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West African Journal of Medicine Nov 2023Meningiomas are the most common neoplasm of the central nervous system. According to the WHO 2020 classification, there are fifteen subtypes that have been grouped into...
INTRODUCTION
Meningiomas are the most common neoplasm of the central nervous system. According to the WHO 2020 classification, there are fifteen subtypes that have been grouped into grades 1, 2, and 3. The WHO grade 1 meningiomas are generally grouped as benign while the WHO grade 2 and 3 tumours are grouped as malignant. Progesterone receptors and P63 are common immunohistochemical markers reported useful in the diagnosis, grading, and prognosis of meningiomas. This study seeks to determine the usefulness of these findings in our population.
METHODOLOGY
A 10-year retrospective review of histologically diagnosed cases of meningioma. Immunostaining for progesterone receptors and P63 were performed and the results were correlated with the histologic grades and sex of the patients.
RESULTS
The three WHO grades of meningioma were assessed in this study. The M:F ratio was 1:1.4 and peak age incidence was seen in the 41 - 50 years age range. The majority of the cases were WHO grade 1 (86.1%) while WHO grades 2 and 3 tumours were 8% and 5.9%. There was no correlation between Progesterone receptor and P63 immunopositivity to the WHO grades or sex.
CONCLUSION
This study concluded 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. Thus, progesterone receptor antagonists may not be an effective alternative for treatment in patients with inoperable meningiomas. Also, P63 immunopositivity may not be a sufficient grading tool in the management of meningiomas in our population.
Topics: Humans; Adult; Middle Aged; Meningioma; Meningeal Neoplasms; Receptors, Progesterone; Prognosis; Retrospective Studies
PubMed: 37976251
DOI: No ID Found -
Endocrine-related Cancer Feb 2024Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have...
Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.
Topics: Humans; Mice; Animals; Female; Mifepristone; Breast Neoplasms; Receptors, Progesterone; Hormone Antagonists; Prognosis
PubMed: 37962553
DOI: 10.1530/ERC-23-0238 -
Archives of Gynecology and Obstetrics Apr 2024The aim of this meta-analysis was comparing the efficacy of GnRH antagonist (GnRH-ant) protocol and progestin-primed ovarian stimulation (PPOS) in polycystic ovarian... (Review)
Review
PURPOSE
The aim of this meta-analysis was comparing the efficacy of GnRH antagonist (GnRH-ant) protocol and progestin-primed ovarian stimulation (PPOS) in polycystic ovarian syndrome (PCOS) women.
METHODS
A search was conducted from PubMed, Embase, The Cochrane library, Web of Science, and Scopus databases to collect clinical papers regarding GnRH-ant protocol and PPOS protocol from inception to September 2023. Subsequently, the retrieved documents were screened, and the content of the documents that conformed to the requirements was extracted. Moreover, statistical meta-analyses were conducted using the RevMan 5.4 software. Furthermore, with the use of a star-based system and the Cochrane handbook, the methodological quality of the covered papers was evaluated on the Ottawa-Newcastle scale.
RESULTS
A total of eight papers were covered in the meta-analysis, with 2156 PCOS women enrolled (i.e., 1085 patients in the GnRH-ant protocol group and 1071 patients in the PPOS group). As indicated by the meta-analysis results, the PPOS group was correlated with a lower risk of ovarian hyperstimulation syndrome (OHSS) (SMD = 9.24, [95% CI: (2.50, 34.21)], P = 0.0009), more gonadotropin (Gn) dose (SMD = - 0.34, [95% CI: (- 0.56, - 0.13)], P = 0.002) compared with GnRH-ant group. No statistical difference was identified on the oocytes condition and pregnancy outcomes.
CONCLUSIONS
As revealed by the data of this study, the progesterone protocol is comparable with the GnRH-ant protocol in oocytes condition and clinical outcomes. The progestin-primed ovarian stimulation could serve as an alternative for polycystic ovarian syndrome women who have failed in GnRH antagonist protocol. The above-described conclusions should be verified by more high-quality papers due to the limitation of the number and quality of included papers.
TRIAL REGISTRATION
PROSPERO registration: CRD42023411284.
Topics: Pregnancy; Humans; Female; Progestins; Polycystic Ovary Syndrome; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Ovulation Induction; Steroids; Hormone Antagonists; Meta-Analysis as Topic; Systematic Reviews as Topic
PubMed: 37957365
DOI: 10.1007/s00404-023-07269-1 -
The Journal of Organic Chemistry Dec 2023An efficient route for the copper(II)-catalyzed synthesis of substituted pyrazolines from readily accessible -propargyl hydrazones has been reported under open flask...
An efficient route for the copper(II)-catalyzed synthesis of substituted pyrazolines from readily accessible -propargyl hydrazones has been reported under open flask conditions via intramolecular C-N bond formation. -acyl and -tosyl-substituted pyrazolines have been prepared in moderate to excellent yields. Mechanistic investigations using NMR, high-resolution mass spectrometry (HRMS), and Hammett analyses suggest that the Cu(II) catalyst generally acts as a Lewis acid to form an iminium-ion intermediate via cyclization, which afforded the desired pyrazolines upon hydrolysis. One progesterone receptor antagonist has also been synthesized utilizing this reaction methodology.
PubMed: 37947756
DOI: 10.1021/acs.joc.3c01848 -
Breastfeeding Medicine : the Official... Nov 2023A growing number of diverse familial structures wish to colactate their infant. For transgender and gender diverse (TGD) individuals, chestfeeding or breastfeeding may...
A growing number of diverse familial structures wish to colactate their infant. For transgender and gender diverse (TGD) individuals, chestfeeding or breastfeeding may be within their goals of parenthood. There is limited evidence on how to induce lactation for a nongestational parent on gender affirming estrogen treatment. We report the case of a transgender woman who successfully underwent lactation induction following a protocol using the galactogue domperidone plus use of a breast pump. The patient had modifications to her hormone therapy with estrogen and progesterone while remaining on antiandrogen therapy with spironolactone. A description of the protocol, medications, laboratory monitoring, human milk analysis including macronutrients, oligosaccharides, and hormones is presented. This is the fourth case to date known in the literature of a transgender woman with successful lactation induction, and the third case to remain on antiandrogen therapy during this process. Our report is the second to demonstrate comparable macronutrients, and the first to report on human milk oligosaccharides and hormones in induced milk compared with term human milk of a gestational parent. The opportunity to chestfeed or breastfeed an infant can be profound for many parents. Further research is needed to meet the needs of TGD individuals who wish to induce lactation as part of their parental goals.
Topics: Female; Humans; Infant; Androgen Antagonists; Breast Feeding; Estrogens; Lactation; Milk, Human; Oligosaccharides; Transgender Persons; Male
PubMed: 37910800
DOI: 10.1089/bfm.2023.0197 -
Journal of Nanobiotechnology Oct 2023Triple-negative breast cancer (TNBC) represents a formidable challenge due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal...
Triple-negative breast cancer (TNBC) represents a formidable challenge due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, rendering it unresponsive to conventional hormonal and targeted therapies. This study introduces the development of mesoporous nanoreactors (NRs), specifically mPDA@CuO NRs, as acid-triggered agents capable of self-supplying HO for chemodynamic therapy (CDT). To enhance therapeutic efficacy, these NRs were further modified with immune checkpoint antagonists, specifically anti-PD-L1 and anti-CD24 antibodies, resulting in the formation of dual antibody-aided mesoporous nanoreactors (dAb-mPDA@CuO NRs). These NRs were designed to combine CDT and checkpoint blockade immunotherapy (CBIT) for precise targeting of 4T1 TNBC cells. Remarkably, dAb-mPDA@CuO NRs exhibited tumor-targeted CDT triggered by HO and successfully activated immune cells including T cells and macrophages. This integrated approach led to a remarkable inhibition of tumor growth by leveraging the collaborative effects of the therapies. The findings of this study introduce a novel and promising strategy for the integrative and collaborative treatment of refractory cancers, providing valuable insights into addressing the challenges posed by aggressive breast cancer, particularly TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; B7-H1 Antigen; Hydrogen Peroxide; Immune Checkpoint Inhibitors; Immunotherapy; Antibodies, Monoclonal; Nanotechnology
PubMed: 37875918
DOI: 10.1186/s12951-023-02154-0 -
Clinical Pharmacokinetics Dec 2023Oral gonadotropin-releasing hormone (GnRH) antagonists are promising agents in the treatment of endometriosis-related pain. Here we assessed the safety, pharmacokinetics... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety, Pharmacokinetics, and Pharmacodynamics of SHR7280, a Non-peptide GnRH Antagonist in Premenopausal Women with Endometriosis: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study.
BACKGROUND
Oral gonadotropin-releasing hormone (GnRH) antagonists are promising agents in the treatment of endometriosis-related pain. Here we assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR7280, an oral non-peptide GnRH antagonist in premenopausal women with endometriosis.
METHODS
In the Phase 1 part of the randomized, double-blinded, placebo-controlled, dose-ascending, Phase 1/2 trial, premenopausal women with endometriosis were randomized (4:1) to receive SHR7280 or placebo treatment for 21 consecutive days. The treatment dose started from 200 mg QD, and then increased to 300 mg QD and 200 mg BID. Safety, PK, and PD parameters were assessed.
RESULTS
In total, 30 patients received assigned treatment, 24 with SHR7280 and 6 with placebo. SHR7280 was well tolerated. Adverse events (AEs) were reported in 19 (79.2%, 19/24) patients in the SHR7280 group and 5 (83.3%, 5/6) patients in the placebo group. Most AEs were mild and no severe AEs occurred. SHR7280 showed a rapid absorption, with a time to maximum plasma concentration (T) of 1.0 h, 1.0 h, and 0.8 h for the 200 mg QD, 300 mg QD, and 200 mg BID regimens, respectively. Plasma concentration of SHR7280 was dose dependent. The mean half-life (t) at steady state was 6.9 h, 7.4 h, and 2.8 h, respectively, and little or no accumulation was observed. Pharmacodynamic analysis showed that SHR7280 could effectively suppress estradiol and luteinizing hormone concentrations and prevent progesterone increase in a dose-dependent manner. SHR7280 at doses of 300 mg QD and 200 mg BID could suppress estradiol levels within the desired therapeutic window of 20-50 pg/mL throughout the treatment period.
CONCLUSIONS
SHR7280 showed favorable safety, PK, and PD profiles in the doses of 200 mg QD, 300 mg QD, and 200 mg BID. The results of this study provide evidence to support the further development of SHR7280 as a GnRH antagonist for the treatment of endometriosis-related pain in the subsequent Phase 2 trial.
TRIAL REGISTRY
Trial registration number: Clinicaltrials.gov, identifier: NCT04417972. Trial registration date: 5 June 2020.
Topics: Humans; Female; Endometriosis; Hormone Antagonists; Estradiol; Pain; Double-Blind Method; Gonadotropin-Releasing Hormone; Dose-Response Relationship, Drug
PubMed: 37838623
DOI: 10.1007/s40262-023-01315-6 -
Journal of Clinical Medicine Sep 2023Uterine Adenomyosis is a benign condition characterized by the presence of endometrium-like epithelial and stromal tissue in the myometrium. Several medical treatments... (Review)
Review
Uterine Adenomyosis is a benign condition characterized by the presence of endometrium-like epithelial and stromal tissue in the myometrium. Several medical treatments have been proposed, but still, no guidelines directing the management of adenomyosis are available. While a hysterectomy is typically regarded as the definitive treatment for adenomyosis, the scarcity of high-quality data leaves patients desiring fertility with limited conservative options. Based on the available data, the levonorgestrel-IUD appears to offer the most favorable outcomes. Other treatments, including GnRH antagonists, dienogest, prolactin, and oxytocin modulators, show promise; however, further data are required to establish their efficacy definitively. Furthermore, there are many emerging therapies that have been developed that seem worthy of consideration in the near future. The aim of this narrative review was to explore the current medical treatments available for adenomyosis and to provide a glimpse of future therapies under assessment. For this scope, we performed a literature search on PubMed and Medline from incept to September 2022 using the keywords: "medical treatment", "non-steroidal anti-inflammatory", "progesterone intrauterine device", "dienogest", "combined oral contraceptives", "gonadotropin releasing hormone agonist", "gonadotropin releasing hormone antagonist", "danazol", "aromatase inhibitors", "ulipristal acetate", "anti-platelet therapy", "dopamine", "oxytocin antagonists", "STAT3", "KRAS", "MAPK", "micro-RNA", "mifepristone", "valproic acid", "levo-tetrahydropalamatine", and "andrographolide". The search was limited to articles in English, with subsequent screening of abstracts. Abstracts were screened to select relevant studies.
PubMed: 37834773
DOI: 10.3390/jcm12196130 -
Frontiers in Endocrinology 2023The pharmacological target for progesterone, different progestins, and Selective Progesterone Receptor Modulators (SPRMs) is the nuclear progesterone receptor (PR)....
INTRODUCTION
The pharmacological target for progesterone, different progestins, and Selective Progesterone Receptor Modulators (SPRMs) is the nuclear progesterone receptor (PR). EC313 is a new member of a subgroup of SPRMs, mesoprogestins, which combine especially PR- agonistic and PR-antagonistic activities in one molecule.
METHODS
The suitable -model for the differentiation of SPRMs from the subgroup of mesoprogestins is the estrogen-primed juvenile rabbit endometrium assay (McPhail Assay). Remarkably, in contrast to other well-known SPRMs with no agonistic effects in this test, EC313 shows clear partial PR-agonistic effects that are higher than that of the well-known mesoprogestin Asoprisnil which already demonstrated remarkable clinical effectiveness for the treatment of uterine fibroids and endometriosis. The findings from the guinea pig studies presented here can be the impetus for further preclinical development of EC313. This model shows the same features for the termination of pregnancy by antiprogestins such as Mifepristone and Ulipristal acetate (UPA) in humans. Moreover, it is possible to distinguish between progestational and anti-progestational activities in the same experiment.
RESULTS
The EC313 treatment reveals PR dominance in the genital tract and inhibits unopposed estrogenic effects. In very high doses (30.0 mg/animal/day subcutaneously (s.c.)) given twice on pregnancy days 43 and 44, no premature labor was induced (in contrast to UPA, dosed at 10.0 and 30. mg/animal/day s.c.). The anti-ovulatory activity of EC313 exceeds that of Ulipristal acetate or Mifepristone. EC313 binds to the steroid receptors with a similar affinity as the natural ligand progesterone. At the glucocorticoid receptor (GR) EC313 acts as a weak inhibitor. Minor activities at the human androgen receptor (AR) and mineralocorticoid receptor (MR) are considered negligible. No binding to the estradiol receptor was detected. In contrast to some -receptor findings, estrogenic, anti-estrogenic, androgenic, anti-androgenic, glucocorticoid, and anti-glucocorticoid actions were absent . The tissue selectivity of EC313 was demonstrated previously by reducing the growth and proliferation of uterine fibroids in animal models (lowest effective dosage 0.1 mg/kg/day s.c.).. As shown in this article, the anti-fibroid activity of EC313 was confirmed with a 10 times lower dosage (0.01 mg/kg/day s.c.). It was also shown that EC313 reduces the growth of endometriotic lesions in a human xenograft immune-deficient (NOD-SCID) mice model with a comparatively very low dosage range. In the aforementioned EC313 activity model, UPA was tested as the reference compound, the clinical effectiveness of which has already been demonstrated.
DISCUSSION
For an explanation of these findings, the possibility is discussed that the mixed agonistic/antagonistic feature of EC313 is tissue target-specific based on its super-additive synergism characteristic for active bifunctional agents. In conclusion, the specific pharmacodynamic profile of this compound opens the possibility for the development of a drug with a distinct pharmaco-endocrinological profile against uterine fibroids, endometriosis, and other PR-dependent gynecological diseases.
Topics: Mice; Female; Pregnancy; Humans; Animals; Guinea Pigs; Rabbits; Mice, Inbred NOD; Mice, SCID; Receptors, Progesterone; Progesterone; Mifepristone; Endometriosis; Progestins; Estrogens
PubMed: 37766684
DOI: 10.3389/fendo.2023.1201547 -
Pharmaceuticals (Basel, Switzerland) Sep 2023In this scoping review, we sought to identify published studies evaluating the drugs currently used in the treatment of endometriosis-related pelvic pain, with... (Review)
Review
BACKGROUND
In this scoping review, we sought to identify published studies evaluating the drugs currently used in the treatment of endometriosis-related pelvic pain, with reflection on their chemical properties, pharmacokinetics, safety profile, and clinical efficacy.
METHODS
A literature search was conducted with the use of the PubMed and EMBASE electronic databases, focusing on identifying articles published in English between January 1990 and 2023.
RESULTS
Based on the included studies, current therapy options for the treatment of endometriosis-related pain identified and reviewed in this article were: (1) non-steroidal anti-inflammatory drugs; (2) combined oral contraceptive (COCs); (3) progestins; (4) gonadotropin-releasing hormone agonists and antagonists; (5) aromatase inhibitors (AIs); (6) selective estrogen and progesterone receptor modulators; and (7) levonorgestrel-intrauterine device.
CONCLUSIONS
Based on the published evidence, clinicians should consider NSAIDs, COCs, and progestins as the first-line medical therapies. Compared with second-line options, such as GnRH agonists/antagonists or AIs, the abovementioned first-line options are well tolerated, efficacious, and exhibit lower overall price. Future research priorities should be to identify novel target therapies and to evaluate the effects of available drugs through different routes of administration.
PubMed: 37765123
DOI: 10.3390/ph16091315