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Frontiers in Endocrinology 2024Progesterone-primed cycles effectively suppress the pituitary LH surge during ovarian stimulation in oocyte donors and in the infertile population. Particularly in...
Micronized natural progesterone (Seidigestan) vs GnRH antagonists for preventing the LH surge during controlled ovarian stimulation (PRO_NAT study): study protocol of a randomized clinical trial.
INTRODUCTION
Progesterone-primed cycles effectively suppress the pituitary LH surge during ovarian stimulation in oocyte donors and in the infertile population. Particularly in oocyte donors, the use of synthetic progesterone (progestins) has been explored in prospective clinical trials, showing mixed results. This trial was designed to determine whether the use of micronized natural progesterone is as effective as the GnRH-antagonist protocol in terms of the number of mature oocytes (MII) retrieved in oocyte donation cycles as a primary outcome, and it also aims to explore the corresponding results in recipients as a secondary outcome.
METHODS
We propose a prospective, open-label, non-inferiority clinical trial to compare a novel approach for oocyte donors with a control group, which follows the standard ovarian stimulation protocol used in our institution. A total of 150 donors (75 in each group) will be recruited and randomized using a computer algorithm. After obtaining informed consent, participants will be randomly assigned to one of two ovarian stimulation protocols: either the standard GnRH antagonist or the oral micronized natural progesterone protocol. Both groups will receive recombinant gonadotropins tailored to their antral follicle count and prior donation experiences, if any. The primary outcome is the number of mature metaphase II (MII) oocytes. Secondary measures include treatment duration, pregnancy outcomes in recipients, as well as the economic cost per MII oocyte obtained in each treatment regimen. Analyses for the primary outcome will be conducted in both the intention-to-treat (ITT) and per-protocol (PP) populations. Each donor can participate only once during the recruitment period. The estimated duration of the study is six months for the primary outcome and 15 months for the secondary outcomes.
DISCUSSION
The outcomes of this trial have the potential to inform evidence-based adjustments in the management of ovarian stimulation protocols for oocyte donors.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier, NCT05954962.
Topics: Female; Humans; Pregnancy; Gonadotropin-Releasing Hormone; Hormone Antagonists; Ovulation Induction; Progesterone; Progestins; Prospective Studies; Randomized Controlled Trials as Topic
PubMed: 38577571
DOI: 10.3389/fendo.2024.1350154 -
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 -
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 -
Journal of Neurosciences in Rural... 2024Meningiomas, a common neoplasm of the central nervous system, is a widely studied meningeal tumor. According to the World Health Organization (WHO) 2021 classification...
OBJECTIVES
Meningiomas, a common neoplasm of the central nervous system, is a widely studied meningeal tumor. According to the World Health Organization (WHO) 2021 classification of meningiomas, there are 15 subtypes that have been grouped into grades 1, 2, and 3. The WHO grade 1 meningiomas are generally grouped as benign while the WHO grades 2 and 3 tumors are grouped as malignant. Progesterone receptors and P63 are common immunohistochemical markers that have proven useful in the diagnosis, grading, and prognostication of many neoplasms such as breast carcinoma, prostate carcinoma, and gastrointestinal tumors in histopathology practice. The application of these immunohistochemical markers to the grading of meningiomas has been reported and their usefulness documented in reports from Africa, Europe, North America, South America, and Asia. This study, therefore, seeks to determine if these findings are applicable to the meningiomas seen in an African population.
MATERIALS AND METHODS
A 10-year review of results and histologically diagnosed cases of meningiomas received in the Department of Morbid Anatomy, University of Nigeria, Enugu. Immunostaining for progesterone receptors (PgRs) and P63 were done and results compared with histologic grades.
RESULTS
The three WHO grades of meningioma were assessed in this study. M: F ratio was 1:1.4 and peak age was 41-50 years age range (SD ± 16.54). The majority of the cases were WHO grade 1 (86.1%) while the WHO grades 2 and 3 tumors were 8% and 5.9%, respectively. The fibrous variant was the most common subtype (27.1%). There was no correlation between progesterone receptor and P63 immunopositivity to the WHO grades of meningioma ( = 0.112 and = 0.138, respectively).
CONCLUSION
Our study showed that progesterone receptors and P63 immunopositivity did not correlate with the WHO grades of meningiomas. This may be due to the predominant variant of meningioma seen in this study. These findings indicate that PgR antagonist may not be an effective alternative for treatment in patients with inoperable meningiomas. Furthermore, P63 immunopositivity may not be a sufficient grading tool for managing meningiomas in our population.
PubMed: 38476431
DOI: 10.25259/JNRP_332_2023 -
Scientific Reports Mar 2024Progesterone receptor (PR)-interacting compounds in the environment are associated with serious health hazards. However, methods for their detection in environmental...
Progesterone receptor (PR)-interacting compounds in the environment are associated with serious health hazards. However, methods for their detection in environmental samples are cumbersome. We report a sensitive activity-based biosensor for rapid and reliable screening of progesterone receptor (PR)-interacting endocrine disrupting chemicals (EDCs). The biosensor is a cell line which expresses nuclear mCherry-NF1 and a green fluorescent protein (GFP)-tagged chimera of glucocorticoid receptor (GR) N terminus fused to the ligand binding domain (LBD) of PR (GFP-GR-PR). As this LBD is shared by the PRA and PRB, the biosensor reports on the activation of both PR isoforms. This GFP-GR-PR chimera is cytoplasmic in the absence of hormone and translocates rapidly to the nucleus in response to PR agonists or antagonists in concentration- and time-dependent manner. In live cells, presence of nuclear NF1 label eliminates cell fixation and nuclear staining resulting in efficient screening. The assay can be used in screens for novel PR ligands and PR-interacting contaminants in environmental samples. A limited screen of river water samples indicated a widespread, low-level contamination with PR-interacting contaminants in all tested samples.
Topics: Endocrine Disruptors; Receptors, Progesterone; Biological Assay; Cell Line; Cytoplasm; Green Fluorescent Proteins; Receptors, Glucocorticoid
PubMed: 38448539
DOI: 10.1038/s41598-024-55254-8 -
International Journal of Women's Health 2024Current medical treatment options for endometriosis associated pains are inadequate. Evidence on effects of nonsteroidal anti-inflammatory drugs is scarce. Around one... (Review)
Review
Oral GnRH Antagonists in Combination with Estradiol and Norethindrone Acetate for Pain Relief Associated with Endometriosis: A Review of Evidence of a Novel Class of Hormonal Agents.
Current medical treatment options for endometriosis associated pains are inadequate. Evidence on effects of nonsteroidal anti-inflammatory drugs is scarce. Around one third of patients are not responsive to oral contraceptives or progestins due to progesterone resistance. Gonadotropin-releasing hormone (GnRH) agonists can only be used for a short duration because of associated side effects. Oral GnRH antagonists, including elagolix, relugolix, and linzagolix allow oral administration, induce dose dependent reduction of estradiol levels, do not cause initial flare up of endometriosis symptoms, and allow the fast return of ovarian function and menstruation after discontinuation. Elagolix at a low dose of 150 mg once daily, or the higher dose of 200 mg twice daily, significantly increased the proportion of women achieving clinically meaningful decline of dysmenorrhea, noncyclic pelvic pain, and dyspareunia. Relugolix at an oral dose of 40 mg/day results in improvement in different forms of endometriosis related pelvic pain, with an efficacy and side effect profile similar to that of GnRH agonists. Adding 1 mg of estradiol and 0.5 mg of norethindrone to 40 mg of relugolix (relugolix combination therapy) allows extension of treatment to 24 weeks with maintained efficacy and an improved side effect profile. Linzagolix, in a dose of 75 mg/day, can be used alone to treat endometriosis associated pain. For severe pelvic pain and dyspareunia, linzagolix can be used in a high dose of 200 mg/day with hormonal add-back therapy to preserve bone health.
PubMed: 38435758
DOI: 10.2147/IJWH.S442357