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Drug Design, Development and Therapy 2018Although early breast cancer (BC) is highly curable, advanced or metastatic disease poses numerous challenges in terms of medical management and treatment decisions and... (Review)
Review
Although early breast cancer (BC) is highly curable, advanced or metastatic disease poses numerous challenges in terms of medical management and treatment decisions and is associated with significantly worse prognosis. Among the new targeted agents, anticancer drugs exploiting the cell-cycle machinery have shown great potential in preclinical studies. CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell-cycle arrest, reduced cell viability and tumor shrinking. As the cyclin D/CDK complex is activated downstream of estrogen signaling, the combination of CDK4/6 inhibitors with standard endocrine therapies represents a rational approach to elicit synergic antitumor activity in hormone receptor-positive BC. The results of clinical trials have indeed confirmed the superiority of the combination of CDK4/6 inhibitors plus endocrine therapies over endocrine therapy alone. Currently approved are three compounds that exhibit similar structural characteristics as well as biological and clinical activities. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration (FDA) in view of the results of the MONARCH 1 and 2 trials. Further trials are ongoing as other important questions await response. In this review, we focus on abemaciclib to examine preclinical and clinical results, describing current therapeutic indications, open questions and ongoing clinical trials.
Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Hormone Antagonists; Humans; Protein Kinase Inhibitors; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Signal Transduction; Treatment Outcome
PubMed: 29497278
DOI: 10.2147/DDDT.S137783 -
Fertility and Sterility Aug 2014To assess the impact of elevated early follicular progesterone (P) levels in gonadotropin-releasing hormone (GnRH) antagonist cycles on clinical outcome using... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To assess the impact of elevated early follicular progesterone (P) levels in gonadotropin-releasing hormone (GnRH) antagonist cycles on clinical outcome using prospective data in combination with a systematic review and meta-analysis.
DESIGN
Nested study within a multicenter randomized controlled trial and a systematic review and meta-analysis.
SETTING
Reproductive medicine center in an university hospital.
PATIENT(S)
158 in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) patients.
INTERVENTION(S)
Recombinant follicle-stimulating hormone (FSH) (150-225 IU) administered daily from cycle day 2 onward; GnRH antagonist treatment randomly started on cycle day 2 or 6; assignment into two groups according to P level on cycle day 2: normal or elevated (>4.77 nmol/L or >1.5 ng/mL, respectively).
MAIN OUTCOME MEASURE(S)
Ongoing pregnancy rate (OPR) per started cycle.
RESULT(S)
The incidence of elevated P was 13.3%. A non-statistically-significant difference in OPR was present between the normal and elevated P groups (27.0% vs. 19.0%). No differential impact of early or late GnRH antagonist initiation on the effect of elevated or normal P on OPR was observed. A systematic search of Medline and EMBASE from 1972-2013 was performed to identify studies analyzing elevated early P levels in GnRH antagonists. The meta-analysis (n=1,052) demonstrated that elevated P levels statistically significantly decreased the OPR with 15% (95% CI -23, -7 %). Heterogeneity across the studies, presumably based on varying protocols, may have modulated the effect of elevated P.
CONCLUSION(S)
From the present meta-analysis it appears that early elevated P levels are associated with a lower OPR in GnRH antagonists. The incidence of such a condition, however, is low.
CLINICAL TRIAL REGISTRATION NUMBER
NCT00866034.
Topics: Adult; Biomarkers; Female; Fertility Agents, Female; Fertilization in Vitro; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Infertility; Netherlands; Ovarian Follicle; Ovulation Induction; Pregnancy; Pregnancy Rate; Progesterone; Randomized Controlled Trials as Topic; Recombinant Proteins; Sperm Injections, Intracytoplasmic; Time Factors; Treatment Outcome; Up-Regulation
PubMed: 24929258
DOI: 10.1016/j.fertnstert.2014.05.002 -
Breast Cancer Research : BCR Dec 2022A preoperative-progesterone intervention increases disease-free survival in patients with breast cancer, with an unknown underlying mechanism. We elucidated the role of...
BACKGROUND
A preoperative-progesterone intervention increases disease-free survival in patients with breast cancer, with an unknown underlying mechanism. We elucidated the role of non-coding RNAs in response to progesterone in human breast cancer.
METHODS
Whole transcriptome sequencing dataset of 30 breast primary tumors (10 tumors exposed to hydroxyprogesterone and 20 tumors as control) were re-analyzed to identify differentially expressed non-coding RNAs followed by real-time PCR analyses to validate the expression of candidates. Functional analyses were performed by genetic knockdown, biochemical, and cell-based assays.
RESULTS
We identified a significant downregulation in the expression of a long non-coding RNA, Down syndrome cell adhesion molecule antisense DSCAM-AS1, in response to progesterone treatment in breast cancer. The progesterone-induced expression of DSCAM-AS1 could be effectively blocked by the knockdown of progesterone receptor (PR) or treatment of cells with mifepristone (PR-antagonist). We further show that knockdown of DSCAM-AS1 mimics the effect of progesterone in impeding cell migration and invasion in PR-positive breast cancer cells, while its overexpression shows an opposite effect. Additionally, DSCAM-AS1 sponges the activity of miR-130a that regulates the expression of ESR1 by binding to its 3'-UTR to mediate the effect of progesterone in breast cancer cells. Consistent with our findings, TCGA analysis suggests that high levels of miR-130a correlate with a tendency toward better overall survival in patients with breast cancer.
CONCLUSION
This study presents a mechanism involving the DSCAM-AS1/miR-130a/ESR1 genomic axis through which progesterone impedes breast cancer cell invasion and migration. The findings highlight the utility of progesterone treatment in impeding metastasis and improving survival outcomes in patients with breast cancer.
Topics: Humans; Female; Breast Neoplasms; MicroRNAs; Progesterone; Cell Proliferation; Cell Line, Tumor; Cell Movement; RNA, Long Noncoding; Gene Expression Regulation, Neoplastic
PubMed: 36578092
DOI: 10.1186/s13058-022-01597-x -
Journal of Neuroendocrinology Feb 2022Trauma-focused psychotherapies show general efficacy in post-traumatic stress disorder (PTSD), although outcomes vary substantially among individuals with PTSD and many... (Review)
Review
Trauma-focused psychotherapies show general efficacy in post-traumatic stress disorder (PTSD), although outcomes vary substantially among individuals with PTSD and many patients do not achieve clinically meaningful symptom improvement. Several factors may contribute to poor treatment response, including genetic or environmental (e.g., stress) effects on neurobiological factors involved in learning and memory processes critical to PTSD recovery. In this review, we discuss the relationship between deficient GABAergic neurosteroid metabolites of progesterone, allopregnanolone (Allo) and pregnanolone (PA), and PTSD symptoms in men and women or PTSD-like behavioral abnormalities observed in male rodent models of PTSD. We also review the role and molecular underpinnings of learning and memory processes relevant to PTSD recovery, including extinction, extinction retention, reconsolidation of reactivated aversive memories and episodic non-aversive memory. We then discuss preclinical and clinical research that supports a role in these learning and memory processes for GABAergic neurosteroids and sulfated metabolites of Allo and PA that allosterically antagonize NMDA receptor function. Studies supporting the possible therapeutic impact of appropriately timed, acutely administered Allo or Allo analogs to facilitate extinction retention and/or block reconsolidation of aversive memories are also reviewed. Finally, we discuss important future directions for research in this area. Examining the varied and composite effects in PTSD of these metabolites of progesterone, as well as neuroactive derivatives of other parent steroids produced in the brain and the periphery, will likely enable a broadening of targets for treatment development. Defining contributions of these neuroactive steroids to common PTSD-comorbid psychiatric and medical conditions, as well as subpopulation-specific underlying dysfunctional physiological processes such as hypothalamic-pituitary-adrenal axis and immune system dysregulation, may also enable development of more effective multisystem precision medicines to prevent and treat the broader, polymorbid sequelae of extreme and chronic stress.
Topics: Female; Humans; Hypothalamo-Hypophyseal System; Male; Neurosteroids; Pituitary-Adrenal System; Pregnanolone; Progesterone; Receptors, N-Methyl-D-Aspartate; Stress Disorders, Post-Traumatic
PubMed: 34962690
DOI: 10.1111/jne.13062 -
Oncology (Williston Park, N.Y.) May 2018The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are rapidly transforming the care of patients with hormone receptor... (Review)
Review
The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are rapidly transforming the care of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) advanced breast cancer. Current clinical questions include how to choose among these agents and how to sequence them with other therapies. Areas of active inquiry include identifying predictive biomarkers for CDK4/6 inhibitors, deciding whether to continue CDK4/6 inhibitors after disease progression, creating novel treatment combinations, and expanding use beyond HR+/HER2- advanced breast cancer. Here, we review the current use of and potential next directions for CDK4/6 inhibitors in the treatment of patients with HR+ breast cancer.
Topics: Antineoplastic Agents; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Molecular Targeted Therapy; Protein Kinase Inhibitors; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Signal Transduction; Treatment Outcome
PubMed: 29847850
DOI: No ID Found -
Seminars in Perinatology Aug 2016Despite major advances in neonatal care, the burden of preterm birth remains high. This is not unexpected since strategies to identify and treat risk factors in early... (Review)
Review
Despite major advances in neonatal care, the burden of preterm birth remains high. This is not unexpected since strategies to identify and treat risk factors in early pregnancy have not been very effective in reducing the preterm birth rate. Initial studies suggested a potential benefit for 17-alpha-hydroxyprogesterone caproate (17-OHPC) in decreasing the risk of recurrent preterm birth women with a singleton gestation. However, the use of 17-OHPC has not conferred benefit for other categories of women at high risk for preterm delivery (twins, triplets, and short cervical length). The increasing body of evidence suggests that preterm birth is a complex condition with variable mechanisms of disease and significant individual heterogeneity. This review will examine the plausibility of 17-OHPC in preventing preterm birth and the investigation of its clinical efficacy. We will also highlight factors to explain variations in clinical trial outcomes and outline the trajectory needed for future investigations.
Topics: 17 alpha-Hydroxyprogesterone Caproate; Adult; Cervical Length Measurement; Cervix Uteri; Estrogen Antagonists; Evidence-Based Medicine; Female; Gestational Age; Humans; Hydroxyprogesterones; Infant, Newborn; Pregnancy; Pregnancy, Multiple; Premature Birth; Progesterone; Progestins; Randomized Controlled Trials as Topic; Recurrence; Treatment Outcome
PubMed: 27105940
DOI: 10.1053/j.semperi.2016.03.002 -
Frontiers in Immunology 2018Progesterone (P4) is an important steroid hormone for the establishment and maintenance of pregnancy and its functional withdrawal in reproductive tissue is linked with...
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.
Topics: Cytokines; Dendritic Cells; Female; Granzymes; Humans; Immune Tolerance; Immunity; Immunologic Memory; Immunomodulation; Leukocytes; Pregnancy; Progesterone; T-Lymphocyte Subsets
PubMed: 29973928
DOI: 10.3389/fimmu.2018.01293 -
European Journal of Endocrinology Jul 2023Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been proposed for treatment of endometriosis and polycystic ovary syndrome. Clinical biomarkers of target engagement, which can greatly facilitate drug development, have not yet been described for AKR1C3 inhibitors. Here, we analyzed pharmacodynamic data from a phase 1 study with a new selective AKR1C3 inhibitor, BAY1128688, to identify response biomarkers and assess effects on ovarian function.
DESIGN
In a multiple-ascending-dose placebo-controlled study, 33 postmenopausal women received BAY1128688 (3, 30, or 90 mg once daily or 60 mg twice daily) or placebo for 14 days. Eighteen premenopausal women received 60 mg BAY1128688 once or twice daily for 28 days.
METHODS
We measured 17 serum steroids by liquid chromatography-tandem mass spectrometry, alongside analysis of pharmacokinetics, menstrual cyclicity, and safety parameters.
RESULTS
In both study populations, we observed substantial, dose-dependent increases in circulating concentrations of the inactive androgen metabolite androsterone and minor increases in circulating etiocholanolone and dihydrotestosterone concentrations. In premenopausal women, androsterone concentrations increased 2.95-fold on average (95% confidence interval: 0.35-3.55) during once- or twice-daily treatment. Note, no concomitant changes in serum 17β-estradiol and progesterone were observed, and menstrual cyclicity and ovarian function were not altered by the treatment.
CONCLUSIONS
Serum androsterone was identified as a robust response biomarker for AKR1C3 inhibitor treatment in women. Aldo-keto reductase 1C3 inhibitor administration for 4 weeks did not affect ovarian function.ClinicalTrials.gov Identifier: NCT02434640; EudraCT Number: 2014-005298-36.
Topics: Female; Humans; Aldo-Keto Reductase Family 1 Member C3; Androgens; Androsterone; Dihydrotestosterone; Hydroxyprostaglandin Dehydrogenases; Progesterone; Steroids
PubMed: 37306288
DOI: 10.1093/ejendo/lvad063 -
Journal of Animal Science Nov 2021Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β family of proteins that have been implicated in the paracrine regulation of granulosa...
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β family of proteins that have been implicated in the paracrine regulation of granulosa cell (GC) function, but whether responses to BMPs change with follicular size or interact with connective tissue growth factor (CTGF) or BMP antagonists (e.g., gremlin [GREM]) to directly affect GC function of cattle is unknown. Therefore, to determine the effects of BMP4 on proliferation and steroidogenesis of GCs and its interaction with GREM or CTGF, experiments were conducted using bovine GC cultures. In vitro, BMP4 (30 ng/mL) inhibited (P < 0.05) follicle-stimulating hormone (FSH) plus insulin-like growth factor 1 (IGF1)-induced progesterone and estradiol production by large- and small-follicle GCs, but the inhibitory effect of BMP4 on estradiol production was much more pronounced in large-follicle GCs. In small-follicle GCs, BMP4 had no effect (P > 0.10) on IGF1-induced proliferation, but GREM inhibited (P < 0.05) cell proliferation and estradiol and progesterone production in IGF1 plus FSH-treated GCs. In large-follicle GCs, BMP4 (10 to 30 ng/mL) increased (P < 0.05) GC numbers and GREM (100 ng/mL) blocked this effect. In large-follicle GCs, CTGF inhibited (P < 0.05) FSH plus IGF1-induced progesterone and estradiol production, and CTGF blocked the stimulatory effect of BMP4 on GC proliferation. These results indicate that BMP4, GREM, and CTGF inhibit GC aromatase activity and progesterone production. Also, the stimulatory effect of BMP4 on GC proliferation and the inhibitory effects of BMP4 on GC steroidogenesis are more pronounced in large vs. small follicles.
Topics: Animals; Bone Morphogenetic Protein 4; Cattle; Cells, Cultured; Connective Tissue Growth Factor; Estradiol; Female; Follicle Stimulating Hormone; Granulosa Cells; Progesterone
PubMed: 34724558
DOI: 10.1093/jas/skab318 -
Reproduction & Fertility Apr 2021Effects of conservative treatment on uterine blood flow and morphometric findings are still unknown in bitches. Thus, this study aimed to compare uterine changes of...
UNLABELLED
Effects of conservative treatment on uterine blood flow and morphometric findings are still unknown in bitches. Thus, this study aimed to compare uterine changes of pyometra bitches subjected to distinct modes of treatment. Pyometra bitches were assigned to: OHE (ovariohysterectomy immediately after diagnosis), Aglepristone (days 1, 2 and 8) and Associative (aglepristone treatment coupled with cloprostenol for 7 days) groups. After 9 days, bitches were ovariohysterectomized. Before surgery, uterine area was measured ultrasonographically and the uterine artery Doppler velocimetry analyzed blood flow velocity and indexes. Uterine horns were classified according to resistance index (RI) as more compromised and less compromised. Endometrial vasculature was quantitatively evaluated by color flow Doppler. Blood samples were collected to determine nitric oxide (NO) concentrations. Histological uterine structures were quantified by stereology and VEGF-A (vascular endothelial growth factor) and eNOS were (endothelial nitric oxide synthase) immunohistochemically analyzed. Aglepristone and Associative groups had lower uterine area and vascularization, and higher blood flow velocity and indexes compared to OHE group. Less compromised horn of Associative group had higher blood flow velocity compared to OHE group. Aglepristone group presented lower inflammatory infiltrate and larger uterine stroma. Associative group had lower volume density and absolute surface of endometrial cysts and lower VEGF-A expression for glandular epithelium and stromal cells. Blood NO and e-NOS immunostaining were not different among groups. In conclusion, association between aglepristone and prostaglandin is more effective in decreasing uterine vascularization and modulating uterine blood flow. Moreover, associative therapy promotes marked morphological changes.
LAY SUMMARY
This research compared two medical protocols of treatment for uterine infection (pyometra) in bitches, using a hormone blocker (anti-progesterone aglepristone) solely or in association with a uterine contraction inducer (prostaglandin; associative therapy). After treatment, bitches were gonadectomized and a microscopic analysis of uterine blood vessel formation and uterine tissue elements were performed as well as uterine blood flow evaluation through Doppler ultrasonography. According to vascular resistance, uterine horns were additionally classified as more compromised and less compromised. Both treatment protocols led to reduction of uterine dimensions and vascularization, and higher blood flow compared to untreated bitches. Less compromised uterine horn of the associative treatment had higher blood flow compared to untreated bitches. The hormone blocker treatment had lower inflammatory cells and larger uterine histological structure, while associative treatment had less uterine pathological cysts and lower blood vessel formation. The associative therapy is effective in decreasing uterine vascularization and modulating uterine blood flow as well as reestablishing endometrium structure in bitches with uterine infection.
Topics: Animals; Cysts; Dog Diseases; Dogs; Endometritis; Female; Hormones; Humans; Pregnancy; Progestins; Prostaglandins; Pyometra; Vascular Endothelial Growth Factor A
PubMed: 35128446
DOI: 10.1530/RAF-20-0020