Conservative surgical treatment for adenomyosis: New options for looking beyond uterus removal.

Adenomyosis is a common benign uterine disorders and patients may present dysmenorrhea, dyspareunia, abnormal uterine bleeding (AUB) and infertility. The treatment is very complex, including medical, surgical or radiological approaches. Hormonal drugs represent the first line therapy of adenomyosis, highly effective on symptoms and uterine volume reduction. Radiological procedures (UAE and HIFU), RFA and hysteroscopy may be proposed in those cases in which medical therapy is ineffective. Considering surgical treatment, hysterectomy remains the only existing definitive treatment but in the last decades the desire of uterus preservation is becoming more and more diffuse. On the other hand, surgical conservative treatments of adenomyosis are very effective in ameliorating AUB and pelvic pain and in reducing uterine volume, with some post-operative risks and obstetrics complications. Cytoreductive surgery for adenomyosis may be very complex, therefore it should be performed by experienced surgeons in dedicated centers, above all in case of concomitant endometriosis.

Society for Endometriosis and Uterine Disorders Forum: Adenomyosis Today, Paris, France, December 12, 2023.

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of Defense, or the United States Government. This symposium was supported by Sumitomo Pharma. However, the authors received no support for the creation of this manuscript, and the manuscript was created, revised and submitted solely by the authors recognized above.

The placenta in fetal death: Molecular evidence of dysregulation of inflammatory, proliferative and fetal protective pathways.

BACKGROUND: It is estimated that over 2 million cases of fetal death occur worldwide every year, but, despite the high incidence, several basic and clinical characteristics of this disorder are still unclear. Placenta is suggested to play a central role in fetal death. Placenta produces hormones, cytokines and growth factors that modulate functions of the placental-maternal unit. Fetal death has been correlated with impaired secretion of some of these regulatory factors. OBJECTIVE(S): The aim of the present study was to evaluate, in placentas collected from fetal death, the gene expression of inflammatory, proliferative and protective factors. STUDY DESIGN: Cases of fetal death in singleton pregnancy were retrospectively selected, excluding pregnancies complicated by fetal anomalies, gestational diabetes, intrauterine growth restriction and moderate to severe maternal diseases. A group of placentas collected from healthy singleton term pregnancies were used as controls. Groups were compared regarding maternal and gestational age, fetal sex and birth weight. Placental mRNA expression of inflammatory (IL-6), proliferative (Activin A, TGF-ß1) and regulatory (VEGF, VEGFR2, ATP-binding cassette (ABC) transporters ABCB1 and ABCG2, sphingosine 1-phosphate (S1P) signaling pathway) markers was conducted using real-time PCR. Statistical analysis and graphical representation of the data were performed using the GraphPad Prism 5 software. For the statistical analysis, Student's t-test was used, and P values < 0.05 were considered significant. RESULTS: Placental mRNA expression of IL-6 and VEGFR2 resulted significantly higher in the fetal death group compared to controls (P<0.01), while activin A, ABCB1 and ABCG2 expression resulted significantly lower (P<0.01). A significant alteration in the S1P signaling pathway was found in the fetal death group, with an increased expression of the specific receptor isoforms sphingosine 1-phosphate receptor 1, 3 and 4 (S1P1, S1P3, S1P4) and of sphingosine kinase 2 (SK2), one of the enzyme isoforms responsible for S1P synthesis (P<0.01). CONCLUSION: (s): The present study confirmed a significantly increased expression of placental IL-6 and VEGFR2 mRNA, and for the first time showed an increased expression of S1P receptors and SK2 as well as a decreased expression of activin A and of selected ATP-binding cassette transporters, suggesting that multiple inflammatory and protective factors are deranged in placenta of fetal death.

The modern management of uterine fibroids-related abnormal uterine bleeding.

Uterine fibroids (UFs) are the most common female benign pelvic tumors, affecting >60% of patients aged 30-44 years. Uterine fibroids are asymptomatic in a large percentage of cases and may be identified incidentally using a transvaginal ultrasound or a magnetic resonance imaging scan. However, in approximately 30% of cases, UFs affect the quality of life and women's health, with abnormal uterine bleeding and heavy menstrual bleeding being the most common complaints, along with iron deficiency (ID) and ID anemia. Medical treatments used for UFs-related abnormal uterine bleeding include symptomatic agents, such as nonsteroidal antiinflammatory drugs and tranexamic acid, and hormonal therapies, including combined oral contraceptives, gonadotropin-releasing hormone agonists or antagonists, levonorgestrel intrauterine systems, selective progesterone receptor modulators, and aromatase inhibitors. Nevertheless, few drugs are approved specifically for UF treatment, and most of them manage the symptoms. Surgical options include fertility-sparing treatments, such as myomectomy, or nonconservative options, such as hysterectomy, especially in perimenopausal women who are not responding to any treatment. Radiologic interventions are also available: uterine artery embolization, high-intensity focused ultrasound or magnetic resonance-guided focused ultrasound, and radiofrequency ablation. Furthermore, the management of ID and ID anemia, as a consequence of acute and chronic bleeding, should be taken into account with the use of iron replacement therapy both during medical treatment and before and after a surgical procedure. In the case of symptomatic UFs, the location, size, multiple UFs, or coexistent adenomyosis should guide the choice with a shared decision-making process, considering long- and short-term treatment goals expected by the patient, including pregnancy desire or wish to preserve the uterus independently of reproductive goals.

Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3).

STUDY QUESTION: Does linzagolix administered orally once daily for up to 3 months at a dose of 75 mg alone or 200 mg in combination with add-back therapy (ABT) (1.0 mg estradiol; 0.5 mg norethindrone acetate, also known as norethisterone acetate [NETA]) demonstrate better efficacy than placebo in the management of endometriosis-related dysmenorrhea and non-menstrual pelvic pain? SUMMARY ANSWER: Combining 200 mg linzagolix with ABT was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain at 3 months of therapy, while a daily dose of 75 mg linzagolix yielded a significant decrease only in dysmenorrhea at 3 months. WHAT IS KNOWN ALREADY?: A previously published Phase 2, dose-finding study reported that at a dose of 200 mg daily, linzagolix promotes full suppression of estradiol secretion to serum levels below 20 pg/ml and noted that the addition of ABT may be needed to manage hypoestrogenic side effects. At lower doses (75 mg and 100 mg/day), linzagolix maintains estradiol values within the target range of 20-60 pg/ml, which could be ideal to alleviate symptoms linked to endometriosis. STUDY DESIGN, SIZE, DURATION: EDELWEISS 3 was a multicenter, prospective, randomized, placebo-controlled, double-blind, double-dummy Phase 3 study to evaluate the safety and efficacy of linzagolix for the treatment of moderate-to-severe endometriosis-associated pain. Treatment was administered orally once daily for up to 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the EDELWEISS 3 trial, 486 subjects with moderate-to-severe endometriosis-associated pain were randomized at a 1:1:1 ratio to one of the three study groups: placebo, 75 mg linzagolix alone or 200 mg linzagolix in association with ABT. Pain was measured daily on a verbal rating scale and recorded in an electronic diary. MAIN RESULTS AND THE ROLE OF CHANCE: At 3 months, the daily 200 mg linzagolix dose with ABT met the primary efficacy objective, showing clinically meaningful and statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain, with stable or decreased use of analgesics. The proportion of responders for dysmenorrhea in the 200 mg linzagolix with ABT group was 72.9% compared with 23.5% in the placebo group (P < 0.001), while the rates of responders for non-menstrual pelvic pain were 47.3% and 30.9% (P = 0.007), respectively. The 75 mg linzagolix daily dose demonstrated a clinically meaningful and statistically significant reduction in dysmenorrhea versus placebo at 3 months. The proportion of responders for dysmenorrhea in the 75 mg linzagolix group was 44.0% compared with 23.5% in the placebo group (P < 0.001). Although the 75 mg dose showed a trend toward reduction in non-menstrual pelvic pain at 3 months relative to the placebo, it was not statistically significant (P = 0.279). Significant improvements in dyschezia and overall pelvic pain were observed in both linzagolix groups when compared to placebo. Small improvements in dyspareunia scores were observed in both linzagolix groups but they were not significant. In both groups, hypoestrogenic effects were mild, with low rates of hot flushes and bone density loss of <1%. A daily dose of 200 mg linzagolix with ABT or 75 mg linzagolix alone was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain also at 6 months of therapy. LIMITATIONS, REASONS FOR CAUTION: Efficacy was compared between linzagolix groups and placebo; however, it would be useful to have results from comparative studies with estro-progestogens or progestogens. It will be important to ascertain whether gonadotropin-releasing hormone antagonists have significant benefits over traditional first-line medications. WIDER IMPLICATIONS OF THE FINDINGS: Linzagolix administered orally once daily at a dose of 200 mg in combination with add-back therapy (ABT) demonstrated better efficacy and safety than placebo in the management of moderate-to-severe endometriosis-associated pain. The quality of life was improved and the risks of bone loss and vasomotor symptoms were minimized due to the ABT. The 75 mg dose alone could be suitable for chronic treatment of endometriosis-associated pain without the need for concomitant hormonal ABT, but further research is needed to confirm this. If confirmed, it would offer a viable option for women who do not want to wish to have ABT or for whom it is contraindicated. STUDY FUNDING/COMPETING INTEREST(S): Funding for the EDELWEISS 3 study was provided by ObsEva (Geneva, Switzerland). Analysis of data and manuscript writing were partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK) and Kissei (Japan) and grant 5/4/150/5 was awarded to M.-M.D. by FNRS. J.D. was a member of the scientific advisory board of ObsEva until August 2022, a member of the scientific advisory board of PregLem, and received personal fees from Gedeon Richter, ObsEva and Theramex. J.D. received consulting fees, speakers' fees, and travel support from Gedeon Richter, Obseva and Theramex, which was paid to their institution. C.B. has received fees from Theramex, Gedeon Richter, and Myovant, and travel support from Gedeon Richter-all funds went to the University of Oxford. He was a member of the data monitoring board supervising the current study, and served at an advisory board for endometriosis studies of Myovant. H.T. has received grants from Abbvie and was past president of ASRM. F.C.H. has received fees from Gedeon Richter and Theramex. O.D. received fees for lectures from Gedeon Richter and ObsEva and research grants for clinical studies from Preglem and ObsEva independent from the current study. A.H. has received grants from NIHR, UKRI, CSO, Wellbeing of Women, and Roche Diagnostics; he has received fees from Theramex. A.H.'s institution has received honoraria for consultancy from Roche Diagnostics, Gesynta, and Joii. M.P. has nothing to declare. F.P. has received fees from Theramex. S.P.R. has been a member of the scientific advisory board of Gedeon Richter and received fees from Gedeon Richter. A.P. and M.B. are employees of Theramex. E.B. was an employee of ObsEva, sponsor chair of the data monitoring board supervising the current study, and has been working as a consultant for Theramex since December 2022; she owns stock options in ObsEva. M.-M.D. has received fees and travel support from Gedeon Richter and Theramex. TRIAL REGISTRATION NUMBER: NCT03992846. TRIAL REGISTRATION DATE: 20 June 2019. DATE OF FIRST PATIENT'S ENROLLMENT: 13 June 2019.

Imaging and molecular features of adenomyosis after menopause.

OBJECTIVES: To explore the imaging features and the molecular characterization of adenomyosis after menopause. STUDY DESIGN: An observational cross-sectional study was performed in a group of postmenopausal patients undergoing a transvaginal ultrasound (TVUS) (n = 468). Among those presenting the US criteria for adenomyosis, also confirmed by magnetic resonance imaging (MRI), previous menstrual symptoms, gynecological and obstetric history were reviewed. In a subgroup undergoing hysterectomy, uterine specimens were analyzed by histology and expression of genes implicated in the epithelial-mesenchymal transition, inflammation and fibrosis, including the sphingosine-1-phosphate (S1P) pathway, was evaluated and compared to matched non-menopausal adenomyosis specimens. MAIN OUTCOME MEASURES: Direct and indirect US features of adenomyosis according to Morphological Uterus Sonographic Assessment at TVUS. Molecular characterization of postmenopausal versus pre-menopausal adenomyosis samples. RESULTS: According to TVUS and MRI, adenomyosis was identified in 49 patients (10.4 %). On US, diffuse adenomyosis was the most common phenotype, whereas internal adenomyosis with diffuse pattern and asymmetric type was the most prevalent on MRI. Molecular analysis showed that adenomyosis lesions express markers of epithelial-mesenchymal transition, inflammation and fibrosis also in postmenopausal women. By comparing the results with those from pre-menopausal samples, the expression of α smooth muscle actin (αSMA), a marker of fibrosis, was significantly greater after menopause, and altered S1P catabolism and signaling were observed. CONCLUSIONS: Adenomyosis may be identified in postmenopausal women by imaging, either TVUS or MRI, and fibrosis is one of the key features on molecular analysis.

Long-term treatment for endometriosis with dienogest: efficacy, side effects and tolerability.

BACKGROUND: Dienogest (DNG) improves endometriosis-associated pain (EAP) and patients' quality of life; however, the modern cornerstone of the management of endometriosis is the long-term adherence of the patient to medical treatment. OBJECTIVE: To evaluate DNG as a long-term treatment of endometriosis, focusing on patients' compliance and side effects, also correlating with different phenotypes of endometriosis. METHODS: This was a cohort study on a group of patients with endometriosis (n = 114) undergoing long-term treatment with DNG. During the follow up visits (12, 24, and 36 months) patients were interviewed: an assessment of EAP was performed by using a visual analogue scale (VAS) and side effects were evaluated by using a specific questionnaire of 15 items. RESULTS: At 12 months, 81% were continuing the DNG treatment, with a significant reduction of dysmenorrhea, dyspareunia, dyschezia, dysuria and chronic pelvic pain. Of the 19% that discontinued the treatment: 62% was due to spotting, reduced sexual drive, vaginal dryness, and mood disorders. The improvement of EAP was significant for all endometriosis phenotypes, especially in patients with the deep infiltrating type. At 36 months, 73% of patients were continuing the treatment, showing a significant reduction of EAP through the follow up, along with an increase of amenorrhea (from 77% at 12 months to 93% at 36 months). In a subgroup of 18 patients with gastrointestinal disorders, DNG was administered vaginally at the same dosage, showing similar results in terms of efficacy and tolerability. CONCLUSIONS: DNG was an effective long-term treatment for all endometriosis phenotypes, with few side effects that caused the discontinuation of the treatment mainly during the first year. Thus, the course of 1-year treatment is a predictive indicator for long-term treatment adherence.

Adenomyosis diagnosis among adolescents and young women with dysmenorrhoea and heavy menstrual bleeding.

RESEARCH QUESTION: What is the prevalence of adenomyosis at ultrasonography among adolescents and young women reporting dysmenorrhoea and/or heavy menstrual bleeding (HMB)? DESIGN: This observational cohort study involved adolescents and young women referred for dysmenorrhoea and/or HMB to the Adolescent Medicine Unit at Careggi University Hospital, Italy. Patients with endometriosis and bleeding disorders were excluded. Transvaginal ultrasonography or transrectal sonography using a transvaginal probe was performed. The myometrium was described according to the Morphological Uterus Sonographic Assessment criteria. Details of baseline characteristics, clinical data and symptoms were collected. The presence of sonographic features of adenomyosis and the association between imaging findings and clinical symptoms were evaluated. RESULTS: The cohort included 95 patients aged between 13 and 25 years, referred for dysmenorrhoea (88.4%), HMB (23.2%) or both (13.7%). According to the MUSA criteria the sonographic diagnosis of adenomyosis was made in 27.4% of patients, with the diffuse type the most prevalent. Uterine wall asymmetry, hyperechoic intramyometrial islands, translesional vascularity and an interrupted junctional zone were the most common features. Patients with imaging findings of adenomyosis had significantly higher rates of HMB than those with a normal myometrial appearance (38.5% versus 17.4%, P = 0.030). In addition, the coexistence of dysmenorrhoea and HMB was significantly associated with adenomyosis (odds ratio 5.68, 95% confidence interval 1.65-19.5). CONCLUSIONS: Adenomyosis may be diagnosed among teenagers and young women referred with dysmenorrhoea and/or HMB. The clinical presentation is relevant for the diagnosis, with HMB alone and HMB plus dysmenorrhoea significantly associated with the sonographic identification of adenomyosis.

Pathogenesis of uterine fibroids: current understanding and future directions.

Fibroids are benign uterine tumors characterized by the proliferation of uterine smooth muscle cells, embedded in an abundant extracellular matrix. Their prevalence is estimated to be >50% in women aged >45 years. Fibroids represent a considerable health burden. It is time to acquire a deeper mechanistic understanding of uterine fibroid-related etiology and pathogenesis, which may help pinpoint new strategies and an individualized approach. There is a need to gather prospective data and conduct studies to compare alternative approaches and assess long-term outcomes with respect to quality of life, recurrence of symptoms (bleeding and bulk symptoms), fertility, and even complications The goal of this review was to evaluate the widely accepted pathogenesis and identify risks factors and future directions for clinical and basic research into fibroids.

Sphingosine 1-phosphate signaling axis mediates neuropeptide S-induced invasive phenotype of endometriotic cells.

Endometriosis is a chronic gynecological syndrome characterized by endometrial cell invasion of the extra-uterine milieu, pelvic pain and infertility. Treatment relies on either symptomatic drugs or hormonal therapies, even though the mechanism involved in the onset of endometriosis is yet to be elucidated. The signaling of sphingolipid sphingosine 1-phosphate (S1P) is profoundly dysregulated in endometriosis. Indeed, sphingosine kinase (SK)1, one of the two isoenzymes responsible for S1P biosynthesis, and S1P1, S1P3 and S1P5, three of its five specific receptors, are more highly expressed in endometriotic lesions compared to healthy endometrium. Recently, missense coding variants of the gene encoding the receptor 1 for neuropeptide S (NPS) have been robustly associated with endometriosis in humans. This study aimed to characterize the biological effect of NPS in endometriotic epithelial cells and the possible involvement of the S1P signaling axis in its action. NPS was found to potently induce cell invasion and actin cytoskeletal remodeling. Of note, the NPS-induced invasive phenotype was dependent on SK1 and SK2 as well as on S1P1 and S1P3, given that the biological action of the neuropeptide was fully prevented when one of the two biosynthetic enzymes or one of the two selective receptors was inhibited or silenced. Furthermore, the RhoA/Rho kinase pathway, downstream to S1P receptor signaling, was found to be critically implicated in invasion and cytoskeletal remodeling elicited by NPS. These findings provide new information to the understanding of the molecular mechanisms implicated in endometriosis pathogenesis, establishing the rationale for non-hormonal therapeutic targets for its treatment.

Sphingosine-1-phosphate receptor 3 is a non-hormonal target to counteract endometriosis-associated fibrosis.

OBJECTIVE: To study the molecular mechanisms responsible for fibrosis in endometriosis by investigating whether the protein expression levels of sphingosine-1-phosphate receptor 3 (S1PR3), one of the five specific receptors of the bioactive sphingolipid sphingosine-1-phosphate (S1P), correlate with fibrosis extent in endometriotic lesions and which are the cellular mechanisms involved in this process. DESIGN: Case-control laboratory study and cultured endometriotic cells. SETTING: University research institute and university hospital. PATIENT(S): A total of 33 women, with and without endometriosis, were included in the study. INTERVENTIONS(S): Endometriotic lesions were obtained from women with endometriosis (ovarian endometrioma, n = 8; deep infiltrating endometriosis, n = 15; [urological n = 5, gastrointestinal n = 6, and posterior n = 4]) and control endometrium from healthy women, n = 10, by means of laparoscopic and hysteroscopic surgery. The expression of S1PR3 was evaluated using immunohistochemistry and the extent of fibrosis was assessed using Masson's trichrome staining. Human-cultured epithelial endometriotic 12Z cells were used to evaluate the mechanisms involved in the profibrotic effect of S1PR3 activation. MAIN OUTCOME MEASURE(S): The expression of S1PR3 in endometriotic lesions is positively correlated with endometriosis-associated fibrosis. In addition, S1P induced epithelial-mesenchymal transition (EMT) and fibrosis in epithelial endometriotic cells. Using RNA interference and pharmacological approaches, the profibrotic effect of S1P was shown to rely on S1PR3, thus unveiling the molecular mechanism implicated in the profibrotic action of the bioactive sphingolipid. RESULT(S): The protein expression levels of S1PR3 were significantly augmented in the glandular sections of endometrioma and deep infiltrating endometriosis of different localizations with respect to the control endometrium and positively correlated with the extent of fibrosis. Sphingosine-1-phosphate was shown to have a crucial role in the onset of fibrosis in epithelial endometriotic cells, stimulating the expression of EMT and fibrotic markers. Genetic approaches have highlighted that S1PR3 mediates the fibrotic effect of S1P. Downstream of S1PR3, ezrin and extracellular-signal-regulated kinases 1 and 2 signaling were found to be critically implicated in the EMT and fibrosis elicited by S1P. CONCLUSION(S): Sphingosine-1-phosphate receptor 3 may represent a possible innovative pharmacological target for endometriosis.

Early Fetal Growth Restriction with or Without Hypertensive Disorders: a Clinical Overview.

Early onset fetal growth restriction (FGR) is one of the main adverse pregnancy conditions, often associated with poor neonatal outcomes. Frequently, early onset FGR is associated with early onset hypertensive disorders of pregnancy (HDP), and in particular preeclampsia (PE). However, to date, it is still an open question whether pregnancies complicated by early FGR plus HDP (FGR-HDP) and those complicated by early onset FGR without HDP (normotensive-FGR (n-FGR)) show different prenatal and postnatal outcomes and, consequently, should benefit from different management and long-term follow-up. Recent data support the hypothesis that the presence of PE may have an additional impact on maternal hemodynamic impairment and placental lesions, increasing the risk of poor neonatal outcomes in pregnancy affected by early onset FGR-HDP compared to pregnancy affected by early onset n-FGR. This review aims to elucidate this poor studied topic, comparing the clinical characteristics, perinatal outcomes, and potential long-term sequelae of early onset FGR-HDP and early onset n-FGR.

Recurrence of Uterine Fibroids After Conservative Surgery or Radiological Procedures: a Narrative Review.

The present narrative review aims to discuss the available data on the incidence and the risk factors of uterine fibroids (UFs) recurrence after different types of conservative surgical or radiologic procedures in women wishing to preserve their uterus. UFs are the most common benign tumors in women all over the world. Clinical presentation, including abnormal uterine bleeding (AUB), pelvic pain, bulky symptoms, and infertility affect patients' quality of life, and a large variety of conservative treatments are available especially for those with desire of pregnancy. Fertility sparing surgery, by either laparoscopy, hysteroscopy or laparotomy, or radiological interventions (uterine artery embolization, high-intensity focused ultrasound or magnetic resonance-guided focused ultrasound), are the most common therapeutic approaches. However, the genetic or acquired predisposition to UFs remain despite the treatments, and the recurrences are frequently described in a large percentage of patients. The most relevant risk factors for recurrence of UFs are young age at the first surgery, incomplete fibroid resection, the presence of multiple lesions, an enlarged uterus, and the coexistence with other pelvic diseases. The discussion on the possible medical strategy to reduce the recurrence is an open field of clinical investigation, in particular by using hormonal drugs.

Relugolix combination therapy in European women with symptomatic uterine fibroids: a subgroup analysis from the randomized phase 3 LIBERTY pivotal trials.

OBJECTIVE: In the 24-week, phase 3 LIBERTY 1 (L1) and LIBERTY 2 (L2) trials, relugolix combination therapy (relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0.5 mg)) reduced uterine fibroid (UF)-associated symptoms. This post hoc analysis assessed safety and efficacy of relugolix-CT in European women from L1/L2. METHODS: Premenopausal women (aged 18-50 years) with UF-associated heavy menstrual bleeding (HMB) were randomized 1:1:1 in L1 (N = 388) and L2 (N = 382) to relugolix-CT or placebo for 24 weeks, or delayed relugolix-CT (relugolix 40 mg then relugolix-CT; 12 weeks each). Primary endpoint: proportion of responders (menstrual blood loss (MBL) <80 mL and reduction of ≥50% from baseline MBL volume) over the last 35 days of treatment. Secondary endpoints: MBL volume, amenorrhea, UF-associated pain, symptom severity, distress related to bleeding and pelvic discomfort, health-related quality of life (HRQoL). Safety endpoints included adverse event (AE) reporting and bone mineral density (BMD) assessment. RESULTS: In European women from L1/L2 (N = 124, 16%), a significantly greater proportion of treatment responders was observed with relugolix-CT vs. placebo (85.4% vs. 19.1%, respectively; nominal p < .0001). There were statistically significant improvements with relugolix-CT vs. placebo for several secondary endpoints: reduction in MBL volume, amenorrhea rate, proportion achieving mild-to-no pain, reduction in symptom severity and distress from bleeding and pelvic discomfort, and improvement in HRQoL. Incidence of AEs and percentage changes in BMD from baseline to week 24 were similar for relugolix-CT and placebo. CONCLUSIONS: In European women with UF and HMB, once-daily relugolix-CT vs. placebo improved UF-associated symptoms and preserved BMD.

Pregorexia: a systematic review and meta-analysis on the constructs of body image dissatisfaction and eating disturbances by gestational age in the peripartum.

PURPOSE: Pregorexia is a phenomenon posited to occur in the peripartum, characterized by an attempt to counter pregnancy's physiological changes in body shape through reduced calorie intake or increased physical activity. METHODS: In this pre-registered systematic review and meta-analysis, body image dissatisfaction and eating psychopathology in the peripartum according to gestational age were formally assessed. PubMed was searched up to May 2023. Selection criteria were represented by studies on body image concerns or eating psychopathology in the peripartum (up to 1 year after delivery). The population needed to include women from the general population or among patients with a history of (or current) eating disorder. For the meta-analysis, 17 studies were included: 10 for body image dissatisfaction (2625 individuals overall), 7 for eating behaviors (2551 individuals overall). The interplay between body image and the following themes was examined in depth: the adoption of breastfeeding, peripartum depression, sociocultural influences on body image, sexual disturbances, experiencing or reporting an altered food intake. RESULTS: Progressive dissatisfaction with body image during pregnancy by gestational age was observed, stably elevated for at least 12 months postpartum. Eating psychopathology was observed as elevated only at 12 months in the postpartum, but not during pregnancy. DISCUSSION: The current work offers normative values of body image satisfaction and eating psychopathology in the peripartum by gestational age. The relevance of current results was discussed, in order to inform both current clinical practice and future public policies. LEVEL OF EVIDENCE: Level I-Evidence obtained from: systematic reviews and meta-analyses.

Sphingosine 1-phosphate elicits a ROS-mediated proinflammatory response in human endometrial stromal cells via ERK5 activation.

Endometriosis is a chronic gynecological disease affecting ~10% women in the reproductive age characterized by the growth of endometrial glands and stroma outside the uterine cavity. The inflammatory process has a key role in the initiation and progression of the disorder. Currently, there are no available early diagnostic tests and therapy relies exclusively on symptomatic drugs, so that elucidation of the complex molecular mechanisms involved in the pathogenesis of endometriosis is an unmet need. The signaling of the bioactive sphingolipid sphingosine 1-phosphate (S1P) is deeply dysregulated in endometriosis. S1P modulates a variety of fundamental cellular processes, including inflammation, neo-angiogenesis, and immune responses acting mainly as ligand of a family of G-protein-coupled receptors named S1P receptors (S1PR), S1P1-5 . Here, we demonstrated that the mitogen-activated protein kinase ERK5, that is expressed in endometriotic lesions as determined by quantitative PCR, is activated by S1P in human endometrial stromal cells. S1P-induced ERK5 activation was shown to be triggered by S1P1/3 receptors via a SFK/MEK5-dependent axis. S1P-induced ERK5 activation was, in turn, responsible for the increase of reactive oxygen species and proinflammatory cytokine expression in human endometrial stromal cells. The present findings indicate that the S1P signaling, via ERK5 activation, supports a proinflammatory response in the endometrium and establish the rationale for the exploitation of innovative therapeutic targets for endometriosis.

The menstrual distress questionnaire (MEDI-Q): reliability and validity of the English version.

BACKGROUND: Menstrual cycle has a significant impact on women's health from different perspectives, both physically and psychologically. The assessment of menstrual-related distress is of pivotal clinical interest, especially in women with chronic exposure to abnormal bleeding or pain. The Menstrual Distress Questionnaire (MEDI-Q) is a new tool originally developed in Italian that comprehensively evaluates menstrual-related distress. OBJECTIVE: To validate the English version of the MEDI-Q in an English-speaking population. METHODS: The study consisted of two phases: an initial translation phase of the original Italian version of the MEDI-Q, and a data collection phase to validate the new English version among 288 native English-speaking women. RESULTS: The English version of MEDI-Q showed excellent psychometric properties, with high internal consistency (Cronbach's alpha = 0.84) and test-retest reliability (intraclass correlation coefficient = 0.95). Construct validity was supported by significant correlations between MEDI-Q scores and scores on measures of psychological distress and premenstrual symptoms. CONCLUSIONS: The English version of the MEDI-Q is a valid and reliable instrument for the assessment of menstrual distress and its impact on psychological well-being. This tool can be utilized in research and clinical settings to comprehensively investigate the impact of menstruation on various populations, identify and monitor menstruation-related disorders promptly and effectively, and to evaluate the effectiveness of targeted treatments for menstrual distress.

Elevated nuchal translucency, is it time to discuss the cut off?

OBJECTIVE: We aimed to evaluate pregnancy and postnatal outcomes of fetuses with NT between 95th and 99th percentile at first trimester and whether they could benefit from further investigations rather that routine scans. METHODS: Multicenter retrospective observational study which involved all cases with NT between 95th and 99th percentile from January 2015 to December 2020. Unfavorable outcome was considered as: miscarriage or intrauterine fetal death (IUFD), chromosomal abnormality/genetic syndrome, major malformation or neurodevelopmental delay. Study population outcomes were compared with general population. RESULTS: The rate of unfavorable outcome was 25.44% (167 out of 667). We reported: 6 (0.90%) second trimester miscarriage or IUFD, 90 (13.49%) chromosomal abnormalities/genetic syndromes, 57 (8.55%) major malformations, 13 (1.95%) cases of neurodevelopmental delay. The incidence of chromosomal abnormalities/genetic syndromes and major malformations were significantly higher (OR 6.99 (IC 95% 4.33-11.28), P < 0.001 and OR 17.77 (IC 95%7.22-43.75), P < 0.001 respectively) compared to the general population. The incidence of neurodevelopmental delay was not increased (OR of 0.64 CI 95% 0.33-1.24 P = 0.185). CONCLUSIONS: Fetuses with NT between 95th and 99th percentile have an increased risk of pregnancy and postnatal adverse outcomes. According to our data it is reasonable to consider a lower cut of NT (NT > 95th percentile) for offering further investigations such as detailed ultrasound scan, fetal echocardiography and counseling where the option of performing fetal karyotype and CGH array should be discussed.

Endometriosis and the diagnosis of different forms of migraine: an association with dysmenorrhoea.

RESEARCH QUESTION: Women with endometriosis are frequently affected by headache. How many of these have a clear diagnosis of migraine? Are the different forms of migraine related to the phenotypes and/or characteristics of endometriosis? DESIGN: This was a prospective nested case-control study. A consecutive series of 131 women with endometriosis who attended the endometriosis clinic were enrolled and examined for the presence of headache. A headache questionnaire was used to determine the characteristics of the headaches, and the diagnosis of migraine was confirmed by a specialist. The case group included women with endometriosis and a diagnosis of migraine, while the control group included women with only endometriosis. History, symptoms and other comorbidities were collected. A pelvic pain score and associated symptoms were assessed using a visual analogue scale. RESULTS: A diagnosis of migraine was made in 53.4% (70/131) of participants. Pure menstrual migraine was reported by 18.6% (13/70), menstrually related migraine by 45.7% (32/70) and non-menstrual migraine by 35.7% (25/70). Dysmenorrhoea and dysuria were significantly more frequent in patients with endometriosis and migraine than in those without migraine (P = 0.03 and P = 0.01). No difference was found for other variables, including age at diagnosis and duration of endometriosis, endometriosis phenotype, the presence of other autoimmune comorbidities or heavy menstrual bleeding. In most patients with migraine (85.7%) the headache symptoms had started years before the diagnosis of endometriosis. CONCLUSION: The occurrence of headache in many patients with endometriosis is associated with the presence of different forms of migraine, is related to pain symptoms and often precedes the diagnosis of endometriosis.