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Human Reproduction Update Jul 2023Abnormal uterine bleeding (AUB) has a significant socioeconomic impact since it considerably impacts quality of life. Therapeutic options are frequently based on trial... (Review)
Review
BACKGROUND
Abnormal uterine bleeding (AUB) has a significant socioeconomic impact since it considerably impacts quality of life. Therapeutic options are frequently based on trial and error and do not target disease aetiology. Pathophysiological insight in this disease is required for the development of novel treatment options. If no underlying cause is found for the AUB (e.g. fibroids, adenomyosis, polyps), endometrial-AUB (AUB-E) is usually caused by a primary endometrium disorder. When AUB is induced by prescribed (exogenous) hormones, it is classified as iatrogenic-AUB (AUB-I). Considering vascular modulation and function, AUB-E and AUB-I both could potentially result from abnormal vascularization in the endometrium due to alterations in the process of angiogenesis and vascular maturation.
OBJECTIVE AND RATIONALE
We aim to investigate the fundamental role of angiogenesis and vascular maturation in patients with AUB and hypothesize that aberrant endometrial angiogenesis has an important role in the aetiology of both AUB-E and AUB-I, possibly through different mechanisms.
SEARCH METHODS
A systematic literature search was performed until September 2021 in the Cochrane Library Databases, Embase, PubMed, and Web of Science, with search terms such as angiogenesis and abnormal uterine bleeding. Included studies reported on angiogenesis in the endometrium of premenopausal women with AUB-E or AUB-I. Case reports, letters, reviews, editorial articles, and studies on AUB with causes classified by the International Federation of Gynecology and Obstetrics as myometrial, oncological, or infectious, were excluded. Study quality was assessed by risk of bias, using the Cochrane tool and the Newcastle-Ottawa Scale.
OUTCOMES
Thirty-five out of 2158 articles were included. In patients with AUB-E, vascular endothelial growth factor A and its receptors (1 and 2), as well as the angiopoietin-1:angiopoietin-2 ratio and Tie-1, were significantly increased. Several studies reported on the differential expression of other pro- and antiangiogenic factors in patients with AUB-E, suggesting aberrant vascular maturation and impaired vessel integrity. Overall, endometrial microvessel density (MVD) was comparable in patients with AUB-E and controls. Interestingly, patients with AUB-I showed a higher MVD and higher expression of proangiogenic factors when compared to controls, in particular after short-term hormone exposure. This effect was gradually lost after longer-term exposure, while alterations in vessel maturation were observed after both short- and long-term exposures.
WIDER IMPLICATIONS
AUB-E and AUB-I are most likely associated with aberrant endometrial angiogenesis and impaired vessel maturation. This review supports existing evidence that increased proangiogenic and decreased antiangiogenic factors cause impaired vessel maturation, resulting in more fragile and permeable vessels. This matches our hypothesis and these mechanisms appear to play an important role in the pathophysiology of AUB-E and AUB-I. Exploring the alterations in angiogenesis in these patients could provide treatment targets for AUB.
Topics: Female; Humans; Endometrium; Quality of Life; Uterine Diseases; Uterine Hemorrhage; Vascular Endothelial Growth Factor A; Angiogenic Proteins; Hormone Antagonists; Metrorrhagia
PubMed: 36857162
DOI: 10.1093/humupd/dmad004 -
Journal of Reproduction & Infertility 2023Endometrial cancer (EC) ranks as the second most common gynaecological cancer worldwide. EC patients are diagnosed at an early clinical stage and generally have a good... (Review)
Review
Endometrial cancer (EC) ranks as the second most common gynaecological cancer worldwide. EC patients are diagnosed at an early clinical stage and generally have a good prognosis. Therefore, there is a dire need for development of a specific marker for early detection of endometrial adenocarcinoma. The development of EC is conditioned by a multistep process of oncogenic upregulation and tumor suppressor downregulation as shown by molecular genetic evidence. In this setting, microRNAs appear as significant regulators of gene expression and several variations in the expression of microRNAs have been implicated in normal endometrium, endometrial tissue, metrorrhagia, and endometrial cancer. Furthermore, microRNAs act as highly precise, sensitive, and robust molecules, making them potential markers for diagnosing specific cancers and their progression. With the rising incidence of EC, its management remains a vexing challenge and diagnostic methods for the disease are limited to invasive, expensive, and inaccurate tools. Therefore, the prospect of exploiting the utility of microRNAs as potential candidates for diagnosis and therapeutic use in EC seems promising.
PubMed: 37663424
DOI: 10.18502/jri.v24i3.13271 -
Cureus Oct 2023Vaccination has a fundamental role in protecting against and modifying the severity of several infectious diseases, including COVID-19. Several immune and non-immune...
INTRODUCTION
Vaccination has a fundamental role in protecting against and modifying the severity of several infectious diseases, including COVID-19. Several immune and non-immune adverse events have been reported post-COVID-19 vaccine. The aim of this study was to assess the effect of the COVID-19 vaccine on women's menstrual bleeding.
METHODS
A cross-sectional study was conducted among 399 vaccinated women in the Eastern Province of Saudi Arabia. Data were collected using a direct interview-based questionnaire including four sections.
RESULTS
A total of 399 women were recruited, with a mean age of 25.54 ± 6.177 years. More than half (53.9%) of the participants reported post-vaccination menstrual bleeding abnormality in terms of a heavy or irregular cycle. Out of the total number, 40 (21.4%) women reported having heavy menstrual flow, and 67 (16.8%) had non-menstrual bleeding after receiving the COVID-19 vaccine. Fully vaccinated women were at a greater risk of post-vaccination menstrual bleeding abnormality (p = 0.058). However, there was no correlation between booster shot type and menstrual bleeding abnormality (p > 0.05). In addition, there was no significant association between non-menstrual bleeding and the type of booster shot, the type of the first dose, and prior history of COVID-19 infection (p > 0.05).
CONCLUSION
Despite vaccination being the most effective way to prevent COVID-19, it does have an impact on menstrual bleeding in terms of menorrhagia and metrorrhagia. Therefore, more studies are needed to understand the mechanism and the long-term impact of COVID-19 vaccines on the hemostatic system.
PubMed: 38021843
DOI: 10.7759/cureus.47360 -
American Journal of Obstetrics and... Aug 2023Some users of the etonogestrel contraceptive implant experience bothersome bleeding, which can reduce contraceptive satisfaction and continuation. Few strategies exist... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Some users of the etonogestrel contraceptive implant experience bothersome bleeding, which can reduce contraceptive satisfaction and continuation. Few strategies exist to manage this bleeding. The exact mechanism of progestin-induced bleeding is unknown, but it is likely multifactorial (eg, impaired angiogenesis, "leaky" fragile vasculature, and inflammation). Curcumin, the active ingredient in turmeric, has anti-inflammatory, antiproliferative, and antiangiogenic properties, which may make it a useful agent for implant-associated bothersome bleeding.
OBJECTIVE
This study aimed to evaluate whether curcumin decreases frequent or prolonged bleeding or spotting in contraceptive implant users.
STUDY DESIGN
The study was a randomized, double-blind, placebo-controlled trial. Here, etonogestrel implant users with frequent or prolonged bleeding or spotting were enrolled and randomized to either 600-mg Theracurmin HP (Immunovites, Las Vegas, NV) or placebo daily for 30 days. The term "frequent" was defined as ≥2 independent bleeding or spotting episodes, and the term "prolonged" was defined as ≥7 consecutive days of bleeding or spotting in a 30-day interval. Implant use was confirmed by clinical examination and negative gonorrhea and chlamydia and pregnancy tests. Enrolled participants initiated study treatment after 3 consecutive days of bleeding or spotting; if no bleeding or spotting occurred within 30 days of enrollment, the participants were withdrawn from the study. Study treatments were encapsulated to maintain a similar appearance. Participants used text messages to record daily bleeding patterns and study drug compliance. Bleeding was defined as a day that required the use of protection with a pad, tampon, or liner, and spotting was defined as a day with minimal blood loss that did not require the use of any protection. Our primary outcome was the total number of days without bleeding or spotting during the 30 days of study drug or placebo exposure. The secondary outcomes included total number of bleeding-free days, bleeding episodes, and satisfaction. A sample size of 22 per group provided 80% power at an alpha level of .05 to demonstrate a 6-day difference between groups.
RESULTS
From February 2021 to November 2022, 58 individuals enrolled in the study with 54 participants (93%) completing 30 days of treatment (26 in the curcumin group and 28 in the placebo group). Of note, 1 individual in the curcumin arm did not experience a qualifying bleeding event and, thus, never initiated treatment and, per protocol, was withdrawn from the study. Participant characteristics did not differ between groups, including length of implant use at study enrollment (placebo, 521±305 days; curcumin, 419±264 days). The study groups did not differ concerning any bleeding-related outcome (mean days without bleeding or spotting: curcumin, 16.7±6.9; placebo, 17.5±4.8; P=.62; mean bleeding-free days: curcumin, 23.4±4.9; placebo, 22.4±4.5; P=.44; bleeding episodes: curcumin, 2.0±0.8; placebo, 2.1±0.8; P=.63). In addition, satisfaction with the implant as contraception and acceptability of bleeding over the study period did not differ by study group (P=.54 and P=.30, respectively).
CONCLUSION
Daily use of curcumin did not improve bleeding patterns in users of the etonogestrel contraceptive implant experiencing frequent or prolonged bleeding patterns.
Topics: Pregnancy; Female; Humans; Uterine Hemorrhage; Curcumin; Contraceptive Agents, Female; Metrorrhagia; Contraception; Levonorgestrel
PubMed: 37116825
DOI: 10.1016/j.ajog.2023.04.028 -
Journal of the Endocrine Society Nov 2023Severe hypothyroidism can affect a variety of organs and can develop atypical manifestations. Peripheral precocious puberty may be secondary to other endocrinological... (Review)
Review
Severe hypothyroidism can affect a variety of organs and can develop atypical manifestations. Peripheral precocious puberty may be secondary to other endocrinological diseases, which must be taken into account in the differential diagnosis in order to avoid unnecessary additional tests. Van Wyk-Grumbach syndrome is an infrequent manifestation characterized by severe hypothyroidism and incomplete precocious puberty. Diagnosis is made by clinical and complementary tests, and the main treatment goal is to achieve euthyroidism through hormone replacement. Prognosis is good once the treatment is established. The aim of this study is to review the available literature about Van Wyk-Grumbach syndrome following the PRISMA statement, and to present the first clinical case published in Spain. We have included the articles published during the period from 1905 to week 40 of 2022. A total of 68 articles have been selected for study and analysis, within which there are 99 published clinical cases. Girls accounted for 92.1% of cases (median age at the diagnosis 8.5 years). Metrorrhagia was the most prevalent symptom, present in 80.5% of the girls. Abdominal ultrasound was performed in 93.3% of the girls and 97.8% of them had at least one ovarian cyst. All cases were treated with levothyroxine, responding satisfactorily after the first doses of treatment. To conclude, Van Wyk-Grumbach syndrome is characterized by severe hypothyroidism and incomplete precocious puberty, which is important to keep in mind in order to avoid complementary exams and unnecessary surgical interventions.
PubMed: 38024650
DOI: 10.1210/jendso/bvad135 -
Journal of Obstetrics and Gynaecology... Mar 2024The primary objective of this clinical practice guideline is to provide gynaecologists with an algorithm and evidence to guide the diagnosis and management of...
OBJECTIVE
The primary objective of this clinical practice guideline is to provide gynaecologists with an algorithm and evidence to guide the diagnosis and management of endometrial polyps.
TARGET POPULATION
All patients with symptomatic or asymptomatic endometrial polyps.
OPTIONS
Options for management of endometrial polyps include expectant, medical, and surgical management. These will depend on symptoms, risks for malignancy, and patient choice.
OUTCOMES
Outcomes include resolution of symptoms, histopathological diagnosis, and complete removal of the polyp.
BENEFITS, HARMS, AND COSTS
The implementation of this guideline aims to benefit patients with symptomatic or asymptomatic endometrial polyps and provide physicians with an evidence-based approach toward diagnosis and management (including expectant, medical, and surgical management) of polyps.
EVIDENCE
The following search terms were entered into PubMed/Medline and Cochrane: endometrial polyps, polyps, endometrial thickening, abnormal uterine bleeding, postmenopausal bleeding, endometrial hyperplasia, endometrial cancer, hormonal therapy, female infertility. All articles were included in the literature search up to 2021 and the following study types were included: randomized controlled trials, meta-analyses, systematic reviews, observational studies, and case reports. Additional publications were identified from the bibliographies of these articles. Only English-language articles were reviewed.
VALIDATION METHODS
The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations).
INTENDED AUDIENCE
Gynaecologists, family physicians, registered nurses, nurse practitioners, medical students, and residents and fellows.
TWEETABLE ABSTRACT
Uterine polyps are common and can cause abnormal bleeding, infertility, or bleeding after menopause. If patients don't experience symptoms, treatment is often not necessary. Polyps can be treated with medication but often a surgery will be necessary.
SUMMARY STATEMENTS
RECOMMENDATIONS.
Topics: Humans; Female; Uterine Neoplasms; Uterine Diseases; Endometrial Neoplasms; Endometrial Hyperplasia; Infertility, Female; Polyps
PubMed: 38325734
DOI: 10.1016/j.jogc.2024.102402 -
Journal of Ethnopharmacology Jan 2024Comfrey root (Symphytum officinale L., Boraginaceae) has been used in folk medicine for a long time to treat different diseases. It is recommended for swellings,...
ETHNOPHARMACOLOGICAL RELEVANCE
Comfrey root (Symphytum officinale L., Boraginaceae) has been used in folk medicine for a long time to treat different diseases. It is recommended for swellings, phlebitis, contusions, gastro-duodenal ulcers, respiratory diseases, and metrorrhagia. Currently, preparations from S. officinale are only topically used due to its wound-healing effects, and for reducing inflammation and the treatment of broken bones, tendon damage, painful joints and muscles. Although it is a widespread plant material, little is known about the interaction of externally applied preparations of comfrey with the human skin microbiome.
AIM OF THE STUDY
The study aims to determine the interaction between human skin microbiota and the comfrey root extracts, by monitoring the biotransformation of the constituents present in the extract and evaluating changes in the population of the skin microbiota in an ex vivo setting.
MATERIAL AND METHODS
The comfrey root extract was incubated with the human skin microbiota from ten healthy donors. The UHPLC-DAD-MS analysis determined the composition of the raw extract and the microbial metabolites. Bacterial genomic DNA was extracted and examined by amplification sequencing of the 16S rDNA to determine changes in the bacterial composition.
RESULTS
The hydroethanolic extract of comfrey root primarily consists of phenolic acids, pyrrolizidine alkaloids, and their derivatives, and lignans. The natural products present in the extract underwent biodegradation by the skin microbiota, leading to the formation of smaller molecules. It was observed that the skin microbial metabolism primarily focused on modifying the derivatives of pyrrolizidine alkaloids. It resulted in the production of deacetylated and deesterificated compounds. However, it did not lead to the conversion of these compounds into free alkaloids.
CONCLUSIONS
The microbiota-triggered biotransformation of the comfrey root extract was observed. A few N-oxides were metabolized to deacetylated and deesterificated forms in ex vivo conditions. It suggests that the intermittent external applications of comfrey preparations perchance are unlikely to pose a substantial risk. While it even may serve as a potential factor influencing the extract activity in treating skin diseases.
Topics: Humans; Comfrey; Plant Extracts; Biological Products; Skin; Pyrrolizidine Alkaloids
PubMed: 37506778
DOI: 10.1016/j.jep.2023.116968 -
Journal of Minimally Invasive Gynecology Jul 2023This study aimed to evaluate the learning curve of vaginal natural orifice transuminal endoscopic surgery (vNOTES) hysterectomy in expert minimal invasive and vaginal...
STUDY OBJECTIVE
This study aimed to evaluate the learning curve of vaginal natural orifice transuminal endoscopic surgery (vNOTES) hysterectomy in expert minimal invasive and vaginal surgery team.
DESIGN
This is a cohort study on a retrospective analysis.
SETTING
Department of Obstetrics and Gynecology of Cannizzaro Hospital in Catania Italy.
PATIENTS
First 50 women underwent vNOTES hysterectomy between February 2021 and February 2022.
INTERVENTION
vNOTES hysterectomy performed by a team with optimal skills in laparoscopic and vaginal surgery.
MEASUREMENT AND MAIN RESULTS
Primary outcome was surgical time. Secondary outcomes were intraoperative and postoperative complications, length of hospitalization, and first 24-hour postoperative pain. All patients underwent hysterectomy for benign indications: 27 fibromatosis, 13 metrorrhagia, and 10 precancerous. Concomitant procedures have been bilateral adnexectomy in 35 cases and bilateral salpingectomy in 15 cases. The median age was 51 years (range, 42-64). Median body mass index was 26 kg/m (range, 21-42). The median operative time was 75 minutes (range, 40-110). The median hospital stay was 2 days (range, 1-4). There was 1 intraoperative adverse event (bladder lesion) and 1 postoperative grade 3 complication (hemoperitoneum). The median visual analog scale score for pain assessment during the first 24 hours after surgery was 3 (range, 1-6). The experience in our surgical center with the first 25 vNOTES hysterectomies showed an accumulation of initial experience in the first 5 cases with stable operating time and a gradual reduction of mean operating time in the subsequent 17 surgeries. The learning curve plotted by cumulative sum analysis shows 3 phases: phase 1 of competence (cases 1-5), phase 2 of proficiency (cases 6-26), and phase 3 of mastering the procedure (after the 31st case) with the management of more complex cases.
CONCLUSION
vNOTES hysterectomy is a feasible and reproducible approach for benign indications with a short learning curve and low rate of perioperative complications. For a team skilled in minimally invasive surgery, 5 cases are required to rich competence and 25 to rich proficiency in vNOTES hysterectomy. Mastering phase, with the introduction of more complex cases, should be addressed after 30 surgeries.
Topics: Pregnancy; Female; Humans; Middle Aged; Retrospective Studies; Cohort Studies; Learning Curve; Hysterectomy, Vaginal; Hysterectomy; Natural Orifice Endoscopic Surgery; Laparoscopy; Postoperative Complications; Vagina
PubMed: 36966920
DOI: 10.1016/j.jmig.2023.03.013 -
Ultrasound in Obstetrics & Gynecology :... May 2024To assess the ultrasonographic, epidemiological, clinical and evolutive characteristics of enhanced myometrial vascularity (EMV) following a first-trimester termination...
OBJECTIVE
To assess the ultrasonographic, epidemiological, clinical and evolutive characteristics of enhanced myometrial vascularity (EMV) following a first-trimester termination of pregnancy (TOP) or management of non-viable pregnancy.
METHODS
This prospective study included women who underwent follow-up ultrasound examination 5-6 weeks after a first-trimester TOP or after management of a first-trimester non-viable pregnancy at the University Hospital Polyclinic San Martino of Genoa between March 2021 and March 2022. EMV was characterized using two- and three-dimensional ultrasound and Virtual Organ Computer-aided Analysis. Ultrasonographic diagnosis of EMV was made when an unusual, tortuous myometrial vessel structure, with high-velocity blood flow, protruding towards the endometrium was observed, while an abnormal junctional zone, absent endometrial midline and heterogeneous endometrium supported the diagnosis. Patients with EMV underwent expectant management with planned ultrasonographic follow-up every 2 weeks until resolution.
RESULTS
During the study period, 305 women underwent TOP, of whom 132 attended the initial follow-up 5-6 weeks later, at which 52 were diagnosed with EMV. Ninety-six women were managed for a non-viable pregnancy, of whom 32 presented for follow-up, at which six had a diagnosis of EMV. Thus, overall, 164 of 401 women were included in the study and EMV was identified in 58 (35%) of these. The prevalence of EMV 5-6 weeks after a TOP was therefore between 52/305 (17%) and 52/132 (39%), and that after management of a non-viable pregnancy was between 6/96 (6%) and 6/32 (19%). Bleeding/pelvic pain was present in half (29/58) of the women with EMV, and serum human chorionic gonadotropin was detectable in 29% (17/58) at the first follow-up examination. At ultrasound assessment, all cases with EMV presented abundant tortuous myometrial vessels with high-velocity flow projecting from the myometrium towards the endometrium, along with non-uniform heterogeneous endometrium in 97% of cases, which often (67% of these) contained cystic areas, absence of the endometrial midline in 98% of cases and an abnormal junctional zone in 97% of cases (64% interrupted, 33% irregular). Most (67%) women with EMV were parous and 90% of them had undergone TOP rather than management for a non-viable pregnancy. Medical management of the TOP or non-viable pregnancy was more frequent in women with than those without EMV (93% vs 77%, P = 0.023). Multiple regression analysis showed the risk of EMV to be increased following TOP vs non-viable pregnancy (odds ratio (OR), 3.67 (95% CI, 1.16-11.56), P = 0.026) and in parous compared with nulliparous women (OR, 2.95 (95% CI, 1.45-6.01), P = 0.002). All women with EMV underwent expectant management. Eleven women did not return for subsequent follow-up examinations and did not present to our outpatient or emergency facilities, so were lost to further follow-up. Spontaneous resolution of the lesion was observed within 7-16 weeks after the procedure in 96% (45/47) of the remaining cases. Two women chose to undergo surgery for pelvic discomfort, and histology showed the presence of neovessels mixed with retained chorionic villi.
CONCLUSIONS
EMV is a transient and common finding 5-6 weeks following first-trimester TOP or management of non-viable pregnancy. TOP and being parous are risk factors for EMV. Expectant management of EMV is appropriate, because, in almost all cases, this resolves spontaneously, without complications, within 2-4 months. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Humans; Female; Pregnancy; Prospective Studies; Adult; Myometrium; Pregnancy Trimester, First; Ultrasonography, Prenatal; Abortion, Induced; Endometrium; Imaging, Three-Dimensional
PubMed: 37984401
DOI: 10.1002/uog.27537 -
International Journal of Molecular... Aug 2023Recurrent pregnancy loss (RPL) refers to two or more miscarriages before 20 weeks gestation. Its prevalence is 1-2%; its pathogenesis remains unexplained in more than...
Recurrent pregnancy loss (RPL) refers to two or more miscarriages before 20 weeks gestation. Its prevalence is 1-2%; its pathogenesis remains unexplained in more than 50% of cases, in which the cause is thought to be abnormal immune activity during placentation leading to a lack of pregnancy-induced immune tolerance. It is unknown whether immune activity is deranged in the endometrium of women with RPL. We studied the gene expression and the quantitative tissue protein levels of three immune checkpoints (CD276, which enhances cytotoxic T-cell activity, cytotoxic T-lymphocyte-associated antigen-4 [CTL-4], which reduces Th1 cytokine production, and lymphocyte activation gene-3 [LAG-3], which shows suppressive activity on Tregs and CD4+ T-cells) in endometrial samples from 27 women with unexplained RPL and in 29 women with dysfunctional uterine bleeding and previous uneventful pregnancies as controls. RNA isolation, real-time PCR, protein isolation, and ELISA were performed. CD276 gene expression and protein tissue levels were significantly lower in the endometrium of the RPL group than in the controls, whereas both CTL-4 and were significantly higher. This difference suggests defective endometrial immune regulation and overactivation of immune response in women with a history of RPL, at least in relation to controls with dysfunctional uterine bleeding and previous normal reproductive history.
Topics: Pregnancy; Female; Humans; Metrorrhagia; Genes, Regulator; Transcription Factors; Abatacept; Abortion, Habitual; B7 Antigens
PubMed: 37685876
DOI: 10.3390/ijms241713071