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Journal of Xenobiotics Mar 2024Spironolactone (SPI) is a diuretic widely used to treat cardiovascular diseases (CVD) and is non-specific for mineralocorticoid receptors (MR) and with an affinity for...
BACKGROUND
Spironolactone (SPI) is a diuretic widely used to treat cardiovascular diseases (CVD) and is non-specific for mineralocorticoid receptors (MR) and with an affinity for progesterone (PR) and androgen (AR) receptors. Since 2009, it has been suggested that pharmaceuticals are emerging contaminants (called EDC), and recently, it was reported that most EDC are AR and MR antagonists and estrogen receptors (ER) agonists. Concerning SPI, endocrine-disrupting effects were observed in female western mosquitofish, but there are still no data regarding the SPI effects as a possible human EDC.
METHODS
In this work, aortic rings were used to analyze the contractility effects of SPI and the mode of action concerning the involvement of Ca channels and endothelial pathways. Moreover, cytotoxic effects were analyzed by MTT assays.
RESULTS
SPI induces vasodilation in the rat aorta by endothelium-dependent mechanisms involving NO and by endothelium-independent mechanisms blocking Ca channels. Moreover, a non-monotonic effect characteristic of EDC was observed for SPI-induced decrease in cell viability.
CONCLUSIONS
Our findings suggest that SPI may act as an EDC at a human level. However, ex vivo studies with human arteries should be carried out to better understand this drug's implications for human health and future generations.
PubMed: 38535495
DOI: 10.3390/jox14010020 -
JBRA Assisted Reproduction Jun 2024Late follicular phase progesterone elevation is a complication that affects approximately 38% of IVF cycles. There is a lack of consensus on the appropriate cut-off...
OBJECTIVE
Late follicular phase progesterone elevation is a complication that affects approximately 38% of IVF cycles. There is a lack of consensus on the appropriate cut-off levels for progesterone on hCG day. Although premature progesterone rise occurs in all kinds of ovarian responses, there is a knowledge gap regarding the ovarian response with the highest risk of this phenomenon. Our study aims to assess the relative risk of each kind of ovarian response for premature progesterone rise and evaluate the prevalence of premature progesterone rise in each ovarian response.
METHODS
A retrospective, cross-sectional, comparative and analytic study was performed at the Reproductive Endocrinology Department in Centro Médico Nacional 20 de Noviembre in Mexico City. All conventional-antagonist cycles were grouped according to their ovarian response and were evaluated from 2015 to 2020. Pearson's Squared-chi, Cramer's V, cross-table and the relative risk were calculated.
RESULTS
The prevalence of premature progesterone rise oscillated from 20.8 to 67.9% for low and high ovarian responders, respectively. After calculating the relative risk, high ovarian responders had a 1.38 higher risk for premature progesterone rise than other groups.
CONCLUSIONS
High ovarian responders have the highest risk for premature progesterone rise compared to normal and low ovarian responders. High ovarian responders have a 67.9% prevalence of premature progesterone rise.
Topics: Humans; Female; Progesterone; Retrospective Studies; Cross-Sectional Studies; Ovulation Induction; Adult; Fertilization in Vitro; Pregnancy; Follicular Phase; Mexico
PubMed: 38530762
DOI: 10.5935/1518-0557.20240004 -
F&S Reports Mar 2024Leiomyomas, or fibroids, are benign uterine tumors that are commonly associated with abnormal uterine bleeding-L particularly heavy menstrual bleeding (HMB). Treatment...
Leiomyomas, or fibroids, are benign uterine tumors that are commonly associated with abnormal uterine bleeding-L particularly heavy menstrual bleeding (HMB). Treatment options include expectant, medical, image-guided, and surgical. Medical management of HMB is the preferred first-line treatment and includes nonsteroidal anti-inflammatory drugs, contraceptive hormones, tranexamic acid, levonorgestrel intrauterine system, gonadotropin-releasing hormone (GnRH) antagonists and antagonists, selective progesterone receptor modulators, selective estrogen receptor modulators, and aromatase inhibitors. Although alternatives such as vitamins and supplements have been suggested, there is currently a lack of robust evidence of their efficacy. Many of these therapies treat the symptoms rather than the underlying pathology. Progestin-based therapies are the most commonly utilized, although research supporting their effectiveness in the treatment of HMB is modest. Although GnRH agonists and antagonists, which are federal drug administration-approved therapies, provide substantial improvement in abnormal uterine bleeding-L with HMB, the effects typically last for the duration of therapy. Patients may also face financial barriers to GnRH analog therapy. Future studies are required to delineate the nonhormonal treatment options and the long-term management of leiomyoma-associated HMB.
PubMed: 38524211
DOI: 10.1016/j.xfre.2023.10.003 -
Clinical & Translational Oncology :... Jul 2024Cyclin-dependent kinases 4/6 inhibitors (CDK 4/6i) combined with endocrine therapy have become the gold standard in hormone receptor-positive (HR +) HER2-negative...
INTRODUCTION
Cyclin-dependent kinases 4/6 inhibitors (CDK 4/6i) combined with endocrine therapy have become the gold standard in hormone receptor-positive (HR +) HER2-negative (HER2-) metastatic breast cancer (MBC). However, there is a significant lack of data regarding the efficacy and safety of these treatments in elderly patients. We present the results of a real-world data (RWD) cohort stratified by age at treatment initiation (≥ 70 years compared to patients < 70 years).
METHODS
Clinico-pathological data of HR + HER2- MBC patients who were candidates for CDK4/6i therapy between January 2017 and December 2020 at the Institut Català d'Oncologia (Spain) were retrospectively collected. The primary goal was to assess Progression-Free Survival (PFS), Overall Survival (OS), and safety outcomes within this patient population.
RESULTS
A total of 274 patients with MBC who received CDK4/6i treatment were included in the study. Among them, 84 patients (30.8%) were aged ≥ 70 years, with a mean age of 75, while 190 patients (69.2%) were under the age of 70, with a mean age of 55.7 years. The most frequently observed grade 3-4 toxicity was neutropenia, with similar rates in both the < 70 group (43.9%) and the ≥ 70 group (47.9%) (p = 0.728). The median Progression-Free Survival (mPFS) for the first-line CDK4/6i treatment was 22 months (95% CI, 15.4-39.8) in the < 70 group and 20.8 months (95% CI 11.2-NR) in the ≥ 70 group (p = 0.67). Similarly, the median PFS for the second-line CDK4/6i treatment was 10.4 months (95% CI, 7.4-15.1) and 7.1 months (95% CI 4.4-21.3) (p = 0.79), respectively. Median overall survival (mOS) was not reached either for the first- and second-line treatment.
CONCLUSIONS
Our RWD suggests that elderly patients, when compared to those under 70, experience similar survival outcomes and exhibit comparable tolerance for CDK4/6i therapy.
Topics: Humans; Female; Breast Neoplasms; Aged; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Receptor, ErbB-2; Middle Aged; Retrospective Studies; Protein Kinase Inhibitors; Aged, 80 and over; Receptors, Progesterone; Progression-Free Survival; Receptors, Estrogen; Adult; Age Factors; Piperazines
PubMed: 38519708
DOI: 10.1007/s12094-024-03399-3 -
Journal of Clinical Oncology : Official... Jun 2024Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor... (Randomized Controlled Trial)
Randomized Controlled Trial
PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer.
PURPOSE
Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting.
METHODS
The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P.
RESULTS
Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; = .62). The median PFS on F + P + A was 8.1 months (HR F, 0.75 [90% CI, 0.50 to 1.12]; = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline and alterations.
CONCLUSION
The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.
Topics: Humans; Female; Breast Neoplasms; Pyridines; Piperazines; Aromatase Inhibitors; Middle Aged; Fulvestrant; Antineoplastic Combined Chemotherapy Protocols; Aged; Cyclin-Dependent Kinase 4; Receptors, Estrogen; Cyclin-Dependent Kinase 6; Adult; Receptor, ErbB-2; Receptors, Progesterone; Antibodies, Monoclonal, Humanized; Aged, 80 and over; Disease Progression; ErbB Receptors; Protein Kinase Inhibitors; Progression-Free Survival
PubMed: 38513188
DOI: 10.1200/JCO.23.01940 -
Theriogenology May 2024The 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...
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 (P) 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 P 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 P concentration was recorded at 50 nM and 100 nM Kp, while KpA did not affect the basal concentration of P. However, the addition of KpA to the Kp-treated group at 100 nM concentration suppressed the Kp-induced P 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 P production, while the addition of KpA suppressed Kp-induced P 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.
Topics: Female; Animals; Luteal Cells; Progesterone; Kisspeptins; Up-Regulation; Extracellular Signal-Regulated MAP Kinases; Cholesterol Side-Chain Cleavage Enzyme; MAP Kinase Signaling System; Corpus Luteum; Multienzyme Complexes
PubMed: 38507824
DOI: 10.1016/j.theriogenology.2024.03.007 -
The Journal of Chemical Physics Mar 2024Nuclear receptors regulate transcriptional programs in response to the binding of natural and synthetic ligands. These ligands modulate the receptor by inducing dynamic...
Nuclear receptors regulate transcriptional programs in response to the binding of natural and synthetic ligands. These ligands modulate the receptor by inducing dynamic changes in the ligand binding domain that shift the C-terminal helix (H12) between active and inactive conformations. Despite decades of study, many questions persist regarding the nature of the inactive state and how ligands shift receptors between different states. Here, we use molecular dynamics (MD) simulations to investigate the timescale and energetic landscape of the conformational transition between inactive and active forms of progesterone receptor (PR) bound to a partial agonist. We observe that the microsecond timescale is insufficient to observe any transitions; only at millisecond timescales achieved via accelerated MD simulations do we find the inactive PR switches to the active state. Energetic analysis reveals that both active and inactive PR states represent energy minima separated by a barrier that can be traversed. In contrast, little or no transition is observed between active and inactive states when an agonist or antagonist is bound, confirming that ligand identity plays a key role in defining the energy landscape of nuclear receptor conformations.
Topics: Ligands; Molecular Dynamics Simulation; Protein Conformation
PubMed: 38501469
DOI: 10.1063/5.0189234 -
Human Reproduction (Oxford, England) May 2024Is there any difference in ovarian response and embryo ploidy following progesterone-primed ovarian stimulation (PPOS) using micronized progesterone or GnRH antagonist...
Ovarian response and embryo ploidy following oral micronized progesterone-primed ovarian stimulation versus GnRH antagonist protocol. A prospective study with repeated ovarian stimulation cycles.
STUDY QUESTION
Is there any difference in ovarian response and embryo ploidy following progesterone-primed ovarian stimulation (PPOS) using micronized progesterone or GnRH antagonist protocol?
SUMMARY ANSWER
Pituitary downregulation with micronized progesterone as PPOS results in higher number of oocytes retrieved and a comparable number of euploid blastocysts to a GnRH antagonist protocol.
WHAT IS KNOWN ALREADY
Although the GnRH antagonist is considered by most the gold standard protocol for controlling the LH surge during ovarian stimulation (OS) for IVF/ICSI, PPOS protocols are being increasingly used in freeze-all protocols. Still, despite the promising results of PPOS protocols, an early randomized trial reported potentially lower live births in recipients of oocytes resulting following downregulation with medroxyprogesterone acetate as compared with a GnRH antagonist protocol. The scope of the current prospective study was to investigate whether PPOS with micronized progesterone results in an equivalent yield of euploid blastocysts to a GnRH antagonist protocol.
STUDY DESIGN, SIZE, DURATION
In this prospective study, performed between September 2019 to January 2022, 44 women underwent two consecutive OS protocols within a period of 6 months in a GnRH antagonist protocol or in a PPOS protocol with oral micronized progesterone.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Overall, 44 women underwent two OS cycles with an identical fixed dose of rFSH (225 or 300 IU) in both cycles. Downregulation in the first cycles was performed with the use of a flexible GnRH antagonist protocol (0.25 mg per day as soon as one follicle of 14 mm) and consecutively, after a washout period of 1 month, control of LH surge was performed with 200 mg of oral micronized progesterone from stimulation Day 1. After the completion of both cycles, all generated blastocysts underwent genetic analysis for aneuploidy screening (preimplantation genetic testing for aneuplody, PGT-A).
MAIN RESULTS AND THE ROLE OF CHANCE
Comparisons between protocols did not reveal differences between the duration of OS. The hormonal profile on the day of trigger revealed statistically significant differences between protocols in all the tested hormones except for FSH: with significantly higher serum E2 levels, more elevated LH levels and higher progesterone levels in PPOS cycles as compared with antagonist cycles, respectively. Compared with the GnRH antagonist protocol, the PPOS protocol resulted in a significantly higher number of oocytes (12.7 ± 8.09 versus 10.3 ± 5.84; difference between means [DBM] -2.4 [95% CI -4.1 to -0.73]), metaphase II (9.1 ± 6.12 versus 7.3 ± 4.15; DBM -1.8 [95% CI -3.1 to -0.43]), and 2 pronuclei (7.1 ± 4.99 versus 5.7 ± 3.35; DBM -1.5 [95% CI -2.6.1 to -0.32]), respectively. Nevertheless, no differences were observed regarding the mean number of blastocysts between the PPOS and GnRH antagonist protocols (2.9 ± 2.11 versus 2.8 ± 2.12; DBM -0.07 [95% CI -0.67 to 0.53]) and the mean number of biopsied blastocysts (2.9 ± 2.16 versus 2.9 ± 2.15; DBM -0.07 [95% CI -0.70 to 0.56]), respectively. Concerning the euploidy rates per biopsied embryo, a 29% [95% CI 21.8-38.1%] and a 35% [95% CI 26.6-43.9%] were noticed in the PPOS and antagonist groups, respectively. Finally, no difference was observed for the primary outcome, with a mean number of euploid embryos of 0.86 ± 0.90 versus 1.00 ± 1.12 for the comparison of PPOS versus GnRh antagonist.
LIMITATIONS, REASONS FOR CAUTION
The study was powered to detect differences in the mean number of euploid embryos and not in terms of pregnancy outcomes. Additionally, per protocol, there was no randomization, the first cycle was always a GnRH antagonist cycle and the second a PPOS with 1 month of washout period in between.
WIDER IMPLICATIONS OF THE FINDINGS
In case of a freeze-all protocol, clinicians may safely consider oral micronized progesterone to control the LH surge and patients could benefit from the advantages of a medication of oral administration, with a potentially higher number of oocytes retrieved at a lower cost, without any compromise in embryo ploidy rates.
STUDY FUNDING/COMPETING INTEREST(S)
This research was supported by an unrestricted grant from Theramex. N.P.P. has received Research grants from Merck Serono, Organon, Ferring Pharmaceutical, Roche, Theramex, IBSA, Gedeon Richter, and Besins Healthcare; honoraria for lectures from: Merck Serono, Organon, Ferring Pharmaceuticals, Besins International, Roche Diagnostics, IBSA, Theramex, and Gedeon Richter; consulting fees from Merck Serono, Organon, Besins Healthcare, and IBSA. M.d.M.V., F.M., and I.R. declared no conflicts of interest.
TRIAL REGISTRATION NUMBER
The study was registered at Clinical Trials Gov. (NCT04108039).
Topics: Female; Humans; Ovulation Induction; Progesterone; Gonadotropin-Releasing Hormone; Adult; Prospective Studies; Pregnancy; Ploidies; Hormone Antagonists; Blastocyst; Pregnancy Rate; Oocyte Retrieval; Embryo Transfer; Administration, Oral; Sperm Injections, Intracytoplasmic
PubMed: 38498835
DOI: 10.1093/humrep/deae047 -
Scientific Reports Mar 2024Allopregnanolone (ALLO) is a known neurosteroid and a progesterone metabolite synthesized in the ovary, CNS, PNS, adrenals and placenta. Its role in the neuroendocrine...
Allopregnanolone (ALLO) is a known neurosteroid and a progesterone metabolite synthesized in the ovary, CNS, PNS, adrenals and placenta. Its role in the neuroendocrine control of ovarian physiology has been studied, but its in situ ovarian effects are still largely unknown. The aims of this work were to characterize the effects of intrabursal ALLO administration on different ovarian parameters, and the probable mechanism of action. ALLO administration increased serum progesterone concentration and ovarian 3β-HSD2 while decreasing 20α-HSD mRNA expression. ALLO increased the number of atretic follicles and the number of positive TUNEL granulosa and theca cells, while decreasing positive PCNA immunostaining. On the other hand, there was an increase in corpora lutea diameter and PCNA immunostaining, whereas the count of TUNEL-positive luteal cells decreased. Ovarian angiogenesis and the immunohistochemical expression of GABA receptor increased after ALLO treatment. To evaluate if the ovarian GABA receptor was involved in these effects, we conducted a functional experiment with a specific antagonist, bicuculline. The administration of bicuculline restored the number of atretic follicles and the diameter of corpora lutea to normal values. These results show the actions of ALLO on the ovarian physiology of the female rat during the follicular phase, some of them through the GABA receptor. Intrabursal ALLO administration alters several processes of the ovarian morpho-physiology of the female rat, related to fertility and oocyte quality.
Topics: Pregnancy; Female; Rats; Animals; Pregnanolone; Progesterone; Proliferating Cell Nuclear Antigen; Bicuculline; Receptors, GABA-A; Corpus Luteum
PubMed: 38493224
DOI: 10.1038/s41598-024-57102-1 -
Scientific Reports Mar 2024This prospective study aimed to test the ability of follicular GnRH agonist challenge test (FACT) to predict suboptimal response to GnRH agonist trigger, assessed by LH...
This prospective study aimed to test the ability of follicular GnRH agonist challenge test (FACT) to predict suboptimal response to GnRH agonist trigger, assessed by LH levels post ovulation trigger in non-medical oocyte cryopreservation program. The study included 91 women that underwent non-medical fertility preservation. On day two to menstrual cycle, blood tests were drawn (basal Estradiol, basal FSH, basal LH, Progesterone) and ultrasound (US) was performed. On that evening, the women were instructed to inject 0.2 mg GnRH agonist (FACT) and arrive for repeated blood workup 10-12 h later in the next morning, followed by a flexible antagonist protocol. LH levels on the morning after ovulation trigger were compared to FACT LH levels. The results demonstrated that LH levels following agonist ovulation trigger below 15IU/L occurred in 1.09% of cycles and were predicted by FACT, r = 0.57, p < 0.001. ROC analysis demonstrated that FACT LH > 42.70 IU/L would predict LH post trigger of more than 30 IU/L with 75% sensitivity and 70% specificity, AUC = 0.81. LH levels post trigger also displayed significant positive correlation to basal FSH (r = 0.35, p = 0.002) and basal LH (r = 0.54, p < 0.001). LH levels post ovulation trigger were not associated with total oocytes number or maturity rate. The strongest correlation to the number of frozen oocytes was progesterone levels post agonist trigger (r = 0.746, p < 0.001). We concluded that suboptimal response to agonist trigger, as assessed by post trigger LH levels was a rare event. FACT could serve as an adjunct pre-trigger, intracycle tool to predict adequate LH levels elevation after agonist ovulation trigger. Future studies should focus on optimization of agonist trigger efficacy assessment and prediction, especially in high responders.
Topics: Female; Humans; Luteinizing Hormone; Gonadotropin-Releasing Hormone; Progesterone; Prospective Studies; Ovulation Induction; Oocytes; Follicle Stimulating Hormone; Cryopreservation
PubMed: 38485977
DOI: 10.1038/s41598-024-56418-2