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Scientific Reports Jun 2024Despite the proven superiority of various luteal phase support protocols (LPS) over placebo in view of improved pregnancy rates in fresh cycles of IVF (in vitro... (Meta-Analysis)
Meta-Analysis Comparative Study
Despite the proven superiority of various luteal phase support protocols (LPS) over placebo in view of improved pregnancy rates in fresh cycles of IVF (in vitro fertilization) and ICSI (intracytoplasmic sperm injection) cycles, there is ongoing controversy over specific LPS protocol selection, dosage, and duration. The aim of the present study was to identify the optimal LPS under six core aspects of ART success, clinical pregnancy, live birth as primary outcomes and biochemical pregnancy, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome (OHSS) events as secondary outcomes. Twelve databases, namely Embase (OVID), MEDLINE (R) (OVID), GlobalHealth (Archive), GlobalHealth, Health and Psychosocial Instruments, Maternity & Infant Care Database (MIDIRS), APA PsycTests, ClinicalTrials.gov, HMIC Health Management Information Consortium, CENTRAL, Web of Science, Scopus and two prospective registers, MedRxiv, Research Square were searched from inception to Aug.1st, 2023, (PROSPERO Registration: CRD42022358986). Only Randomised Controlled Trials (RCTs) were included. Bayesian network meta-analysis (NMA) model was employed for outcome analysis, presenting fixed effects, odds ratios (ORs) with 95% credibility intervals (CrIs). Vaginal Progesterone (VP) was considered the reference LPS given its' clinical relevance. Seventy-six RCTs, comparing 22 interventions, and including 26,536 participants were included in the present NMA. Overall CiNeMa risk of bias was deemed moderate, and network inconsistency per outcome was deemed low (Multiple pregnancy χ: 0.11, OHSS χ: 0.26), moderate (Clinical Pregnancy: χ: 7.02, Live birth χ: 10.95, Biochemical pregnancy: χ: 6.60, Miscarriage: χ: 11.305). Combinatorial regimens, with subcutaneous GnRH-a (SCGnRH-a) on a vaginal progesterone base and oral oestrogen (OE) appeared to overall improve clinical pregnancy events; VP + OE + SCGnRH-a [OR 1.57 (95% CrI 1.11 to 2.22)], VP + SCGnRH-a [OR 1.28 (95% CrI 1.05 to 1.55)] as well as live pregnancy events, VP + OE + SCGnRH-a [OR 8.81 (95% CrI 2.35 to 39.1)], VP + SCGnRH-a [OR 1.76 (95% CrI 1.45 to 2.15)]. Equally, the progesterone free LPS, intramuscular human chorionic gonadotrophin, [OR 9.67 (95% CrI 2.34, 73.2)] was also found to increase live birth events, however was also associated with an increased probability of ovarian hyperstimulation, [OR 1.64 (95% CrI 0.75, 3.71)]. The combination of intramuscular and vaginal progesterone was associated with higher multiple pregnancy events, [OR 7.09 (95% CrI 2.49, 31.)]. Of all LPS protocols, VP + SC GnRH-a was found to significantly reduce miscarriage events, OR 0.54 (95% CrI 0.37 to 0.80). Subgroup analysis according to ovarian stimulation (OS) protocol revealed that the optimal LPS across both long and short OS, taking into account increase in live birth and reduction in miscarriage as well as OHSS events, was VP + SCGnRH-a, with an OR 2.89 [95% CrI 1.08, 2.96] and OR 2.84 [95% CrI 1.35, 6.26] respectively. Overall, NMA data suggest that combinatorial treatments, with the addition of SCGnRH-a on a VP base result in improved clinical pregnancy and live birth events in both GnRH-agonist and antagonist ovarian stimulation protocols.
Topics: Humans; Female; Sperm Injections, Intracytoplasmic; Pregnancy; Network Meta-Analysis; Fertilization in Vitro; Luteal Phase; Pregnancy Rate; Progesterone; Live Birth; Bayes Theorem; Ovulation Induction; Randomized Controlled Trials as Topic; Ovarian Hyperstimulation Syndrome; Abortion, Spontaneous
PubMed: 38914570
DOI: 10.1038/s41598-024-64804-z -
International Journal of Applied &... 2024Angiogenesis, the formation of new blood vessels from preexisting vascular network, is essential for tumor growth and spread. Vascular endothelial growth factor (VEGF)...
CONTEXT
Angiogenesis, the formation of new blood vessels from preexisting vascular network, is essential for tumor growth and spread. Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor.
AIMS
To assess the expression of VEGF in invasive carcinoma of no special type and its correlation with all the known prognostic factors of breast carcinoma.
SETTINGS AND DESIGN
Descriptive.
MATERIALS AND METHODS
Mastectomy specimens were studied noting the clinical details. The formalin-fixed tissues were subjected to routine processing and hematoxylin and eosin sections and studied extensively for all the histological prognostic factors. Representative sections from each case with the tumor were subjected to immunohistochemistry (IHC) staining with VEGF, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) antibodies.
STATISTICAL ANALYSIS USED
Descriptive statistics, Chi-square tests, contingency table analysis using SPSS for Windows.
RESULTS
One hundred and twelve cases of invasive carcinoma of special type were studied to evaluate various clinicopathological parameters. The association of VEGF with clinicopathological parameters and all the known prognostic factors was studied to note its significance. VEGF overexpression was observed in 69% of the cases. It was noted that larger tumor size, higher histological grade, lymphovascular invasion, nodal involvement, tumor necrosis, high microvessel density, ER negativity, PR negativity, and HER2/neu positivity had a significant statistical association with VEGF overexpression.
CONCLUSIONS
We conclude that incorporating VEGF as a biomarker along with the known factors into a prognostic index will not only help predict clinical outcome more accurately, but also determines the patient who can be benefited with combinational therapy including anti-VEGF factors.
PubMed: 38912361
DOI: 10.4103/ijabmr.ijabmr_17_24 -
Ochsner Journal 2024Male breast cancer remains relatively underexplored in the medical literature. At present, male patients with breast cancer follow the same treatment guidelines as...
Male breast cancer remains relatively underexplored in the medical literature. At present, male patients with breast cancer follow the same treatment guidelines as female patients with breast cancer, principally because of similar outcomes with treatment. However, this practice should not preclude generating evidence for male breast cancer surveillance, diagnosis, and management. BRCA2 gene mutations are associated with an increased risk of male breast cancer, along with lesser-known gene mutations that could also increase this risk, such as mutations of the BRIP1 gene. This case report presents a male patient with dual BRCA2 and BRIP1 deleterious gene mutations. To our knowledge, this combination has not been reported in the medical literature to date. A 53-year-old male presented with a palpable symptomatic mass underneath the right nipple-areolar complex. Biopsies confirmed a poorly differentiated, infiltrating ductal carcinoma that was estrogen and progesterone receptor positive and human epidermal growth factor receptor-2 negative. The patient underwent a left modified radical mastectomy, with a right prophylactic simple mastectomy. Postoperatively, he underwent adjuvant chemotherapy and endocrine therapy. This novel case of genetically based male breast cancer with dual deleterious gene mutations provides insight into current treatment recommendations and the subtle differences between male breast cancer and female breast cancer. Engaging in discussions surrounding such rare cases not only raises awareness of male breast cancer but also indicates the need for further research aimed at establishing evidence-based management strategies for male patients with breast cancer.
PubMed: 38912178
DOI: 10.31486/toj.23.0119 -
Frontiers in Physiology 2024The neuropeptides kisspeptin, neurokinin B, and dynorphin A are imperative for the pulsatile secretion of gonadotropin-releasing hormone and luteinizing hormone to...
The neuropeptides kisspeptin, neurokinin B, and dynorphin A are imperative for the pulsatile secretion of gonadotropin-releasing hormone and luteinizing hormone to ultimately regulate reproductive cyclicity. A population of neurons co-expressing these neuropeptides, KNDy neurons, within the arcuate nucleus of the hypothalamus (ARC) are positioned to integrate energy status from afferent neuronal and glial cells. We hypothesized that KNDy-expressing neurons in the ARC of mature ewes are influenced by energy balance. To test this hypothesis, ovary-intact, mature ewes were fed to lose, maintain, or gain body weight and hypothalamic tissue harvested during the luteal phase of the estrous cycle. Fluorescent, multiplex immunohistochemistry with direct antibody conjugation was employed to identify and quantify neurons expressing a single neuropeptide, as well as for the first time report co-expression of kisspeptin, neurokinin B, and dynorphin A protein in the ARC. Previous reports using this population of ewes demonstrated that concentrations of insulin and leptin differed between ewes fed to achieve different body weights and that ewes fed to gain body weight had increased concentrations of progesterone. Moreover, within this population of ewes tanycyte density and cellular penetration into the ARC was increased in ewes fed to gain body weight. Within the current report we have revealed that the number of neurons in the ARC expressing kisspeptin, neurokinin B, and dynorphin A protein was increased in ewes fed to gain body weight. Moreover, the number of KNDy neurons in the ARC expressing all three neuropeptides within a single neuron was decreased in ewes fed to lose body weight and increased in ewes fed to gain body weight when compared to ewes fed to maintain body weight. The cumulative findings of this experimental model suggest that expression of kisspeptin, neurokinin B, and dynorphin A protein in the ARC during the luteal phase of the estrous cycle are influenced by energy balance-induced alterations in circulating concentrations of progesterone that drive changes in morphology and density of tanycytes to ultimately regulate central perception of global energy status. Moreover, these results demonstrate that changes in KNDy neurons within the ARC occur as an adaptation to energy balance, potentially regulated divergently by metabolic milieu via proopiomelanocortin afferents.
PubMed: 38911326
DOI: 10.3389/fphys.2024.1372944 -
Indian Journal of Endocrinology and... 2024Congenital adrenal hyperplasia (CAH) comprises a heterogeneous group of autosomal recessive disorders impairing adrenal steroidogenesis. Most cases are caused by... (Review)
Review
Congenital adrenal hyperplasia (CAH) comprises a heterogeneous group of autosomal recessive disorders impairing adrenal steroidogenesis. Most cases are caused by mutations in the gene resulting in 21-hydroxylase (21-OH) deficiency (21-OHD). The genetics of 21-OH CAH is complexed by a highly homologous pseudogene imposing several limitations in the molecular analysis. Therefore, genetic testing is still not a part of routine CAH diagnosis and is mainly dependent on 17-hydroxy progesterone (OHP) measurements. There are very few reports of gene analysis from India and there is no comprehensive review available on genetic testing and the spectrum of mutations from the country. This review focuses on the molecular aspects of 21-OHD and the genetic studies on gene reported from India. The results of these studies insist the compelling need for large-scale genetic testing and newborn screening (NBS) in India. With a high disease prevalence and consanguinity rates, robust and cost-effective genetic testing for 21-OH CAH would enable an accurate diagnosis in routine clinical practice. Whereas establishing affordable genotyping assays even in secondary care or resource-poor settings of the country can identify 90% of the mutations that are pseudogene derived, initiatives on reference laboratories for CAH across the nation with comprehensive genetic testing facilities will be beneficial in those requiring extended analysis of gene. Further to this, incorporating genetic testing in NBS and carrier screening programmes will enable early diagnosis, better risk assessment and community-based management.
PubMed: 38911104
DOI: 10.4103/ijem.ijem_303_23 -
Veterinary World May 2024Progesterone (P4) is the main hormone for pregnancy maintenance, occurring approximately 62-64 days after ovulation in bitches. Progesterone acts by binding to specific...
BACKGROUND AND AIM
Progesterone (P4) is the main hormone for pregnancy maintenance, occurring approximately 62-64 days after ovulation in bitches. Progesterone acts by binding to specific receptors. Aglepristone is a progesterone receptor (PR) antagonist with a higher affinity for PR binding. There are no published studies on cell proliferation and apoptosis in the canine uterus at the time of parturition. Therefore, this study aimed to determine the local effects of aglepristone on cell proliferation and apoptosis of interplacental uterine tissue during planned cesarean section (C-section) in bitches.
MATERIALS AND METHODS
In this study, 13 client-owned French bulldogs were examined. Bitches were divided into treatment (n = 8) and control (n = 5) groups. Ovulation timing was predicted based on the serum P4 level on 62-64 days post-ovulation for parturition. Serum P4 levels were measured before (on 60-day post-ovulation) and on C-section day (on 61-day post-ovulation). Aglepristone (Alizine), 15 mg/kg subcutaneously (SC), was administered on 60 days post-ovulation in the treatment group. A C-section was planned 20-24 h later, and interplacental uterine areas were collected from both groups during the C-section. Immunohistochemistry based on Ki-67 and TUNEL assay was used to evaluate cell proliferation and apoptosis in four different interplacental uterine tissue layers (epithelium, stroma, glandular epithelium, and myometrium). Data are reported as mean ± standard deviation. Kruskal-Wallis test was used for comparisons of more than two independent groups. P value of 0.05 was considered statistically significant.
RESULTS
One bitch in the treatment group was excluded due to emergency C-section 8 h after aglepristone administration. Serum P4 levels (ng/mL) at 20-24 h before and at C-section were 6.09 ± 2.72 and 4.32 ± 2.2 in the treatment group (n = 7) and 5.45 ± 1.28 and 3.67 ± 1.89 in the control group (n = 5), respectively. Proliferation (PI) and apoptotic (AI) indices were <5% and >45%, respectively, in both the treatment (n = 5) and control (n = 3) groups. PI and AI were detected at interplacental areas.
CONCLUSION
There were no significant differences in serum P4 levels or PI and AI indices between the groups. The PI <5% and AI was higher than 45% in both groups. Aglepristone did not have a direct effect on the serum P4 levels in both groups. These results correlated with the natural physiology of parturition preparation. Aglepristone 15 mg/kg SC injected 20-24 h before parturition had no effect on the P4 level, nor were any harmful effects observed for a planned C-section in pregnant bitches.
PubMed: 38911094
DOI: 10.14202/vetworld.2024.956-962 -
Hormones and Behavior Jun 2024Autism Spectrum Disorder (ASD) is characterized by differences in social communication and interaction, as well as areas of focused interests and/or repetitive...
Autism Spectrum Disorder (ASD) is characterized by differences in social communication and interaction, as well as areas of focused interests and/or repetitive behaviors. Recent studies have highlighted a higher prevalence of endocrine and reproductive disturbances among females on the autism spectrum, hinting at potential disruptions within the hypothalamus-pituitary-ovary (HPO) axis. This research aims to explore the reproductive health disparities in ASD using an animal model of autism, the C58/J inbred mouse strain, with a focus on reproductive performance and hormonal profiles compared to the C57BL/6J control strain. Our findings revealed that the estrous cycle in C58/J females is disrupted, as evidenced by a lower frequency of complete cycles and a lack of cyclical release of estradiol and progesterone compared to control mice. C58/J females also exhibited poor performance in several reproductive parameters, including reproductive lifespan and fertility index. Furthermore, estrogen receptor alpha content showed a marked decrease in the hypothalamus of C58/J mice. These alterations in the estrous cycle, hormonal imbalances, and reduced reproductive function imply dysregulation in the HPO axis. Additionally, our in-silico study identified a group of genes involved in infertility carrying single-nucleotide polymorphisms (SNPs) in the C58/J strain, which also have human orthologs associated with autism. These findings could offer valuable insights into the molecular underpinnings of neuroendocrine axis disruption and reproductive issues observed in ASD.
PubMed: 38909429
DOI: 10.1016/j.yhbeh.2024.105593 -
Nature Communications Jun 2024Drug exposure during pregnancy lacks global fetal safety data. The maternal drug exposure birth cohort (DEBC) study, a prospective longitudinal investigation, aims to...
Drug exposure during pregnancy lacks global fetal safety data. The maternal drug exposure birth cohort (DEBC) study, a prospective longitudinal investigation, aims to explore the correlation of maternal drug exposure during pregnancy with pregnancy outcomes, and establish a human biospecimen biobank. Here we describe the process of establishing DEBC and show that the drug exposure rate in the first trimester of pregnant women in DEBC (n = 112,986) is 30.70%. Among the drugs used, dydrogesterone and progesterone have the highest exposure rates, which are 11.97% and 10.82%, respectively. The overall incidence of adverse pregnancy outcomes is 13.49%. Dydrogesterone exposure during the first trimester is correlated with higher incidences of stillbirth, preterm birth, low birth weight, and birth defects, along with a lower incidence of miscarriage/abortion. Due to the limitations of this cohort study, causative conclusions cannot be drawn. Further follow-up and in-depth data analysis are planned for future studies.
Topics: Humans; Female; Pregnancy; China; Maternal Exposure; Adult; Premature Birth; Pregnancy Trimester, First; Prospective Studies; Pregnancy Outcome; Dydrogesterone; Progesterone; Birth Cohort; Infant, Newborn; Abortion, Spontaneous; Stillbirth; Infant, Low Birth Weight; Longitudinal Studies; Incidence; Young Adult
PubMed: 38906856
DOI: 10.1038/s41467-024-49623-0 -
European Journal of Radiology Jun 2024To evaluate the effectiveness of both synthetic magnetic resonance imaging (SyMRI) and conventional diffusion-weighted imaging (DWI) for identifying the human epidermal...
Noninvasive identification of HER2-zero, -low, or -overexpressing breast cancers: Multiparametric MRI-based quantitative characterization in predicting HER2-low status of breast cancer.
PURPOSE
To evaluate the effectiveness of both synthetic magnetic resonance imaging (SyMRI) and conventional diffusion-weighted imaging (DWI) for identifying the human epidermal growth factor receptor 2 (HER2) status in breast cancer (BC) patients.
METHOD
In this retrospective study, 114 women with DWI and SyMRI were pathologically classified into three groups: HER2-overexpressing (n = 40), HER2-low-expressing (n = 53), and HER2-zero-expressing (n = 21). T1 and T2 relaxation times and proton density (PD) were assessed before and after enhancement, and the resulting quantitative parameters produced by SyMRI were recorded as T1, T2, and PD and T1e, T2e, and PDe. Logistic regression was used to identify the best indicators for classifying patients based on HER2 expression. The discriminative performance of the models was evaluated using receiver operating characteristic (ROC) curves.
RESULTS
Our preliminary study revealed significant differences in progesterone receptor (PR) status, Ki-67 index, and axillary lymph node (ALN) count among the HER2-zero, -low, and -overexpressing groups (p < 0.001 to p = 0.03). SyMRI quantitative indices showed significant differences among BCs in the three HER2 subgroups, except for ΔT2 (p < 0.05). our results indicate that PDe achieved an area under the curve(AUC)of 0.849 (95 % CI: 0.760-0.915) for distinguishing HER2-low and -overexpressing BCs. Further investigation revealed that both the PDe and ADC were indicators for predicting differences among patients with HER2-zero and HER2-low-expressing BC, with AUCs of 0.765(95 % CI: 0.652-0.855) and 0.684(95 % CI: 0.565-0.787), respectively. The addition of the PDe to the ADC improved the AUC to 0.825(95 % CI: 0.719-0.903).
CONCLUSIONS
SyMRI could noninvasively and robustly predict the HER2 expression status of patients with BC.
PubMed: 38905803
DOI: 10.1016/j.ejrad.2024.111573 -
Human Reproduction Open 2024Is acute haemoperitoneum that is managed conservatively a precursor of deep endometriosis?
STUDY QUESTION
Is acute haemoperitoneum that is managed conservatively a precursor of deep endometriosis?
SUMMARY ANSWER
Our study provides evidence to suggest that acute haemoperitoneum may lead to the development of deep endometriosis in a significant proportion of cases.
WHAT IS KNOWN ALREADY
A recent pilot study was the first to suggest that acute haemoperitoneum could be a precursor of deep endometriosis. However, the sample size was small, and the follow-up was not standardized owing to unknown rates of clot absorption and development of endometriosis.
STUDY DESIGN SIZE DURATION
This was a prospective observational cohort study conducted at a single centre over a 31-month period. A required sample size of 30 was calculated using results from a previous study, with a minimum of 15 women each in the groups with and without significant haemoperitoneum (study and control groups, respectively). A total of 59 women were recruited to the study and eight were lost to follow-up. The final sample comprised 51 women, 15 in the study group and 36 in the control group.
PARTICIPANTS/MATERIALS SETTING METHODS
All non-pregnant, premenopausal women aged 18-50 years who consecutively presented to our dedicated gynaecological diagnostic unit with severe acute lower abdominal pain were eligible for this study. We only included women who were clinically stable and were suitable for conservative management. Those with prior history or evidence of endometriosis on their initial ultrasound scan, previous hysterectomy, or bilateral oophorectomy were excluded. Participants had standardized follow-up visits for 6 months, with pelvic ultrasound scans and the British Society of Gynaecological Endoscopy pelvic pain questionnaires completed at each visit. The primary outcome was the sonographically confirmed presence of newly formed endometriosis. Secondary outcomes were the presence and change of pelvic pain symptoms and health-related quality of life (HR-QOL).
MAIN RESULTS AND THE ROLE OF CHANCE
After completion of follow-up, 7/15 (47%; 95% CI 21.3-71.4%) women presenting with acute haemoperitoneum (study group) developed sonographic evidence of deep endometriosis, compared to 0/36 (0%; 97.5% CI 0.0-9.7%) women in the control group. A ruptured functional haemorrhagic cyst was the most common cause of haemoperitoneum, occurring in 13/15 cases (87%). The time from the initial event to sonographic evidence of endometriosis varied from 2 to 6 months. The EuroQol visual analogue scores were not significantly different at baseline between the groups that developed and did not develop endometriosis [28 (interquartile range (IQR) 15-40, n = 6) vs 56 (IQR 35-75, n = 44), =0.09], while the EuroQol-5D values were lower in the endometriosis group [-0.01 (IQR -0.07 to 0.19, n = 6) vs 0.62 (IQR 0.24-0.73, n = 44), =0.002]. At 6 months, the EuroQol-5D scores were improved in both groups, but remained significantly lower in the endometriosis group compared to the no endometriosis group [0.69 (IQR 0.66-0.80, n = 6) vs 0.85 (IQR 0.76-1.00, n = 44), =0.03]. There was no clinically relevant difference in the pelvic pain scores at either time point.
LIMITATIONS REASONS FOR CAUTION
It remains uncertain whether minimal, superficial endometriosis existed at commencement of the study and had a role in the development of deep endometriosis. Although the ultrasound findings were in keeping with deep endometriosis, this was not confirmed histologically. The pelvic pain and HR-QOL findings could have been influenced by the baseline scores being taken when the patient was admitted with acute pain. Also, the sample size was too small to draw reliable conclusions regarding the impact of newly developed endometriosis on QoL.
WIDER IMPLICATIONS OF THE FINDINGS
Our study provides further evidence showing that significant haemoperitoneum may be a precursor of deep endometriosis. Haemodynamically stable women presenting with acute pelvic pain and significant haemoperitoneum should be counselled about the risk of developing deep endometriosis. Interventional studies should be carried out in the future to see whether laparoscopy and pelvic washout could prevent development of deep endometriosis. Preventative strategies, including treatment to suppress ovulation and formation of functional cysts, should be further investigated. This includes the combined and progesterone-only contraceptive pills. Larger future studies are also required to assess women over a longer period of time, with adjustment for confounding factors, to evaluate a possible effect on HR-QOL and pain symptoms.
STUDY FUNDING/COMPETING INTERESTS
Funding was obtained from The Gynaecology Ultrasound Centre, London, UK. TT received personal fees from GE, Samsung, Medtronic, and Merck for lectures on ultrasound. TT also received a postdoctoral grant from the South-Eastern Norwegian Health Authority (grant number 2020083).
TRIAL REGISTRATION NUMBER
researchregistry6472.
PubMed: 38905001
DOI: 10.1093/hropen/hoae036