Combined Progesterone Administration Versus Single-Route Administration for Luteal Phase Support in IVF: A Narrative Review of Current Evidence

Background: Luteal phase support (LPS) with progesterone is essential for successful implantation and early pregnancy maintenance in IVF cycles. Although various administration routes exist (oral, vaginal, intramuscular, subcutaneous), the comparative effectiveness of combined (dual or triple) versus single-route progesterone regimens remains uncertain due to limited high-quality randomized controlled trials.
Methods: A narrative review was conducted to evaluate studies comparing pregnancy outcomes in IVF cycles using combined versus single-route progesterone administration for LPS. A comprehensive literature search was performed to identify retrospective, prospective, and randomized controlled studies published in peer-reviewed journals. Data regarding clinical pregnancy, live birth, miscarriage, and implantation rates were collected and synthesized narratively due to heterogeneity among included studies.
Results: Most studies did not demonstrate statistically significant differences in outcomes between single-route and combined progesterone regimens, particularly when dydrogesterone was included. However, certain combinations, especially those involving oral dydrogesterone alongside vaginal or intramuscular progesterone, were associated with improved live birth and clinical pregnancy rates. Despite these encouraging findings, the lack of adequately powered RCTs and the methodological variability among studies limit the generalizability of the results.
Conclusion: While single-route progesterone administration remains effective for luteal phase support in IVF cycles, emerging evidence suggests that individualized combined regimens may enhance pregnancy outcomes. The physiological rationale for combined administration, offering both systemic and local endometrial support, is compelling. Further well-designed randomized controlled trials with standardized protocols are necessary to establish evidence-based guidelines for optimal LPS.

Inter-chromosomal Effect in a Robertsonian Translocation (13;14) Carrier with a Child Affected by Down Syndrome: A Case Report

Background: Although the balanced carriers of Robertsonian translocations (ROBs) typically exhibit normal phenotypes, they may experience recurrent abortions or have offspring with chromosomal disorders. A proposed mechanism is the inter-chromosomal effect (ICE), where disrupted meiotic segregation may increase aneuploid gamete production. This study presents a male case carrier of t(13;14) who had a deceased child with Down syndrome (DS) and investigates t(13;14) as a potential factor contributing to the birth of a child with DS.
Case Presentation: A couple with a history of recurrent abortions and a deceased child with DS was referred to a medical genetics laboratory. Karyotype analysis revealed that the male partner was a carrier of t(13;14) (45,XY,t(13;14)), while the female partner had a normal karyotype. The couple’s subsequent pregnancy resulted in a healthy female fetus inheriting t(13;14). The deceased child had a karyotype of 47, XY, +21, consistent with DS. In this study, the role of t(13;14) and ICE as potential contributors to the birth of a child with DS was explored.
Conclusion: Prenatal screening for carriers of ROBs is strongly recommended to assess the risk of unbalanced chromosomal disorders in offspring.

Prevalence and Factors Associated with Primary and Secondary Infertility Among Currently Married Women in India: A Secondary Analysis of National Family Health Survey-5 Data

Background: Infertility is a important reproductive health issue that affects people worldwide. Despite its psychosocial and public health implications, population-level evidence on primary and secondary infertility remains limited. The purpose of study was to estimate the prevalence and determinants of primary and secondary infertility among married women of reproductive age in India using National Family Health Survey-5 (NFHS-5) data.
Methods: A cross-sectional secondary data analysis of NFHS-5 (2019-2021) was conducted among 512,408 currently married women aged 15-49 years. Descriptive analysis was used to estimate prevalence of primary and secondary infertility. Chi-square test and multivariable logistic regression analysis were performed to identify factors associated with infertility.
Results: The prevalence of primary infertility was 3.28% (95%CI:3.23-3.33), while secondary infertility was 13.9% (95%CI:13.85-14.05), indicating a higher burden of secondary infertility. Considerable state-wise variation was observed. Higher prevalence of primary infertility was reported in Karnataka, Telangana, Lakshadweep, and Goa, whereas secondary infertility was highest in Mizoram, Meghalaya, and Ladakh. Urban residence, smoking, overweight/obesity, thyroid disorders, and diabetes were significantly associated with both primary and secondary infertility. Delayed age at first marriage was positively associated with primary infertility, whereas increasing age was strongly associated with secondary infertility. Educational attainment and wealth index demonstrated varying associations across infertility types.
Conclusion: Infertility affects a considerable proportion of married women in India, with secondary infertility contributing the larger share of the burden. The substantial regional and socio-demographic disparities observed highlight the need to integrate infertility prevention, surveillance, and equitable access to fertility care within reproductive health programs in India.

Altered Expression of GABPB1-IT1 and SLC9A3-AS1 Long Non-Coding RNAs in Recurrent Implantation Failure

Background: Recurrent implantation failure (RIF) impairs assisted reproductive technology (ART) success, though its mechanisms remain unclear. Studies have implicated altered miRNA expression in the plasma and endometrium of patients with RIF. In this study, long non-coding RNA (lncRNA) expression in plasma was investigated, using RIF-specific lncRNA-miRNA-mRNA network as guide.
Methods: This study included 30 women with RIF and 30 age-matched controls (Not RIF). RIF miRNA RNA-seq data (GSE108966) was downloaded from the Gene Expression Omnibus (GEO) database and used to identify differentially expressed miRNAs. Next, miRNet 2.0 database was used to integrate the latest miRNA-mRNA interactions; also, the linkages between lncRNA and miRNA were identified and the networks created. Plasma samples were collected from participants during the implantation window. Cell-free RNA was extracted from 500 µl of plasma using the TRIzol method, and statistical analyses were performed using Prism version 8.0.
Results: Based on a lncRNA-miRNA-mRNA network analysis, two lncRNAs, including GABPB1-IT1 and SLC9A3-AS1, were selected for expression analysis in plasma. Notably, GABPB1-IT1 and SLC9A3-AS1 were significantly downregulated in RIF samples compared to controls.
Conclusion: Our findings show that GABPB1-IT1 and SLC9A3-AS1 are significantly downregulated in the plasma of women with recurrent implantation failure. These findings suggest their potential involvement in RIF and warrant further studies to elucidate their biological functions and evaluate their utility as non-invasive biomarkers.

Investigation of the Relationship between Vitamin D Levels and Oocyte Quality in Women Undergoing Intracytoplasmic Sperm Injection

Background: Vitamin D supports oocyte development and ovarian steroidogenesis; deficiency is linked to preeclampsia and poor oocyte quality. The purpose of the current study was to investigate the relationship between vitamin D levels and oocyte quality in women undergoing ICSI cycles.
Methods: In this case-control study, 252 women were identified from medical records and classified into high-quality (n=126) and low-quality oocyte groups (n=126). Serum vitamin D levels and anti-Müllerian hormone (AMH) were recorded. Oocyte quality was assessed by an embryologist using predefined criteria for morphology and maturity. Statistical analysis included Mann–Whitney tests and multivariable logistic regression (p<0.05). ROC analysis was applied to determine the optimal vitamin D cutoff, reporting AUC, sensitivity, and specificity and statistical significance was set at p<0.05.
Results: Patients in the high-quality oocyte group had a higher median serum vitamin D level compared with those in the low-quality group (25.2 vs. 21.9 ng/ml). Logistic regression showed that sufficient vitamin D levels (≥18 ng/ml) were associated with increased odds of having high-quality oocytes (OR=1.85, 95%CI: 1.07–3.22). AMH levels were also positively associated with oocyte quality (OR=1.42, 95%CI: 1.11–1.82). The ROC analysis yielded an AUC of 0.61 (95%CI: 0.53–0.68), indicating modest discriminatory ability.
Conclusion: Serum vitamin D levels are associated with oocyte quality in women undergoing ICSI cycles. While higher vitamin D levels are linked to better oocyte quality, no causal inference can be drawn from this case–control study design, and interventional studies are needed to evaluate whether correction of vitamin D deficiency improves reproductive outcomes.

Diagnostic Accuracy of the Kissing Ovaries Sign on Transvaginal Ultrasound for Prediction of Bowel Endometriosis in Women with Surgically Confirmed Endometriosis

Background: Endometriosis is a common gynecological disorder. Non-invasive imaging markers that predict disease severity and bowel involvement are clinically valuable. The purpose of the current study was to evaluate the diagnostic performance of the kissing ovaries (KO) sign on transvaginal ultrasound for predicting bowel endometriosis and advanced disease.
Methods: This retrospective diagnostic accuracy study included 252 women with surgically and histopathologically confirmed endometriosis who underwent laparoscopic surgery at Avicenna Fertility Center between 2019 and 2021. Preoperative transvaginal ultrasound findings were reviewed, and the presence of the KO sign was assessed. Associations with bowel endometriosis and disease severity were analyzed. Diagnostic performance metrics, chi-square and independent t-tests, ORs with 95% CIs, and multivariable logistic regression were used to evaluate predictors of bowel endometriosis. The p<0.05 was considered statistically significant.
Results: The KO sign was significantly associated with advanced-stage disease (stage IV: 88.1% vs. 22.2%) and bowel involvement (61.1% vs. 12.7%; OR=10.3, 95%CI: 5.47–19.4). It also showed significant associations with pouch of Douglas obliteration, uterosacral ligament involvement, and fallopian tube involvement. No significant association was observed for bladder or appendiceal involvement. The KO sign demonstrated a sensitivity of 82.8%, specificity of 69.2%, and accuracy of 74.2% for predicting bowel endometriosis. In multivariable analysis, it remained an independent predictor of bowel involvement (adjusted OR=8.45, 95%CI: 4.62–15.48). The area under the ROC curve was 0.76.
Conclusion: The KO sign on transvaginal ultrasound is a useful non-invasive imaging marker for predicting bowel endometriosis and advanced-stage disease, with good diagnostic performance and potential value in preoperative surgical planning.

Successful Intrauterine Insemination Following Estradiol Pretreatment in a Patient with Primary Ovarian Insufficiency: A Case Report

characterized by impaired ovarian function to secrete gonadal hormones, leading to hypoestrogenism and amenorrhea before the age of 40. Oocyte depletion in POI significantly reduces the chance of spontaneous conception, making infertility a key concern. Various in vitro fertilization (IVF) stimulation protocols, including estrogen pretreatment, have been investigated to facilitate conception with autologous oocytes in patients with POI. The principle of estrogen pretreatment involves administering exogenous estrogen to suppress elevated pituitary gonadotropins (FSH and LH), thereby restoring normal follicular development.
Case Presentation: This article presents a case of a 32-year-old patient with POI, characterized by severely diminished ovarian reserve, as evidenced by an AMH level of 0.03 ng/ml and an antral follicle count (AFC) of 1. Our patient had been attempting to conceive for 14 months and reported shortened menstrual cycles. Hysterosalpingography revealed bilaterally patent fallopian tubes, and the patient’s partner demonstrated normozoospermia. The patient was initially scheduled for IVF with controlled ovarian stimulation and estrogen pretreatment. However, a spontaneously matured follicle was detected during the course of estrogen therapy. Consequently, the patient was advised to undergo intrauterine insemination (IUI) following ovulation triggering with human chorionic gonadotropin (hCG). The procedure resulted in a clinical pregnancy and culminated in a term live birth.
Conclusion: In POI patients using for estrogen pretreatment autologous oocytes, may enhance ovarian responsiveness. If a mature follicle emerges during estrogen pretreatment, ovulation induction with IUI offers a viable path to natural conception.

Embryo Culture Systems and Morphokinetics in IVF: The Role of Time-Lapse Monitoring and Artificial Intelligence in Embryo Selection

Background: Embryo selection and culture conditions are critical determinants of success in assisted reproductive technology (ART). Despite advances, implantation and live birth rates following in vitro fertilization (IVF) remain suboptimal. This systematic review evaluated the effects of embryo culture media (sequential versus single-step), time-lapse monitoring (TLM), and artificial intelligence (AI)-based embryo selection on IVF outcomes.
Methods: This systematic review followed PRISMA guidelines. PubMed, Scopus, and Web of Science were searched through June 2025. Twenty-nine studies involving over 18,500 IVF/intracytoplasmic sperm injection (ICSI) cycles were included. Methodological quality was assessed using RoB2, the Newcastle–Ottawa Scale, and CLAIM according to study design. Outcomes related to culture media, TLM-derived morphokinetics, and AI-based embryo assessment were synthesized narratively.
Results: Sequential and single-step culture media produced comparable clinical outcomes, although single-step media showed a modest increase in blastocyst formation (57.1% vs. 53.2%; p=0.03). No significant differences were observed in clinical pregnancy or live birth rates. TLM was associated with higher ongoing pregnancy rates in descriptive analyses (45.1% vs. 34.8%; p<0.01) and reduced early pregnancy loss. AI-based embryo selection demonstrated strong predictive performance (AUC 0.76–0.91), although clinical validation varied across algorithms, indicating differences in predictive accuracy rather than consistent improvements in clinical outcomes.
Conclusion: Culture media selection appears to have limited influence on clinical outcomes, whereas TLM and AI-assisted embryo selection show promise for improving embryo assessment. Integration of validated AI-driven TLM systems into IVF practice may enhance embryo selection efficiency. Further large, prospective studies are needed to establish standardized clinical protocols.

The First Successful Capacitation In Vitro Maturation of Oocyte in Indonesia: A Promising Strategy to Enhance IVF Accessibility for Infertile Couples

Background: The identification of c-type natriuretic peptide (CNP) as a key upstream regulator of cyclic GMP (cGMP) levels has paved the way for innova-tive in vitro maturation (IVM) techniques, the so-called biphasic CAPA-IVM (capacitation IVM) approach. This method uses CNP to prevent early meiosis progression and has demonstrated enhanced oocyte maturation rates. This report highlights the successful use of the CAPA-IVM method in Indonesia.
Case Presentation: Immature cumulus-oocyte complexes (COCs) were successfully retrieved from an infertile woman aged 37 years without prior ovarian stimulation. The obtained COCs were incubated in CAPA medium for 24 hr and then transferred to a maturation medium containing amphiregulin, insulin, human serum albumin, and recombinant FSH. After 30 hr, all immature oocytes reached the metaphase II (MII) stage, as evidenced by the first polar body extrusion and confirmed through spindle formation.
Conclusion: CAPA-IVM system enabled all retrieved immature oocytes to reach the MII stage without prior ovarian stimulation. This finding supports its feasibility as a simplified IVF approach with the potential to reduce treatment costs, particularly in resource-limited settings. However, further clinical evalua-tion is required to confirm its effectiveness.

The Effect of Serine Proteases and Their Inhibitors on In Vitro Fertilization Outcomes

Background: Proteolysis imbalance can result in infertility. The purpose of the current study was to investigate the function of kininogen, neutrophil elastase, trypsin-like proteases, α1-protease inhibitor (α1-PI), and α2-macroglobulin (α2-MG) in blood, saliva, and follicular fluid as an indicator of the success of in vitro fertilization (IVF).
Methods: In general, twenty-one women undergoing an IVF cycle, as well as a control group consisting of ten healthy women, were included. The proteinase activity was measured by the rate of hydrolysis of specific substrates. The proteinase inhibitor activity was determined by the intensity of trypsin inhibition. The analysis was conducted using R software (version 4.4.1). The significance level was set at p<0.05.
Results: In women with infertility, blood activities of neutrophil elastase, α1-PI, and α2-MG were elevated, whereas kallikrein and prekallikrein activities were decreased, compared with controls. In follicular fluid, neutrophil elastase activity increased 3.4-fold, α1-PI 1.8-fold, and α2-MG 5.6-fold, whereas prekallikrein decreased by 85%, compared with women who had been infertile for fewer than five years (p<0.05). During pregnancy, kallikrein and α1- PI levels in follicular fluid were low, and unsuccessful IVF was associated with higher trypsin-like protease activity and an increased kallikrein/α1- PI ratio.
Conclusion: High elastase- and trypsin-like proteinase activity, along with elevated α1- PI and α2- MG levels in blood was associated with IVF benefits. Salivary kininogenase and α2-MG can be early prognostic indicators for IVF outcomes.

Sustainable IVF: The Next Revolution in ART