Experimental and new investigational drugs for the treatment of uterine fibroids.

INTRODUCTION: Uterine fibroids, the most prevalent benign tumors among reproductive-age women, pose treatment challenges that range from surgical interventions to medical therapies for symptom control. Progestins and estroprogestins effectively manage uterine bleeding by suppressing dysfunctional endometrium over fibroids. While GnRH agonists represent a crucial milestone in symptom treatment, their prolonged use results in menopausal-like symptoms and irreversible bone mineral density loss. Advancements in understanding fibroid pathophysiology have prompted the exploration of new compounds to overcome current therapy limitations. AREAS COVERED: This manuscript offers an updated overview of investigational drugs for symptomatic uterine fibroids. EXPERT OPINION: Despite ulipristal acetate's well-established efficacy as a selective progesterone receptor modulator (SPRM) in fibroid treatment, its prescription has declined due to the rare but severe risk of liver damage. Oral GnRH antagonists, like elagolix, relugolix, and linzagolix, with their novel pharmacodynamic properties, are gaining traction in fibroid management, inducing a dose-dependent reduction in circulating sex hormone levels. Ongoing research on natural compounds, such as vitamin D and epigallocatechin gallate (EGCG), presents emerging options for treating uterine fibroids. This evolving landscape reflects the ongoing efforts to improve therapeutic outcomes for individuals with symptomatic uterine fibroids.

A review of phase II and III drugs for the treatment and management of endometriosis.

INTRODUCTION: Endometriosis is an estrogen-dependent disease that gives rise to pelvic pain and infertility. Although estroprogestins and progestins currently stand as the first-line treatments for this condition, demonstrating efficacy in two-thirds of patients, a significant portion of individuals experience only partial relief or symptom recurrence following the cessation of these therapies. The coexistence of superficial, deep endometriosis, and ovarian endometriomas, as three distinct phenotypes with unique pathogenetic and molecular characteristics, may elucidate the current heterogeneous biological response to available therapy. AREAS COVERED: The objective of this review is to furnish the reader with a comprehensive summary pertaining to phase II-III hormonal treatments for endometriosis. EXPERT OPINION: Ongoing research endeavors are directed toward the development of novel hormonal options for this benign yet debilitating disease. Among them, oral GnRH antagonists emerge as a noteworthy option, furnishing rapid therapeutic onset without an initial flare-up; these drugs facilitate partial or complete estrogen suppression, and promote prompt ovarian function recovery upon discontinuation, effectively surmounting the limitations associated with previously employed GnRH agonists. Limited evidence supports the use of selective estrogen and progesterone receptor modulators. Consequently, further extensive clinical research is imperative to garner a more profound understanding of innovative targets for novel hormonal options.

Rituximab for endometriosis: Unlikely translatability from oncology due to safety concerns?

This letter discusses the article "The Effects of Rituximab on Experimental Endometriosis Model in Rats" by Dogan et al., which evaluated the potential therapeutic efficacy of rituximab in an experimental animal model of endometriosis. While the study showed promising results in decreasing the volume of endometriotic implants and differences in B-cell count and fibrosis score, rituximab is typically used as a therapy for B lymphocyte malignancies and has potential short-term and long-term side effects. Additionally, animal models for endometriosis have limitations, and novel models are still being developed. Therefore, further preclinical research is necessary to evaluate the safety and efficacy of rituximab as a potential treatment for endometriosis in humans.

Incidence and ultrasonographic characteristics of cesarean scar niches after uterine closure by double-layer barbed suture: A prospective comparative study.

OBJECTIVE: To compare the ultrasonographic features of uterine scars and clinical symptoms after cesarean delivery (CD) using barbed and conventional smooth sutures. METHODS: This case-control study enrolled women who underwent primary CD at 37 weeks of pregnancy or later. The uterus was closed using either double-layer unidirectional barbed suture or conventional double-layer smooth suture. Ultrasound scans of the uterine scar and evaluations of menstrual patterns were performed at 6, 12, and 24 months after surgery. RESULTS: In all, 102 patients underwent uterine closure with barbed suture, while 135 patients underwent smooth suture. At 6 months, patients in the barbed group had a lower incidence of uterine niches (20.2% vs 32.6%) that were also shallower in depth (P < 0.001). Lower incidence of niches was also observed in the barbed group at 12 and 24 months (P = 0.043 and 0.048, respectively). At these two follow-up times, the smooth group had a higher number of patients reporting postmenstrual spotting (P < 0.05) and more postmenstrual spotting days per month (P < 0.050). CONCLUSION: The use of double-layer barbed suture during CD was associated with a lower incidence of scar niches and a more favorable menstrual pattern compared with the use of smooth suture.

Ultrasonographic Findings Indirectly Predicting Parametrial Involvement in Patients with Deep Endometriosis: The ULTRA-PARAMETRENDO I Study.

STUDY OBJECTIVE: To evaluate ultrasonographic findings as a first-line imaging tool to indirectly predict the presence of parametrial endometriosis (PE) in women with suspected deep endometriosis (DE) undergoing surgery. DESIGN: Retrospective analysis of a prospectively collected database (ULTRA-PARAMETRENDO I study; NCT05239871). SETTING: Referral center for DE. PATIENTS: Consecutive patients undergoing laparoscopic surgery for DE. INTERVENTIONS: Preoperative transvaginal ultrasonography was done according to the International Deep Endometriosis Analysis consensus statement. A stepwise forward regression analysis was performed considering the simultaneous presence of DE nodules and the following ultrasonographic indirect signs of DE: diffuse adenomyosis, endometriomas, ovary fixed to the lateral pelvic wall or the uterine wall, absence of anterior/posterior sliding sign, and hydronephrosis. The gold standard for the presence of PE was surgery with histologic confirmation. MEASUREMENTS AND MAIN RESULTS: Of 1079 patients, 212 had a surgical diagnosis of PE (left: 18.5%; right: 17.0%; bilateral: 15.9%). The obtained prediction model (χ2 = 222.530; p <.001) for PE included, as independent indirect DE signs presence of hydronephrosis (odds ratio [OR] = 14.5; p = .002), complete absence of posterior sliding sign (OR = 3.3; p <.001), presence of multiple endometriomas per ovary (OR = 3.0; p = .001), and ovary fixation to the uterine wall (OR = 2.4; p <.001); as independent concomitant DE nodules, presence of uterosacral nodules with the largest diameter >10 mm (OR = 3.2; p <.001), presence of rectal endometriosis with the largest diameter >25 mm (OR = 2.3; p = .004), and rectovaginal septum infiltration (OR = 2.3; p = .003). The optimal diagnostic balance was obtained considering at least 2 concomitant DE nodules and at least 1 indirect DE sign (area under the curve 0.75; 95% confidence interval, 0.72-0.79). CONCLUSION: Specific indirect ultrasonographic findings should raise suspicion of PE in women undergoing preoperative assessment for DE. The suspicion of parametrial invasion may be critical to address patients to expert leading centers, where proper diagnosis and surgical treatment for PE can be performed.

BRCA mutation carriers' perception about benefits and risks associated with combined hormonal contraceptives use.

OBJECTIVE: To evaluate the actual perceptions about combined hormonal contraceptives (CHCs) use in BRCA mutation carriers in comparison to women from the general population. METHODS: This was a cross-sectional, observational study involving two Italian referral centres for hereditary cancers. An identical questionnaire investigating how CHC use could affect the risk of developing some types of cancer, specific diseases, and symptoms was administered to 85 BRCA mutation carriers and 85 healthy women without this genetic mutation (control group). Women's perceptions were evaluated using specific questions and Likert scales (-5 to +5). RESULTS: Perceptions about the effects of CHC use on developing specific diseases and symptoms did not differ between BRCA mutation carriers and controls. Conversely, the protective effects of CHC use on colorectal (p = .02), uterine body (p = .01) and ovarian (p = .01) cancers were unknown by BRCA mutation carriers. Moreover, BRCA mutation carriers recognised the association between CHC use and a higher risk of breast (p = .0008) and uterine cervix cancer (p = .007). CONCLUSIONS: Investing time and effort in transmitting the correct key messages about oncological risk related to CHC use could potentially increase their use in BRCA mutation carriers.

Full longitudinal nailfold videocapillaroscopy analysis of microvascular changes during normal pregnancy.

BACKGROUND: Microvascular remodeling is one major responsible for vascular adaptation in pregnancy, still it is not routinely evaluated in the obstetric field. This pilot study aimed to explore the role of nailfold capillaroscopy (NCV) in detecting microvascular changes during normal pregnancy. METHODS: A population of 30 healthy pregnant women was longitudinally followed performing clinical assessment and NVC evaluation at each trimester and post-partum. Thirty non-pregnant age-matched healthy women having received at least two NVCs with a minimum 9 to 12-month interval were selected as controls. All NVC images were evaluated by a qualitative and semi-quantitative assessment using current standardised approach. Statistical analyses were conducted to assess NVC trend throughout gestation and its possible association with pregnancy course. RESULTS: A progressive significant increase of NVC neoangiogenesis and a specular reduction in capillary dilations was observed during pregnancy (p < 0.05). These variations were not found in age-matched controls, who showed stable NVC parameters over a similar time frame (p < 0.05). Additionally, a significant inverse correlation was found between NVC neoangiogenesis rate and maternal systemic BP (rho = -0.72, p < 0.005). CONCLUSION: This first comprehensive longitudinal NVC evaluation during normal pregnancy reports significant but physiological microvascular variations throughout gestation, suggesting NVC as a safe and promising technique for further investigate and define patterns of microvascular changes also in pathological pregnancies.

Concerns on ranibizumab and zoledronic acid safety for experimentally treating women with endometriosis.

Correspondence to the original research entitled "Effects of ranibizumab and zoledronic acid on endometriosis in a rat model" published by Ozdemir et al.

Systematic review and meta-analysis on the impact of the levonorgestrel-releasing intrauterine system in reducing risk of ovarian cancer.

BACKGROUND: Ovarian carcinoma (OC) is one of the most widespread tumors in the world and is characterized by low survival rates. OBJECTIVE: To determine whether the levonorgestrel-releasing intrauterine system (LNG-IUS) can prevent OC. SEARCH STRATEGY: The literature until December 2020 were systematically reviewed according to the PRISMA Statement for Reporting Systematic Reviews (PROSPERO: CRD42019137957). SELECTION CRITERIA: Studies assessing the impact of LNG-IUS on the risk of OC were included. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two authors to ensure accuracy and consistency. MAIN RESULTS: A total of 34 323 records were obtained, of which three satisfied the inclusion criteria. In total, 1687 events of OC in a population of 20 461 311 person-years were considered. Data pooling revealed that the use of LNG-IUS did not confer a lower risk of OC relative to the never-use of LNG-IUS, with an estimated odds ratio of 0.66 (95% confidence interval 0.41-1.08; I2  = 84%; P = 0.002). CONCLUSION: The meta-analysis did not demonstrate a preventive role of LNG-IUS on OC. However, it was carried out on a few papers, and a definitive conclusion on the topic still cannot be drawn. Further studies are indicated in the future to define the impact of LNG-IUS on OC. The meta-analysis carried out on three papers did not demonstrate a preventive role of the levonorgestrel-releasing intrauterine device on ovarian cancer.

Efficacy and safety of prolonged-release hyaluronic acid derivative vaginal application in the postpartum period: a prospective randomised clinical trial.

INTRODUCTION: In puerperium, the hypoestrogenic state induced by delivery and subsequently sustained by lactation may lead to vaginal dryness, burning, and itching sensation, contributing to the onset of sexual dysfunction. MATERIAL AND METHODS: This was a prospective, randomized, controlled, open-label study (NCT04560283) for evaluating the effects of application of a prolonged-release hyaluronic acid derivative vaginal gel in restoring sexual function during the postpartum period. Eighty-five patients were randomized to apply prolonged-release Hydeal-D 0.2% vaginal gel (Fidia Farmaceutici, Abano Terme, Italy; n = 43) every three days for 12 consecutive weeks or expectant management (n = 42). RESULTS: Women undergoing treatment had a more elevate increase in Female Sexual Function Index (FSFI) total score (+15.1 ± 11.9 vs +6.5 ± 8.9, p < 0.001) and a higher decrease in vaginal pH (-1.2 ± 0.7 vs -0.2 ± 1.1; p < 0.001). Moreover, the proportion of vaginal smears with maturation index (VMI) >65 was significantly higher in patients treated (80.6% vs 35.3%; p = 0.004). Edinburgh Postnatal Depression Scale (EPDS) decreased significantly in both groups with no inter-group difference (p = 0.459). Only two cases (4.8%) of moderate vaginal burning sensation were reported in patients undergoing local vaginal therapy. CONCLUSIONS: The results of our study demonstrated that hyaluronic acid derivative vaginal gel (Hydeal-D) was able to improve sexual function of puerperal women in the short-term treatment.KEY MESSAGEIn the puerperium, the hypoestrogenic state induced by delivery and subsequently sustained by lactation may lead to vaginal dryness, burning, and itching sensation, contributing to the onset of sexual dysfunction.Hydeal-D is a prolonged-release hyaluronic acid derivative characterised by elevated resistance to enzymatic breakdown. During puerperium, its local application may improve the vaginal microenvironment by ensuring a better migration and proliferation of cells involved in local tissue repair.Among puerperal women, Hydeal-D vaginal gel causes a significant improvement of sexual function, including desire, arousal, and lubrification, compared to expectant management. Furthermore, it leads to a decrease in vaginal pH and an increase of the trophic status of vaginal epithelium.

Fishbone double-layer barbed suture in cesarean section: a help in preventing long-term obstetric sequelae?

Due to the high number of cesarean sections over the last two decades, there has been a growing awareness of the post-surgical obstetric long-term sequelae (i.e., uterine scar defects and abnormal placentation) following this surgical procedure. Knotless barbed suture is an absorbable bidirectional and unidirectional monofilament, characterized by the presence of "barbs" along its length. After being introduced in gynecology, the favorable features of the knotless barbed suture, such as the uniform distribution of tensile force, provide the rationale for studying its benefits in obstetric surgery. Recently, our research group has investigated a double-layer barbed suture ("fishbone" suture) for closing the uterine wall during cesarean section by a case-control study, reporting a low incidence of uterine scar defects and a reduced size of defects in women who had developed them (NCT04825821). In the near future, large prospective studies are strongly awaited to investigate reproductive outcomes and long-term sequelae after cesarean section performed with knotless barbed suture.

Erythropoietin therapy in a case of neonatal anemia after exposure to natalizumab throughout pregnancy.

BACKGROUND: Natalizumab is a monoclonal antibody approved for the treatment of patients with relapsing-remitting multiple sclerosis. According to the current clinical recommendations, its use during pregnancy should be carefully evaluated only in women with highly active disease who plan a pregnancy or have an unplanned pregnancy, after accurate counseling about eventual maternal disease relapse due to therapy suspension. CASE PRESENTATION: This brief case report describes a case of documented anemia that we observed in a newborn whose mother with relapsing-remitting multiple sclerosis was treated with an extended dosing protocol of natalizumab throughout pregnancy. The newborn received the infusion of erythropoietin every seven days from the fortieth day of life; subsequently, the status of anemia underwent clinical resolution. CONCLUSIONS: This case report confirmed that natalizumab can cause disorders of hematopoiesis, including anemia, thrombocytopenia, or pancytopenia, in newborns of patients treated during pregnancy. A multidisciplinary team, including experienced pediatricians and pediatric hematologists, has a critical role in managing newborns delivered by women, being treated with natalizumab for treating relapsing-remitting multiple sclerosis during pregnancy.

Asymptomatic SARS-CoV-2 infections in pregnant patients in an Italian city during the complete lockdown.

Data from both New York and London report a high prevalence of the asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnant patients admitted for delivery, raising questions on the possible correlated dangers (ie, contacts with healthcare workers; the possible creation of an intrahospital outbreak at birth; and conflicting evidence on vertical transmission). For this study, results from SARS-CoV-2 screening via nasopharyngeal swab from maternity wards of the four hospitals of Genoa, Italy, were collected during a month of complete lockdown from 1 April to 30 April 2020. Out of 333 tested women, only 9 were symptomatic. Only one symptomatic patient (0.3%) and six asymptomatic ones (1.8%) tested positive. Out of the six positive asymptomatic patients, five were from the most disadvantaged neighborhood of the city (assessed by postal code). In conclusion, even if Italy was badly affected by coronavirus disease 2019 in the studied month, the reported prevalence of SARS-CoV-2 infections in asymptomatic pregnant patients at term was lower than the ones reported in the literature.

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6±9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; p<0.001), birthweight (OR: 1.17, 95% CI 1.09-1.12.7 per 100 g decrease; p=0.012) and maternal ventilatory support, including either need for oxygen or CPAP (OR: 4.12, 95% CI 2.3-7.9; p=0.001) were independently associated with composite adverse fetal outcome. Conclusions Early gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible.

Current and experimental drug therapy for the treatment of polycystic ovarian syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 8-13% of reproductive-age women. Irregular periods, hirsutism, or infertility are the most common clinical presentations of patients affected by PCOS. This syndrome is also linked to metabolic abnormalities such as type 2 diabetes, insulin resistance and obesity. The optimal therapeutic approach is still unknown. AREAS COVERED: This narrative review offers an overview of the literature on current and experimental pharmacological options for treating PCOS and highlights ongoing clinical trials. Several electronic databases were searched and current research registers were analyzed to the present year. The papers selected for this review were critically analyzed, and all data available were summarized, organized, and explored to derive key information. EXPERT OPINION: The main goal of PCOS treatment is to obtain a metabolic and hormonal balance. Optimal PCOS therapy should be direct to the reproductive abnormalities and the entire spectrum of endocrine and metabolic complications that appear to have a long-term negative impact on PCOS patient health, as in post-menopausal period. The discovery of new mechanisms in PCOS pathogenesis will offer the possibility of testing new drug classes.

Prexasertib: an investigational checkpoint kinase inhibitor for the treatment of high-grade serous ovarian cancer.

Introduction Patients with high-grade serous ovarian cancer (HGSOC) have a poor prognosis, and current chemotherapy regimens for treating advanced disease are far from satisfactory. Prexasertib (LY2606368) is a novel checkpoint kinase inhibitor (CHK) under investigation for the treatment of HGSOC. Data from a recent phase II trial showed promising efficacy and safety results for treating wild-type BRCA HGSOC. Areas covered This article reviews the available data on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of prexasertib in the treatment of HGSOC. Expert opinion Until now, prexasertib demonstrated clinical activity in phase I and II clinical trial for treating wild-type BRCA HGSOC, whereas its promising efficacy as monotherapy and combined with olaparib in BRCA-mutated HGSOC has been preliminary evidenced only in phase I studies. Compared to other drugs of the same class, prexasertib showed a better tolerability profile, causing moderate hematological toxicity. Further studies are needed to confirm efficacy and safety profiles of prexasertib in combined regimens. New early clinical trials may investigate prexasertib administered with programmed cell death ligand 1 (PD-L1) and PI3 K inhibitors due to the preclinical evidence of a synergic action.