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European Journal of Obstetrics,... Mar 2024Are circulating luteinizing hormone (LH) levels predictive of ovarian response in oocyte donors triggered with gonadotropin-releasing hormone (GnRH) agonists?
OBJECTIVE
Are circulating luteinizing hormone (LH) levels predictive of ovarian response in oocyte donors triggered with gonadotropin-releasing hormone (GnRH) agonists?
STUDY DESIGN
A prospective cohort study with 224 oocyte donation cycles between 2021 and 2022 at a single center, examined the relationship between circulating luteinizing hormone (LH) levels and ovarian response. Oocyte donors underwent GnRH antagonist downregulation followed by GnRH agonist trigger. LH, estradiol, and progesterone levels were measured on day one of stimulation, trigger-day and 12 h post-trigger. Oocyte retrieval and maturity rates were analyzed using univariate and multivariate analyses, and the correlation between post-trigger LH levels and outcomes was assessed by Pearson's correlation test. A significance level of p < 0.05 was used.
RESULTS
Mean age was 26 ± 4.3 years, mean body mass index (BMI, kg/m2) was 22.6 ± 3.2 and mean antral follicle count (AFC) was 21.7 ± 8.2. Post-trigger LH levels averaged 51.3 IU/L (SD 34.8), and oocyte retrieval rate and maturity rates were 112,7% (+/-48,1%) and 77,8% (+/- 17,2%), respectively. No significant differences were found in these outcomes for donors with post-trigger LH values below and above 15 IU/L (Mann Whitney's p > 0.05). However, exploratory analyses revealed that post-trigger LH values < 22 IU/L and basal LH levels < 4 IU/L were associated with significantly lower oocyte retrieval rate (90 % vs 110 %, p = 0.019 and 100 % vs 110 %, p = 0.019, respectively).
CONCLUSIONS
This study, a first in exclusively focusing on oocyte donors, did not support the previously reported LH value of 15 IU/L as predictive of suboptimal ovarian response.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov Identifier: NCT05109403.
Topics: Female; Humans; Young Adult; Adult; Prospective Studies; Gonadotropin-Releasing Hormone; Ovulation Induction; Oocytes; Luteinizing Hormone; Fertilization in Vitro
PubMed: 38266482
DOI: 10.1016/j.ejogrb.2024.01.022 -
Fertility and Sterility May 2024To broadly assess the efficacy of medroxyprogesterone acetate (MPA) for ovulatory suppression during in vitro stimulation compared with gonadotropin-releasing hormone...
OBJECTIVE
To broadly assess the efficacy of medroxyprogesterone acetate (MPA) for ovulatory suppression during in vitro stimulation compared with gonadotropin-releasing hormone (GnRH) antagonist cycles.
DESIGN
Cohort trial.
SETTING
A single academic-affiliated private fertility practice.
PATIENTS
Patients of all diagnoses aged 18-44 years undergoing autologous in vitro fertilization (IVF) for fertility treatment between 2020 and 2023.
INTERVENTIONS
Comparison of MPA vs. antagonist IVF stimulation cycles.
MAIN OUTCOME MEASURES
Rates of premature ovulation, oocyte and embryo yield, embryo quality, pregnancy rates, and logistical benefits.
RESULTS
Prospective data was collected on 418 patients who underwent MPA protocol ovarian stimulation (MPA group), which was compared with 419 historical control gonadotropin hormone-releasing hormone antagonist cycles (control group). Age was similar between groups (35.6 ± 4.6 vs. 35.7 ± 4.8 years; P = .75). There were no cases of premature ovulation in the MPA group compared with a total of five cases in the control group (0% vs. 1.2%; risk ratio [RR] = 0.09; 95% confidence interval [CI], 0.01, 1.66). No differences were seen between number of oocytes retrieved (14.3 ± 10.2 vs. 14.3 ± 9.7; P = .83), blastocysts (4.9 ± 4.6 vs. 5.0 ± 4.6; P = .89), or euploid blastocysts (2.4 ± 2.6 vs. 2.2 ± 2.4; P = .18) in the MPA vs. control group respectively. Clinical pregnancy rate was similar between groups (70.4% vs. 64.2%; RR = 0.92; 95% CI, 0.72, 1.18). There was no difference in length of IVF stimulation or dose of stimulation medications. Patients in the MPA group saved an average of $491 ± $119 on medications, had an average of one less monitoring visit (4.4 ± 0.9 vs. 5.6 ± 1.1; P<.01), and 5.0 ± 1.2 less injections per cycle. When adjusting for age and ovarian reserve, protocol group (MPA vs. control) did not influence having an embryo available for transfer (76.6% vs. 73.4%; adjusted RR = 1.05; 95% CI, 0.94, 1.14).
CONCLUSION
For ovulatory suppression during IVF cycles, MPA was effective at preventing ovulation while demonstrating similar cycle and reproductive outcomes, with the additional benefits of patient cost savings, increased convenience with decreased number of visits, and fewer injections.
Topics: Humans; Female; Medroxyprogesterone Acetate; Fertilization in Vitro; Adult; Pregnancy; Ovulation Induction; Pregnancy Rate; Young Adult; Administration, Oral; Ovulation Inhibition; Prospective Studies; Fertility Agents, Female; Adolescent; Cohort Studies; Ovulation; Treatment Outcome; Gonadotropin-Releasing Hormone
PubMed: 38253117
DOI: 10.1016/j.fertnstert.2024.01.026 -
Journal of Drug Targeting Dec 2024Triple-negative breast cancer (TNBC) lacks the expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2),... (Review)
Review
Triple-negative breast cancer (TNBC) lacks the expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), rendering it unresponsive to endocrine therapy and HER2 targeted treatments. Though certain chemotherapeutics targeting the cell cycle have shown efficacy to a certain extent, the presence of chemotherapy-resistant cancer stem cells (CSCs) presents a significant challenge in tackling TNBC. Multiple lines of evidence suggest the upregulation of neuropeptide Substance P (SP), its NK-1 receptor (NK1R) and the Cyclooxygenase-2 (COX-2) enzyme in TNBC patients. Upregulation of the SP/NK1R system and COX-2 influences major signalling pathways involved in cell proliferation, growth, survival, angiogenesis, inflammation, metastasis and stem cell activity. The simultaneous activation and crosstalk between the pathways activated by SP/NK1R and COX-2 consequently increase the levels of key regulators of self-renewal pathways in CSCs, promoting stemness. The combination therapy with NK1R antagonists and COX-2 inhibitors can simultaneously target TNBC cells and CSCs, thereby enhancing treatment efficacy and reducing the risk of recurrence and relapse. This review discusses the rationale for combining NK1R antagonists and COX-2 inhibitors for the better management of TNBC and a novel strategy to deliver drug cargo precisely to the tumour site to address the challenges associated with off-target binding.
Topics: Humans; Triple Negative Breast Neoplasms; Cyclooxygenase 2 Inhibitors; Cyclooxygenase 2; Signal Transduction; Receptors, Estrogen; Neoplastic Stem Cells; Cell Line, Tumor
PubMed: 38252517
DOI: 10.1080/1061186X.2024.2309568 -
The Journal of Steroid Biochemistry and... Apr 2024The expression of adipokines is well-known in the ovary and uterus. Recently we have shown that apelin and its receptor, APJ are developmentally regulated in the ovary...
The expression of adipokines is well-known in the ovary and uterus. Recently we have shown that apelin and its receptor, APJ are developmentally regulated in the ovary and uterus of mice with elevation at postnatal day 14 (PND14). However, its role in the ovary and uterus of PND14 has not been investigated. Thus, we aimed to unravel the role of the apelin system (by APJ antagonist, ML221) on ovarian steroid secretion, proliferation, and apoptosis along with its role in uterine apoptosis in PND14 mice by in vitro approaches. The treatment of ML221 decreased estrogen, testosterone, and androstenedione secretion while increasing the progesterone secretion from the infantile ovary. These results suggest that apelin signaling would be important for ovarian estrogen synthesis in infantile mice (PND14). The abundance of 3β-HSD, 17β-HSD, aromatase, and active caspase3 increased in the infantile ovary after ML221 treatment. The expression of ERs and BCL2 were also down-regulated by ML221 treatment. The decreased BCL2 and increased active caspase3 by ML221 suggest the suppressive role of apelin on ovarian apoptosis. The APJ antagonist treatment also down-regulated the ER expression in the uterus along with increased active caspase3 and decreased BCL2 expression. In conclusion, apelin signaling inhibits the ovarian and uterine apoptosis via estrogen signaling in the ovary and uterus.
Topics: Animals; Female; Mice; Apelin; Apoptosis; Estrogens; Nitrobenzoates; Ovary; Proto-Oncogene Proteins c-bcl-2; Pyrans; Uterus
PubMed: 38246202
DOI: 10.1016/j.jsbmb.2024.106463 -
Cancer Cell International Jan 2024Although meningioma is the most common primary brain tumor, treatments rely on surgery and radiotherapy, and recurrent meningiomas have no standard therapeutic options...
BACKGROUND
Although meningioma is the most common primary brain tumor, treatments rely on surgery and radiotherapy, and recurrent meningiomas have no standard therapeutic options due to a lack of clinically relevant research models. Current meningioma cell lines or organoids cannot reflect biological features of patient tumors since they undergo transformation along culture and consist of only tumor cells without microenvironment. We aim to establish patient-derived meningioma organoids (MNOs) preserving diverse cell types representative of the tumor microenvironment.
METHODS
The biological features of MNOs were evaluated using WST, LDH, and collagen-based 3D invasion assays. Cellular identities in MNOs were confirmed by immunohistochemistry (IHC). Genetic alteration profiles of MNOs and their corresponding parental tumors were obtained by whole-exome sequencing.
RESULTS
MNOs were established from four patients with meningioma (two grade 1 and two grade 2) at a 100% succession rate. Exclusion of enzymatic dissociation-reaggregation steps endowed MNOs with original histology and tumor microenvironment. In addition, we used a liquid media culture system instead of embedding samples into Matrigel, resulting in an easy-to-handle, cost-efficient, and time-saving system. MNOs maintained their functionality and morphology after long-term culture (> 9 wk) and repeated cryopreserving-recovery cycles. The similarities between MNOs and their corresponding parental tumors were confirmed by both IHC and whole-exome sequencing. As a representative application, we utilized MNOs in drug screening, and mifepristone, an antagonist of progesterone receptor, showed prominent antitumor efficacy with respect to viability, invasiveness, and protein expression.
CONCLUSION
Taken together, our MNO model overcame limitations of previous meningioma models and showed superior resemblance to parental tumors. Thus, our model could facilitate translational research identifying and selecting drugs for meningioma in the era of precision medicine.
PubMed: 38238738
DOI: 10.1186/s12935-024-03225-4 -
International Journal of Molecular... Dec 2023This research aimed at obtaining new derivatives of pregn-1,4-diene-3,20-dione (Δ-progesterone) () through microbiological transformation. For the role of catalysts, we...
This research aimed at obtaining new derivatives of pregn-1,4-diene-3,20-dione (Δ-progesterone) () through microbiological transformation. For the role of catalysts, we used six strains of entomopathogenic filamentous fungi ( KCh J1.5, KCh J3.3, KCh J2, KCh KW1.1, MU35, and MU4). The substrate () was obtained by carrying out an enzymatic 1,2-dehydrogenation on an increased scale (3.5 g/L) using a recombinant cholest-4-en-3-one Δ-dehydrogenase (AcmB) from . All selected strains were characterized by the high biotransformation capacity for the used substrate. As a result of the biotransformation, six steroid derivatives were obtained: 11α-hydroxypregn-1,4-diene-3,20-dione (), 6β,11α-dihydroxypregn-1,4-diene-3,20-dione (), 6β-hydroxypregn-1,4-diene-3,11,20-trione (), 6β,17α-dihydroxypregn-1,4-diene-3,20-dione (), 6β,17β-dihydroxyandrost-1,4-diene-3-one (), and 12β,17α-dihydroxypregn-1,4-diene-3,20-dione (). The results show evident variability of the biotransformation process between strains of the tested biocatalysts from different species described as entomopathogenic filamentous fungi. The obtained products were tested in silico using cheminformatics tools for their pharmacokinetic and pharmacodynamic properties, proving their potentially high biological activities. This study showed that the obtained compounds may have applications as effective inhibitors of testosterone 17β-dehydrogenase. Most of the obtained products should, also with a high probability, find potential uses as androgen antagonists, a prostate as well as menopausal disorders treatment. They should also demonstrate immunosuppressive, erythropoiesis-stimulating, and anti-inflammatory properties.
Topics: Male; Humans; Progesterone; Biotransformation; Androgen Antagonists; Immunosuppressive Agents; Cheminformatics
PubMed: 38203679
DOI: 10.3390/ijms25010508 -
International Journal of Molecular... Dec 2023C11-oxy C and C11-oxy C steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation...
C11-oxy C and C11-oxy C steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation of C11-oxy steroids by 11β-hydroxysteroid dehydrogenase (11βHSD) interconversion and potential agonist and antagonist activity associated with the androgen (AR) and progesterone receptors (PRA and PRB). Steroid conversions were investigated in transiently transfected HEK293 cells expressing 11βHSD1 and 11βHSD2, while CV1 cells were utilised for agonist and antagonist assays. The conversion of C11-hydroxy steroids to C11-oxo steroids by 11βHSD2 occurred more readily than the reverse reaction catalysed by 11βHSD1, while the interconversion of C11-oxy C steroids was more efficient than C11-oxy C steroids. Furthermore, 11-ketodihydrotestosterone (11KDHT), 11-ketotestosterone (11KT) and 11β-hydroxydihydrotestosterone (11OHDHT) were AR agonists, while only progestogens, 11β-hydroxyprogesterone (11βOHP4), 11β-hydroxydihydroprogesterone (11βOHDHP4), 11α-hydroxyprogesterone (11αOHP4), 11α-hydroxydihydroprogesterone (11αOHDHP4), 11-ketoprogesterone (11KP4), 5α-pregnan-17α-diol-3,11,20-trione (11KPdione) and 21-deoxycortisone (21dE) exhibited antagonist activity. C11-hydroxy C steroids, 11βOHP4, 11βOHDHP4 and 11αOHP4 exhibited PRA and PRB agonistic activity, while only C11-oxo steroids, 11KP4 and 11-ketoandrostanediol (11K3αdiol) demonstrated PRB agonism. While no steroids antagonised the PRA, 11OHA4, 11β-hydroxytestosterone (11OHT), 11KT and 11KDHT exhibited PRB antagonism. The regulatory role of 11βHSD isozymes impacting receptor activation is clear-C11-oxo androgens exhibit AR agonist activity; only C11-hydroxy progestogens exhibit PRA and PRB agonist activity. Regulation by the downstream metabolites of active C11-oxy steroids at the receptor level is apparent-C11-hydroxy and C11-oxo metabolites antagonize the AR and PRB, progestogens the former, androgens the latter. The findings highlight the intricate interplay between receptors and active as well as "inactive" C11-oxy steroids, suggesting novel regulatory tiers.
Topics: Humans; Progesterone; Receptors, Progesterone; Androgens; Progestins; HEK293 Cells; Steroids; Receptors, Steroid; 11-beta-Hydroxysteroid Dehydrogenases
PubMed: 38203272
DOI: 10.3390/ijms25010101 -
Steroids Mar 2024Decidualization, a crucial process for successful pregnancy establishment and maintenance, involves endometrial stromal cell differentiation. This process is...
Decidualization, a crucial process for successful pregnancy establishment and maintenance, involves endometrial stromal cell differentiation. This process is orchestrated by estradiol (E2), progesterone, and other stimuli that increase intracellular cyclic adenosine monophosphate (cAMP) levels. The intracellular progesterone receptor (PR), encoded by the PGR gene, has a key role in decidualization. This study aimed to understand the role of sex steroids and cAMP in regulating PGR expression during the in vitro decidualization of the human immortalized endometrial stromal cell line, T-HESC. We subjected the cells to individual and combined treatments of E2, medroxyprogesterone (MPA), and cAMP. Additionally, we treated cells with PR and estrogen receptor antagonists and a protein kinase A (PKA) inhibitor. We evaluated the expression of PGR isoforms and decidualization-associated genes by RT-qPCR. Our findings revealed that cAMP induced PGR-B and PGR-AB expression by activating the PKA signaling pathway, while MPA downregulated their expression through the PR. Furthermore, downstream genes involved in decidualization, such as those coding for prolactin (PRL), insulin-like growth factor-binding protein-1 (IGFBP1), and Dickkopf-1 (DKK1), exhibited positive regulation via the cAMP-PKA pathway. Remarkably, MPA-activated PR signaling induced the expression of IGFBP1 and DKK1 but inhibited that of PRL. In conclusion, we have demonstrated that the PKA signaling pathway induces PGR gene expression during in vitro decidualization of the T-HESC human endometrial stromal cell line. This study has unraveled some of the intricate regulatory mechanisms governing PGR expression during this fundamental process for implantation and pregnancy maintenance.
Topics: Pregnancy; Female; Humans; Decidua; Receptors, Progesterone; Cyclic AMP-Dependent Protein Kinases; Endometrium; Progesterone; Cyclic AMP; Stromal Cells; Gene Expression; Cells, Cultured
PubMed: 38182066
DOI: 10.1016/j.steroids.2024.109363 -
The Oncologist May 2024The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains controversial, with lack of randomized trials comparing cyclin-dependent kinase (CDK)4/6-inhibitors (CDK4/6i) + endocrine therapy (ET) with chemotherapy + ET.
MATERIALS AND METHODS
We conducted an open-label randomized phase II trial (NCT03227328) to investigate whether chemotherapy + ET is superior to CDK4/6i + ET for HR+/HER2-negative MBC with aggressive features. PAM50 intrinsic subtypes (IS), immunological features, and gene expression were assessed on baseline samples.
RESULTS
Among 49 randomized patients (median follow-up: 35.2 months), median progression-free survival (mPFS) with chemotherapy + ET (11.2 months, 95% confidence interval [CI]: 7.7-15.4) was numerically shorter than mPFS (19.9 months, 95% CI: 9.0-30.6) with CDK4/6i + ET (hazard ratio: 1.41, 95% CI: 0.75-2.64). Basal-like tumors under CDK4/6i + ET exhibited worse PFS (mPFS: 11.4 months, 95% CI: 3.00-not reached [NR]) and overall survival (OS; mOS: 18.8 months, 95% CI: 18.8-NR) compared to other subtypes (mPFS: 20.7 months, 95% CI: 9.00-33.4; mOS: NR, 95% CI: 24.4-NR). In the chemotherapy arm, luminal A tumors showed poorer PFS (mPFS: 5.1 months, 95% CI: 2.7-NR) than other IS (mPFS: 13.2 months, 95% CI: 10.6-28.1). Genes/pathways involved in BC cell survival and proliferation were associated with worse outcomes, as opposite to most immune-related genes/signatures, especially in the CDK4/6i arm. CD24 was the only gene significantly associated with worse PFS in both arms. Tertiary lymphoid structures and higher tumor-infiltrating lymphocytes also showed favorable survival trends in the CDK4/6i arm.
CONCLUSIONS
The KENDO trial, although closed prematurely, adds further evidence supporting CDK4/6i + ET use in aggressive HR+/HER2-negative MBC instead of chemotherapy. PAM50 IS, genomic, and immunological features are promising biomarkers to personalize therapeutic choices.
Topics: Humans; Female; Breast Neoplasms; Cyclin-Dependent Kinase 4; Middle Aged; Cyclin-Dependent Kinase 6; Biomarkers, Tumor; Receptor, ErbB-2; Aged; Adult; Protein Kinase Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Receptors, Estrogen; Receptors, Progesterone
PubMed: 38175669
DOI: 10.1093/oncolo/oyad337 -
Nursing For Women's Health Feb 2024Vasomotor symptoms of menopause, more commonly called hot flashes and night sweats, affect up to 80% of individuals going through the menopausal transition. Hormone...
Vasomotor symptoms of menopause, more commonly called hot flashes and night sweats, affect up to 80% of individuals going through the menopausal transition. Hormone therapy with estrogen and often progesterone is the most effective treatment for these symptoms. Many people, however, cannot take estrogen or do not want to take hormones. Many individuals seek nonhormonal, over-the-counter treatment options that have little safety and efficacy information to support their use. In March 2023, the U.S. Food and Drug Administration approved fezolinetant (Veozah), a neurokinin 3 receptor antagonist for the treatment of vasomotor symptoms of menopause. This article presents an overview of fezolinetant, including appropriate usage, adverse effects, its use in special populations, and implications for nursing practice.
Topics: Female; Humans; Menopause; Hot Flashes; Heterocyclic Compounds, 2-Ring; Estrogens; Thiadiazoles
PubMed: 38161058
DOI: 10.1016/j.nwh.2023.11.005