A unicornuate uterus with a non-communicating rudimentary horn is a rare Müllerian duct anomaly that is frequently underdiagnosed because of its variable clinical presentation and the limitations of conventional imaging modalities. Although not considered a direct cause of infertility, it may coexist with other reproductive pathologies and contribute to adverse reproductive outcomes. Presented here is a case series of three infertile women aged 30–36 years who were diagnosed with a unicornuate uterus and non-communicating rudimentary horn during fertility evaluation. Patient A presented with primary infertility, cyclic pelvic pain, endometriosis, and bilateral tubal disease; Patient B had a seven-year history of primary infertility and was initially suspected to have unilateral tubal obstruction; and Patient C was referred with a presumed diagnosis of uterine didelphys and was subsequently found to have a unicornuate uterus with a non-communicating rudimentary horn and ipsilateral renal agenesis. In all three cases, preoperative imaging failed to establish the definitive diagnosis, which was confirmed intraoperatively through laparoscopy, chromotubation, and hysteroscopy. Patients A and B underwent laparoscopic excision of the rudimentary horn with ipsilateral salpingectomy, while Patient C underwent only ipsilateral salpingectomy. Hysteroscopic transillumination was utilized in one case to facilitate safe laparoscopic dissection and delineation of the hemiuterine anatomy. All patients had uneventful postoperative recovery and were subsequently counseled regarding fertility options. This case series highlights the diagnostic challenges posed by unicornuate uterus with a non-communicating rudimentary horn, emphasizes the importance of a high index of suspicion during infertility work-up, and demonstrates the value of minimally invasive surgical management and hysteroscopic transillumination in selected cases. Early recognition and individualized treatment may help reduce reproductive complications and improve fertility counseling and management.

Human ; Female ; Adult: 25-44 Yrs Old ; Infertility, Female ; Laparoscopy ; Salpingectomy ; Hysteroscopy ; Pathology ; Endometriosis ; Fallopian Tube Diseases ; Transillumination ; Uterine Didelphys

OBJECTIVE: To analyze a patient with infertility due to complex chromosome rearrangement by optical genome mapping (OGM). METHODS: A female patient who was diagnosed with "primary infertility" at Shenzhen Longhua District Maternal and Child Health Care Hospital in April 2024 was selected as the study subject. Clinical data of the patient was collected. Chromosome G banding karyotyping analysis was carried out for the patient and her parents, in addition with OGM and copy number variation sequencing (CNV-seq). This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2023052504). RESULTS: The patient, a 33-year-old female, had infertility for the past 5 years. OGM revealed formation of two derivative chromosomes through rearrangement of chromosomes 5 and 18. A loss of heterozygosity on chromosome 5 was also detected by OGM and CNV-seq techniques. Both of her parents had a normal karyotype. CONCLUSION The OGM technique can refine the position of chromosomal breakpoints and determine the direction and position of insertional fragment. Combined with karyotype analysis, the OGM can accurately determine the chromosomal karyotype of the patient and facilitate genetic counseling.
Humans ; Female ; Adult ; Karyotyping ; DNA Copy Number Variations/genetics* ; Chromosome Mapping/methods* ; Chromosome Aberrations ; Infertility, Female/diagnosis*

OBJECTIVE: To explore the genetic basis for a woman with oocyte maturation disorder during assisted reproductive treatment (ART), and to verify the source of the variant and its impact on oocyte maturation through family verification. METHODS: A 35-year-old infertile woman presented at the Reproductive Medicine Center of Gansu Provincial Maternal and Child Health Care Hospital on 20 October 2023 for a 10-year history of infertility despite unprotected intercourse was selected as study subject. Peripheral venous blood sample was collected from the proband. Next-generation sequencing (NGS) was used to detect the potential variant. Candidate variants were validated within her family by Sanger sequencing, and their deleteriousness was assessed with comprehensive bioinformatic analyses to elucidate their origin and impact on oocyte maturation. According to the Standards and Guidelines for the Interpretation of Sequence Variants (hereinafter referred to as ACMG Guidelines) formulated by the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of the candidate variant was rated. This study was approved by the Medical Ethics Committee of Gansu Provincial Maternal and Child Health Care Hospital (Ethics No.: 2023GSFYLS78). RESULTS: The proband underwent three controlled ovarian-stimulation cycles as part of assisted reproductive technology, yielding a total of 29 oocytes, among which only three were mature, whilst the remainders exhibited maturation arrest. Targeted sequencing of peripheral-blood DNA revealed a heterozygous c.728C>T (p.P243L) missense variant of the TUBB8 gene. While the same variant was detected in the proband's father. Based on the ACMG guidelines, the variant was classified to be likely pathogenic (PS4_Supporting+PM2_Supporting+PP2+PP3+PP4). CONCLUSION The heterozygous c.728C>T (p.P243L) missense variant of the TUBB8 gene probably underlay the oocyte maturation disorder in the proband, which may be either autosomal dominant or autosomal recessive. For probands with oocyte maturation disorders caused by the heterozygous c.728C>T variant of the TUBB8 gene, oocyte donation may be considered.
Humans ; Female ; Adult ; Mutation, Missense ; Oocytes/metabolism* ; Heterozygote ; Tubulin/genetics* ; Infertility, Female/genetics* ; High-Throughput Nucleotide Sequencing ; Pedigree

OBJECTIVE: To investigate the clinical phenotype and genetic characteristics of an infertile woman carrying a novel PADI6 gene variant. METHODS: An infertile woman who visited the Medical Genetics Center of Henan Provincial People's Hospital on April 29, 2024 was selected as the study subject. Clinical data of the proband and her family members were collected. Peripheral blood samples were obtained from the proband and her husband for genomic DNA extraction. Whole-exome sequencing (WES) was performed. Candidate variant was verified among the family members by Sanger sequencing. The pathogenicity of candidate variant was classified according to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants. Relevant literature on the pathogenic variants of the PADI6 gene was reviewed for genotype-phenotype correlation analysis. This study was approved by the Medical Ethics Committee of Henan Provincial People's Hospital (Ethics No.: 2021-171). RESULTS: The proband was a 35-year-old woman who underwent two oocyte retrieval cycles, yielding a total of five oocytes, with all embryos arrested at day 3 post-fertilization. WES identified a homozygous PADI6 variant, c.367+4_367+7del. In vitro splicing assay confirmed that this variant can cause skipping of exon 3, leading to a frameshift and alterations in the protein structure or premature termination of translation. Literature review identified 12 relevant publications, and the PADI6 c.367+4_367+7del was determined to be a novel variant. CONCLUSION The homozygous PADI6 c.367+4_367+7del variant probably underlay the pathogenesis of infertility in the proband.
Humans ; Female ; Infertility, Female/genetics* ; Adult ; Protein-Arginine Deiminase Type 6/genetics* ; Pedigree ; Exome Sequencing ; Mutation

OBJECTIVE: To investigate the clinical phenotype and genetic etiology of a patient with primary infertility accompanied by Oocyte maturation defect (OOMD). METHODS: A 24-year-old female patient who visited the Reproductive Medicine Center of Gansu Provincial Maternity and Child Care Hospital in April 2024 was selected as the study subject. Whole-exome sequencing (WES) was performed on the proband and her husband. Candidate gene variants were validated in the family using Sanger sequencing, and compound heterozygous variants were confirmed through vector construction. Candidate variants were classified for pathogenicity according to the "Standards and Guidelines for the Interpretation of Sequence Variants" established by the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the Hospital [Ethics No.: (2023) GSFYLS(78)]. RESULTS: The proband, a 24-year-old female, had been unable to conceive for four years without contraception after marriage. She had undergone two ovarian stimulation cycles using the antagonist protocol and the PPOS protocol, respectively. A total of 74 oocytes were retrieved, with all showing OOMD and some oocytes exhibiting abnormal morphology and poor quality. WES results revealed two heterozygous missense variants in exons 14 and 16 of the PATL2 gene: c.1127G>A (p.R376Q) and c.1388C>G (p.A463G). Family validation results indicated that the missense variant in exon 14 was inherited from the proband's father, while the variant in exon 16 was de novo. CONCLUSION The compound heterozygous variants of the PATL2 gene probably underlay the OOMD and infertility in this proband. Further analysis based on the variant sites and protein structures is needed to determine whether PATL2 gene variants can fully affect oocyte development, thereby providing a personalized treatment plan for the proband.
Female ; Humans ; Young Adult ; Exome Sequencing ; Infertility, Female/genetics* ; Oocytes/metabolism* ; Pedigree ; Phenotype

OBJECTIVE: To explore the clinical features and genetic basis of a male patient with Kennedy disease(KD) presenting as secondary infertility. METHODS: A male patient who had presented at Yantai Yuhuangding Hospital in August 2023 for secondary infertility for 5 years was selected as the study subject. Clinical data, laboratory findings, and auxiliary examination of the patient were collected. Peripheral blood samples were obtained from the patient and his family members. Following DNA extraction, whole-exome sequencing (WES) was carried out. Pathogenicity of candidate variant was predicted by bioinformatics analysis. Fluorescence probe PCR-capillary electrophoresis was employed to analyze the trinucleotide CAG repeat sequence variation in the AR gene to rule out dynamic mutation. This study was approved by the Ethics Committee of Yantai Yuhuangding Hospital (Ethics No.: 2024-697). RESULTS: The patient had presented with non-obstructive azoospermia and elevated androgen sensitivity index. Ultrasound scan indicated small testicular volume and seminal vesicle atrophy. WES and bioinformatics analysis revealed abnormal amplification in the patient's AR gene. Fluorescence probe PCR and capillary electrophoresis confirmed that both the proband and his nephew had harbored 52 CAG trinucleotide repeats in exon 1 of the AR gene, confirming the diagnosis of KD. The proband's mother, elder sister, and daughter were identified as carriers of the variant, while his second elder sister did not carry the mutation. CONCLUSION As a rare X-linked recessive genetic disease, KD mainly manifests with muscle weakness, myasthenia gravis and myofascial tremor, while cases with infertility and non-obstructive azoospermia as the initial symptoms are rare and can be easily missed. Diagnosis made by genetic testing needs to be taken seriously by the clinicians.
Humans ; Male ; Bulbo-Spinal Atrophy, X-Linked/diagnosis* ; Adult ; Infertility, Male/genetics* ; Receptors, Androgen/genetics* ; Exome Sequencing ; Mutation ; Pedigree ; Trinucleotide Repeats

OBJECTIVE: To observe the effect of "Zhibian" (BL54)-to-"Shuidao" (ST28) needling technique on the reproductive function of the mice with poor ovarian response (POR) and explore the molecular mechanism of acupuncture on early embryos after in vitro fertilization-embryo transfer (IVF-ET) in POR mice. METHODS: Of 70 female C57BL/6 mice, 60 mice with regular estrous cycle were screened and 30 of them were randomly divided into a blank group, a model group, and an acupuncture group, 10 mice in each one. Mice in the model and acupuncture groups were administered with tripterygium glycosides suspension (50 mg·kg^-1·d^-1) via gavage for 2 weeks to prepare POR models; while in the blank group, the mice received an equal volume of 0.9% sodium chloride solution via gavage. After successful modeling, mice in the acupuncture group underwent "Zhibian" (BL54)-to-"Shuidao" (ST28) needling technique, once daily, for 20 min each time and lasting 2 consecutive weeks. After intervention completion, subsequently, all the three groups underwent ovulation induction, orbital blood collection, and ovary extraction and fresh denuded oocyte collection. Denuded oocytes, after incubated, together with the sperms from 15 male C57BL/6 mice, were transferred into the oviducts of 30 donor pseudopregnant C57BL/6 female mice via IVF-ET; and the embryonic tissue was collected on day 7 of implantation. After successful modeling and intervention completion, the general conditions of mice in each group were observed, and the estrous cycle disorder rate was compared among the groups. After intervention completion, the numbers of oocyte, ovarian wet weight and ovarian index were recorded in each group; the levels of anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) in the serum were measured using ELISA; and ovarian morphology and mitochondrial ultrastructure were examined using HE staining and transmission electron microscopy. The transcriptome sequencing technology was employed to identify differentially expressed genes (DEGs) in early embryos of each group, followed by bioinformatics analysis; and the reversed DEGs with significant difference were verified using quantitative real-time PCR (qRT-PCR). RESULTS: After intervention, compared with the blank group, the mice in the model group presented poor spirits and declined water and food intake, reduced activity, the higher rate of estrous cycle disorder (P< 0.01); the decrease of the numbers of oocyte, ovarian wet weight, and ovarian index (P<0.01), reduced AMH and E2 in the serum (P<0.01), elevated FSH and LH in the serum (P<0.01); more atresia follicles in ovarian tissue, disorganized granulosa cells, reduced the numbers of mitochondria, vacuoles appeared and cristae breakage. When compared with the model group, in the acupuncture group, the spirits of mice, food intake and activity were improved, the rate of estrous cycle disorder was reduced (P<0.01); the numbers of oocyte, ovarian wet weight, and ovarian index were higher (P<0.01, P<0.05), the levels of AMH and E2 in the serum increased (P<0.01), the levels of FSH and LH in the serum decreased (P<0.01); the atresia follicles were reduced, the numbers of follicle increased at all levels, the numbers of mitochondria got higher, vacuoles and cristae breakage were declined. In comparison between the blank group and the model group, and between the model group and the acupuncture group, a total of 258 intersecting DEGs were identified, and 194 DEGs of them exhibited a trend of reversion before and after intervention. The top 5 reversed DEGs with significant difference included dexamethasone-induced Ras-related protein 1 (Rasd1), gene regulated by estrogen in breast cancer 1 (Greb1), leucine-rich repeat-containing G protein-coupled receptor 6 (Lgr6), Fraser syndrome 1 (Fras1), and apolipoprotein D (Apod). Compared with the blank group, the mRNA expression of Rasd1, Greb1, Lgr6, Fras1 and Apod in embryonic tissues decreased in the model group (P<0.01, P<0.05); and when compared with the model group, the mRNA expression of Rasd1, Greb1, Lgr6, Fras1 and Apod in embryonic tissues increased in the acupuncture group (P<0.05, P<0.01). These findings were consistent with the DEGs screening results. Gene ontology (GO) analysis revealed that the reversed genes of co-expression were primarily participated in the biological processes such as myoblast differentiation, endocardial cushion development, and cardiac morphogenesis. Kyoto encyclopedia of genes and genomes (KEGG) analysis indicated that the reversed genes of co-expression are enriched in the Wnt signaling pathway, and they were associated with various types of cardiac diseases. CONCLUSION The "Zhibian" (BL54)-to-"Shuidao" (ST28) needling technique may ameliorate the decline of ovarian response in mice with POR, promote normal follicle development and ovulation, thereby improve embryo quality and reduce the risk of developmental defects and deformity in the organs such as the embryonic heart. The underlying mechanism may be related to the regulation of the expression pattern of embryonic key genes through the Wnt signaling pathway.
Animals ; Female ; Mice ; Mice, Inbred C57BL ; Acupuncture Therapy ; Ovary/physiopathology* ; Humans ; Fertilization in Vitro ; Transcriptome ; Embryo Transfer ; Infertility, Female/physiopathology*

Male infertility has become a global concern, accounting for 20-70% of infertility. Dysfunctional spermatogenesis is the most common cause of male infertility; thus, treating abnormal spermatogenesis may improve male infertility and has attracted the attention of the medical community. Mitochondria are essential organelles that maintain cell homeostasis and normal physiological functions in various ways, such as mitochondrial oxidative phosphorylation (OXPHOS). Mitochondrial OXPHOS transmits electrons through the respiratory chain, synthesizes adenosine triphosphate (ATP), and produces reactive oxygen species (ROS). These mechanisms are vital for spermatogenesis, especially to maintain the normal function of testicular Sertoli cells and germ cells. The disruption of mitochondrial OXPHOS caused by external factors can result in inadequate cellular energy supply, oxidative stress, apoptosis, or ferroptosis, all inhibiting spermatogenesis and damaging the male reproductive system, leading to male infertility. This article summarizes the latest pathological mechanism of mitochondrial OXPHOS disorder in testicular Sertoli cells and germ cells, which disrupts spermatogenesis and results in male infertility. In addition, we also briefly outline the current treatment of spermatogenic malfunction caused by mitochondrial OXPHOS disorders. However, relevant treatments have not been fully elucidated. Therefore, targeting mitochondrial OXPHOS disorders in Sertoli cells and germ cells is a research direction worthy of attention. We believe this review will provide new and more accurate ideas for treating male infertility.
Male ; Humans ; Infertility, Male/metabolism* ; Oxidative Phosphorylation ; Mitochondria/metabolism* ; Spermatogenesis/physiology* ; Sertoli Cells/metabolism* ; Oxidative Stress/physiology* ; Animals ; Reactive Oxygen Species/metabolism*

BACKGROUND: Infertility is a burdensome, often overlooked condition. This study aimed to investigate the global distribution and trends in the burden of infertility from 1990 to 2021. METHODS: We obtained data on the prevalence and years lived with disability (YLDs) related to infertility from the Global Burden of Disease 2021 study and evaluated them by calculating the estimated annual percentage change in age-standardized rates. We investigated the relationship between sociodemographic index (SDI) and the burden of infertility on the global, regional, and national levels. RESULTS: In 2021, there were 143,261,562 female and 55,481,380 male infertility cases worldwide, respectively. In China, female and male infertility cases accounted for 23.59% and 21.47% of the global totals, reaching 33,795,944 and 11,909,889, respectively. Compared with 2019, the global number of female and male infertility cases increased by 5,286,227 in females and 2,017,271 in males. In contrast, China saw a decline in both female and male infertility cases, with reductions of 698,735 and 154,591, respectively. From 1990 to 2021, the age-standardized prevalence rate (ASPR) and age-standardized YLDs rate (ASYR) for female infertility both increased by 0.59% annually, whereas these two corresponding indicators for male infertility increased by 0.50% annually worldwide. The burden of female infertility was consistently higher than that of male infertility and demonstrated a faster rate of increase. East Asia had the highest ASPR and ASYR for female infertility, whereas Eastern Europe had the highest metrics for male infertility. A horizontal S-shaped association was observed between the SDI and ASPR and ASYR of infertility, with a rapid decline in the infertility burden when the SDI exceeded 0.7. CONCLUSIONS The global burden of infertility has increased over the years, with a higher burden on women and underdeveloped regions. These findings emphasize the need to prioritize healthcare for patients with infertility to address the rising burden.
Humans ; Female ; Male ; Global Burden of Disease ; Prevalence ; Infertility/epidemiology* ; Adult ; Infertility, Male/epidemiology* ; Persons with Disabilities/statistics & numerical data* ; Middle Aged ; Infertility, Female/epidemiology* ; China/epidemiology* ; Disability-Adjusted Life Years

Recently, male reproductive health has attracted extensive attention, with the adverse effects of circadian disruption on male fertility gradually gaining recognition. However, the mechanism by which circadian disruption leads to damage to male reproductive system remains unclear. In this review, we first summarized the dual regulatory roles of circadian clock genes on the male reproductive system: (1) circadian regulation of testosterone synthesis via the hypothalamic-pituitary-testicular (HPT) and hypothalamic-pituitary-adrenal (HPA) axes; (2) non-circadian regulation of spermatogenesis. Next, we further listed the possible mechanisms by which circadian disruption impairs male fertility, including interference with the oscillatory function of the reproductive system, i.e., synchronization of the HPT axis, crosstalk between the HPT axis and the HPA axis, as well as direct damage to germ cells by disturbing the non-oscillatory function of the reproductive system. Future research using spatiotemporal omics, epigenomic assays, and neural circuit mapping in studying the male reproductive system may provide new clues to systematically unravel the mechanisms by which circadian disruption affects male reproductive system through circadian clock genes.
Male ; Humans ; Animals ; Circadian Clocks/physiology* ; Hypothalamo-Hypophyseal System/physiology* ; Circadian Rhythm/genetics* ; Spermatogenesis/physiology* ; Pituitary-Adrenal System/physiology* ; Testis/physiology* ; Testosterone/biosynthesis* ; CLOCK Proteins ; Infertility, Male/physiopathology*