Risk of endometrial cancer in asymptomatic postmenopausal women in relation to ultrasonographic endometrial thickness: systematic review and diagnostic test accuracy meta-analysis.

OBJECTIVE: This study aimed to evaluate the risk of endometrial carcinoma and atypical endometrial hyperplasia in asymptomatic postmenopausal women concerning the endometrial thickness measured by stratified threshold categories used for performing subsequent endometrial sampling and histologic evaluation. DATA SOURCES: MEDLINE, Scopus, ClinicalTrials.gov, SciELO, Embase, the Cochrane Central Register of Controlled Trials, LILACS, conference proceedings, and international controlled trials registries were searched without temporal, geographic, or language restrictions. STUDY ELIGIBILITY CRITERIA: Studies were selected if they had a crossover design evaluating the risk of atypical endometrial hyperplasia and endometrial carcinoma in postmenopausal asymptomatic women and calculated the diagnostic accuracy of transvaginal ultrasonography thresholds (at least 3.0 mm) confirmed by histopathologic diagnosis. METHODS: This was a systematic review and diagnostic test accuracy meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy and Synthesizing Evidence from Diagnostic Accuracy Tests guidelines. Endometrial thickness thresholds were grouped as follows: from 3.0 to 5.9 mm; between 6.0 and 9.9 mm; between 10.0 and 13.9 mm; and ≥14.0 mm. Quality assessment was performed using the Quality Assessment Tool for Diagnostic Accuracy Studies 2 tool. Publication bias was quantified using the Deek funnel plot test. Coprimary outcomes were the risk of atypical endometrial hyperplasia or endometrial carcinoma according to the endometrial thickness and diagnostic accuracy of each threshold group. RESULTS: A total of 18 studies provided the data of 10,334 women who were all included in the final analysis. Overall, at an endometrial thickness threshold of at least 3.0 mm, the risk of atypical endometrial hyperplasia or endometrial carcinoma was increased 3-fold relative to women below the cutoff (relative risk, 3.77; 95% confidence interval, 2.26-6.32; I2=74%). Similar degrees of risk were reported for thresholds between 3.0 and 5.9 mm (relative risk, 5.08; 95% confidence interval, 2.26-11.41; I2=0%), 6.0 and 9.9 mm (relative risk, 4.34; 95% confidence interval, 1.68-11.23; I2=0%), 10.0 and 13.9 mm (relative risk, 4.11; 95% confidence interval, 1.55-10.87; I2=86%), and ≥14.0 mm (relative risk, 2.53; 95% confidence interval, 1.04-6.16; I2=78%) with no significant difference among subgroups (P=.885). Regarding diagnostic accuracy, the pooled sensitivity decreased from thresholds below 5.9 mm (relative risk, 0.81; 95% confidence interval, 0.49-0.85) to above 14.0 mm (relative risk, 0.28; 95% confidence interval, 0.18-0.40). Furthermore, the specificity increased from 0.70 (95% confidence interval, 0.61-0.78) for endometrial thickness between 3.0 and 5.9 mm to 0.86 (95% confidence interval, 0.71-0.94) when the endometrial thickness is ≥14.0 mm. For 3.0 to 5.9 mm and 10.0 to 13.9 mm thresholds, the highest diagnostic odds ratios of 10 (95% confidence interval, 3-41) and 11 (95% confidence interval, 2-49), with areas under the curve of 0.81 (95% confidence interval, 0.77-0.84) and 0.82 (95% confidence interval, 0.79-0.86), respectively, were retrieved. The summary point analysis revealed that the 3.0 to 5.9 mm cutoff point was placed higher in the summary receiver operator curve space than the other subgroups, indicating increased endometrial carcinoma or atypical endometrial hyperplasia diagnosis using these cutoffs. CONCLUSION: Both low and high endometrial thickness thresholds in postmenopausal asymptomatic women seem equally effective in detecting endometrial carcinoma and atypical endometrial hyperplasia. However, although using a 3.0 to 5.9 mm cutoff results in a lower specificity, the offsetting improvement in sensitivity may justify using this cutoff for further endometrial evaluation in patients with suspected endometrial malignancy.

Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection.

Numerous pharmaceutical drugs have been repurposed for use as treatments for COVID-19 disease. These drugs have not consistently demonstrated high efficacy in preventing or treating this serious condition and all have side effects to differing degrees. We encourage the continued consideration of the use of the antioxidant and anti-inflammatory agent, melatonin, as a countermeasure to a SARS-CoV-2 infection. More than 140 scientific publications have identified melatonin as a likely useful agent to treat this disease. Moreover, the publications cited provide the rationale for the use of melatonin as a prophylactic agent against this condition. Melatonin has pan-antiviral effects and it diminishes the severity of viral infections and reduces the death of animals infected with numerous different viruses, including three different coronaviruses. Network analyses, which compared drugs used to treat SARS-CoV-2 in humans, also predicted that melatonin would be the most effective agent for preventing/treating COVID-19. Finally, when seriously infected COVID-19 patients were treated with melatonin, either alone or in combination with other medications, these treatments reduced the severity of infection, lowered the death rate, and shortened the duration of hospitalization. Melatonin's ability to arrest SARS-CoV-2 infections may reduce health care exhaustion by limiting the need for hospitalization. Importantly, melatonin has a high safety profile over a wide range of doses and lacks significant toxicity. Some molecular processes by which melatonin resists a SARS-CoV-2 infection are summarized. The authors believe that all available, potentially beneficial drugs, including melatonin, that lack toxicity should be used in pandemics such as that caused by SARS-CoV-2.

Complementarity between Early Embryogenesis and Uterine Receptivity: Toward Integrative Approach to Female Infertility Management. Editorial to the Special Issue "Molecular Mechanisms of Human Oogenesis and Early Embryogenesis".

Two highly relevant papers were recently been published in the Special Issue of Molecular Sciences entitled "Molecular Mechanisms of Human Oogenesis and Early Embryogenesis" [...].

Multiple Mechanisms Controlling Uterine Function: Editorial to Special Issue "Molecular Mechanisms of Uterine Receptivity for Embryo Implantation".

Uterine (endometrial) receptivity is the ability of the endometrium to successfully attach to the embryo, to promote its implantation, to nourish it and keep it alive [...].

Mitochondria in Human Fertility and Infertility.

In human spermatozoa and oocytes (and their surrounding granulosa cells), mitochondria carry out important functions relating to human fertility and infertility. Sperm mitochondria are not transmitted to the future embryo, but are closely related to the generation of energy needed for sperm movement, capacitation, and acrosome reactions, as well as for sperm-oocyte fusion. On the other hand, oocyte mitochondria produce energy required for oocyte meiotic division and their abnormalities can thus cause oocyte and embryo aneuploidy. In addition, they play a role in oocyte calcium metabolism and in essential epigenetic events during the oocyte-to-embryo transition. They are transmitted to the future embryos and may thus cause hereditary diseases in the offspring. Due to the long life span of the female germ cells, the accumulation of mitochondrial DNA abnormalities often causes ovarian aging. Mitochondrial substitution therapy is the only way of dealing with these issues nowadays. New therapies based on mitochondrial DNA editing are under investigation.

Control of Maternal-to-Zygotic Transition in Human Embryos and Other Animal Species (Especially Mouse): Similarities and Differences.

Maternal-to-zygotic transition (MZT) of the control of early post-fertilization development is a key-event conditioning the fate of the future embryo, fetus and newborn. Because of the relative paucity of data concerning human embryos, due to ethical concerns and the poor availability of human embryos donated for research, most data have to be derived from animal models, among which those obtained using mouse embryos are most prevalent. However, data obtained by studies performed in non-mammalian specie can also provide useful information. For this reason, this review focuses on similarities and differences of MZT control mechanisms in humans and other species, with particular attention to the mouse. A number of molecular pathways controlling MZT in mice and humans are compared, pointing out those that could be at the origin of further focused experimental studies and the development of new diagnostic tools based on the translational medicine principles. Data concerning possible candidate molecules to be included in these studies are identified.

Cyclic Adenosine Monophosphate: A Central Player in Gamete Development and Fertilization, and Possible Target for Infertility Therapies.

Human infertility, of both male and female origin, is often caused by the deficient response of the testis and the ovary to hormonal stimuli that govern sperm and oocyte development and fertilization. The effects of hormones and other extracellular ligands involved in these events are often mediated by G-protein-coupled receptors that employ cyclic adenosine monophosphate (cAMP) as the principal second messenger transducing the receptor-generated signal to downstream elements. This opinion article summarizes the actions of cAMP in sperm and oocyte development and fertilization, leading to therapeutic actions targeting cAMP metabolism to alleviate human male and female infertility.

Molecular Clues to Understanding Causes of Human-Assisted Reproduction Treatment Failures and Possible Treatment Options.

More than forty years after the first birth following in vitro fertilization (IVF), the success rates of IVF and of IVF-derived assisted reproduction techniques (ART) still remain relatively low. Interindividual differences between infertile couples and the nature of the problems underlying their infertility appear to be underestimated nowadays. Consequently, the molecular basis of each couple's reproductive function and of its disturbances is needed to offer an individualized diagnostic and therapeutic approaches to each couple, instead of applying a standard or minimally adapted protocols to everybody. Interindividual differences include sperm and oocyte function and health status, early (preimplantation) embryonic development, the optimal window of uterine receptivity for the implanting embryo, the function of the corpus luteum as the main source of progesterone production during the first days of pregnancy, the timing of the subsequent luteoplacental shift in progesterone production, and aberrant reactions of the uterine immune cells to the implanting and recently implanted embryos. In this article, the molecular basis that underlies each of these abnormalities is reviewed and discussed, with the aim to design specific treatment options to be used for each of them.

Assessing the testicular sperm microbiome: a low-biomass site with abundant contamination.

RESEARCH QUESTION: The semen harbours a diverse range of microorganisms. The origin of the seminal microbes, however, has not yet been established. Do testicular spermatozoa harbour microbes and could they potentially contribute to the seminal microbiome composition? DESIGN: The study included 24 samples, comprising a total of 307 testicular maturing spermatozoa. A high-throughput sequencing method targeting V3 and V4 regions of 16S rRNA gene was applied. A series of negative controls together with stringent in-silico decontamination methods were analysed. RESULTS: Between 50 and 70% of all the detected bacterial reads accounted for contamination in the testicular sperm samples. After stringent decontamination, Blautia (P = 0.04), Cellulosibacter (P = 0.02), Clostridium XIVa (P = 0.01), Clostridium XIVb (P = 0.04), Clostridium XVIII (P = 0.02), Collinsella (P = 0.005), Prevotella (P = 0.04), Prolixibacter (P = 0.02), Robinsoniella (P = 0.04), and Wandonia (P = 0.04) genera demonstrated statistically significant abundance among immature spermatozoa. CONCLUSIONS: Our results indicate that the human testicle harbours potential bacterial signature, though in a low-biomass, and could contribute to the seminal microbiome composition. Further, applying stringent decontamination methods is crucial for analysing microbiome in low-biomass site.

Toward Molecular Medicine in Female Infertility Management: Editorial to the Special Issue "Molecular Mechanisms of Human Oogenesis and Early Embryogenesis".

Female infertility is the main reason for involuntary childlessness nowadays [...].

Ovarian Aging: Molecular Mechanisms and Medical Management.

This is a short review of the basic molecular mechanisms of ovarian aging, written with a particular focus on the use of this data to improve the diagnostic and therapeutic protocols both for women affected by physiological (age-related) ovarian decay and for those suffering premature ovarian insufficiency. Ovarian aging has a genetic basis that conditions the ovarian activity via a plethora of cell-signaling pathways that control the functions of different types of cells in the ovary. There are various factors that can influence these pathways so as to reduce their efficiency. Oxidative stress, often related to mitochondrial dysfunction, leading to the apoptosis of ovarian cells, can be at the origin of vicious circles in which the primary cause feeds back other abnormalities, resulting in an overall decline in the ovarian activity and in the quantity and quality of oocytes. The correct diagnosis of the molecular mechanisms involved in ovarian aging can serve to design treatment strategies that can slow down ovarian decay and increase the quantity and quality of oocytes that can be obtained for an in vitro fertilization attempt. The available treatment options include the use of antioxidants, melatonin, growth hormones, and mitochondrial therapies. All of these treatments have to be considered in the context of each couple's history and current clinical condition, and a customized (patient-tailored) treatment protocol is to be elaborated.

Novel diagnostic approaches to intrauterine neoplasm in fertile age: sonography and hysteroscopy.

Endometrial carcinoma (EC) is the most common gynecological malignancy in the world. It is mostly detected in postmenopausal women, but it can also occur in women of fertile age who need fertility-sparing therapy. An early diagnosis is the main objective for the correct management of these patients, making it possible to use a fertility-sparing treatment approach without exposing the patients to the risk of cancer progression. In this review, we discuss the role of sonography and hysteroscopy in the detection of intrauterine neoplasm in women of childbearing age.

Classification systems of Asherman's syndrome. An old problem with new directions.

Intrauterine adhesion (IUA) formation and the resulting Asherman's syndrome (AS) is an unfortunate clinical condition that occurs when the endometrium is damaged as a consequence of trauma, such as vigorous curettage, infection, or some Müllerian anomaly. The most frequent symptoms include hypo/amenorrhea, infertility, and adverse reproductive outcomes. Prevention of IUA formation is essential; however, when present, accurate diagnosis and surgical intervention (hysteroscopic adhesiolysis) are required. The outcome of this treatment is based on the technique and the extent of surgery performed which depends on the severity and complexity of the disease. Hence its classification becomes particularly important to determine a standardized therapy for each case and patient counseling regarding the prognosis. In this article, we aim to describe the IUAs classification systems that have been proposed comparing the merits and demerits of each one.

Hysteroscopic endometrial biopsy: from indications to instrumentation and techniques. A call to action.

During the last twenty years, the diagnostic approach to endometrial pathology has radically evolved. For over a century, intrauterine blind biopsy techniques were considered the gold standard procedure for the histopathological diagnosis of intrauterine diseases. The advent of hysteroscopy, which made it possible to directly visualize the uterine cavity, and the subsequent miniaturization of the instruments allowing its use in the office setting without anesthesia are considered game-changers. To date, it is feasible to retrieve a targeted eye specimen of endometrial tissue with little or no discomfort for the patient in the office setting. To pursue this aim, several technological upgrades have improved the diagnostic accuracy of hysteroscopic endometrial biopsy. In this paper we provide an up-to-date review of the latest evidence regarding indications, instrumentations, and techniques for hysteroscopic endometrial biopsy, to help the operator in providing an adequate endometrial sampling for histopathological analysis.

After corona: there is life after the pandemic.

The current pandemic of Coronavirus Disease 2019 (COVID-19) has focused the attention of medical-care providers away from non-life-threatening diseases, including infertility. Although infertility does not jeopardize the physical survival of infertile couples, it does jeopardize their future quality of life. Human infertility can be caused by a number of factors, some of which are age-dependent, and their effects may become irreversible if appropriate measures are not taken in time to prevent irreversible childlessness. Accordingly, each case of infertility should be evaluated comprehensively to establish its position of priority. Assisted reproductive technology (ART) makes it possible to separate fertilization and pregnancy in time. Whereas pregnant women infected with coronavirus may have an increased risk of adverse neonatal outcomes, gametes do not transmit COVID-19. Thus, performing ovarian stimulation and fertilization without delay, freezing the resulting embryos and delaying embryo transfer until the end of the pandemic appears to be the best strategy at present.

Hysteroscopic endometrial resection vs. hysterectomy for abnormal uterine bleeding: impact on quality of life and sexuality. Evidence from a systematic review of randomized controlled trials.

PURPOSE OF REVIEW: The aim of this systematic review is to summarize the current evidence regarding the effectiveness of hysterectomy and hysteroscopic endometrial resection in improving quality of life (QoL), sexual function and psychological wellbeing of women abnormal uterine bleeding. RECENT FINDINGS: We performed a systematic literature search in PubMed/MEDLINE and Embase for original studies written in English (registered in PROSPERO 2019 CRD42019133632), using the terms 'endometrial ablation', 'endometrial destruction', 'endometrial resection', 'hysterectomy', 'menorrhagia', 'dysfunctional uterine bleeding', 'quality of life', 'sexuality' published up to April 2019. Our literature search produced 159 records. After exclusions, nine studies were included showing the following results: both types of treatment significantly improve QoL and psychological wellbeing; hysterectomy is associated with higher rates of satisfaction; hysterectomy is not associated with a significant deterioration in sexual function. SUMMARY: Hysterectomy is currently more advantageous in terms of improving abnormal uterine bleeding and satisfaction rates than hysteroscopic endometrial destruction techniques. Furthermore, there is some evidence of a greater improvement in general health for women undergoing hysterectomy. However, high-quality prospective randomized controlled trials should be implemented to investigate the effectiveness of hysterectomy and endometrial ablation in the improvement of QoL outcomes in larger patient cohorts.

High dose of d-chiro-inositol improves oocyte quality in women with polycystic ovary syndrome undergoing ICSI: a randomized controlled trial.

The aim of this study was to evaluate the effect of two doses of d-chiro-inositol (DCI) in combination with Myo-inositol (MYO) on the oocyte quality (OQ) of women with polycystic ovarian syndrome (PCOS) undergoing intracytoplasmic sperm injection (ICSI). Methods: This was a controlled, randomized, double-blind, parallel group study on 172 oocytes from 11 women. The study compared the effect of two MYO-DCI formulations given over 12 weeks on OQ. Five women received 550 mg of MYO + 300 mg of DCI daily (high DCI content group), while 6 women were given a daily dose of 550 mg of MYO with the only 27.6 mg of DCI (low DCI content group). Results: According to a multivariate analysis using linear mixed effect models, high doses of DCI have a positive influence on the quality of the cytoplasm of the oocyte (ß = 1.631, χ2 = 7.347, d.f. = 1, p = .00672). Zona pellucida, plasma membrane, cytoplasm, and sperm reception have also been improved with any combination of MYO/DCI by decreasing testosterone or improving insulin sensitivity, regardless of age and body mass index. Conclusion: The combination of MYO with high doses of DCI improved oocyte cytoplasm quality in women with PCOS undergoing ICSI.

From hysteroscopy to laparoendoscopic surgery: what is the best surgical approach for symptomatic isthmocele? A systematic review and meta-analysis.

PURPOSE: To investigate the effectiveness and risks of different surgical therapies for isthmocele in symptomatic women with abnormal uterine bleeding, infertility, or for the prevention of obstetric complications, considering safety and surgical complications. METHODS: PubMed/MEDLINE, Scopus, Embase, Science Direct, and Cochrane Library were systematically searched (n° CRD4201912035) for original articles on the surgical treatment of isthmocele published between 1950 and 2018. Data synthesis was completed using MedCalc 16.4.3. The body of evidence was assessed using the GRADE methodology. RESULTS: We retrieved 33 publications: 28 focused on a single surgical technique, and five comparing different techniques. Meta-analysis showed an improvement of symptoms in 85.00% (75.05-92.76%) of women after hysteroscopic correction, 92.77% (85.53-97.64%) after laparoscopic/robotic correction, and 82.52% (67.53-93.57%) after vaginal correction. Hysteroscopic surgery was associated with the lowest risk of complications (0.76%, 0.20-1.66%). CONCLUSIONS: We found adequate evidence supporting the use of surgery for the treatment of symptomatic isthmocele, as it was found to improve the bleeding symptoms in more than 80% of patients. Differently, we found a lack of evidence regarding the role of surgery with the purpose of improving fertility or reducing the risk of obstetric complications in women with asymptomatic isthmocele. The hysteroscopic correction of isthmocele may be the safest and most effective strategy in those patients with adequate residual myometrial thickness overlying the isthmocele. Laparoscopic and vaginal surgeries may be the preferred options for patients with a thinner residual myometrium over the defect (< 2.5 mm) and when hysteroscopic treatment is inconclusive.

Management of anxiety and pain perception in women undergoing office hysteroscopy: a systematic review.

PURPOSE: The aim of this review is to provide an overview of the literature about the perception and management of anxiety and pain in women undergoing an office hysteroscopic procedure. METHODS: We performed a systematic literature search in Embase, PubMed/MEDLINE, Cochrane Library and Web of Science for original studies written in English (registered in PROSPERO 2019-CRD42019132341), using the terms 'hysteroscopy' AND 'pain' AND 'anxiety' published up to January 2019. Only original articles (randomized, observational and retrospective studies) about management of anxiety and pain related to the hysteroscopic procedure were considered eligible. RESULTS: Our literature search produced 84 records. After exclusions, 11 studies including 2222 patients showed the following results: (a) pain experienced during hysteroscopy is negatively affected by preprocedural anxiety; (b) pharmacological interventions seem to be help in reducing pain during hysteroscopy; (c) waiting time before the procedure is a significant factor affecting patients' anxiety; (d) music during the procedure may be helpful in reducing anxiety. CONCLUSIONS: The utilization of office hysteroscopy is hampered by varying levels of anxiety and pain perceived by women who are candidates for the procedure. For these reasons, it is essential to identify effective pharmacological and non-pharmacological strategies to alleviate these factors. We recommend further studies especially focusing on non-pharmacological interventions to facilitate the dissemination of good clinical practices among hysteroscopists.

Vitamin D, reproductive disorders and assisted reproduction: evidences and perspectives.

Vitamin D is an important nutrient involved in many fundamental health outcomes. However, its influence on female reproductive function remains ambiguous. Cholecalciferol seems to have a role in the reproductive processes and in the patients affected by polycystic ovary syndrome, endometriosis, uterine myomas and premature ovarian failure. Moreover, it may play an important role in the assisted reproductive techniques, given that it is capable of influencing oocyte quality, but also an adequate preparation of the endometrium for embryonic implantation. Although promising, available evidence is based on a limited number of in vitro, in vivo and clinical studies. We provide an overview of the association between vitamin D and female infertility reporting the most recent data published in the literature. Nevertheless, properly randomised clinical trials are mandatory to achieve more conclusive results about the promising role of vitamin D in the management of female assisted reproduction.