Progesterone Modulation Research Articles

Enhancement of progesterone biosynthesis via kisspeptin stimulation: Upregulation of steroidogenic transcripts and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) expression in the buffalo luteal cells

The presence of Kisspeptin (Kp) and its receptors in the corpus luteum (CL) of buffalo has recently been demonstrated. In this study, we investigated the role of Kp in the modulation of progesterone (P4) synthesis in vitro. The primary culture of bubaline luteal cells (LCs) was treated with 10, 50, and 100 nM of Kp and Kp antagonist (KpA) alongside a vehicle control. The combined effect of Kp and KpA was assessed at 100 nM concentration. Intracellular response to Kp treatment in the LCs was assessed by examining transcript profiles (LHR, STAR, CYP11A1, HSD3B1, and ERK1/2) using quantitative polymerase chain reaction (qPCR). In addition, the immunolocalization of ERK1/2 and phosphorylated ERK1/2 (p-ERK1/2) in the LCs was studied using immunocytochemistry. Accumulation of P4 from the culture supernatant was determined using enzyme-linked immunosorbent assay (ELISA). The results indicated that LCs had a greater p-ERK1/2 expression in the Kp treatment groups. A significant increase in the P4 concentration was recorded at 50 nM and 100 nM Kp, while KpA did not affect the basal concentration of P4. However, the addition of KpA to the Kp-treated group at 100 nM concentration suppressed the Kp-induced P4 accumulation into a concentration similar to the control. There was significant upregulation of ERK1/2 and CYP11A1 expressions in the Kp-treated LCs at 100 nM (18.1 and 37fold, respectively, p < 0.01). However, the addition of KpA to Kp-treated LCs modulated ERK1/2, LHR, STAR, CYP11A1, and HSD3B1 at 100 nM concentration. It can be concluded that Kp at 100 nM stimulated P4 production, while the addition of KpA suppressed Kp-induced P4 production in the buffalo LCs culture. Furthermore, an increment in p-ERK1/2 expression in the LCs indicated activation of the Kp signaling pathway was associated with luteal steroidogenesis.

Progesterone-mediated immunoregulation of cytokine signaling by miRNA-133a and 101-3p in Chlamydia trachomatis-associated recurrent spontaneous abortion

miRNAs regulate the expression of various genes involved in cellular and metabolic pathways in pregnancy related complications including recurrent spontaneous abortion (RSA). Modulation of progesterone and associated pro-inflammatory cytokines by miRNAs in Chlamydia trachomatis-associated RSA is still under investigation. Present study aimed to evaluate the expression/correlation of serum-circulating miRNAs-133a, 101-3p, 320b, 146b-5p, 24, 559, progesterone and few cytokines in C. trachomatis-positive spontaneous aborters. Non-heparinized blood and urine was collected from 120 patients with history of RSA (Group I) and 120 patients with ≥ 2 successful deliveries (Group II) attending Department of Obstetrics and Gynecology, Safdarjung hospital, New Delhi, India. C. trachomatis detection was performed by PCR and chlamydial load by real time PCR. Progesterone concentration was estimated by ELISA. miRNAs and cytokine expression was studied by quantitative real-time PCR and correlated with progesterone expression. Twenty six patients were found to be positive for C. trachomatis. miRNAs- 133a, 101-3p showed maximum upregulation in infected versus control patients. miRNA expression showed positive correlation with chlamydial load. Progesterone concentration showed significant decrease while cytokines (IL-6, IFN-γ, TNF-α) were significantly upregulated in C. trachomatis-positive patients. Positive correlation was observed between expression of miRNAs-133a and 101-3p and cytokines while negative correlation was observed with progesterone in infected RSA patients. Correlation between progesterone and cytokines was found to be significantly negative in infected RSA patients. Although further validation is required, the study concludes that miR-133a and 101-3p are of clinical importance and have a role in immunoregulation of progesterone and cytokines in infection associated RSA.

Follicular-Stimulating Hormone, Luteinizing Hormone, and Prolactin Serum Level in Patients with Oral Lichen Planus in Comparison to Healthy Population.

Materials and Methods In this cross-sectional case control study, the serum level of LH, FSH, and prolactin of 40 women with lichen planus who have been referred to Shiraz Dental Faculty, Oral and Maxillofacial Disease Department during 2018-2019 has been evaluated in comparison to 40 healthy controls. Data were analyzed by SPSS version 18. Two-way ANOVA and Mann–Whitney test were used for data analysis. Results The mean serum level of FSH and LH was significantly higher in OLP patients while this difference was not reported for prolactin. Only FSH mean serum level was significantly higher in nonmenopausal OLP patients. The distribution of prolactin and FSH hormones' serum level was in normal range. Conclusions The high serum level of FSH and LH can affect OLP pathogenesis by estrogen and progesterone modulation.

The Role of Atorvastatin in Suppressing Fibroid Related Symptom and Fibroid Size in Perimenopausal Women

Background: Uterine fibroids are the most common benign gynecologic tumors, with a lifetime incidence of approximately 70%. They are associated with multiple symptoms, including heavy uterine bleeding and pelvic pain. Currently used treatments include contraceptive steroids, Gonadotropin-releasing hormone agonist (GnRHa), progesterone modulators, uterine artery embolization (UAE), magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS), and radiofrequency ablation (RFA). Objective: To evaluate the effect of atorvastatin on decreasing fibroid related symptoms and fibroid size, endometrial thickness and cholesterol level in perimenopausal women. Patients and methods: Prospective randomized controlled trial that was conducted over a period of 12 months during 2019 and 2021 on 105 patients with symptomatic uterine fibroid in perimenopausal age, admitted to emergency unit and gynecology outpatient clinic at Mansoura University Hospital and after obtaining acceptance from institutional research board faculty of medicine then patients were prospectively recruited and randomized by computer program. Results: All groups at presentation demonstrated insignificant differences concerning demographic characteristics, gravidity and symptoms of uterine fibroid. Uterine fibroid demonstrated significant reduction in size as well as significant changes following the atorvastatin treatment after 6 months in a dose dependent manner, while endometrial thickness demonstrated insignificant differences as measured by transvaginal ultrasound (TVS). Cholesterol level demonstrated highly statistically significant decrease following atorvastatin treatment in a dose dependent manner. Conclusion: The current study demonstrated that atorvastatin has promising effects in cases with uterine fibroids as it was associated with a reduction of fibroid size with reduction of fibroid related symptom (menorrhagia, dysmenorrhea).

Progesterone Modulator May Offer PMDD Relief

Progesterone Modulator May Offer PMDD Relief

Cytostatic Activity and Ligand-Receptor Interaction Energy of the Novel Russian-Produced Gestagen Gestobutanoil and its Metabolites

With the aim of clarifying the cytostatic effect of the Russian-made gestagen gestobutanoil (17α-acetoxy-3β-hydroxy-6-methylpregna-4,6-dien-20-one butyl ester), which is a member of an original group of transformed gestagens containing an ester substituent in place of the 3-keto group, the cytostatic activities of its metabolites (17α-acetoxy-3β-hydroxy-6-methylpregna-4,6-dien-20-one (AMP-17) and megestrol acetate) and a reference agent (progesterone) were studied in uterine cervical tumor line HeLa. Complex formation by these steroids with progesterone receptor binding sites was evaluated by computer modeling (docking) by determination of the interaction energy of the partner molecules. The cytostatic activity of gestobutanoil was greater than that of reference compound and may be associated with the formation of its active metabolites. Conformations of the gestobutanoil-receptor complex with binding energies significantly different from those of complexes with progesterone, AMP-17, and megestrol acetate were demonstrated; this may be the cause of changes in the affinity of gestobutanoil for progesterone receptors and modulation of its biological activity.

Liver Injury Associated with the Selective Progesterone Modulator Ulipristal.

Liver Injury Associated with the Selective Progesterone Modulator Ulipristal.

Depletion of cholesterol could be associated with modulation of progesterone but not other sex hormone levels during Plasmodium falciparum infection in humans: a cross-sectional study from Zaria, Nigeria.

In order for Plasmodium falciparum to grow and survive in its host, membrane biogenesis, fueled by host cholesterol, is essential for these processes. Consistent with this essential role, more insights into the cholesterol pathway would enhance the current understanding of the pathophysiology of malaria infection. To explore its broader potential, we conducted a cross-sectional study and assayed for the serum levels of cholesterol, vitamin D, progesterone, testosterone, estradiol and bile acid in both P. falciparum-infected patients and apparently healthy sex-matched participants. Our results revealed that the levels of cholesterol, vitamin D, progesterone, testosterone and estradiol in P. falciparum-infected patients were significantly (p <0.05) lower compared to those in control groups whereas the level of bile acid in P. falciparum-infected patients was significantly (p <0.05) higher compared to that in control groups. Additionally, cholesterol and the metabolic products with the exception of bile acid had a significant (p <0.05) association with the parasite density in P. falciparum-infected patients with moderate and high P. falciparum infections. Furthermore, all the metabolic products of cholesterol had an insignificant (p >0.05) association with the cholesterol in P. falciparum-infected patients with the exception of progesterone which showed a significant (p <0.05) association with cholesterol in the malaria-infected female patients. Data from the present study demonstrated that progesterone depletion in P. falciparum-infected female patients could be a consequence of P. falciparum-induced decrease in cholesterol.

The Selective Progesterone Receptor Modulator Ulipristal Acetate Inhibits the Activity of the Glucocorticoid Receptor.

The selective progesterone modulator ulipristal acetate (ulipristal) offers a much-needed therapeutic option for the clinical management of uterine fibroids. Although ulipristal initially passed safety evaluations in Europe, postmarketing analysis identified cases of hepatic injury and failure, leading to restrictions on the long-term use of ulipristal. One of the factors potentially contributing to significant side effects with the selective progesterone modulators is cross-reactivity with other steroid receptors. To determine whether ulipristal can alter the activity of the endogenous glucocorticoid receptor (GR) in relevant cell types. Immortalized human uterine fibroid cells (UtLM) and hepatocytes (HepG2) were treated with the synthetic glucocorticoid dexamethasone and/or ulipristal. Primary uterine fibroid tissue was isolated from patients undergoing elective gynecological surgery and treated ex vivo with dexamethasone and/or ulipristal. In vivo ulipristal exposure was performed in C57Bl/6 mice to measure the effect on basal gene expression in target tissues throughout the body. Dexamethasone induced the expression of established glucocorticoid-target genes period 1 (PER1), FK506 binding protein 51 (FKBP5), and glucocorticoid-induced leucine zipper (GILZ) in UtLM and HepG2 cells, whereas cotreatment with ulipristal blocked the transcriptional response to glucocorticoids in a dose-dependent manner. Ulipristal inhibited glucocorticoid-mediated phosphorylation, nuclear translocation, and DNA interactions of GR. Glucocorticoid stimulation of PER1, FKBP5, and GILZ was abolished by cotreatment with ulipristal in primary uterine fibroid tissue. The expression of glucocorticoid-responsive genes was decreased in the lung, liver, and uterus of mice exposed to 2 mg/kg ulipristal. Interestingly, transcript levels of Fkbp5 and Gilz were increased in the hippocampus and pituitary. These studies demonstrate that ulipristal inhibits endogenous glucocorticoid signaling in human fibroid and liver cells, which is an important consideration for its use as a long-term therapeutic agent.

Effect of insulin or insulin-like growth factor-I administration at mid-luteal phase of the estrous cycle during superovulation on hormonal profile of Sahiwal cows.

Aim:The present study was designed to study the effect of insulin and insulin-like growth factor-1 (IGF-I) administration during luteal phase of the estrous cycle on the hormonal profile of Sahiwal embryo donor cows during superovulation.Materials and Methods:Cows (n=18) were selected and divided into three groups; control (n=6, untreated), T-I (n=6, insulin-treated), and T-II (n=6, IGF-I treated). Insulin and IGF-I were given S/C on 5th, 6th, 7th, and 8th days of estrous cycle. Superovulatory treatment was started on day 9th of the estrous cycle. With the sixth dose of follicle-stimulating hormone, prostaglandin was injected to induce superovulatory heat. The superovulated cows were bred, and superovulatory response of each animal was recorded. The embryos were collected non-surgically on the 7th day of superovulatory estrus. About 15 ml blood without anticoagulant was collected on days 5, 7, 9, 11, 13, 15, 17, 19, and 21 or day of embryo recovery where day 0 of estrous cycle was taken as day of estrus. Serum was separated, centrifuged, and transferred into sterilized serum vials. All samples were stored at −20°C till analysis. Progesterone, insulin, and IGF-I were estimated in blood serum by radioimmunoassay using radioimmunoassay kits.Results and Discussion:The mean concentration of progesterone on days 7 and 11, insulin on days 7 and 9, and IGF-I on days 5, 7, 9, 11, and 15 was significantly higher in insulin-treated T-I groups as compared to untreated control.Conclusion:It may be concluded that exogenous insulin administration during mid-luteal phase may be helpful in follicular and embryonic development through modulation of progesterone, insulin, and IGF-I in indigenous (Bos indicus) Sahiwal embryo donor cows.

Progesterone Modulation of Pregnancy-Related Immune Responses.

Progesterone (P4) is an important steroid hormone for the establishment and maintenance of pregnancy and its functional withdrawal in reproductive tissue is linked with the onset of parturition. However, the effects of P4 on adaptive immune responses are poorly understood. In this study, we took a novel approach by comparing the effects of P4 supplementation longitudinally, with treatment using a P4 antagonist mifepristone (RU486) in mid-trimester pregnancies. Thus, we were able to demonstrate the immune-modulatory functions of P4. We show that, in pregnancy, the immune system is increasingly activated (CD38, CCR6) with greater antigen-specific cytotoxic T cell responses (granzyme B). Simultaneously, pregnancy promotes a tolerant immune environment (IL-10 and regulatory-T cells) that gradually reverses prior to the onset of labor. P4 suppresses and RU486 enhances antigen-specific CD4 and CD8 T cell inflammatory cytokine (IFN-γ) and cytotoxic molecule release (granzyme B). P4 and RU486 effectively modulate immune cell-mediated interactions, by regulating differentiated memory T cell subset sensitivity to antigen stimulation. Our results indicate that P4 and RU486, as immune modulators, share a reciprocal relationship. These data unveil key contributions of P4 to the modulation of the maternal immune system and suggests targets for future modulation of maternal immune function during pregnancy.

Effect of Doublesynch and Estradoublesynch protocols on estrus induction, conception rate, plasma progesterone, protein, and cholesterol profile in anestrus Gir heifers.

AimThis study aimed to evaluate the efficacy of Doublesynch and Estradoublesynch protocols on estrus induction, conception rates, plasma progesterone, protein, and cholesterol profile in anestrus Gir heifers.Materials and MethodsIn this study, 50 pubertal anestrus Gir heifers were selected from the field and farm conditions. The heifers were dewormed (injection ivermectin, 100 mg, s/c) and supplemented with minerals and vitamins (injection organic phosphorus 800 mg and injection Vitamin AD3E and Biotin 10 ml i/m) and multi-mineral bolus at 1 bolus daily for 7 days. The heifers were randomly divided into three groups: Doublesynch (n=20), Estradoublesynch (n=20), and control (n=10). The animals were monitored for estrus response, estrus interval, behavioral signs, and conception rates after induced/first, second, and third cycle post-treatment. Blood samples were obtained on day 0, day 9, day 12, and on day 12 post-artificial insemination (AI) for determination of plasma progesterone, protein, and cholesterol profile.ResultsThe estrus response rate between Doublesynch and Estradoublesynch protocols was similar between treated heifers (85% and 95%). The interval from the second prostaglandin F2α (PGF2α) injection to estrus induction did not differ between the groups (63.87±4.19 vs. 58.27±3.83 h). The conception rates following induced estrus (20% vs. 30%), at the second cycle (23.07% vs. 16.66%), at the third cycle (22.22% vs. 30.00%), and the overall conception rate (45% and 55%) within 27.89±5.75 and 26.45±5.48 days were the same across the treatment groups. The mean plasma progesterone concentrations were significantly (p<0.01) higher on day 9 (second PGF2α injection) and day 12 post-AI compared to day 0 (first PGF2α injection) and the day of fixed-timed artificial insemination. The concentrations were also significantly (p<0.05) higher in conceived than non-conceived heifers on day 9 of treatment and day 12 post-AI in both the protocols. The mean plasma cholesterol concentrations were significantly higher during peak follicular and luteal phases compared to the initial anestrus phase in both the protocols. The values were also higher in non-conceived than conceived animals in both the protocols. The plasma protein profile was not influenced by the sampling days or conceived and non-conceived status.ConclusionThe results showed that both Doublesynch and Estradoublesynch protocols resulted in similar estrus induction and conception rates with modulation of plasma progesterone and cholesterol profile in anestrus Gir heifers.

Rapid and sensitive determination of selective progesterone modulator ulipristal acetate in human plasma

Ulipristal acetate is a new synthetic selective progesterone receptor modulator developed mainly as emergency contraceptive (EC) and also used for the treatment of uterine fibroids. A cost effective, sensitive, simple and rapid high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the analysis of ulipristal acetate in human plasma. Following liquid-liquid extraction, the analyte (Ulipristal acetate) and internal standard (Levonorgestrel) were chromatographed using mobile phase in an isocratic elution mode on a reverse phase C18 column. The LC-MS/MS operated in multiple reaction monitoring mode for respective [M+H] + ions, m/z 476.2/134.1 for analyte and 313.3/245.1 for internal standard. The assay exhibited linear dynamic range of 1-300 ng/mL. The lower limit of quantification was 1 ng/mL with relative standard deviation of 7.0%. The intra-batch and inter-batch results were precise with coefficient variation of 2.7 to 7.0 (%) and accuracy of 94.2-99.8 (%). The validated method was simple, fast and repeatable for bioequivalence, pharmacokinetic and therapeutic monitoring studies.

Ulipristal Acetate: A Review in Symptomatic Uterine Fibroids.

Oral ulipristal acetate (Esmya®; Fibristal®), a synthetic selective progesterone receptor modulator, is the first selective progesterone modulator to be approved for the treatment of uterine fibroids. It was initially approved for the preoperative treatment of moderate to severe uterine fibroid symptoms in women of reproductive age. Recently, the indication was extended in the EU to include the intermittent treatment of moderate to severe uterine fibroid symptoms. This narrative review summarizes pharmacological, efficacy and tolerability data relevant to the preoperative and intermittent use of ulipristal acetate in patients with symptomatic uterine fibroids. Ulipristal acetate is an effective and generally well tolerated treatment for patients with symptomatic uterine fibroids, both as preoperative, single-course treatment and as intermittent, longer-term treatment. It is noninferior in efficacy to intramuscular leuprolide acetate, as a preoperative treatment, and is associated with a lower rate of hot flashes, a common adverse event with gonadotropin-releasing hormone analogues. Thus, ulipristal acetate is an effective option for both preoperative and intermittent treatment of moderate to severe, symptomatic uterine fibroids in women of reproductive age.

Sperm gamma-aminobutyric acid type A receptor delta subunit (GABRD) and its interaction with purinergic P2X2 receptors in progesterone-induced acrosome reaction and male fertility.

The mechanism underlying the non-genomic action of progesterone in sperm functions and related Ca2+ mobilisation remains elusive. Herein we report the expression of gamma-aminobutyric acid type A receptor delta subunit (GABRD) in human and rodent sperm and its involvement in mediating the progesterone-induced acrosome reaction. GABRD was localised in the sperm head/neck region. A δ(392-422)-specific inhibitory peptide against GABRD blocked the progesterone-induced acrosome reaction and the associated increase in intracellular Ca2+. Similarly, an inhibitory effect against both progesterone-induced Ca2+ influx and the acrosome reaction was observed with a P2X2 receptor antagonist. The lack of synergism between the GABRD and P2X2 inhibitors suggests that these two receptors are playing a role in the same pathway. Furthermore, a co-immunoprecipitation experiment demonstrated that GABRD could undergo protein-protein interactions with the Ca2+-conducting P2X2 receptor. This interaction between the receptors could be reduced following progesterone (10μM) inducement. Significantly reduced GABRD expression was observed in spermatozoa from infertile patients with reduced acrosome reaction capacity, suggesting that normal expression of GABRD is critical for the sperm acrosome reaction and thus male fertility. The results of the present study indicate that GABRD represents a novel progesterone receptor or modulator in spermatozoa that is responsible for the progesterone-induced Ca2+ influx required for the acrosome reaction through its interaction with the P2X2 receptor.

In vitro progesterone modulation on bacterial endotoxin-induced production of IL-1β, TNFα, IL-6, IL-8, IL-10, MIP-1α, and MMP-9 in pre-labor human term placenta.

BackgroundDuring human pregnancy, infection/inflammation represents an important factor that increases the risk of developing preterm labor. The purpose of this study was to determine if pre-treatment with progesterone has an immunomodulatory effect on human placenta production of endotoxin-induced inflammation and degradation of extracellular matrix markers.MethodsPlacentas were obtained under sterile conditions from pregnancies delivered at term before the onset of labor by cesarean section. Explants from central cotyledons of 10 human placentas were pre-treated with different concentrations of progesterone (0.01, 01, 1.0 μM) and then stimulated with 1000 ng/mL of LPS of Escherichia coli. Cytokines TNFα, IL-1β, IL-6, IL-8, MIP-1α, IL-10 concentrations in the culture medium were then measured by specific ELISA. Secretion profile of MMP-9 was evaluated by ELISA and zymogram. Statistical differences were determined by one-way ANOVA followed by the appropriate ad hoc test; P < 0.05 was considered statistically significant.ResultsIn comparison to the explants incubated with vehicle, the LPS treatment led to a significant increase in the level of all cytokines. In comparison to the explants treated only with LPS, pre-treatment with 0.01–1.0 μM progesterone significantly blunted (73, 56, 56, 75, 25, 48 %) the secretion of TNF-α, IL-1β, IL-6, IL-8, MIP-1α, IL-10, respectively. The MMP-9 induced by LPS treatment was inhibited only with the highest concentration of progesterone. Mifepristone (RU486) blocked the immunosuppressive effect of progesterone.ConclusionsThe present results support the concept that progesterone could be part of the compensatory mechanism that limits the inflammation-induced cytotoxic effects associated with an infection process during gestation.

Immunohistochemical characteristic of myoma tissue in patients with uterine leiomyoma after treatment with ulipristal acetate.

Background. Uterine leiomyoma is one of the most common benign tumors of the female genital organs. The main conservative treatment of leiomyoma is progesterone receptor blockers that suppress myoma growth and may lead to its regression. Objective. To study the immunohistochemical features of myoma tissue in patients with uterine leiomyoma after treatment with selective progesterone modulator - ulipristal acetate. Methods. Leiomyoma tissue obtained from 9 patients after ulipristal acetate treatment were investigated. Group for comparison - leiomyoma from patients without hormonal therapy. Immunohistochemical study of progesterone and estrogen receptors, proliferative activity marker Ki-67 and inhibitor of apoptosis Bcl-2 was performed. Results. In the group of patients without preoperative hormonal treatment progesterone receptors were expressed in 76,4±6,8% of the nuclei, estrogen receptors - in 32,8±2,6%. In the group of patients after treatment with ulipristal acetate there was a significant decrease of progesterone receptor expression – 36,8±1,28% (p &lt;0,05) and a nonsignificant decrease of estrogen expression – 30,7±3,4% (p&gt; 0,05) . Bcl-2 in the control group was found in 65,4±7,2% cells, in leiomyoma after treatment there was a significant decrease of bcl-2 – 42,6±3,2% (p &lt;0, 05). In leiomyomas without hormonal treatment Ki-67 was determined in 11,8% of the nuclei of smooth muscle cells, and in leiomyomas after ulipristal acetate – in 7,2% leiomyoma cells. Conclusions. In patients after three months of ulipristal acetate treatment there was a significant decrease of expression of progesterone receptor, bcl-2, and Ki-67. Taken together these data evidence reduced action of progesterone on leiomyoma cells, induction of apoptosis and decreased proliferation processes that may cause involution of fibroids.

P-glycoprotein mediates the collateral sensitivity of multidrug resistant cells to steroid hormones

The overexpression of P-glycoprotein (P-gp, ABCB1) in cancer cells often leads to multidrug resistance (MDR) through reduced drug accumulation. However, certain P-gp-positive cells display hypersensitivity, or collateral sensitivity, to certain compounds that are believed to induce Pgp-dependent oxidative stress. We have previously reported that MDR P-gp-positive CHO cells are collaterally sensitive to verapamil (VRP; Laberge et al. (2009) [1]). In this report we extend our previous findings and show that drug resistant CHO cells are also collaterally sensitive to physiologic levels of progesterone (PRO) and deoxycorticosterone (DOC). Both PRO and DOC collateral sensitivities in CHRC5 cells are dependent on P-gp-expression and ATPase, as knockdown of P-gp expression with siRNA or inhibition of P-gp-ATPase with PSC833 reverses PRO- and DOC-induced collateral sensitivity. Moreover, the mitochondrial complexes I and III inhibitors (antimycin-A and rotenone, respectively) synergize with PRO and DOC-induced collateral sensitivity. We also show that VRP inhibits PRO and DOC collateral sensitivity, consistent with earlier findings relating to the VRP’s modulation of PRO and DOC-stimulation of P-gp ATPase. The findings of this study demonstrate a P-gp-dependent collateral sensitivity of MDR cells in the presence of physiologically achievable concentrations of progesterone and deoxycorticosterone.

Frequency-dependent acceleration of cardiac repolarization by progesterone underlying its cardiac protection against drug-induced proarrhythmic effects in female rabbits

Concurrent supplement of estradiol and progesterone has been shown to reduce the cardiac sensitivity to class III antiarrhythmic agent-induced arrhythmias in ovariectomized rabbits. To understand the underlying cardiac electrophysiological mechanisms of the hormones, present study explored the modulation of progesterone and estradiol on repolarization and its frequency dependence in papillary muscles of female rabbit right ventricles by glass microelectrode technique. Results showed that progesterone shortened action potential duration for 90% repolarization (APD90) whereas estradiol prolonged APD90 and those actions on APD90 were concentration-dependent for both hormones at 1.0–30μM (P<0.05 or P<0.01). Further, the action of both hormones on APD90 was found to be dependent on stimulation frequencies (0.2–3.3Hz). The shortening of APD90 by progesterone (10μM) was enhanced with the increase in frequencies reaching a statistic significance at frequencies ≥1.0Hz, whereas the prolongation of APD90 by estradiol (3μM) was weakened with the increase in frequencies and the significant change was observed at frequencies ≤2.0Hz (P<0.05 or P<0.01). More interestingly, the relative change of APD90 and the incidence of early afterdepolarization induced after by dofetilide (0.1μM), a class III antiarrhythmic agent, were significantly less or lower in the papillary muscles pretreated with progesterone than in those pretreated with estradiol (P<0.01 or P<0.05). In conclusion, progesterone has a reverse modulating affect on cardiac repolarization to that of estradiol. By acceleration of ventricular repolarization, progesterone may reduce the susceptibility of females to class III antiarrhythmic agents-induced proarrhythmic affection.

Novel Therapies Targeting Endometriosis

Endometriosis is an often painful disorder in which the endometrial glands and stroma grow outside the uterus. The disease affects women's quality of life and is a common cause of infertility. In this review, we describe promising new developments in the field based on in vitro assays and rodent models, each of which has the potential to be beneficial in the treatment of this disease. We will specifically describe the role of anti-inflammatory drugs, selective estrogen, or progesterone modulators, statins, antiangiogenic agents, and the potential for targeting stem cells as likely methods to hone in and eliminate endometriosis. The most promising of these potential therapies are currently slated for further testing in both rodent and nonhuman primate trials.