrapone challenge and ACTH, progesterone, and allopregnanolone were obtained by repeated blood sampling. The increase in ACTH response to metyrapone was higher in PTSD subjects compared to controls and in women compared to men. Contrary to our initial prediction of an inverse relationship, progesterone and allopregnanolone were positively associated with ACTH. Progesterone and allopregnanolone partially mediated the relationship between PTSD and ACTH. Our findings of increased ACTH to metyrapone in PTSD and in women may reflect heightened hypothalamic CRF hypersecretion. Progesterone and allopregnanolone partially mediated the ACTH response in PTSD. Further characterizing sex differences in these processes will advance our understanding of the pathophysiology of PTSD, and may ultimately lead to better-targeted, more effective treatment.

On the time course, generality, and regulation of plasma progesterone release in male rats by stress exposure.

Although progesterone is most commonly regarded in terms of its role in the female estrous cycle, reproductive behavior, and pregnancy, progesterone is also a precursor to corticosterone (CORT) and is released from the adrenal glands of both sexes in response to stress. However, the relationship between plasma CORT and progesterone during times of stress has not been well established. To better characterize dynamic changes in progesterone release as a result of stressor exposure, plasma progesterone levels were measured using enzyme immunoassay under multiple conditions, including after stress exposure (footshock, restraint, and forced swim), manipulations of the hypothalamic-pituitary-adrenal axis (injection of metyrapone or dexamethasone, or adrenalectomy), and in response to CRH and ACTH injections. When plasma levels of ACTH, CORT, and progesterone were analyzed across studies, CORT and progesterone were found to be highly correlated and rarely dissociated. Additionally, it appears that in male rats, the adrenal glands are the principle source of circulating progesterone in response to stress. Interestingly, a detailed time course indicated lack of a circadian rhythm of progesterone secretion, despite a robust rhythm of circulating CORT. The current studies provide critical new information on the coincident release of progesterone and CORT in response to stress and their somewhat paradoxical dissociation across the circadian rhythm. These findings provide an important foundation for future studies that will examine the role of stress-induced progesterone in behavioral, neuroimmune, and neuroendocrine responses to stress.

Early adolescent stress alters behavior and the HPA axis response in male and female adult rats: the relevance of the nature and duration of the stressor

Adolescence is a period of transition from childhood to adulthood that involves the maturation of social and cognitive behavior. The activation of the stress system during this phase can lead to long-lasting adverse effects. We aimed to verify whether the nature and duration of stressors applied in adolescent female and male rats would alter their exploratory behavior and stress responses as adults. Wistar rats on day P26 were divided into groups that were subjected to 1 (acute) or 7 (chronic) insulin or lipopolysaccharide (LPS) injections or restraint stress for 1h. At P60, the rats were subjected to the elevated plus-maze, and at P61, they were subjected to 30min of restraint stress after which plasma samples and brains were collected. LPS acute injection promoted anxiolytic effects in male adults. Acute LPS treatment and acute or chronic restraint induced anxiolytic behavior in female adults. The administration of adolescent chronic stimuli to males decreased the adult plasma corticosterone (CORT) and progesterone levels after restraint. Adolescent acute restraint or LPS injection decreased the CORT response in female adults. The adult neuronal activation of the corticotrophin-releasing hormone and vasopressin on the paraventricular nucleus did not vary according to the type of adolescent stress or sex. Our results indicate that both adult behavior and the glucocorticoid stress response are affected differently in males versus females by adolescent stress. The duration of stressors had a greater effect on the CORT and progesterone response in males, whereas the nature of the stressor had a greater effect on exploratory behavior in females.

Molecular screening of Chinese medicinal plants for progestogenic and anti-progestogenic activity.

Estrogen and progestins have adverse effects, and many of these adverse effects are caused by progestins. Due to this, many women choose to use botanical alternatives for hormone replacement therapy, which does not trigger steroidogenic properties. Therefore, it is necessary to screen these herbs for progestogenic and anti-progestogenic properties. Extract of 13 Chinese medicinal plants were analysed for progestogenic and anti-progestogenic activities by using progesterone response element-driven luciferase reporter gene bioassay. MTT assay was carried out to investigate the cytotoxic effect of herb extract on PAE cells. Among the 13 herbs, Dipsacus asperoides extract exhibited progestogenic activity, and 10 species - Cortex eucommiae, Folium artemisiae argyi, Glycyrrhiza uralensis, Angelica sinensis, Atractylodes macrocephala koidz, Scutellaria baicalensis, Cuscuta chinensis, Euscaphis japonica, Ailanthus altissima, and Dioscorea opposita - were recognized to have anti-progestogenic like activities. Extract of Dipsacus asperoides demonstrated dose-dependent progestogenic activity, and the progestogenic activity of 100 (mu)g/mL extracts was equivalent to 31.45 ng/mL progesterone activity. Herbs extracts that exhibited anti-progestogenic-like activity also inhibited the 314.46 ng/mL progesterone activity in a dose-response manner. None of the herb extracts shown significant toxic effect on PAE cells at 40-100 (mu)g/mL compared to control. This discovery will aid selection of suitable herbs for hormone replacement therapy.

Validation of a luciferase bioassay to detect the progestative activity in gilts whose estrus was induced by an uterotonic herb (Ligusticum chuanxiong)

Ligusticum chuanxiong (LC) is an uterotonic herb. Ethanol extract of LC has potent progestative activity. The progestative activity in rat serum was well documented after oral and subcutaneous administration of LC. The objective of this study was to investigate the possibility of LC for estrus synchronization of gilts in place of synthetic progesterone. Eighteen gilts were randomly assigned into three groups, control group fed normal feed, positive control group supplemented with 20mg of altrenogest (Regumate®) and treatment group supplemented with 100g of LC daily for 22 consecutive days in feed. Blood samples were collected from jugular vein of gilts on the 22nd day before altrenogest or LC feeding. Estrus was monitored every day in the morning and the evening by observing the vulva swelling and reddening as well as nose to nose fence line contact between the boar and sow. Estrus was confirmed by testing the standing reflex in the presence of boar. All gilts in LC-fed group and 5 gilts in altrenogest-fed group came in estrus within 2–6 days after withdrawal of feeding, but did not show estrus during the feeding period. Whereas, all gilts in control group came in estrus during the feeding period. Progesterone responsive reporter plasmid was constructed by incorporating the progesterone response elements and TATA box at the multiple cloning site of pGL3 basic vector. Gilts serum progestative activities were measured by using luciferase reporter gene bioassay. Serum analysis showed that progestative activities of altrenogest- and LC-supplemented groups had a similar pattern. It is concluded that LC is a potential feed additive to be used for estrus cycle synchronization in swine industry.

Expression Patterns of Progesterone Receptor Membrane Components 1 and 2 in Endometria From Women With and Without Endometriosis

Endometriosis is a hormone-dependent inflammatory condition associated with pain and infertility. A growing body of evidence supports attenuated secretory-phase progesterone responsiveness in women with this disease. Herein, we compare the expression of progesterone receptor membrane components (PGRMC) 1 and 2 in eutopic endometrium from 11 women with laparoscopically and/or histologically proven stage III/IV endometriosis and 23 disease-free women. Menstrual cycle phase was determined using a combination of reported cycle day, serum hormone profile, and endometrial histologic dating. The PGRMC-1 (fold change -3.3; P < .05) and PGRMC-2 (fold-change -8.8; P < .05) gene expression were significantly downregulated in secretory phase, eutopic endometrium from women with endometriosis. Immunohistochemistry demonstrated decreased PGRMC-1 and PGRMC-2 protein expression in the secretory phase endometrial stroma cells of women with endometriosis. Consistent with the preclinical work of others, our results reflect downregulation of endometrial PGRMC-1 and PGRMC-2 expression in secretory phase endometrium from women with advanced stage endometriosis. Understanding the molecular mechanisms of attenuated progesterone action in endometriosis has important diagnostic and therapeutic implications.

Integrity of the LXXLL motif in Stat6 is required for the inhibition of breast cancer cell growth and enhancement of differentiation in the context of progesterone

BackgroundProgesterone is essential for the proliferation and differentiation of mammary gland epithelium. Studies of breast cancer cells have demonstrated a biphasic progesterone response consisting of an initial proliferative burst followed by sustained growth arrest. However, the transcriptional factors acting with the progesterone receptor (PR) to mediate the effects of progesterone on mammary cell growth and differentiation remain to be determined. Recently, it was demonstrated that signal transducer and activator of transcription 6 (Stat6) is a cell growth suppressor. Similar to progesterone-bound PR, Stat6 acts by inducing the expression of the G1 cyclin-dependent kinase inhibitors p21 and p27. The possible interaction between Stat6 and progesterone pathways in mammary cells was therefore investigated in the present study.MethodsChIP and luciferase were assayed to determine whether Stat6 induces p21 and p27 expression by recruitment at the proximal Sp1-binding sites of the gene promoters. Immunoprecipitation and Western blotting were performed to investigate the interaction between Stat6 and PR-B. The cellular DNA content and cell cycle distribution in breast cancer cells were analyzed by FACS.ResultsWe found that Stat6 interacts with progesterone-activated PR in T47D cells. Stat6 synergizes with progesterone-bound PR to transactivate the p21 and p27 gene promoters at the proximal Sp1-binding sites. Moreover, Stat6 overexpression and knockdown, respectively, increased or prevented the induction of p21 and p27 gene expression by progesterone. Stat6 knockdown also abolished the inhibitory effects of progesterone on pRB phosphorylation, G1/S cell cycle progression, and cell proliferation. In addition, knockdown of Stat6 expression prevented the induction of breast cell differentiation markers, previously identified as progesterone target genes. Finally, Stat6 gene expression levels increased following progesterone treatment, indicating a positive auto-regulatory loop between PR and Stat6.ConclusionsTaken together, these data identify Stat6 as a coactivator of PR mediating the growth-inhibitory and differentiation effects of progesterone on breast cancer cells.

Acetylation at Lysine 183 of Progesterone Receptor by p300 Accelerates DNA Binding Kinetics and Transactivation of Direct Target Genes

The identification of lysine acetylation of steroid hormone receptors has previously been based on the presence of consensus motif (K/R)XKK. This study reports the discovery by mass spectrometry of a novel progesterone receptor acetylation site at Lys-183 that is not in the consensus motif. In vivo acetylation and mutagenesis experiments revealed that Lys-183 is a primary site of progesterone receptor (PR) acetylation. Lys-183 acetylation is enhanced by p300 overexpression and abrogated by p300 gene silencing, suggesting that p300 is the major acetyltransferase for Lys-183 acetylation. Furthermore, p300-mediated Lys-183 acetylation is associated with heightened PR activity. Accordingly, the acetylation-mimicking mutant PRB-K183Q exhibited accelerated DNA binding kinetics and greater activity compared with the wild-type PRB on genes containing progesterone response element. In contrast, Lys-183 acetylation had no influence on PR tethering effect on the nuclear factor κ-light chain enhancer of activated B cells (NFκB). Additionally, increases of Lys-183 acetylation by p300 overexpression or inhibition of deacetylation resulted in increases of Ser-294 phosphorylation levels. In conclusion, PR acetylation at Lys-183 by p300 potentiates PR activity through accelerated binding of its direct target genes without affecting PR tethering on other transcription factors. The effect may be mediated by enhancing Ser-294 phosphorylation.

Comment on “Progesterone/RANKL Is a Major Regulatory Axis in the Human Breast”

In vivo menstrual cycle data support the findings by Tanos et al. that progesterone regulates RANKL in an ex vivo microstructure model of the human breast, but dispute the suppression of estradiol on progesterone-stimulated RANKL expression. RANKL responds to progesterone in a three-dimensional organoid culture model under conditions mimicking luteal-phase hormone concentration, suggesting that the microstructure may not be crucial to demonstrate progesterone responsiveness.

Novel Association Between CD74 Polymorphisms and Hematologic Toxicity in Patients With NSCLC After Platinum-Based Chemotherapy

BackgroundPlatinum-based chemotherapy regimens can cause DNA damage. Macrophage migration inhibitory factor (MIF) plays an important role in the regulation of the cell cycle by either controlling the activity of the SKP1-Cullin/Cdc53-F-box protein ubiquitin ligase (SCF) complex or activating its receptor, CD74. Patients and MethodsWe used a pathway-based approach to investigate the association between genetic polymorphisms in MIF-pathway genes and the outcomes of platinum-based chemotherapy in advanced non–small-cell lung cancer (NSCLC). We used iSelect 24×1 HD BeadChip (Illumina, Inc, San Diego, CA) to genotype 32 tag and potentially functional single nucleotide polymorphisms (SNPs) of 8 selected genes and evaluated their associations with different outcomes for 1004 patients with advanced NSCLC treated with platinum-based chemotherapy. In particular, gastrointestinal toxicity and hematologic toxicity were analyzed for associations with specific genotypes, alleles, and haplotypes. ResultsTwo polymorphisms of CD74, rs2748249 (C/A) and rs1560661 (A/G), were significantly associated with hematologic toxicity. Carrying an A allele in rs2748249 was associated with higher hematologic toxicity (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.24-2.39; P = .001) and carrying a G allele in rs1560661 was associated with lower hematologic toxicity (OR, 0.42; 95% CI, 0.25-0.70; P = .00099) compared with the wild type. Haplotype analysis revealed that the patients with the CG haplotype (consisting of rs2748249 and rs1560661) had reduced hematologic toxicity compared with patients with other haplotypes (OR, 0.70; 95% CI, 0.56-0.87; P = .0013). The binding domain shared by 3 transcription factors (activator protein-2α [AP-2α], progesterone response A/B, and TFII-I) comprised the 2 SNPs that may be involved in the regulation of CD74-related B-cell survival. ConclusionOur study is the first to suggest, to our knowledge, that polymorphisms in CD74 might be a marker of lower hematologic toxicity for patients with advanced NSCLC receiving platinum-based chemotherapy.

Cyclic AMP enhances progesterone action in human myometrial cells

Cyclic AMP (cAMP) has been shown to promote progesterone and glucocorticoid action in a variety of cellular settings. In this study, we have used human myometrial cells to investigate whether cAMP potentiates the ability of progesterone to repress IL-1β-driven COX-2 expression. We found that forskolin enhanced progesterone-repression of IL-1β-driven COX-2 expression in association with delayed IL-1β-induced nuclear phospho-p65 entry and reduced NF-κB binding to the COX-2 promoter. Further, forskolin enhanced the progesterone-induced expression of FKBP5 and 11βHSD1, progesterone-driven activity of a progesterone response element (PRE) and progesterone receptor (PR)-B binding to a transfected PRE. In addition, forskolin treatment increased PR-B levels and reduced the PR-A:PR-B ratio while acutely decreasing the association between PR and nuclear receptor co-repressor (NCoR) and reducing NCoR levels after 6h. These findings are of importance in situations where enhancing progesterone activity is desirable, for example in the management of endometrial cancer, the promotion of endometrial receptivity or the maintenance of myometrial quiescence during pregnancy.

Oxidative stress and phthalate-induced down-regulation of steroidogenesis in MA-10 Leydig cells

Previous studies have shown that phthalate exposure can suppress steroidogenesis. However, the affected components of the steroidogenic pathway, and the mechanisms involved, remain uncertain. We show that incubating MA-10 Leydig cells with mono-(2-ethylhexyl) phthalate (MEHP) resulted in reductions in luteinizing hormone (LH)-stimulated cAMP and progesterone productions. cAMP did not decrease in response to MEHP when the cells were incubated with cholera toxin or forskolin. Incubation of MEHP-treated cells with dibutyryl-cAMP, 22-hydroxycholesterol or pregnenolone inhibited the reductions in progesterone. Increased levels of reactive oxygen species (ROS) occurred in response to MEHP. In cells in which intracellular glutathione was depleted by buthionine sulfoximine pretreatment, the increases in ROS and decreases in progesterone in response to MEHP treatment were exacerbated. These results indicate that MEHP inhibits MA-10 Leydig cell steroidogenesis by targeting LH-stimulated cAMP production and cholesterol transport, and that a likely mechanism by which MEHP acts is through increased oxidative stress.

Progesterone and estrogen responsiveness to father‐toddler interaction

We assessed the responsiveness of salivary progesterone (P4) and estradiol (E2) to father-child interaction, including testing for differences in short-term hormonal change based on paternal characteristics. We also predicted that P4 exposure during the study period would relate positively to post-interaction paternal mood. We conducted an in-home intervention study in which fathers (n = 44) played with their toddlers. Subjects provided saliva samples before interacting with their children, with additional collections 40 and 70 min later. E2 did not significantly change over the study period (P > 0.4). P4 declined significantly from baseline to 40 min (P < 0.05) and 70 min (P < 0.001). Men reporting that the interaction made them feel very happy/relaxed had greater P4 exposure from baseline through 70 min (area under the curve) compared with men reporting less positive post-interaction mood (P < 0.05). This relationship persisted after controlling for cortisol. Men's % decrease in P4 (baseline to 40 min) was significantly greater if they had an infant (P < 0.05), while fathers' % decline in E2 (baseline to 70 min) was larger if they had more children (P < 0.05). These results require replication but could indicate that grouping fathers with different levels of experience obscures meaningful variation in hormonal responses to child interaction. Our findings appear consistent with the effects of P4 as a mood enhancer and suggest future research should explore the possible role of P4 as hormonal mechanism that could reinforce or facilitate paternal investment.

Regulated Expression of Rhox8 in the Mouse Ovary: Evidence for the Role of Progesterone and RHOX5 in Granulosa Cells1

The gonadotropin surge is the essential trigger to stimulate ovulation and luteinization of ovarian follicles. While the hormone signals from the brain that initiate ovulation are known, the specific targets which regulate this process are not well known. In this study, we assessed the suitability of the Rhox homeobox gene cluster to serve as the master regulators of folliculogenesis. In superovulated (equine chorionic gonadotropin [eCG]/human chorionic gonadotropin [hCG]) mice, the Rhox genes exhibited four distinct windows of peak expression, suggesting that these genes may regulate specific events during the ovulatory cycle. Like many members of the cluster, Rhox8 mRNA and protein were induced by follicle stimulating hormone [FSH]/eCG in granulosa cells. However, Rhox8 displayed unique peak expression at 8 h post-hCG administration, implying it might be the lone member of the cluster regulated by progesterone. Subsequent promoter analysis in granulosa cells revealed relevant homeobox binding and progesterone response elements within Rhox8's 5'-flanking region. In superovulated mice, progesterone receptor (PGR) is recruited to the Rhox8 promoter, as assessed by chromatin immunoprecipitation. In Rhox5-null mice, Rhox8 mRNA was reduced at 2 h and 4 h post-hCG administration but recovered once the follicles passed the antral stage of development. Conversely, in progesterone receptor knockout mice, Rhox8 exhibited normal stimulation by eCG but failed to reach its peak mRNA level at 8 h post-hCG found in wild-type mice. This suggests a model in which Rhox8 transcription is dependent upon RHOX5 during early folliculogenesis and upon progesterone during the periovulatory window when RHOX5 normally wanes. In support of this model, transfection of RHOX5 and PGR expression plasmids stimulated, whereas dominant negative and mutant constructs inhibited, Rhox8 promoter activity.

Expression of CCT6A mRNA in chicken granulosa cells is regulated by progesterone

CCT6A, the zeta subunit of the chaperonin containing TCP1 complex, is the only cytosolic chaperonin in eukaryotes and is estimated to assist in the folding of multiple proteins including actin, tubulin, cyclin E, myosin, transducin and the Von Hippel Lindau tumor suppressor. In this study, we examined the expression of CCT6A and progesterone receptor (PGR) mRNA in various tissues of chickens and the regulation of CCT6A and PGR mRNA in ovarian granulosa cells. Northern blot analysis revealed that CCT6A had one transcript and was highly expressed in the ovary tissues from chickens at both the sexually immature and mature stages. CCT6A mRNA expression was increased maximally from pre-hierarchy follicles to F5 follicles and subsequently declined in pre-ovulatory and post-ovulatory follicles. The expression of PGR mRNA exhibited the similar pattern to CCT6A. In granulosa cells isolated from pre-ovulatory follicles, follicle-stimulating hormone (FSH) inhibited the expression of CCT6A mRNA, whereas progesterone activated CCT6A and suppressed PGR expression in a time-dependent manner. We further investigated the regulation of CCT6A transcription by progesterone by constructing various progressive deletions and mutants and identified the core promoter element of CCT6A and the binding region of progesterone, which is located from −2056 to −2051. Taken together, our results indicate that CCT6A likely plays an important role in follicle growth, and in granulosa cells, progesterone activates CCT6A transcription via a progesterone response element (PRE) located in the distal promoter of CCT6A.

Progesterone utilizes the PI3K-AKT pathway in human spermatozoa to regulate motility and hyperactivation but not acrosome reaction

Progesterone is a physiologic regulator of sperm hyperactivation and acrosome reaction and it does so by activating a range of kinases present in the spermatozoa. In the present study, the involvement of the AKT- phosphatidylinositol 3-kinase (PI3K) signaling pathway in mediating progesterone response in human spermatozoa was investigated. In capacitated spermatozoa, progesterone transiently and concentration dependently lead to phosphorylation of AKT at both Thr 308 and Ser 473 in the tail region. This phosphorylation was inhibited by the PI3K inhibitor wortmannin, suggesting that progesterone leads to activation of PI3K-AKT pathway. The activation of AKT in response to progesterone is calcium dependent and the CatSper channel inhibitor mibefradil significantly reduced progesterone mediated AKT phosphorylation. Preincubation of spermatozoa with wortmannin inhibited the progesterone mediated increase in tyrosine phosphorylation and also attenuated the increase in number of motile, progressively motile and hyperactive spermatozoa but not the number of acrosome reacted spermatozoa. These observations imply that progesterone via CatSper activates the PI3K-AKT pathway required for motility and hyperactivation but not for acrosome reaction.

Control of endothelin-a receptor expression by progesterone is enhanced by synergy with Gata2.

The endothelin-A receptor (Ednra) is involved in several physiological, pathological, and developmental pathways. Known for its function in vasoconstriction after being activated by endothelin-1, Ednra also controls cephalic neural crest cell development and appears to play a role in several pathologies, including cancer and periodontitis. However, the mechanisms regulating Ednra expression have not been identified despite its important functions. In this study, we investigated the role progesterone plays in Ednra gene expression in vivo and in vitro. In mice, pregnancy promotes Ednra expression in the heart, kidney, lung, uterus, and placenta, and the up-regulation is mediated by progesterone. We determined that the conserved region between -5.7 and -4.2 kb upstream of the mouse Ednra gene is necessary for the progesterone response. We also found that progesterone mediates Ednra activation through progesterone receptor B activation by its recruitment to PRE6, one of the 6 progesterone response elements found in that locus. However, gene activation by means of a GATA2 site was also necessary for the progesterone response. The Gata2 transcription factor enhances the progesterone response mediated by the progesterone receptor B. Together these results indicate that progesterone regulates Ednra expression by synergizing with Gata2 activity, a previously unknown mechanism. This mechanism may have an impact on pathologies involving the endothelin signaling.

Role of sex steroids in progesterone and corticosterone response to acute restraint stress in rats: sex differences

Adrenal progesterone secretion increases along with corticosterone in response to stress in male and female rats to modulate some stress responses. Here we investigated the role of sex steroids in sex differences in the progesterone response to 60 min of restraint stress in adult male and female rats. Comparisons between males and females in the progesterone response were evaluated in parallel with corticosterone responses. From day 5 to 7 after gonadectomy, female and male rats were treated with estradiol or testosterone, respectively (OVX-E and ORCH-T groups), or oil (OVX and ORCH groups). Female rats in proestrus, intact and 7 d adrenalectomized (ADX) male rats were also studied. At 10:00 h, blood samples were withdrawn via an implanted jugular cannula before (−5 min), during (15, 30, 45, 60 min) and after (90 and 120 min) restraint stress to measure plasma progesterone and corticosterone concentrations by radioimmunoassay. Intact male and proestrus female rats exhibited similar progesterone responses to stress. Gonadectomy did not alter the amount of progesterone secreted during stress in female rats but decreased secretion in male rats. Unlike corticosterone, the progesterone response to stress in females was not influenced by estradiol. In males, testosterone replacement attenuated the progesterone and corticosterone responses to stress. Basal secretion of progesterone among intact, ORCH and ADX males was similar, but ADX-stressed rats secreted little progesterone. Hence, the gonads differently modulate adrenal progesterone and corticosterone responses to stress in female and male rats. The ovaries enhance corticosterone but not progesterone secretion, while the testes stimulate progesterone but not corticosterone secretion.

Regulation of Gene Expression by Progesterone in Cancer Cells: Effects on Cyclin D1, EGFR and VEGF

Progesterone (P4) participates in the regulation of several physiological and pathological processes in mammals through the interaction with its intracellular receptors (PR), which are ligand-dependent transcription factors.Many human cancers depend on P4 for growth and metastasis, especially cancers of reproductive tissues. In women,administration of combined estrogen and progestin hormone replacement therapy for postmenopausal symptoms increases the risk of breast cancer relative to women taking estrogens alone. P4 exerts its actions through various mechanisms classified as classical and non-classical. PR has dual functions as a nuclear transcription factor and as a modulator of cell signaling pathways. Many PR target genes do not contain canonical progesterone response elements (PRE) in their promoter regions and may thus be regulated by PR tethering to other transcription factors and/or rapid signaling,independent of direct PR DNA binding. We review the mechanisms involved in P4 effects on genes implicated in control of cell cycle, proliferation, angiogenesis and metastasis, such as cyclin D1 and epidermal growth factor receptor (EGFR)whose promoters lack PRE sequences, and vascular endothelial growth factor (VEGF) which gene contains PRE in its promoter region. The understanding of the molecular mechanisms involved in the regulation of cyclin D1, EGFR and VEGF expression by P4 will be helpful for the development of new cancer therapies.