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18 pages, 2085 KB  
Review
Cervical and Cesarean Scar Pregnancy in One Patient: A Sequential Case with Literature Review
by Zofia Malczewska, Agata Chojnicka, Łucja Zaborowska and Artur Ludwin
J. Clin. Med. 2026, 15(10), 3949; https://doi.org/10.3390/jcm15103949 - 20 May 2026
Viewed by 214
Abstract
Background: Cervical pregnancy and cesarean scar pregnancy are rare forms of non-tubal ectopic pregnancy associated with a high risk of severe hemorrhage, surgical intervention, and potential loss of fertility. We describe a unique case of sequential abnormal implantation in which a cervical [...] Read more.
Background: Cervical pregnancy and cesarean scar pregnancy are rare forms of non-tubal ectopic pregnancy associated with a high risk of severe hemorrhage, surgical intervention, and potential loss of fertility. We describe a unique case of sequential abnormal implantation in which a cervical pregnancy was followed by a cesarean scar pregnancy one year later. The occurrence of two distinct forms of non-tubal ectopic pregnancy in a single patient represents an exceptionally uncommon clinical scenario, underscoring the importance of early diagnosis and carefully planned treatment. Case presentation: A 39-year-old woman, gravida 4 para 3, was diagnosed with two distinct non-tubal ectopic pregnancies over a 1-year period. The first pregnancy was implanted in the cervical canal, whereas the second was located within the cesarean section scar. In each episode, the diagnosis was established early by transvaginal ultrasound. As the patient was hemodynamically stable and wished to preserve fertility, minimally invasive hysteroscopic evacuation was performed in both pregnancies. The procedures were completed without significant intraoperative bleeding, and no additional hemostatic interventions were required. Follow-up serum β-hCG levels became negative after treatment, confirming complete resolution of pregnancies. Conclusions: This case demonstrates that early ultrasonographic diagnosis and careful individualized management may enable successful fertility-preserving treatment even in exceptionally rare cases. It also supports the potential role of minimally invasive approaches in selected hemodynamically stable patients and highlights the need for standardized management protocols for cervical and cesarean scar pregnancy. Full article
(This article belongs to the Section Nuclear Medicine & Radiology)
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7 pages, 1695 KB  
Case Report
Hepatic Ectopic Pregnancy: A Diagnostic Challenge Highlighted by Multimodal Imaging
by Puja Punukollu, Lindsey Grater, Claudia Szlek, Rebecca Joseph, John Lue, James Maher and Lawrence Devoe
J. Clin. Med. 2026, 15(6), 2388; https://doi.org/10.3390/jcm15062388 - 20 Mar 2026
Viewed by 630
Abstract
Background: Ectopic pregnancy occurs in about 1–2% of all pregnancies, with 95% implanting in the fallopian tubes. Hepatic implantation is one of the rarest and most dangerous forms of abdominal ectopic pregnancy. Its diagnosis is often delayed because of nonspecific symptoms, and it [...] Read more.
Background: Ectopic pregnancy occurs in about 1–2% of all pregnancies, with 95% implanting in the fallopian tubes. Hepatic implantation is one of the rarest and most dangerous forms of abdominal ectopic pregnancy. Its diagnosis is often delayed because of nonspecific symptoms, and it is also often difficult for routine ultrasound imaging to visualize ectopic pregnancy sites that are not in the pelvis. Since this type of pregnancy carries a risk of severe hemorrhage, early identification is crucial. Case: A 30-year-old woman, gravida 3 para 2, presented with a serum β-hCG of 66,408 mIU/mL, but no intrauterine pregnancy was detected on ultrasound imaging. At an outside facility, a laparoscopy was performed, which also failed to show a pelvic ectopic pregnancy. The patient then received her first dose of methotrexate and was subsequently transferred to a tertiary care center for further evaluation. MRI and liver ultrasound showed a 2.3 cm subcapsular lesion in segment 5 of the liver that was suspicious for a hepatic ectopic pregnancy. However, these imaging studies could not exclude a gestational trophoblastic disease or hepatic neoplasm. A dilation and curettage revealed no trophoblastic tissue. The patient next received two additional doses of methotrexate on hospital days 4 and 7 due to an inadequate decline in interval β-hCG; β-hCG levels declined gradually but steadily over several months until they became undetectable and indicated a successful medical treatment of her hepatic ectopic pregnancy. Conclusions: This case highlights the complex diagnostic and treatment challenges presented by a hepatic ectopic pregnancy. Multimodal imaging, serial monitoring of β-hCG levels, and the engagement of a multidisciplinary team were essential factors in achieving a safe, nonsurgical, and successful resolution of this condition. When a pregnancy of unknown location is suspected, extended imaging studies are critical tools for patient evaluation after initial imaging studies and laparoscopy are inconclusive. Full article
(This article belongs to the Special Issue Recent Advancements in Nuclear Medicine and Radiology: 2nd Edition)
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11 pages, 383 KB  
Systematic Review
The Role of Hysteroscopy for the Treatment of Interstitial Ectopic Pregnancy: A Systematic Review
by Guglielmo Stabile, Laura Vona, Stefania Carlucci, Francesco Nappi, Stefania Biffi, Anna Pitsillidi, Stefano Restaino, Giuseppe Vizzielli and Luigi Nappi
J. Clin. Med. 2026, 15(6), 2158; https://doi.org/10.3390/jcm15062158 - 12 Mar 2026
Viewed by 457
Abstract
Background/Objectives: Interstitial ectopic pregnancy is a rare and potentially life-threatening condition, accounting for 1–6% of ectopic pregnancies. Its location complicates diagnosis and management, and no standardized treatment guidelines exist. Fertility-preserving, minimally invasive approaches have been proposed as alternatives to medical therapy or radical [...] Read more.
Background/Objectives: Interstitial ectopic pregnancy is a rare and potentially life-threatening condition, accounting for 1–6% of ectopic pregnancies. Its location complicates diagnosis and management, and no standardized treatment guidelines exist. Fertility-preserving, minimally invasive approaches have been proposed as alternatives to medical therapy or radical surgery. This systematic review evaluates the safety and effectiveness of hysteroscopic treatment, focusing on uterine preservation and reproductive outcomes. Methods: This systematic review was conducted according to PRISMA guidelines and registered in PROSPERO (CRD420251249508). Web of Science, Scopus, and PubMed were searched from inception to January 2026. Eligible articles included case reports and case series describing interstitial pregnancies managed hysteroscopically, alone or combined with minimally invasive treatments, without medical therapy. Study quality was assessed using the JBI Checklist. Results: Eight studies comprising 21 patients were included. Mean gestational age at diagnosis was 55 days, and mean β-hCG level was 7981 IU/L (range 1440–32,000 IU/L). Hysteroscopic management was successful in 16 of 21 cases (76%). Five patients required rescue therapy. Reduced residual myometrial thickness was the main factor associated with treatment failure. Mean time to β-hCG normalization was 32 days. Conclusions: Hysteroscopic management is a safe and effective minimally invasive option for clinically stable patients with interstitial ectopic pregnancy. It allows direct visualization, targeted tissue removal, and preservation of uterine integrity and fertility, with limited morbidity. Ultrasound guidance is generally sufficient, reserving laparoscopy for high-risk cases. These findings support hysteroscopy as a fertility-preserving strategy, though larger prospective studies are needed to confirm long-term reproductive outcomes. Full article
(This article belongs to the Special Issue Advanced Hysteroscopic Technology for Gynecological Disease)
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27 pages, 898 KB  
Review
Diagnostic and Therapeutic Challenges in Rare and Non-Tubal Ectopic Pregnancies: A Narrative Review
by Stefan Ivanovic, Milica Ivanovic, Dragana Maglic, Milica Mandic, Lidija Tulic, Katarina Ivanovic, Milos Milincic, Nikola Jovic and Rastko Maglic
Diagnostics 2026, 16(5), 793; https://doi.org/10.3390/diagnostics16050793 - 7 Mar 2026
Viewed by 753
Abstract
In relation to the most commonly described ampullary ectopic pregnancies in contemporary gynecological practice, rare localizations of ectopic pregnancies represent a diagnostic and therapeutic challenge whose clinical significance far exceeds their frequency. In contrast to tubal ectopic pregnancy, these implantation localizations are characterized [...] Read more.
In relation to the most commonly described ampullary ectopic pregnancies in contemporary gynecological practice, rare localizations of ectopic pregnancies represent a diagnostic and therapeutic challenge whose clinical significance far exceeds their frequency. In contrast to tubal ectopic pregnancy, these implantation localizations are characterized by specific anatomical relationships and early trophoblastic invasion into highly vascularized tissues, which is why classical diagnostic algorithms and therapeutic patterns are often not applicable in clinical practice. Clinical uncertainty is further increased by the fact that a large proportion of these pregnancies in early gestation cannot be precisely mapped and initially present as pregnancies of unknown location. This narrative review integrates contemporary evidence and guidelines of relevant professional societies with the aim of highlighting patterns of diagnostic errors, systemic weaknesses of existing approaches, and key points for safe clinical decision-making. Special emphasis is placed on the role of disciplined transvaginal ultrasound evaluation, terminological precision, and timely recognition of high-risk and nonspecific implantations. Analysis of the available literature indicates that therapeutic decisions must be individualized and guided by the implantation site and assessment of hemorrhagic risk, rather than gestational age or absolute β-hCG values. Understanding these principles represents the basis for reducing serious complications and for the development of future diagnostic and therapeutic algorithms, thereby improving treatment outcomes. Full article
(This article belongs to the Section Clinical Diagnosis and Prognosis)
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12 pages, 255 KB  
Article
Sex-Specific Variation in Maternal Serum Screening Markers Across the First and Second Trimesters: Evidence from 10,384 Screened Pregnancies
by Mehmet Çopuroğlu, Hüseyin Aksoy, Mehmet Genco, Merve Genco and Cemal Ünlü
J. Clin. Med. 2026, 15(3), 1276; https://doi.org/10.3390/jcm15031276 - 5 Feb 2026
Viewed by 748
Abstract
Background: Maternal serum screening remains widely implemented for prenatal aneuploidy assessment despite increased uptake of cell-free DNA testing. Evidence suggests that fetal sex may influence placental endocrine function and maternal serum biomarker levels; however, available studies are inconsistent and often limited by [...] Read more.
Background: Maternal serum screening remains widely implemented for prenatal aneuploidy assessment despite increased uptake of cell-free DNA testing. Evidence suggests that fetal sex may influence placental endocrine function and maternal serum biomarker levels; however, available studies are inconsistent and often limited by sample size or incomplete adjustment for maternal factors. Objective: The aim of this study was to determine whether fetal sex independently modifies first- and second-trimester maternal serum marker Multiple of the Median (MoM) values and whether sex-related biochemical variation affects trisomy-21 screen-positive classification. Methods: A retrospective cohort was identified from institutional screening records (10,384 screened pregnancies), of which 5040 first-trimester and 1476 second-trimester cases had complete biochemical data. First-trimester PAPP-A and free β-hCG, as well as second-trimester AFP, uE3, and free β-hCG, were measured. Implausible MoM values (<0.10 or >5.00) were excluded. Multivariable linear and logistic regression models adjusted for maternal age, maternal weight, gestational age at sampling, and parity assessed independent associations. Results: Pregnancies with female fetuses showed significantly higher MoM values for first-trimester PAPP-A and free β-hCG as well as second-trimester AFP and uE3. The magnitude of these differences was small, and no significant differences were observed in trisomy-21 screen-positive rates between fetal sex groups. Conclusions: Fetal sex independently influences several maternal serum markers across both trimesters but does not result in clinically meaningful differences in trisomy-21 screening outcomes under current algorithms. Any potential relevance of fetal sex for risk interpretation should be regarded as hypothesis-generating and requires outcome-validated investigation before clinical application. Full article
(This article belongs to the Special Issue Advances in Maternal Fetal Medicine)
17 pages, 747 KB  
Article
Minimal Dose Paradigm in IUI Stimulation for Unexplained Infertility: Letrozole-Initiated Late Gonadotropin Protocol
by Evren Yeşildağer, Ufuk Yeşildağer and Sefa Arlıer
J. Clin. Med. 2026, 15(3), 1050; https://doi.org/10.3390/jcm15031050 - 28 Jan 2026
Viewed by 1001
Abstract
Background: Optimizing pregnancy outcomes while minimizing gonadotropin exposure and treatment burden remains a major goal in ovulation induction for intrauterine insemination (IUI), particularly for patients with polycystic ovary syndrome (PCOS) or high ovarian reserve. Sequential protocols combining early letrozole with late-onset recombinant FSH [...] Read more.
Background: Optimizing pregnancy outcomes while minimizing gonadotropin exposure and treatment burden remains a major goal in ovulation induction for intrauterine insemination (IUI), particularly for patients with polycystic ovary syndrome (PCOS) or high ovarian reserve. Sequential protocols combining early letrozole with late-onset recombinant FSH (rFSH) have been proposed to enhance efficiency while reducing medication requirements. However, real-world comparative data adjusting for baseline differences are limited. Methods: This retrospective comparative cohort study included 764 IUI cycles performed between January 2022 and October 2025. Cycles were stimulated either with conventional rFSH (n = 372) or letrozole plus late-onset rFSH (n = 392). The primary outcome was pregnancy per cycle, defined by a positive serum β-hCG. Secondary outcomes included clinical pregnancy, total gonadotropin dose, endometrial thickness, cycle cancelation, and obstetric outcomes. Confounding was addressed using multivariable logistic regression, propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and doubly robust estimation. Results: The crude pregnancy rate was higher in the letrozole plus late rFSH group compared with conventional rFSH (14.8% vs. 9.9%, p = 0.042). Women in the sequential stimulation group had higher AMH levels, higher antral follicle counts, and a higher prevalence of PCOS (32.4% vs. 16.3%, p = 0.001). After adjustment for age, ovarian reserve, and other baseline characteristics using regression, PSM, and IPTW, the stimulation protocol was not independently associated with pregnancy (adjusted OR 1.09, 95% CI 0.68–1.74; p = 0.657). Female age remained the strongest predictor of pregnancy (adjusted OR 0.70 per year increase; p < 0.001). The sequential protocol required a significantly lower total gonadotropin dose (median 375 IU vs. 750 IU; p < 0.001) while maintaining comparable cycle cancellation and safety outcomes. Conclusions: Sequential stimulation with letrozole plus late-onset rFSH achieves pregnancy outcomes comparable to conventional rFSH stimulation while significantly reducing gonadotropin requirements. After adjustment for PCOS status and ovarian reserve, the protocol itself did not independently influence pregnancy, suggesting that crude differences reflected baseline imbalances rather than true treatment effects. This approach represents a clinically efficient, gonadotropin-sparing option for IUI, particularly in patients at risk for excessive ovarian response. Full article
(This article belongs to the Special Issue Female Infertility: Clinical Diagnosis and Treatment—Second Edition)
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27 pages, 687 KB  
Article
The Potential of Volatilomics as Female Fertilization Biomarkers in Assisted Reproductive Techniques
by Ana Teresa Brinca, Maria Manuel Casteleiro Alves, Ana M. Peiró, Pilar Matallín Evangelio, Irene Eleno Buendicho, Antonio Helio Oliani, Vladimiro Silva, Ana Torgal, Luís F. Vicente, Ana Cristina Ramalhinho and Eugenia Gallardo
Biomedicines 2026, 14(2), 264; https://doi.org/10.3390/biomedicines14020264 - 24 Jan 2026
Cited by 1 | Viewed by 808
Abstract
Background/Objectives: Volatile organic compounds (VOCs) have emerged as promising non-invasive biomarkers for assessing metabolic and reproductive health. In the context of assisted reproductive techniques (ARTs), the volatilomic composition of follicular fluid (FF) may reflect the biochemical environment surrounding the oocyte, influencing fertilization success [...] Read more.
Background/Objectives: Volatile organic compounds (VOCs) have emerged as promising non-invasive biomarkers for assessing metabolic and reproductive health. In the context of assisted reproductive techniques (ARTs), the volatilomic composition of follicular fluid (FF) may reflect the biochemical environment surrounding the oocyte, influencing fertilization success and embryo development. This study aimed to characterize the volatilomic profile of FF in women undergoing ARTs and to explore associations between specific VOCs and female fertilization-related parameters (FFRPs). Methods: A total of 54 Caucasian women aged 19–39 years, enrolled between October 2015 and July 2019, were recruited at the Assisted Reproduction Laboratory of the Local Health Unit of Cova da Beira, Covilhã. FF samples were analyzed via gas chromatography–mass spectrometry (GC–MS) in scan mode, identifying 136 VOCs, of which 72 were selected based on prevalence. Sixteen FFRPs were evaluated, including age, body mass index (BMI), smoking habits, infertility factor, oocyte yield, embryo quality, β-hCG levels, country of birth, and reproductive history. Associations between VOCs and FFRPs were assessed using the Chi-square (χ2) test. Results: Significant correlations (p ≤ 0.05) were identified between 45 VOCs and 11 FFRPs. The detected compounds comprised alkanes, siloxanes, aromatics, alcohols, ketones, aldehydes, carboxylic acids and esters, fatty acid derivatives, epoxides, acrylates, nitriles, and sterols. Several VOCs were associated with more than one FFRP, indicating overlapping metabolic pathways that may influence reproductive performance. Conclusions: The volatilomic profile of FF demonstrates significant variability linked to individual reproductive and metabolic factors. VOC analysis may provide novel insights into follicular physiology, representing a promising approach for identifying potential biomarkers of infertility and ART outcomes. Full article
(This article belongs to the Special Issue Gynecological Diseases in Cellular and Molecular Perspectives)
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13 pages, 778 KB  
Article
Low PAPP-A Levels and Growth in Twin Pregnancies
by Ioakeim Sapantzoglou, Dimitrios Papageorgiou, Afroditi Maria Kontopoulou, Christina Karasmani, Angeliki Rouvali, Afroditi Pegkou, Maria Simou, Ioannis Pafilis, Athina Souka, Marianna Theodora, Panagiotis Antsaklis and Georgios Daskalakis
Life 2026, 16(1), 149; https://doi.org/10.3390/life16010149 - 16 Jan 2026
Viewed by 713
Abstract
Background/Objectives: It is well established in the modern literature that newborns delivered from multiple gestations are more predisposed to low birthweight in comparison to their singleton equivalents. In this study, we sought to explore the potential of first-trimester biochemical (PAPP-A and free β-hCG) [...] Read more.
Background/Objectives: It is well established in the modern literature that newborns delivered from multiple gestations are more predisposed to low birthweight in comparison to their singleton equivalents. In this study, we sought to explore the potential of first-trimester biochemical (PAPP-A and free β-hCG) and biophysical indices (uterine artery Doppler) to predict low birthweight in one or both twins. Methods: This is a retrospective cohort analysis of 400 twin viable pregnancies presenting for routine first-trimester assessment in four fetal medicine centers between 2014 and 2025. The examination included the recording of maternal demographic characteristics and medical history, the assessment of markers of aneuploidy and the fetal anatomy, the measurement of mean arterial pressure, the assessment of uterine arteries and the measurement of serum concentration of PAPP-A and free β-hCG. The evaluated outcomes included BW ≤ 3rd centile and BW ≤ 10th centile in one or both twins based on local population birthweight reference charts. Results: The study cohort consisted of 400 twin pregnancies. BW ≤ 3rd centile in one or both twins was reported in 1.5 and 3.8% of cases, respectively, and there was no association of BW ≤ 3rd centile with any of the studied parameters. BW ≤ 10th centile in one or both twins was reported in 14.8 and 9.8% of the cases, respectively. PAPP-A MoM values were significantly lower in cases complicated by BW ≤ 10th centile in one and in both twins, remaining statistically significant even after the appropriate multiple logistic regression. PAPP-A MoM demonstrated statistically significant but low prognostic value for BW ≤ 10th centile in either one or both twins. Conclusions: Low PAPP-A levels were associated with BW ≤ 10th centile in one and both twins and its significant value as a risk marker was demonstrated. Higher PAPP-A MoM halves the risk of having at least one twin with low BW. Other maternal biophysical and biochemical indices did not seem to be predictive of low birthweight. Full article
(This article belongs to the Section Reproductive and Developmental Biology)
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28 pages, 11543 KB  
Article
From Suspicion to Confirmation: An Original Study on a Complete Diagnostic Pathway for Ectopic Pregnancy
by Marian Valentin Zorilă, Dominic-Gabriel Iliescu, George-Lucian Zorilă, Daniel Pirici, Anca-Maria Istrate-Ofiţeru, Camelia-Gabriela Roşu, Cristina Jana Busuioc, Laurențiu Mogoantă, Vanda Roxana Nimigean, Răzvan Grigoraș Căpitănescu, Elena Iuliana Anamaria Berbecaru, Roxana-Cristina Drăgușin, Maria-Cristina Comănescu and Stefan Paitici
J. Clin. Med. 2026, 15(2), 507; https://doi.org/10.3390/jcm15020507 - 8 Jan 2026
Viewed by 1467
Abstract
Background/Objectives: Ectopic pregnancy (EP) remains a major cause of maternal morbidity. This study aimed to describe the clinical, ultrasonographic and histopathological features of EP, including changes following methotrexate (MTX) therapy. Methods: A retrospective analysis was conducted on 60 patients diagnosed with EP between [...] Read more.
Background/Objectives: Ectopic pregnancy (EP) remains a major cause of maternal morbidity. This study aimed to describe the clinical, ultrasonographic and histopathological features of EP, including changes following methotrexate (MTX) therapy. Methods: A retrospective analysis was conducted on 60 patients diagnosed with EP between 2018 and 2024. Clinical characteristics, serum β-hCG (beta-human chorionic gonadotropin) dynamics, treatment type, site-specific ultrasonographic features, and histopathological aspects were evaluated. Results: Extrauterine EPs accounted for 63.3% of cases, predominantly tubal ectopic pregnancy (T-EP), while uterine ectopic pregnancy represented 33.3%, including cesarean scar pregnancy (CSP) in 20%. Heterotopic pregnancy was identified in 3.3%. T-EP most frequently required surgical management, whereas MTX was effective in selected T-EP and CSP cases, as demonstrated by a ≥ 15% decline in serum β-hCG levels at 7 days. Transvaginal ultrasonography (TVUS) enabled accurate site-specific localization of ectopic implantation. Histopathological evaluation confirmed ectopic implantation and MTX-related changes in treated cases. Conclusions: Integrating clinical findings, β-hCG dynamics, and targeted TVUS allows accurate diagnosis and individualized management of EP, with histopathology providing definitive confirmation and insight into treatment-related changes. Full article
(This article belongs to the Section Obstetrics & Gynecology)
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25 pages, 18578 KB  
Article
CDK5RAP3 Regulates Testosterone Production in Mouse Leydig Cells
by Jian Ruan, Qianyi Dong, Yufan Jin, Yuhong Yang, Jun Li and Yafei Cai
Int. J. Mol. Sci. 2026, 27(2), 586; https://doi.org/10.3390/ijms27020586 - 6 Jan 2026
Viewed by 855
Abstract
Testosterone (T) produced by Leydig cells (LCs) is essential for male reproduction; yet, the regulatory mechanisms underlying steroidogenesis remain incompletely understood. Here, we investigated the role of cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) in Leydig cell development and steroidogenesis, based on [...] Read more.
Testosterone (T) produced by Leydig cells (LCs) is essential for male reproduction; yet, the regulatory mechanisms underlying steroidogenesis remain incompletely understood. Here, we investigated the role of cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) in Leydig cell development and steroidogenesis, based on its identification by immunoprecipitation-mass spectrometry (IP-MS) as a protein associated with steroidogenesis and cholesterol metabolism in mouse testicular tissue. Using human samples, we found that CDK5RAP3 expression was significantly reduced in Leydig cells from patients with spermatogenic failure (T < 10.4 nmol/L). Notably, CDK5RAP3 expression increased during mouse postnatal Leydig cell maturation and regeneration in an ethane dimethanesulfonate (EDS)-induced rat model. Functional analyses in primary LCs and MLTC-1 cells showed that hCG stimulation triggered CDK5RAP3 nuclear translocation without altering its overall expression, while CDK5RAP3 knockdown markedly impaired hCG-induced testosterone production and reduced the expression of the steroidogenic regulator steroidogenic acute regulatory (STAR) protein, as well as key steroidgenic enzymes, including cytochrome P450 family 11 subfamily A member 1 (CYP11A1), 17a-hydroxylase (CYP17A1), and 3β-hydroxysteroid dehydrogenase (HSD3B). Conversely, CDK5RAP3 overexpression enhanced testosterone production in the absence of hCG. In vivo, AAV2/9-mediated CDK5RAP3 silencing in adult mouse testes resulted in a significant reduction in serum testosterone levels compared with controls (3.60 ± 0.38 ng/mL vs. 1.83 ± 0.37 ng/mL). Mechanistically, CDK5RAP3 interacted with SMAD4 and CEBPB, and BMP pathway inhibition by Noggin rescued the testosterone deficit caused by CDK5RAP3 loss. Together, these findings identify CDK5RAP3 as an essential regulator of Leydig cell steroidogenesis and provide insight into its potential relevance to male infertility associated with low testosterone. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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31 pages, 992 KB  
Systematic Review
Tubal Stump Ectopic Pregnancy After IVF-ET in Patients Who Underwent Salpingectomy or Adnexectomy: A Qualitative Systematic Review
by Massimo Criscione, Giorgio Maria Baldini, Elisa Sanna, Laura Saderi, Giovanni Sotgiu, Mario Palumbo, Marco Petrillo and Giampiero Capobianco
Medicina 2026, 62(1), 83; https://doi.org/10.3390/medicina62010083 - 31 Dec 2025
Viewed by 2082
Abstract
Background and Objectives: Ectopic pregnancy (EP) is a life-threatening medical and surgical condition. Tubal stump EPs and heterotopic pregnancies can occur after in vitro fertilization-embryo transfer (IVF-ET), even after salpingectomy. The purpose of this study is to investigate the risk factors, diagnosis, and [...] Read more.
Background and Objectives: Ectopic pregnancy (EP) is a life-threatening medical and surgical condition. Tubal stump EPs and heterotopic pregnancies can occur after in vitro fertilization-embryo transfer (IVF-ET), even after salpingectomy. The purpose of this study is to investigate the risk factors, diagnosis, and treatment of tubal stump EPs after IVF-ET in patients with prior salpingectomy or adnexectomy. We also aim to evaluate the intrauterine pregnancy (IUP) outcome in cases of heterotopic pregnancy in this population. Materials and Methods: This systematic review (PROSPERO CRD42023352959) followed PRISMA guidelines. A literature search of MEDLINE®, Scopus, Web of Science, and clinicaltrials.gov was conducted on 30 April 2024. We included studies on tubal stump EP after IVF-ET in patients with previous salpingectomy or adnexectomy and created a qualitative summary. Results: We included 40 studies reporting on 57 patients (58 EP episodes). Most patients (69.0%) had prior bilateral salpingectomy. Tubal rupture occurred in 69.6% of cases, with 69.0% of these cases reporting hemoperitoneum. Abdominal pain was the most frequent symptom (71.7%). Heterotopic pregnancy occurred in 60.0% of cases (82.7% singletons). The IUP outcome was delivery in 81.9% of cases, with 95.5% of singletons delivering at term, compared with 40.0% of twins. The surgical approach (laparoscopy vs. laparotomy) did not change the IUP outcome. Tubal stump excision (74.1%) was the most common treatment. Overall, the certainty of the evidence was judged as moderate to very low according to the GRADE-CERQual approach, mainly due to small sample sizes, observational designs, and heterogeneity among studies. Conclusions: This review, the first on this topic, provides key data for counselling patients with a tubal stump heterotopic pregnancy. Despite its rarity, close follow-up until 8–10 weeks is recommended for IVF-ET patients with positive β-hCG, monitoring for abdominal pain. Successful management (expectant, medical, or surgical) should be guided by β-hCG levels and ultrasound findings (e.g., absence of heartbeat). Medical treatment shows encouraging obstetric outcomes and warrants further research. Full article
(This article belongs to the Special Issue Advances in Laparoscopic Surgery)
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13 pages, 1516 KB  
Review
Ectopic Pregnancy with a Normally Located Levonorgestrel-Releasing Intrauterine System in a Woman with Adenomyosis: Case Report and Literature Review
by Francesco Giuseppe Martire, Eugenia Costantini, Errico Zupi and Lucia Lazzeri
J. Clin. Med. 2026, 15(1), 272; https://doi.org/10.3390/jcm15010272 - 29 Dec 2025
Viewed by 1072
Abstract
Background: Ectopic pregnancy (EP) is a potentially life-threatening condition, often associated with acute abdominal pain and hemoperitoneum. Certain conditions, such as adenomyosis and the use of long-acting reversible contraceptives (LARC), may represent risk factors for the development of ectopic pregnancy. Management is [...] Read more.
Background: Ectopic pregnancy (EP) is a potentially life-threatening condition, often associated with acute abdominal pain and hemoperitoneum. Certain conditions, such as adenomyosis and the use of long-acting reversible contraceptives (LARC), may represent risk factors for the development of ectopic pregnancy. Management is tailored according to hemodynamic stability, reproductive desires, and associated comorbidities. Case Presentation: We report the case of a 39-year-old Caucasian woman with a history of adenomyosis and heavy menstrual bleeding (HMB) treated with a levonorgestrel-releasing intrauterine system (LNG-IUS). She presented to the emergency department with acute abdominal pain, vaginal bleeding, and a rising serum β-human Chorionic Gonadotrophin (β-hCG > 4000 mIU/mL). Transvaginal ultrasound revealed an adnexal mass (24 mm × 19 mm) consistent with a right tubal ectopic pregnancy, associated with hemoperitoneum. The patient, who expressed a desire for definitive sterilization, underwent laparoscopic bilateral salpingectomy. The procedure was uneventful with minimal intraoperative blood loss. Histopathological examination confirmed the diagnosis of right tubal ectopic pregnancy. Literature Review: A case report prompted a focused search of MEDLINE and Scopus (2015–2025) on ectopic pregnancy in users of levonorgestrel-releasing intrauterine systems. Eight eligible case-report studies assessing ectopic pregnancy type and device positioning were ultimately included. Conclusions: This case highlights the importance of early diagnosis of ectopic pregnancy, paying attention to any comorbidities, particularly adenomyosis, the role of minimally invasive surgery, and the possibility of adapting surgical management to the patient’s reproductive wishes. Full article
(This article belongs to the Section Reproductive Medicine & Andrology)
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18 pages, 4388 KB  
Article
Hydatidiform Moles: The Contribution of Ancillary Techniques in Refining Their Histopathological Diagnosis
by Teodora Ana Balan, Raluca Anca Balan, Cornelia Amalinei, Simona Eliza Giușcă and Irina-Draga Căruntu
Int. J. Mol. Sci. 2026, 27(1), 142; https://doi.org/10.3390/ijms27010142 - 23 Dec 2025
Cited by 1 | Viewed by 996
Abstract
A hydatidiform mole (HM) is the most common form of gestational trophoblastic disease (GTD). Differentiating hydatidiform moles (HMs) from non-molar pregnancies and distinguishing complete HMs (CHMs) from partial HMs (PHMs) remains challenging due to overlapping morphological features and a high rate of misclassification. [...] Read more.
A hydatidiform mole (HM) is the most common form of gestational trophoblastic disease (GTD). Differentiating hydatidiform moles (HMs) from non-molar pregnancies and distinguishing complete HMs (CHMs) from partial HMs (PHMs) remains challenging due to overlapping morphological features and a high rate of misclassification. This study aimed to evaluate reliable immunohistochemical markers for improving diagnostic accuracy and addressing the limitations of current molecular techniques. We retrospectively analyzed 64 cases of HMs and hydropic abortions (HAs), diagnosed in women aged 17–36 years between 2010 and 2024, at the Pathology Department of “Elena Doamna” Clinical Hospital, Iași, Romania. Routine histology was supplemented with immunohistochemistry (IHC) using p57, Ki-67, β-hCG, and E-cadherin, with semiquantitative immunoscores applied. Histology revealed 38 PHMs (59.37%), 16 CHMs (23.88%), and 10 HAs (15.62%). p57 was positive in 100% of PHMs and HAs but only in 18% of CHMs. Ki-67 expression was predominantly strong in CHMs, variable in PHMs, and weak in all HAs. β-hCG showed the highest expression in CHMs, followed by PHMs and HAs, while E-cadherin was strongest in HAs. Morphological features alone are insufficient for HM diagnosis; thus, ancillary techniques like p57 IHC and DNA genotyping are crucial to differentiate complete, partial moles, and non-molar specimens by revealing unique genetic patterns, especially p57 absence in CHMs and ploidy/parental origin in PHMs. In this context, an algorithmic approach integrating histology, immunohistochemistry, and genotyping reduces interobserver variability and refines diagnostic precision. Full article
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15 pages, 831 KB  
Article
Association Between Serum Progesterone Levels on the Day of Frozen–Thawed Embryo Transfer and Pregnancy and Neonatal Outcomes
by Cristiana Ribeiro Silva, Ana Beatriz de Almeida, Carolina Lemos, Carla Leal, Hélder Ferreira and Márcia Barreiro
Reprod. Med. 2025, 6(4), 39; https://doi.org/10.3390/reprodmed6040039 - 1 Dec 2025
Cited by 1 | Viewed by 3319
Abstract
Background/Objectives: Serum progesterone (P) levels on the day of frozen–thawed embryo transfer (FET) appear to influence treatment success. Some studies suggest that low P levels may negatively affect pregnancy outcomes, whereas others report a detrimental impact of elevated p values. Although a [...] Read more.
Background/Objectives: Serum progesterone (P) levels on the day of frozen–thawed embryo transfer (FET) appear to influence treatment success. Some studies suggest that low P levels may negatively affect pregnancy outcomes, whereas others report a detrimental impact of elevated p values. Although a threshold of 10 ng/mL is frequently cited as indicative of adequate luteal support, the optimal P cut-off on the FET day remains unclear. This study aims to identify a predictive serum p value above which pregnancy rates do not decline in artificial FET cycles. Methods: A retrospective cohort study comprising 236 women who underwent FET between November 2021 and July 2023 was conducted at the Center of Assisted Medical Procreation of Centro Materno-Infantil do Norte. Serum P levels were measured on the day of FET. Three analytical approaches were used in assessing the association between P levels and FET outcomes: (1) fixed threshold of 10 ng/mL; (2) stratification into quartiles (Q1 < 7.30; Q2: 7.30–10.26; Q3: 10.27–13.42; Q4 > 13.42 ng/mL); (3) optimal P cut-off derived from ROC analysis (9.34 ng/mL). Continuous variables were compared using T-test or One-Way ANOVA. Categorical variables were analyzed using Chi-square test or Fisher’s exact test. Associations between P levels and pregnancy outcomes were further examined using logistic regression. Results: Using the P threshold of 10 ng/mL, women with p < 10 ng/mL showed significantly lower positive β-hCG rates (p = 0.020), implantation rates (p = 0.002), and clinical pregnancy rates (CPRs) (p = 0.019). Quartile-based comparisons revealed no significant differences. Regarding the ROC-derived cut-off, women with p ≥ 9.34 ng/mL had significantly higher positive β-hCG rates (38.5% vs. 52.8%, p = 0.012), implantation rates (30.0% vs. 45.5%, p = 0.002), CPR (36.3% vs. 50.0%, p = 0.016), ongoing pregnancy rates (24.4% vs. 37.6%, p = 0.013), and live birth rates (24.4% vs. 37.6%, p = 0.013). p ≥ 9.34 ng/mL remained an independent predictor of improved pregnancy outcomes in multivariate analysis. Conclusions: Serum P levels ≥ 9.34 ng/mL on the day of FET were associated with significantly higher pregnancy success, supporting the relevance of center-specific P thresholds and suggesting potential benefit in individualized luteal phase support strategies. Full article
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12 pages, 1080 KB  
Article
Single-Session No-Touch Hysteroscopic Mechanical Resection for Cesarean Scar Pregnancy: A Novel Primary Treatment Approach
by Cihan Bademkiran, Kevser Arkan, Mehmet Yaman, Ihsan Bagli, Mehmet Obut, Mesut Bala, Mesut Ali Haliscelik, Muhammed Hanifi Bademkiran and Pelin Bademkiran
Diagnostics 2025, 15(23), 3030; https://doi.org/10.3390/diagnostics15233030 - 28 Nov 2025
Viewed by 1020
Abstract
Background/Objective: Cesarean scar pregnancy (CSP) represents a challenging and potentially life-threatening form of ectopic pregnancy. This study aims to assess the feasibility, safety, and clinical efficacy of employing the hysteroscopic mechanical tissue removal system as a primary treatment modality for CSP. Methods [...] Read more.
Background/Objective: Cesarean scar pregnancy (CSP) represents a challenging and potentially life-threatening form of ectopic pregnancy. This study aims to assess the feasibility, safety, and clinical efficacy of employing the hysteroscopic mechanical tissue removal system as a primary treatment modality for CSP. Methods: This retrospective cohort study included 53 patients diagnosed with CSP who underwent primary hysteroscopic resection at a tertiary care center. The surgical procedure was performed by prioritizing the “no-touch” vaginoscopic approach, which avoids instrumentation. Success rates, operation time, time to negative serum β-hCG, complications, and differences between the anatomical types of CSP (Type 1 vs. Type 2) were analyzed. Results: Primary hysteroscopic treatment was successful in 51 of 53 patients (96.2%). For the entire cohort, the median operative time was 7 min (range: 2–30), and the median interval to β-hCG negativization was 11 days (range: 6–45). The overall major complication rate was 3.8% (n = 2). One case was deemed unsuccessful due to conversion to laparotomy following uterine perforation during cervical dilation. Another patient, diagnosed with persistent trophoblastic disease requiring methotrexate (MTX) therapy, was also considered a treatment failure. Operative time was significantly longer in patients with Type II CSP compared with Type I (median 9 min vs. 5 min; p = 0.0004). Conclusions: Hysteroscopic mechanical tissue removal as a primary treatment for cesarean scar pregnancy represents an effective and safe “one-step” approach, characterized by a high success rate, rapid β-hCG resolution, and a low incidence of complications. This fertility-preserving, minimally invasive technique may be considered a primary treatment option for hemodynamically stable patients with CSP, provided that appropriate patient selection is undertaken and sufficient surgical expertise is available. Full article
(This article belongs to the Special Issue Advances in Diagnostic and Operative Hysteroscopy, 2nd Edition)
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