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International Journal of Molecular... Feb 2024Breast cancer is a major cause of death worldwide. The complexity of endocrine regulation in breast cancer may allow the cancer cells to escape from a particular... (Review)
Review
Breast cancer is a major cause of death worldwide. The complexity of endocrine regulation in breast cancer may allow the cancer cells to escape from a particular treatment and result in resistant and aggressive disease. These breast cancers usually have fewer treatment options. Targeted therapies for cancer patients may offer fewer adverse side effects because of specificity compared to conventional chemotherapy. Signaling pathways of nuclear receptors, such as the estrogen receptor (ER), have been intensively studied and used as therapeutic targets. Recently, the role of the androgen receptor (AR) in breast cancer is gaining greater attention as a therapeutic target and as a prognostic biomarker. The expression of constitutively active truncated AR splice variants in breast cancer is a possible mechanism contributing to treatment resistance. Therefore, targeting both the full-length AR and AR variants, either through the activation or suppression of AR function, depending on the status of the ER, progesterone receptor, or human epidermal growth factor receptor 2, may provide additional treatment options. Studies targeting AR in combination with other treatment strategies are ongoing in clinical trials. The determination of the status of nuclear receptors to classify and identify patient subgroups will facilitate optimized and targeted combination therapies.
Topics: Humans; Male; Receptors, Androgen; Breast Neoplasms; Androgen Receptor Antagonists; Prostatic Neoplasms, Castration-Resistant
PubMed: 38339092
DOI: 10.3390/ijms25031817 -
Journal of Human Reproductive Sciences 2023Patients with polycystic ovarian syndrome (PCOS) have unique characteristics depending on its phenotype. Therefore, prediction of controlled ovarian stimulation (COS)...
BACKGROUND
Patients with polycystic ovarian syndrome (PCOS) have unique characteristics depending on its phenotype. Therefore, prediction of controlled ovarian stimulation (COS) response and assisted reproductive technique (ART) outcome in these becomes challenging.
AIMS
To assess the outcomes of assisted reproductive technology (ART) in various polycystic ovary syndrome (PCOS) phenotypes and to evaluate the predictive value of anti-Mullerian hormone (AMH) and total testosterone on ART success. Clinical pregnancy rate (CPR) was measured as the primary outcome.
SETTINGS AND DESIGN
This was a prospective observational study conducted at a tertiary care centre.
MATERIALS AND METHODS
A total of 190 infertile women with PCOS (Rotterdam criteria) were enrolled and were subdivided into four phenotypes. Baseline screening and transvaginal scan were done. All patients underwent COS using antagonist protocol with recombinant follicle-stimulating hormone, and an agonist trigger was given for follicular maturation. One or two blastocysts were transferred in a frozen-thawed embryo transfer cycle. Luteal phase support was given with vaginal progesterone.
STATISTICAL ANALYSIS USED
For quantitative variables, we employed the Kruskal-Wallis Test with post hoc Tukey's analysis. For continuous or ordinal variables, the Mann-Whitney U test was utilized. The analysis of categorical data was conducted using the Chi-square (χ2) test with SPSS 21 software.
RESULTS
Phenotype A was the most prevalent (37%). CPR was the highest in phenotype D (57.7%), followed by phenotype C (53.06%), A (43%) and B (36%). The mean serum AMH level was the highest in phenotype A (9.7 ± 4.3 ng/dL) and the lowest in phenotype B (5.9 ± 1.8 ng/dL). The mean total testosterone level was 103 ± 15.68 ng/mL in Type A, 109.46 ± 37.08 ng/mL in Type B and 48.52 ± 17.07 ng/ml in Type D.
CONCLUSION
Phenotype D showed higher CPR and lower miscarriage rate compared to other phenotypes (not significant) and was associated with good clinical outcome. No correlation could be established with serum AMH, total testosterone levels and CPR.
PubMed: 38322632
DOI: 10.4103/jhrs.jhrs_145_23 -
Anticancer Research Feb 2024Progesterone receptor antagonists have been found to provide significant extension of life and considerable palliative benefits in a large variety of very advanced...
BACKGROUND/AIM
Progesterone receptor antagonists have been found to provide significant extension of life and considerable palliative benefits in a large variety of very advanced cancers. Most of these treated cancers lack the classical nuclear progesterone receptor (nPR). The hypothesized targets are membrane (m) PRs to inhibit progesterone induced blocking factor (PIBF). To date, there have been no case reports documenting the efficacy of PR antagonists for small cell lung cancer (SCLC) confirmed by pathological analysis. The case reported here demonstrates the efficacy of the single oral agent mifepristone in treating resistant SCLC.
CASE REPORT
A 58-year-old man, presenting with a persistent cough, dyspnea on exertion, and marked weakness, was diagnosed with stage IV non-SCLC (NSCLC) that tested positive for the EGFR mutation. He was treated with the single agent osimertinib. When symptoms returned eight months later, along with radiographic evidence of marked cancer progression, a lung biopsy showed SCLC. He failed to respond to pembrolizumab and subsequently to atezolizumab. He was then treated with the single agent mifepristone 200 mg per day orally. He showed marked clinical improvement associated with marked radiographic improvement. Though clinically doing very well, after one year, his dominant lesion increased in size. His oncologist elected to stop mifepristone and treat with camrelizumab with anlototinib. His clinical condition deteriorated on these drugs, and he died five months later.
CONCLUSION
SCLC can be added to the long list of very advanced cancers that are treatment resistant to standard therapy, but respond well to PR antagonists.
Topics: Male; Humans; Middle Aged; Mifepristone; Receptors, Progesterone; Lung Neoplasms; Small Cell Lung Carcinoma; Progesterone; Carcinoma, Non-Small-Cell Lung
PubMed: 38307551
DOI: 10.21873/anticanres.16855 -
Hormones and Behavior Apr 2024Research in women showed that testosterone is associated with decreased selective attention towards infant stimuli, which can be compensated for by oxytocin...
Research in women showed that testosterone is associated with decreased selective attention towards infant stimuli, which can be compensated for by oxytocin administration. In theory, caregiving behavior is thought to be mediated by oxytocin. Oxytocin binds to dopaminergic neurons and thus supposedly motivates aspects of caregiving through its influence on dopaminergic transmission. Most previous studies on caregiving behaviors were thereby performed in women under hormonal contraception to avoid hormonal fluctuations. However, recent studies repeatedly demonstrated decisive influences of the hormonal changes across the female menstrual cycle on dopamine-mediated behaviors, suggesting that estradiol acts as dopamine agonist in the follicular phase and progesterone as dopamine antagonist in the luteal phase. In the present study, we investigated selective attention towards infants as one central aspect of caregiving behavior over the natural menstrual cycle and in relation to interindividual differences of estradiol and progesterone. As expected, we found that women with higher estradiol in the follicular phase also showed higher selective attention towards infant faces among adult distractors, whereas the correlation disappeared in the luteal phase. In contrast, progesterone did not correlate with selective attention towards infants. The present findings collectively support the assumption that estradiol may act as dopamine agonist in the follicular phase, thereby supposedly promoting an important aspect of caretaking behavior.
Topics: Adult; Female; Humans; Progesterone; Oxytocin; Dopamine Agonists; Menstrual Cycle; Luteal Phase; Follicular Phase; Estradiol; Attention
PubMed: 38306878
DOI: 10.1016/j.yhbeh.2024.105492 -
Human Reproduction (Oxford, England) Mar 2024What is the temporal activity and the concentration in follicular fluid (FF) of the anti-inflammatory steroid cortisol during the ovulatory process in humans?
STUDY QUESTION
What is the temporal activity and the concentration in follicular fluid (FF) of the anti-inflammatory steroid cortisol during the ovulatory process in humans?
SUMMARY ANSWER
Intrafollicular concentrations of cortisol become massively upregulated close to ovulation concomitant with an exceptionally high biological activity securing a timely and efficient termination of inflammatory processes.
WHAT IS KNOWN ALREADY
Ovulation has been described as a local, controlled inflammatory process resulting in the degeneration of the follicle wall which facilitate oocyte extrusion. Ovulation also affects the glucocorticoid metabolism of granulosa cells (GCs) and although de novo synthesis of cortisol only occurs in the adrenal cortex, the mid-cycle surge has been shown to induce a change from high expression of HSD11B2, inactivating cortisol to cortisone, to high expression of HSD11B1 which reversibly catalyses cortisol production from cortisone. Furthermore, high concentrations of progesterone and 17OH-progesterone within follicles may cause dislodging of cortisol from cortisol binding protein (CBP) thereby activating the biological activity of cortisol.
STUDY DESIGN, SIZE, DURATION
This prospective cohort study included 50 women undergoing fertility treatment according to a standard antagonist protocol at a university hospital-affiliated fertility clinic in Denmark.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Women donated FF and GCs from one follicle for research purpose aspirated at one of four time points during the process of final maturation of follicles: T = 0 h, T = 12 h, T = 17 h, T = 32 h. A second sample was collected at oocyte pick up at T = 36 h. The concentration of cortisol and cortisone together with a range of sex steroids was measured by LC-MS/MS in FF collected at the five time points mentioned above. Whole genome microarray data, validated by q-PCR analysis, was used to evaluate gene expression of CYP11B1, CYP21A2, HSD11B1, HSD11B2, and NR3C1 in GCs at the same time points.
MAIN RESULTS AND THE ROLE OF CHANCE
The concentration of cortisol was significantly increased from a few nM at 0 h to around 100-140 nM (P ≤ 0.0001) at 32-36 h, whilst cortisone was almost constant from 0 to 17 h at a concentration of between 90 and 100 nM being significantly reduced to 25-40 nM (P ≤ 0.0001) at 32-36 h. This was paralleled by a 690-fold upregulation of HSD11B1 from 0 to 12 h increasing to a more than 20.000-fold change at 36 h. HSD11B2 was quickly downregulated 15- to 20-fold after ovulation induction. Concentrations of progesterone and 17OH-progesterone increased during the ovulatory process to high levels which in essence displaces cortisol from its binding protein CBP due to similar binding affinities. Furthermore, a significant decrease in 11-deoxycortisol expression was seen, but CYP11B1 expression was below detection limit in GCs.
LIMITATIONS, REASONS FOR CAUTION
The study included women undergoing ovarian stimulation and results may differ from the natural cycle. More observations at each specific time point may have strengthened the conclusions. Furthermore, we have not been able to measure the actual active biological concentration of cortisol.
WIDER IMPLICATIONS OF THE FINDINGS
For the first time, this study collectively evaluated the temporal pattern of cortisol and cortisone concentrations during human ovulation, rendering a physiological framework for understanding potential dysregulations in the inflammatory reaction of ovulation.
STUDY FUNDING/COMPETING INTEREST(S)
This research was supported by the University Hospital of Copenhagen, Rigshospitalet, and Novo Nordisk Foundation grant number NNF21OC00700556. Interreg V ÔKS through ReproUnion (www.reprounion.eu); Region Zealand Research Foundation. The funders had no role in study design, collection of data, analyses, writing of the article, or the decision to submit it for publication. The authors have no conflicts of interest to declare.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Female; Humans; Progesterone; Hydrocortisone; Prospective Studies; Cortisone; Steroid 11-beta-Hydroxylase; Chromatography, Liquid; Fertilization in Vitro; Tandem Mass Spectrometry; Ovulation; Ovulation Induction; Steroid 21-Hydroxylase
PubMed: 38268234
DOI: 10.1093/humrep/deae003 -
Reproduction in Domestic Animals =... Jan 2024Kisspeptin (Kp), an upstream regulator of GnRH release, is essential for the development and function of reproductive axis. Previously, we demonstrated the localization...
Kisspeptin (Kp), an upstream regulator of GnRH release, is essential for the development and function of reproductive axis. Previously, we demonstrated the localization of Kp and its receptor (Kiss1r) in the active follicle in the bubaline ovary. Present study aimed to determine the effect of Kp on granulosa cell (GCs) functions, especially oestradiol (E ) and progesterone (P ) production, and differential expression of genes regulating the proliferation, apoptosis and steroidogenesis in the buffalo. The ovaries with 6-10 mm size follicles obtained from the cyclic buffaloes after slaughtering were used for isolation of GCs for in vitro study. The primary GCs culture was treated with Kp (0, 10, 50 and 100 nM) and incubated for 48 h. Production of E and P was estimated in the culture supernatant by ELISA. The expression of gonadotropin receptors (FSHR and LHR), steroidogenic genes (STAR, 3β-HSD, CYP19A1), proliferation marker (PCNA), apoptotic factors (CASP3 and BCL2) and Kp signalling molecule (extracellular signal-regulated kinase 1/2, ERK1/2 and p-ERK1/2) was studied in the GCs by qPCR. Significant E production was found in the Kp 50 and 100 nM groups (p < .05), whereas P production was reduced in Kp 100 nM group (p < .05). There was concomitant upregulation of FSHR, ERK1/2, STAR and CYP19A1 in the Kp 100 nM treated GCs. In addition, Kp at 100 nM stimulated the proliferation of GCs by upregulating the expression of BCL2 (5.0 fold) and PCNA (94.9 fold). Further, high immunoreactivity of p-ERK1/2 was observed in the Kp-treated GCs. It was concluded that Kp at 100 nM concentration stimulated E production by upregulating the steroidogenic pathway through ERK1/2, STAR and CYP19A1 and modulating PCNA and BCL2 expressions in the GCs. Further experiments are warranted using Kp antagonist in different combinations to establish the signalling pathway in Kp-mediated steroidogenesis in the GCs for developing strategies to control ovarian functions.
Topics: Animals; Female; Estradiol; Kisspeptins; Proliferating Cell Nuclear Antigen; Granulosa Cells; Bison; Cell Proliferation; Proto-Oncogene Proteins c-bcl-2
PubMed: 38268209
DOI: 10.1111/rda.14523 -
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