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Cancer May 2024Nirogacestat is a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors. In the phase 3 DeFi study (NCT03785964) of...
INTRODUCTION
Nirogacestat is a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors. In the phase 3 DeFi study (NCT03785964) of nirogacestat, ovarian toxicity (OT) was identified as a safety signal among females of reproductive potential (FORP). This analysis further describes the incidence, presentation, and resolution of OT.
METHODS
Patients were randomized to twice-daily oral nirogacestat (150 mg) or placebo, taken in continuous 28-day cycles. Investigator-identified OT in FORP was based on abnormal reproductive hormone values or perimenopausal symptoms (or both). Adverse event follow-up was conducted to assess OT resolution. Post hoc analyses included return of menstruation and return of follicle-stimulating hormone (FSH) to within normal limits (WNL) (≤20.4 mIU/mL).
RESULTS
Of 92 randomized females, 73 in the safety population were FORP (n = 36 nirogacestat, n = 37 placebo). OT was identified in 75% (27 of 36) receiving nirogacestat and 0% (0 of 37) receiving placebo. As of October 24, 2022, investigators reported OT resolution in 78% (21 of 27) of patients, with median OT duration of 19.1 weeks. Off-treatment resolution was reported in all 11 patients (100%) who stopped nirogacestat treatment; of these, all nine with available menstruation information experienced return of menstruation and eight had FSH WNL at last reported assessment. Resolution was reported in 10 of 14 (71%) while on nirogacestat; of these, all 10 experienced return of menstruation and seven had FSH WNL. Two patients were lost to follow-up.
CONCLUSION
Most FORP treated with nirogacestat experienced OT, with the majority resolving, including all who stopped treatment, suggesting that OT is transient.
PubMed: 38703010
DOI: 10.1002/cncr.35324 -
Journal of Medicinal Food Apr 2024Tao-Hong-Si-Wu-Tang (THSWT), a traditional Chinese herbal remedy, is commonly utilized for the treatment of female perimenopausal depression through regulating...
Tao-Hong-Si-Wu-Tang Improves the Depressive-like Behaviors in Mice Experiencing Perimenopausal Depression Through Modulating Activity of the Hypothalamic-Pituitary-Adrenal-Ovary Axis and Activating the BDNF-TrkB-CREB Signaling Pathway.
Tao-Hong-Si-Wu-Tang (THSWT), a traditional Chinese herbal remedy, is commonly utilized for the treatment of female perimenopausal depression through regulating menstruation, but the mechanism remains unknown. In this study, ICR mice were randomly divided into six groups: low, medium, and high dose of THSWT (0.5, 1.5, and 4.5 g/kg), soy isoflavone (250 mg/kg), ovariectomy group, and control group. All mice, except the control group, had ovaries removed and were exposed to hypoxic stimulation for 28 days to establish a perimenopausal depression mice model. The mice, having unrestricted access to food and water, were administered THSWT treatment for a duration of 14 days. The Western blotting and Enzyme linked immunosorbent assay kits were used to determine protein and hormone levels, respectively. Experimental results showed that THSWT reduced the immobility time of mice from 150.8 s to 104.9 s in the tail suspension test, and it decreased the immobility time of mice from 165.7 s to 119.0 s in the forced swimming test, outperforming the results obtained with soy isoflavones. In addition, THSWT upregulated the protein expression of follicle-stimulating hormone receptor and downregulated the protein expression of corticotropin-releasing hormone-receptor 1 in the hippocampus. Compared with the oophorectomized group, treatment with THSWT decreased the levels of corticosterone and adrenocorticotropic hormone in serum by 173.7 and 23.4 ng/mL, respectively. These findings showed that THSWT could stimulate the perimenopausal nerve tissue and regulate the level of serum hormones in mice. THSWT exhibited promising potential as a viable alternative drug for hormone treatment of perimenopause in clinical use.
PubMed: 38682284
DOI: 10.1089/jmf.2023.k.0042 -
Biomedicines Apr 2024Endometrial cancer is the most common gynecologic malignancy in developed countries, and the incidence is rising in premenopausal females. Type I EC is more common than... (Review)
Review
Endometrial cancer is the most common gynecologic malignancy in developed countries, and the incidence is rising in premenopausal females. Type I EC is more common than Type II EC (80% vs. 20%) and is associated with a hyperestrogenic state. Estrogen unopposed by progesterone is considered to be the main driving factor in the pathogenesis of EC. Studies show that BMI > 30 kg/m, prolonged duration of menses, nulliparity, presence of polycystic ovarian syndrome, and Lynch syndrome are the most common causes of EC in premenopausal women. Currently, there are no guidelines established to indicate premenopausal patients who should be screened. This review aims to synthesize current data on the etiology, risk factors, presentation, evaluation, and prognosis of endometrial cancer in this population.
PubMed: 38672240
DOI: 10.3390/biomedicines12040886 -
The Journal of International Medical... Apr 2024We investigated the efficacy of a combination of laparoscopy and bilateral uterine artery occlusion (BUAO) for the treatment of type II cesarean scar pregnancy (CSP).
OBJECTIVE
We investigated the efficacy of a combination of laparoscopy and bilateral uterine artery occlusion (BUAO) for the treatment of type II cesarean scar pregnancy (CSP).
METHODS
Patients with type II CSP underwent laparoscopy + bilateral uterine artery embolization (control group) or laparoscopy + BUAO (study group). Data regarding the duration of surgery, intraoperative hemorrhage, postoperative complications, the duration of the hospital stay, and the costs of hospitalization were retrospectively collected. One year later, the time to the return of the β-human chorionic gonadotropin (β-hCG) concentration to normal and to the return of menstruation were compared.
RESULTS
The duration of surgery, time to the return of menstruation, and incidence of postoperative complications in the study group were significantly less than in the control group, but there was no significant difference in the time for β-hCG to return to normal or the volume of intraoperative hemorrhage. The duration of hospitalization and costs for the control group were higher than those for the study group.
CONCLUSION
Laparoscopy in combination with BUAO is associated with minimal trauma, rapid recovery, a short duration of surgery, low cost of hospitalization, and a low postoperative complication rate. Thus, it represents a useful new surgical treatment for type II CSP.
Topics: Humans; Female; Laparoscopy; Pregnancy; Adult; Cesarean Section; Retrospective Studies; Cicatrix; Uterine Artery Embolization; Pregnancy, Ectopic; Uterine Artery; Postoperative Complications; Length of Stay; Treatment Outcome; Chorionic Gonadotropin, beta Subunit, Human
PubMed: 38663910
DOI: 10.1177/03000605241241010 -
Medicina Clinica Jun 2024To elucidate the presence, importance, and characteristics of menstrual changes related to stressful circumstances during the COVID-19 lockdown in Spain.
OBJECTIVE
To elucidate the presence, importance, and characteristics of menstrual changes related to stressful circumstances during the COVID-19 lockdown in Spain.
STUDY DESIGN
An online survey was administered in Spain to menstruating women aged 15-55 who had not contracted COVID-19. It collected information on activities during the lockdown, sexual activity, perceptions of emotional status, any changes in menstrual characteristics, and impact on quality of life. The analysis of menstrual changes was limited to responders who did not use hormonal contraception.
RESULTS
A total of 6449 women answered the survey, and 4989 surveys were valid for the final analysis. 92.3% of women had at least one menstruation period during the lockdown, while 7.7% had amenorrhea. Quality of life (QoL) associated with menstruation worsened in 19% of women, did not change in 71.7%, and improved in 1.6%. For 50.1% of the women, global QoL worsened during the lockdown; 41.3% remained about the same and 8.7% reported improvement. Sexual activity during the lockdown decreased in 49.8% of the respondents, remained unchanged in 40.7%, and increased in 9.5%. As far the menstrual changes are concerned, there were no statistically significant differences in amenorrhea incidence, regularity of the menstrual cycle, or the amount or duration of menstrual bleeding in non-hormonal contraceptive users when evaluated by the length and characteristics of isolation, the perception of exposure to COVID-19 and the economic or employment situation. Conversely, we found statistically significant differences according to the intensity of changes in emotional status due to lockdown stressors and changes in regularity, duration, and heaviness of menstruation.
CONCLUSION
Changes in emotional status, but not the length and intensity of the isolation or exposure to the disease, significantly influenced menstrual disturbances during the COVID-19 lockdown.
Topics: Humans; Female; COVID-19; Adult; Quality of Life; Young Adult; Spain; Middle Aged; Adolescent; Menstruation; SARS-CoV-2; Pandemics; Quarantine; Sexual Behavior; Surveys and Questionnaires; Cross-Sectional Studies; Stress, Psychological; Pneumonia, Viral; Coronavirus Infections; Betacoronavirus
PubMed: 38614906
DOI: 10.1016/j.medcli.2024.01.016 -
Archives of Gynecology and Obstetrics Jun 2024To investigate the effect and safety of ovarian tissue cryopreservation (OTC) for fertility preservation in female patients with hematological diseases.
PURPOSES
To investigate the effect and safety of ovarian tissue cryopreservation (OTC) for fertility preservation in female patients with hematological diseases.
METHODS
We designed a retrospective study. The clinical data of patients with hematological diseases undergoing OTC admitted to Peking University People's Hospital from April 2017 to January 2023 were analyzed and summarized.
RESULTS
A total of 24 patients were included in the study, including 19 patients with malignant hematological diseases and 5 patients with non-malignant hematological diseases. The former included 14 patients with acute leukemia, 1 patient with chronic leukemia, and 4 patients with myelodysplastic syndrome, while the latter 5 patients were aplastic anemia (AA). 16 patients had received chemotherapy before OTC. The average age of 24 patients was 22.80 ± 6.81 years. The average anti-Mullerian hormone (AMH) was 1.97 ± 2.12 ng/mL, and the average follicle-stimulating hormone (FSH) was 7.01 ± 4.24 IU/L in examination before OTC. FSH was greater than 10.0 IU/L in 4 cases. The pre-OTC laboratory tests showed that the average white blood cell (WBC) count was (3.33 ± 1.35) × 10/L, the average hemoglobin was 91.42 ± 22.84 g/L, and the average platelet was (147.38 ± 114.46) × 10/L. After injection of recombinant human granulocyte colony-stimulating factor (rhG-CSF), blood transfusion, and iron supplementation in pre-OTC treatment, the average WBC count was (4.91 ± 3.07) × 10/L, the average hemoglobin was 98.67 ± 15.43 g/L, and the average platelet was (156.38 ± 103.22) × 10/L. Of the 24 patients, 22 underwent laparoscopic bilateral partial oophorectomy and oophoroplasty, and 2 underwent laparoscopic unilateral oophorectomy. The average duration of OTC was 59.54 ± 17.58 min, and the average blood loss was 32.1 ± 41.6 mL. The maximum blood loss was 200 mL. There was no significant difference in WBC count and hemoglobin concentration after OTC compared to pre-OTC period. Only the platelet count after OTC surgery was significantly different from that before surgery ([134.54 ± 80.84 vs. 156.38 ± 103.22] × 10/L, p < 0.05). None of the 24 patients had serious complications after OTC. 2 patients had mild infection symptoms, but both recovered well. 23 patients underwent hematopoietic stem cell transplantation (HSCT) after OTC. The median and interquartile range from OTC to the pretreatment of HSCT was 33 (57) days, and the median and interquartile range from OTC to HSCT was 41 (57) days. Seven of them began pretreatment of HSCT within 20 days and began HSCT within 30 days after OTC. All patients were followed up. Of the 23 patients who underwent HSCT after surgery, 22 presented with amenorrhea and 1 with scanty menstrual episodes. Seven patients underwent hormone replacement therapy (HRT) after HSCT. A patient with AA underwent ovarian tissue transplantation (OTT) 3 years after HSCT and resumed regular menstruation 6 months after OTT.
CONCLUSIONS
Ovarian tissue cryopreservation has a promising future in fertility protection in patients with hematological diseases. However, patients with hematological malignancies often have received gonadotoxic therapy before OTC, which may be accompanied by myelosuppression while patients with non-malignant hematological diseases often present with severe hemocytopenia. So perioperative complete blood count of patients should be paid attention to. There was no significant difference in the WBC count and hemoglobin concentration in patients with hematological diseases before and after OTC surgery, and the platelet count decreased slightly within the normal range. Infection is the most common post-OTC complication, and HSCT pretreatment can be accepted as early as the 10th day after OTC. OTC has no adverse effects on patients with hematological diseases and does not delay HSCT treatment. For young patients with hematological diseases, OTC is an effective method of fertility preservation.
Topics: Humans; Female; Fertility Preservation; Retrospective Studies; Cryopreservation; Adult; Ovary; Young Adult; Adolescent; Hematologic Diseases; Anti-Mullerian Hormone; Follicle Stimulating Hormone; Myelodysplastic Syndromes
PubMed: 38575798
DOI: 10.1007/s00404-024-07484-4 -
Cureus Feb 2024Adults in Saudi Arabia are more likely to be obese, which has negative effects on reproductive health, especially for women. While bariatric surgery (BS) provides a...
BACKGROUND
Adults in Saudi Arabia are more likely to be obese, which has negative effects on reproductive health, especially for women. While bariatric surgery (BS) provides a sustainable approach, little is known about how it affects menstrual health and requires a study among the Saudi demographic.
METHODS
The current investigation is a cross-sectional study conducted in Saudi Arabia. Data were collected using an online questionnaire to assess the impact of BS on menstrual abnormalities in women. Data were cleaned in Excel and analyzed using the Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 24.0, Armonk, NY).
RESULTS
This study included 516 Saudi women who underwent various BS procedures, with 37.2% aged 18-30 years and 97.9% residing in Saudi Arabia. Approximately 85.9% underwent sleeve gastrectomy (SG), experiencing a mean weight loss of 54.2 kg. Co-morbidities included polycystic ovary syndrome (PCOS) (12.4%), hypothyroidism or hyperthyroidism (11%), uterine fibroids (4.7%), and hormonal imbalances (2.5%). Post-surgery, 18% encountered BS complications from BS, while 8.3% used antidepressants. Moderate sports participation ranged from 12.2% (five or more days) to 36.2% (one to three days). In particular, no significant associations were found between complications and various parameters, except a marginal association with educational level (p=0.071). The number of menstruations per year did not change statistically significantly, remaining constant at 10.6±4.8 before surgery and 10.6±4.9 after surgery (p = 0.859). However, there was a mild decrease in the amount and duration of menstruation, reported by 23.3% and 27.3% of the participants preoperatively and post-operatively, respectively.
CONCLUSION
The study demonstrates the impact of BS on menstrual abnormalities in Saudi women. Despite a significant weight reduction, we found mild improvement in the amount and duration of menstruation with no substantial effect observed on the menstrual cycle frequency. Psychological support after surgery is crucial, considering the increased use of antidepressants.
PubMed: 38544663
DOI: 10.7759/cureus.54964 -
Human Reproduction (Oxford, England) May 2024What are the characteristics of adolescents diagnosed with polycystic ovary syndrome (PCOS) based on the 2003 Rotterdam criteria, but who do not meet the diagnosis...
STUDY QUESTION
What are the characteristics of adolescents diagnosed with polycystic ovary syndrome (PCOS) based on the 2003 Rotterdam criteria, but who do not meet the diagnosis according to the international evidence-based guideline?
SUMMARY ANSWER
Adolescents who had features of PCOS but did not meet the evidence-based guideline adolescent criteria exhibited unfavorable metabolic profiles compared to controls and shared considerable metabolic and hormonal features with adolescents who did meet the adolescent criteria.
WHAT IS KNOWN ALREADY
The international evidence-based PCOS guideline recommended that ultrasound should not be used for the diagnosis of PCOS in girls with a gynecological age of <8 years. Thus far, few studies have evaluated the clinical characteristics of the girls diagnosed with PCOS based on the Rotterdam criteria but who do not meet the diagnosis according to the updated guideline.
STUDY DESIGN, SIZE, DURATION
This is a retrospective study, and subjects attended for care from 2004 to 2022.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Adolescent girls with PCOS diagnosed according to the 2003 Rotterdam criteria and healthy controls. All participants were between 2 and 8 years since menarche.
MAIN RESULTS AND THE ROLE OF CHANCE
Of the 315 girls diagnosed with PCOS according to the Rotterdam criteria, those with irregular menstruation (IM)/hyperandrogenism (HA)/polycystic ovary (PCO), IM/HA, HA/PCO, and IM/PCO phenotypes accounted for 206 (65.4%), 30 (9.5%), 12 (3.8%), and 67 (21.3%) participants, respectively. According to the evidence-based guideline, 79 girls (25.1%) with the HA/PCO or IM/PCO phenotypes were not diagnosed with PCOS, and aligned to the international guideline; they were designated as the 'at-risk' group. As expected, the girls meeting the evidence-based guideline adolescent criteria showed the worst metabolic profiles (degree of generalized or central obesity, frequency of insulin resistance, prediabetes or diabetes, and metabolic syndrome) and higher hirsutism scores than the at-risk group or controls. Approximately 90% of the at-risk group were not overweight or obese, which was similar to the controls. However, they showed worse metabolic profiles, with higher blood pressure, triglyceride, and insulin resistance parameters than controls; furthermore, these profiles were similar to those of the girls meeting the adolescent criteria. The at-risk group showed similarly elevated serum LH levels and LH/FSH ratio with the girls meeting adolescent criteria.
LIMITATIONS, REASONS FOR CAUTION
We could not evaluate hormonal or ultrasound parameters in controls.
WIDER IMPLICATIONS OF THE FINDINGS
Compared to the conventional Rotterdam criteria, the recent international evidence-based guideline-avoiding ultrasound in PCOS diagnosis in adolescents-still gives the opportunity to identify young girls at risk, aligned to the findings in this study. A practical approach to this adolescent population would involve establishing IM or HA (with ultrasound not indicated) and designating 'at-risk' PCOS status with regular check-ups for newly developed or worsening PCOS-related symptoms or metabolic abnormalities, with subsequent reassessment including ultrasound or anti-Müllerian hormone, once 8 years post-menarche.
STUDY FUNDING/COMPETING INTEREST(S)
No funding was received in support of this study. The authors have no conflicts of interest to disclose.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Humans; Polycystic Ovary Syndrome; Female; Adolescent; Retrospective Studies; Hyperandrogenism; Practice Guidelines as Topic; Child; Ultrasonography; Insulin Resistance; Case-Control Studies
PubMed: 38514450
DOI: 10.1093/humrep/deae042 -
Human Reproduction (Oxford, England) May 2024How does osteopontin (OPN) in endometriosis ectopic stromal cells (EESCs) participate in the pathogenesis of endometriosis and achieve non-invasive detection in vitro?
STUDY QUESTION
How does osteopontin (OPN) in endometriosis ectopic stromal cells (EESCs) participate in the pathogenesis of endometriosis and achieve non-invasive detection in vitro?
SUMMARY ANSWER
Targeted OPN regulates endometriosis's necroptosis and inflammatory state by inhibiting the RhoA/reactive oxygen species (ROS) axis, thereby alleviating endometriosis and enabling non-invasive detection of menstrual blood in vitro.
WHAT IS KNOWN ALREADY
Endometriosis is a chronic inflammatory disease. Recent studies have shown that OPN plays an important role in disease progression by regulating cell death and inflammation.
STUDY DESIGN, SIZE, DURATION
The study included 20 patients diagnosed with endometriosis (confirmed by laparoscopy and histology) and 10 controls without endometriosis. Endometriotic stromal cells were isolated from endometrial samples, while menstrual blood endometrial cells (MESCs) were isolated from menstrual blood. These cells were then cultured in vitro and utilized in subsequent experiments.
PARTICIPANTS/MATERIALS, SETTING, METHODS
OPN expression in EESCs was assessed using inflammatory factor sequencing, immunohistochemical staining (IHC), quantitative real-time PCR (qRT-PCR) analysis, and Western blotting (WB). The biological behavior of OPN and its effects on inflammatory factors were examined using EdU, wound-healing, Transwell, and ELISA assays. Necroptosis in EESCs and its impact on inflammatory factors were detected through qRT-PCR, WB, and Calcein-AM/PI fluorescence assays. The examination of mitochondrial stress in EESCs involved the use of the Mitochondrial Membrane Potential (ΔΨm) Assay, ROS detection, and Calcein-AM Loading/cobalt chloride Quenching. qRT-PCR, WB, and other experiments were conducted to verify the regulation of necroptosis and inflammatory factor levels in EESCs by OPN through the RhoA/ROS axis. Knockdown of OPN and its inhibitory effect on endometriosis lesion size were confirmed using AAV9 virus, IHC, qRT-PCR, WB, and other experiments. Additionally, OPN expression in MESCs was detected using transcriptome sequencing, RT-PCR, WB, and other experiments.
MAIN RESULTS AND THE ROLE OF CHANCE
In vitro assays demonstrated a significant upregulation of OPN in EESCs, and the knockdown of OPN effectively inhibited necroptosis and the release of inflammatory factors. OPN inhibited necroptosis and inflammatory factor release by mediating RhoA-dependent ROS production and blocking mixed lineage kinase domain-like protein phosphorylation at the cell membrane. In vivo, targeting of OPN can inhibit the growth of endometriosis lesions. Clinically, OPN was also significantly upregulated in the menstrual blood of patients with endometriosis.
LARGE SCALE DATA
N/A.
LIMITATIONS, REASONS FOR CAUTION
Due to limitations in obtaining surgical specimens, our study primarily involved collecting endometriosis tissues from women during the proliferative and secretory phases of the menstrual cycle. We observed a significant overexpression of OPN in the samples used for our investigation. However, the expression of OPN in endometriosis tissues during the intermenstrual phase remains unknown.
WIDER IMPLICATIONS OF THE FINDINGS
Our findings highlight the pivotal role of the OPN/RhoA/ROS axis in the regulation of necroptosis and the release of inflammatory factors. OPN knockdown exerts a therapeutic effect in vivo, and the high expression detection of OPN in menstrual blood in vitro. In summary, targeting OPN provides possibilities for the treatment and detection of endometriosis.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the National Natural Science Foundation of China (82071626), the Zhejiang Province Public Welfare Technology Application Research Project (LGF21H040010), and the Clinical Research project of the Second Affiliated Hospital of Wenzhou Medical University (1010293). The authors have no conflicts of interest.
Topics: Adult; Female; Humans; Cells, Cultured; Endometriosis; Endometrium; Inflammation; Menstruation; Osteopontin; Reactive Oxygen Species; rhoA GTP-Binding Protein; Signal Transduction; Stromal Cells
PubMed: 38511216
DOI: 10.1093/humrep/deae052 -
Archives of Gynecology and Obstetrics May 2024Menstrual characteristics can affect a woman's productivity at work and college, but studies in a general population of adult women are scarce. In addition, it is...
PURPOSE
Menstrual characteristics can affect a woman's productivity at work and college, but studies in a general population of adult women are scarce. In addition, it is important to know which menstrual symptoms are most associated with presenteeism in women to promote specific health actions. The present study aimed to assess menstrual symptoms associated with presenteeism in adult women.
METHODS
Online cross-sectional study in which menstrual characteristics, including menstrual flow, age of menarche, menstrual pain and cycle duration were assessed by a self-report questionnaire. The menstrual pain intensity was assessed by Numerical Rating Scale, and the presenteeism, by the Stanford Presenteeism Scale-6 (SPS-6). Women were divided in two groups, with and without presenteeism, based on the SPS-6 cutoff point. Data were analyzed by binary logistic regression and presented as odds ratios (OR).
RESULTS
Among the 430 women who participated in the study, 44.2% were classified as with presenteeism. Women with severe menstrual flow were more likely to have presenteeism (OR = 2.12) compared with women with mild and moderate menstrual flow. The higher menstrual pain intensity the higher the chances of a woman presenting with presenteeism (OR = 1.29).
CONCLUSIONS
These menstrual characteristics (intensity of menstrual flow and menstrual pain) seem to affect women's productivity at work and/or college, and should be assessed in research and clinical practice. Thus, public policies on women's health can be carried out based on these results.
Topics: Adult; Humans; Female; Dysmenorrhea; Presenteeism; Cross-Sectional Studies; Menstruation; Surveys and Questionnaires
PubMed: 38502189
DOI: 10.1007/s00404-024-07425-1