RARE DISEASE
Rare female infertility
Rare female infertility
Rare female infertility
Drug discovery
1
drug
With orphan designation
Overview
Rare female infertility encompasses conditions such as congenital uterine anomalies (e.g., septate uterus), premature ovarian insufficiency, severe endometriosis, and genetic disorders (e.g., Turner syndrome). These etiologies often require specialized diagnostic approaches, including imaging and genetic testing, and may involve advanced assisted reproductive technologies (ART) or surgical interventions for management [4][5][11][16].
Population
Affects ~16.2% of women with uterine abnormalities (polyps, fibroids, adhesions) and 10–15% with tubal disorders linked to untreated infections or endometriosis [4][5][14].
Premature ovarian insufficiency impacts 1% of women under 40, while severe endometriosis affects ~30–50% of infertile women [9][16].
Burden
Psychological distress, social stigma, and financial strain due to high treatment costs (e.g., IVF cycle costs $12,000–$25,000) [12][16][18].
Delayed diagnosis (e.g., endometriosis: 7–8 years average delay) exacerbates complications like chronic pain and reduced quality of life [16][20].
Disproportionate access barriers in low-resource settings, where <30% of countries prioritize fertility care [4][10].
Categories: rare infertility disorders
Research Papers
298 drug discovery papers about Rare female infertility, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
298 drug discovery papers about Rare female infertility, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-31 | Utility of homoeopathic medicines in management of cases of PCOS - A retrospective hospital based study
Introduction: This comprehensive study evaluates the effectiveness of Homoeopathic medicines in the management of PCOS cases through a hospital based retrospective study & identifies frequently used Homoeopathic medicines and the prominent miasm in the reported outcomes. PCOS is a multisystem disorder on the rise in the last few years. It is marked by irregular menses, Hyperandrogenism, hirsutism, acne, infertility with global prevalence of 6% to 26%.Homoeopathy is a holistic system, which helps in this endocrine disorder. Aim:To identify utility of homoeopathic medicines,the predominant miasm in cases of PCOS/PCOD through retrospective hospital based study. Materials and methods: It includes analysis of 792 female patients treated in the last 3 years (January 2021 - January 2024) of reproductive age (12 to 50 years) from a Govt. homoeo Medical College & Hospital, Rajamahendravaram, India. The data collected in specifically designed formats the master charts and details shown in the form of Tables and charts. Results: Most patients presented with irregular menses, dysmenorrhea, acne, weight gain, hirsutism, and infertility. Individualized homoeopathic medicines, mainly polycrests were frequently used with positive outcomes including menstrual regularization in over 60% of cases. Antimiasmatics and rare remedies were also applied. The predominant miasm identified through retrospective study was psoro-sycotic. Conclusion: This retrospective study data indicates individualized/constitutional homoeopathic medicines like polycrests playing a significant role in managing PCOS symptoms, particularly menstrual irregularities and infertility. The predominant miasm identified is Psorosycotic, antimiasmatics complement treatment success. It shows that polycrests are proven effective in treating PCOS. There is a requirement for well documented case formats in hospital settings, well planned, pragmatic research studies and RCTs.
2026-07-31 | Therapeutic Roles and Safety Profiles of Non-Vitamin Antioxidant Supplements in Female Infertility: A Narrative Review.
Treatment of female infertility consists different strategies including metabolic, hormonal and surgical therapeutic modalities. Non-vitamin supplements with antioxidant activity as carnitines, Inositols, Poly Unsaturated Fatty Acids (PUFAs), coenzyme Q10 and melatonin are among those with most popularity, but their prescription may confer some warnings. This review narrates the antioxidant mechanism of these supplements, beside their effect on outcomes of infertility treatment while considering side effects, warnings and ranges of doses. Carnitines are used for energy production and fat metabolism, while they have anti-aging and antioxidant effects. Supplementation with carnitines improve obesity outcomes, especially in Poly Cystic Ovarian Disease (PCOS) patients. Rare cases have shown increasing risk of seizure with levocarnitine. Coenzyme Q10 (Ubiquinone) has shown benefit in patients with PCOS or poor ovarian responders. It significantly increased live birth rate and the side effects are minimal even in higher doses. Poly Unsaturated Fatty Acids (PUFAs) have shown impact on follicular development and embryo quality. The hazard is increasing lipid low density lipoprotein (LDL) in high doses. Use of inositols in female infertility treatment is due to its metabolic effect and insulin resistance in PCOS patients resulting in decreasing use of gonadotropins. They have produced acceptable results about count of follicles and oocyte quality. Hypoglycemic effects of inositols have been reported as side effect, especially in combination with other hypoglycemic agents. Melatonin can increase the clinical pregnancy rate, and improve the outcomes about oocyte and quality of embryo via receptor- and non-receptor- action. Dizziness, drowsiness, and headache are reported in higher doses of melatonin. The attitude that all supplement can be prescribed without restriction endangers susceptible patients. Hence, increasing our knowledge about efficacy and safety profile can help individualize prescription of supplements for female infertility.
2026-06-29 | Clinical pregnancy outcomes with assisted reproduction in patients with 17α-Hydroxylase/17, 20-lyase deficiency: a single center cohort study and integrated analysis with reported cases
Background 17α-hydroxylase/17, 20-lyase deficiency (17OHD) represents a rare form of congenital adrenal hyperplasia. Affected 46, XX females typically present with sexual development abnormalities, endocrine disturbances and infertility. While assisted reproductive technology (ART) enables pregnancies in these patients, our knowledge about optimal management strategies and pregnancy outcomes remains limited. Methods We conducted a retrospective cohort study of women with 17OHD who achieved clinical pregnancy at our center between January 2009 and August 2025, followed until December 2025. Moreover, we performed a systematic review of published cases, extracting and analyzing demographic, clinical, laboratory, treatment, and outcome data. Results Among 20 female patients with 17OHD at our center, six desired fertility and three achieved clinical pregnancy with ART. Combined with 17 reported cases from 12 studies, a total of 20 pregnancies resulted in 23 live births. Median age at pregnancy preparation was 29 (range 21–42) years. The prevalence rates of hypertension and adrenal insufficiency were 25.0% (5/20) and 50.0% (10/20), respectively. Median follicular-phase progesterone was 20.8 nmol/L. Seventeen women conceived via frozen embryo transfer (FET) following ovarian stimulation, including nine with GnRH agonists (GnRHa), six with progestin-primed ovarian stimulation, one with GnRH antagonists, and one with GnRHa short protocol, respectively. Nearly 95% (18/19) participants received glucocorticoids before embryo transfer. Pregnancy complications (including gestational hypertension, diabetes, preeclampsia, and HELLP syndrome) occurred in 46.2% (6/13) cases. Only 25% (5/20) of the participants had term vaginal deliveries. All five offspring that were followed up developed normally. Conclusions For women with 17OHD, a treatment protocol combining glucocorticoid-assisted progesterone suppression with FET represents a viable strategy to achieve pregnancy. However, such patients face high risks of adverse maternal and perinatal outcomes, requiring multidisciplinary management throughout gestation.
2026-04-01 | Comment on “Farnesylation-Dependent Kinetochore Targeting of Centromere Protein F Is Essential for Oocyte Meiotic Progression and Female Fertility”
Successful cell division during meiosis is dependent on accurate chromosome segregation; the role of centromeres, kinetochores, and spindle microtubules is well characterized in mitosis, but the role of certain proteins surrounding them remains uncertain in meiosis. This is important to understand because the arrest of maturation of oocytes is a common origin of female infertility, but the mechanisms for this are largely unknown. This study was designed to assess the regulatory mechanism of the farnesylation of centromere protein F on its meiotic function as well as evaluate any association between mutations in centromere protein F and female oocyte maturation disorders. This study used oocyte microinjection, western blotting, co-immunoprecipitation, and immunofluorescence to characterize the role of centromere protein F. During mitosis, this protein assists in chromosome segregation, but it is currently unknown if its role remains the same during meiosis. This study used a mouse model to explore both genetic and pharmacologic methods of farnesylation, and to verify the mechanism of mutations in oocyte maturation. Microinjection of centromere protein F siRNA reduced maturation rates significantly, with many halting maturation at metaphase I ( P <0.05). Farnesylation likewise reduced the rate of oocyte maturation ( P <0.01), and additionally weakened the interationc between centromere protein F and Aurora kinase B, which was confirmed by co-immunoprecipitation ( P <0.01). Farnesylation also disrupted kinetochore localization, contributing to the arrest of oocyte maturation. Immunofluorescence analysis further showed that centromere protein F localized at kinetochores by metaphase I, causing arrested development. Screening human patients with infertility resulted in the identification of 4 individuals with rare heterozygous variants in the CENP-F gene that were associated with the arrest of oocyte maturation. When testing centromere protein F derived from patients who were identified to have a genetic mutation in this protein, microinjection of the patient-derived centromere protein F also caused significantly reduced maturation in mouse oocytes ( P <0.01). Two identified mutations reduced the fanesylation of centromere protein F as well as disrupted kinetochore localization and damaged the Aurora kinase B interaction. These results indicate that there is a direct association between centromere protein F mutations and infertility, specifically the arrest of oocyte maturation during meiosis. These findings contribute evidence to the controversy surrounding the influence of farnesylation on the localization of CENP- F, with some previous studies showing no effect of farneslyation and others showing a direct interaction between molecules that is dependent on farneslyation. This study emphasizes the need for further clinical research to validate the pathology of these mutations in diverse populations. Future studies should also attempt to ethically validate the results of these mouse models in human models and examine other possible mechanisms for arrested maturation of oocytes such as disruption of microtubule binding. (Summarized from Zhong O, Wang C, Zhang J, et al. Farnesylation-dependent kinetochore targeting of centromere protein F is essential for oocyte meiotic progression and female fertility. Am J Obstet Gynecol. 2026;234:116-140. doi: 10.1016/j.ajog.2025.08.031)
2026-03-25 | FEMALE GENITAL TUBERCULOSIS: A NEGLECTED CAUSE OF INFERTILITY IN DEVELOPING COUNTRIES
Background: Female genital tuberculosis (FGTB) is an important form of extrapulmonary tuberculosis and a leading, yet often under recognized, cause of infertility in women of reproductive age, particularly in developing countries. The disease is frequently asymptomatic and under diagnosed due to its nonspecific clinical presentation, contributing to delays in management and poor reproductive outcomes. Methods: This review summarizes current knowledge on the epidemiology, pathogenesis, clinical manifestations, diagnostic approaches, treatment strategies, drug resistance, and public health implications of FGTB. Data were synthesized from epidemiological studies, clinical reports, and molecular diagnostic research. Results: FGTB primarily affects the fallopian tubes (90–100%), followed by the endometrium (50–60%) and ovaries (20–30%), with rare involvement of the cervix, vagina, or vulva. Clinical presentation ranges from infertility, menstrual irregularities, and pelvic pain to asymptomatic cases. Diagnosis requires a combination of imaging (hysterosalpingography, ultrasonography, laparoscopy), histopathology, microbiological testing (Ziehl–Neelsen staining, culture), molecular methods (PCR, gene amplification, BACTEC), and immunological tests. Standard antitubercular therapy (ATT) for 6–9 months remains the cornerstone of treatment, with surgical intervention reserved for complicated cases. Drug-resistant tuberculosis, particularly multidrug-resistant TB (MDR-TB), poses a significant therapeutic challenge. FGTB causes structural and functional damage to the reproductive tract, resulting in tubal obstruction, endometrial destruction, pelvic adhesions, and ovarian dysfunction, leading to infertility in 40–80% of affected women, often necessitating assisted reproductive techniques such as in vitro fertilization. Conclusion: FGTB represents a significant reproductive health burden in endemic regions. Early detection through improved awareness, screening of infertile women, and use of molecular diagnostics is essential to prevent irreversible reproductive damage. Strengthening tuberculosis control programs and public health strategies is critical for reducing the incidence of this neglected cause of female infertility.
proteins
2026-07-30 | Hemoperitoneum after oocyte retrieval in women undergoing ART: A 2017-2022 retrospective cohort study with a historical comparison to 1996-2016.
To estimate the incidence and predictors of severity-defined hemoperitoneum after oocyte retrieval in a contemporary 2017-2022 cohort, and to place these findings in context with the center's previously published 1996-2016 experience. Retrospective cohort study including all 13,192 oocyte retrieval procedures performed at a single fertility center from January 2017 to December 2022 in 9,346 women. The primary endpoint was documented hemoperitoneum associated with hemoglobin decrease ≥ 2 g/dL and/or hospital admission, surgery or blood transfusion. The 1996-2016 cohort was retained only as an aggregate historical comparator. Predictors were estimated with robust Poisson regression clustered by patient identifier. Severity-defined hemoperitoneum was identified among 50 retrievals (0.379 %), including 46 cases with hemoglobin decrease ≥ 2 g/dL, 44 admissions, 20 surgical procedures and 12 transfusions. The contemporary primary endpoint was recorded more frequently than the historical aggregate hemorrhagic comparator (RR 1.67, 95 % CI 1.14-2.46, p = 0.010), whereas surgery did not differ significantly (RR 1.81, 95 % CI 0.97-3.36, p = 0.069). In the primary contemporary model, lower BMI (RR 0.80 per kg/m2, 95 % CI 0.73-0.88, p < 0.001), higher AMH (RR 1.08, 95 % CI 1.02-1.14, p = 0.010) and longer total retrieval time (RR 1.03 per minute, 95 % CI 1.00-1.06, p = 0.044) were associated with severity-defined hemoperitoneum. Hemoperitoneum after oocyte retrieval was rare, but associated with substantial morbidity when it occurred. Lower BMI and higher AMH were the main patient-level risk markers. Total retrieval time remained modestly associated with the risk, and should be interpreted as a marker of ovarian response and procedural complexity. The higher rate observed in the contemporary cohort should be interpreted cautiously, as surgery did not increase significantly. NCT05895227, May 31st, 2023.
2026-02-23 | The Clinico-radiological Perspective of Kartagener's Syndrome.
Kartagener's syndrome is a rare autosomal recessive genetic disorder, a subset of primary ciliary dyskinesia. It comprises the triad of situs inversus totalis, bronchiectasis, and chronic paranasal sinusitis. The incidence is 1:30,000 live births, while the male: female ratio is 1:1. Most patients of Kartagener's syndrome present in early childhood with common symptoms of frequent colds, chronic cough with excessive production of purulent sputum, and recurrent lower respiratory tract infections affecting respiratory functions. Kartagener's syndrome commonly presents as infertility in males and subfertility in females. We present the clinical and radiological findings in a patient of Kartagener's syndrome referred to us with recurrent lower respiratory tract infections.
2026-01-31 | TURNER SYNDROME: CLINICAL FEATURES AND CONTEMPORARY DIAGNOSTIC APPROACHES
Turner syndrome (TS) is a rare chromosomal disorder affecting approximately 1 in 2,500–3,000 live female births and caused by complete or partial monosomy of one X chromosome, most commonly presenting as a 45, X karyotype or mosaic forms. The syndrome is associated with a wide spectrum of clinical manifestations, including short stature, ovarian dysgenesis, delayed puberty, infertility, and congenital anomalies, particularly cardiovascular malformations such as coarctation of the aorta and bicuspid aortic valve.
2025-11-21 | Turner disease: A contemporary clinical approach
Turner syndrome (TS) is a rare genetic disorder in females caused by partial or complete loss of one X chromosome. It presents with multisystem clinical manifestations that require lifelong multidisciplinary care and monitoring. Phenotypically, TS is characterized by short stature, short neck with lateral skin folds (pterygium colli), low-set ears, and a low posterior hairline. Clinically, it is associated with cardiovascular diseases (CVD) and primary hypogonadism. The diagnosis of TS is based on clinical presentation and genetic analysis, with early prenatal detection possible. In newborns, TS should be suspected in the presence of oedema of the hands and feet. Short stature becomes evident in early childhood, while delayed puberty and primary amenorrhea are common later findings. CVDs may be congenital or acquired; coarctation of the aorta is a key diagnostic sign, whereas aortic dissection and rupture of an aortic aneurysm are life-threatening complications. Most women with TS have primary hypogonadism and high infertility rates. Spontaneous pregnancies are rare, and fertility preservation options, such as oocyte or embryo cryopreservation, should be considered early. Associated autoimmune diseases, kidney anomalies, liver disorders, and hearing loss are also common. Hormone replacement therapy is essential for pubertal induction, maintenance of general health, and prevention of long-term complications of untreated hypogonadism. Due to numerous comorbidities and variable phenotypes, an individualized multidisciplinary approach is required. With early diagnosis, appropriate management, and psychosocial support, individuals with TS can lead a good quality of life despite ongoing health risks.
2025-06-13 | Identification of Novel Genetic Variants in a Cohort of Congenital Hypogonadotropic Hypogonadism: Computational Analysis of Pathogenicity Predictions.
Congenital hypogonadotropic hypogonadism (CHH) is a rare and heterogeneous genetic disorder with variable penetrance caused by GnRH deficiency, leading to delayed puberty and infertility. In 50-60% of cases, CHH is associated with non-reproductive abnormalities, most commonly anosmia/hyposmia (Kallmann syndrome, KS). Over 60 genes have been implicated in CHH pathogenesis. We aimed to perform genetic screening in a cohort of 14 patients (10 males, 4 females; mean age 22 ± 7.72 years) with suspected or diagnosed HH/KS. Genetic analysis was conducted using next-generation sequencing (NGS) with a custom panel of 46 candidate genes. Variant interpretation followed ACMG standards and guidelines. Multiple tools were used to predict the structural effects of variants on tertiary protein structure, assessing their pathogenicity. Novel variants were functionally characterized by qRT-PCR on mRNA extracted from peripheral leukocytes. NGS identified nine rare variants and four novel variants in genes previously associated with normosmic isolated HH (nHH) and/or KS (FGFR1, PROK2, TAC3R, DCC, WDR11, IL17RD, DUSP6, KAL1, FGF8, IL17RD and DCC). The variant in TAC3R (p.Trp275Ter) was pathogenic; variants in ANOS1 (c.541+1G>A), IL17RD (c.1303_1304dup, p.Lys436ThrfsTer58), and TAC3R (p.Lys361Ter) were likely pathogenic. Nine variants were classified as variants of uncertain significance (VUS). Our study identified a possible genetic cause in 71% of the CHH/KS cohort, emphasizing the importance of genetic screening and functional characterization of genetic variants in patients with a phenotypically and genetically heterogeneous disorder like CHH.
cell therapies
2026-03-10 | Reproductive Challenges of the Ageing Female: A Comprehensive Narrative Review.
Changes in societal norms over the last few decades have resulted in novel family planning trends, notably delayed childbearing and increased maternal age at the birth of the first child. Despite advances in reproductive medicine, ageing poses significant challenges. Natural conception in women ≥ 45 years of age is rare, with high rates of pregnancy loss, and assisted reproduction using autologous oocytes yields limited success. Oocyte donation offers higher live birth rates, exceeding 50%. Elective oocyte cryopreservation could aid in family planning; nevertheless, its success depends on the age at which cryopreservation is performed. These facts highlight the correlation between advancing age and a decline in oocyte quality and quantity. An age-related decline in endometrial receptivity could pose an additional barrier, although the evidence remains controversial. Furthermore, pregnancies in older women carry high risks for both the mother and child, which should be considered before assisted conception attempts. This comprehensive narrative review examines the advancements in assisted reproductive technology that have expanded the possibilities for delayed childbearing, while underlining at the same time the major challenges in the field. Innovations such as ovarian tissue cryopreservation and stem cell-based therapies have the potential to reshape reproductive options for these women. However, thorough counselling and tailored management remain of paramount importance.
2025-12-12 | The Doing/Undoing of MRKH and the Doing of Gestational Pregnancy and Gender Through Uterus Transplants.
Women with the rare Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome are born without a uterus. Following international interviews with 34 women with MRKH and 15 surgeons and specialists, we explore how the usually invisible condition of MRKH is made visible and "done" through biomedicine. MRKH is highly medicalized, with much work undertaken to make MRKH bodies fit heteronormative standards. Some people with MRKH prefer to define themselves as intersex. Others undertake uterus transplants (UTx), to experience menstruation, gestation, and birth. UTx reconstructs their bodies to heteronormative expectations at the same time as it reinforces gendered identity as normative women, and potentially as mothers.
2025-11-26 | Endometrial Injury and Its Rescue by Mesenchymal Stem Cells Is Dependent on Estrous Cycle Phase.
Asherman Syndrome (AS) is caused by injury to the endometrium leading to uterine scarring, decreased menstruation and infertility; it typically occurs after surgical curettage of the uterus. AS is treated surgically albeit with limited success. Administration of bone marrow-derived mesenchymal stem cells (MSCs) has recently been demonstrated to restore uterine function in AS; however, there is no data available on the role of the estrous cycle phase on outcomes. Here, we describe endometrial injury during estrus or diestrus, its differential effect on fertility, and its response after bone marrow MSC treatment to reverse the infertility in a murine model. Endometrial injury in the estrus phase did not affect fertility outcomes whereas injury in the diestrus phase resulted in infertility. Bone marrow (BM)-derived MSC treatment without injury in the estrus or diestrus phase did not affect the pregnancy outcomes. BM MSC treatment following endometrial injury in the diestrus phase restored fertility. Immunofluorescence analysis revealed that vimentin or cytokeratin-positive BM-derived cells in the uterus were extremely rare. BM MSC treatment after injury increased CD45+ cells, indicating a role for immunomodulation in endometrial repair. Finally, qRT-PCR showed that Ccl3, Il-1β and Mmp3 gene expression was significantly higher in the endometrium of the injury + BM MSC group than in other groups. In summary, injury to the endometrium during the diestrus phase results in infertility that can be restored by the treatment of BM MSCs. The therapeutic effect of BM MSCs on the endometrium appears to be mediated primarily by immunomodulation rather than BM MSC engraftment.
2025-11-18 | The Danish Turner Syndrome Cryopreservation study: PROTOCOL for a prospective cohort Study on reproductive outcomes after ovarian tissue cryopreservation in girls with Turner syndrome.
BACKGROUND: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial loss of one X chromosome, resulting in a high risk of premature ovarian insufficiency (POI) and infertility. While the underlying mechanisms are not fully understood, oocyte loss is known to begin in fetal life and continue throughout childhood, often leading to ovarian failure before the onset of puberty. Ovarian tissue cryopreservation (OTC) offers a potential method to preserve fertility in girls with TS, but the procedure remains experimental in this group. To date, only three cases of autotransplantation have been reported, and no live births have occurred in women with TS. Moreover, predictors of residual ovarian function and eligibility for OTC are poorly defined, and the long-term effects of unilateral oophorectomy in girls with already limited ovarian reserve are unknown. OBJECTIVE: To investigate long-term reproductive outcomes following OTC in girls with TS. METHODS: The Danish Turner Syndrome Cryopreservation Study is a nationwide, prospective cohort study with long-term follow-up, combining observational and interventional elements. Girls with TS aged 2–17 years are invited to participate. As ovarian reserve is depleted before adulthood in most girls with TS, all participants undergo ovarian function assessment to evaluate the likelihood of remaining viable follicles. If follicles are deemed present, unilateral OTC may be offered. The primary outcome is the number of pregnancies, miscarriages, and live births following autotransplantation of cryopreserved and thawed ovarian tissue in adulthood. Secondary objectives include identifying early predictors of POI, assessing the impact of oophorectomy on ovarian function and pubertal progression, and exploring molecular mechanisms of ovarian dysgenesis through genetic and epigenetic analyses of ovarian and peripheral tissues. Recruitment began in January 2024 and is ongoing at three university hospitals across Denmark. Follow-up is expected to continue until 2050. CONCLUSION: This study addresses a critical gap in fertility preservation for girls with TS by evaluating the feasibility and long-term outcomes of OTC. The findings will improve understanding of POI progression, refine selection criteria for OTC, and support evidence-based counselling for girls with TS and their families. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05740579. Registered 13 February 2023. https//clinicaltrials.gov/study/NCT05740579.
2025-08-20 | A rare association of Craniopharyngioma and Meyer-Rokitansky-Kuster-Hauser Syndrome in a patient with primary amenorrhea and delayed puberty – A Case Report
Background: Meyer-Rokitansky-Kuster-Hauser Syndrome (MRKH) is a congenital abnormality of the uterus and the upper two-thirds of the vagina in women showing normal development of secondary sexual characteristics with a normal karyotype of 46, XY. Craniopharyngioma is a rare intracranial neoplasm found in seller/suprasellar region with two distinct histologic phenotypes – adamantinoma Tous and papillary. It has insidious onset of symptoms and presents as headache, visual impairment and hormonal imbalances secondary to compression of adjacent pituitary manifesting commonly as sexual dysfunction in adults and growth failure in children. This case report presents a 20 years female with primary amenorrhea and absence of secondary sex characteristics, headache and visual field defect who was subsequently diagnosed as adamant nous craniopharyngioma with multiple pituitary hormones deficiency with Type 1 MRKH. Patient underwent transsphenoidal resection and replacement of levothyroxine and corticosteroid with further plan of reassessing pituitary gonadal axis, creation of a neovagina, addressing puberty induction and infertility (in vitro fertilization and surrogacy). It is too early to say that there may be an association between craniopharyngioma and MRKH. Whether craniopharyngioma and MRKH share a similar etiology is unclear. With increasing genetic testing, in the future, we may get some correlation.
gene therapies
2023-11-21 | Homozygous missense variant in MEIOSIN causes premature ovarian insufficiency.
Are variants of genes involved in meiosis initiation responsible for premature ovarian insufficiency (POI)? A MEIOSIN variant participates in the pathogenesis of human POI by impairing meiosis due to insufficient transcriptional activation of essential meiotic genes. Meiosis is the key event for the establishment of the ovarian reserve, and several gene defects impairing meiotic homologous recombination have been found to contribute to the pathogenesis of POI. Although STRA8 and MEIOISN variants have been found to associate with POI in a recent study, the condition of other meiosis initiation genes is unknown and direct evidence of variants participating in the pathogenesis of POI is still lacking. This was a retrospective genetic study. An in-house whole exome sequencing (WES) database of 1030 idiopathic POI patients was screened for variations of meiosis initiation genes. Homozygous or compound heterozygous variations of genes involved in meiosis initiation were screened in the in-house WES database. The pathogenicity of the variation was verified by in vitro experiments, including protein structure prediction and dual-luciferase reporter assay. The effect of the variant on ovarian function and meiosis was demonstrated through histological analyses in a point mutation mouse model. One homozygous variant in MEIOSIN (c.1735C>T, p.R579W) and one in STRA8 (c.258 + 1G>A), which initiates meiosis via the retinoic acid-dependent pathway, were identified in a patient with idiopathic POI respectively. The STRA8 variation has been reported in the recently published work. For the MEIOSIN variation, the dual-luciferase reporter assay revealed that the variant adversely affected the transcriptional function of MEIOSIN in upregulating meiotic genes. Furthermore, knock-in mice with the homologous mutation confirmed that the variation impacted the meiotic prophase I program and accelerated oocyte depletion. Moreover, the variant p.R579W localizing in the high-mobility group (HMG) box domain disrupted the nuclear localization of the MEIOSIN protein but was dispensable for the cell-cycle switch of oocytes, suggesting a unique role of the MEIOSIN HMG box domain in meiosis initiation. Further studies are needed to explore the role of other meiosis initiation genes in the pathogenesis of POI. The MEIOSIN variant was verified to cause POI by impaired transcriptional regulation of meiotic genes and was inherited by a recessive mode. The function of HMG box domain in MEIOSIN protein was also expanded by this study. Although causative variations in meiotic initiation genes are rare in POI, our study confirmed the pathogenicity of a MEIOSIN variant and elucidated another mechanism of human infertility. This work was supported by the National Key Research & Developmental Program of China (2022YFC2703800, 2022YFC2703000), National Natural Science Foundation for Distinguished Young Scholars (82125014), National Natural Science Foundation of China (32070847, 32170867, 82071609), Basic Science Center Program of NSFC (31988101), Natural Science Foundation of Shandong Province for Grand Basic Projects (ZR2021ZD33), Natural Science Foundation of Shandong Province for Excellent Young Scholars (ZR2022YQ69), Taishan Scholars Program for Young Experts of Shandong Province (tsqn202211371), and Qilu Young Scholars Program of Shandong University. The authors declare no conflict of interest. N/A.
2019-07-15 | Novel WEE2 gene variants identified in patients with fertilization failure and female infertility.
To determine whether variants in the WEE2 (WEE1 homolog 2, also known as WEE1B) gene, which has been known to function in the formation of pronuclei during fertilization, contribute to fertilization failure. Case-control genetic study. University hospital. Ninety infertile women with repeated cycles of pronucleus formation failure undergoing in vitro fertilization and/or intracytoplasmic sperm injection treatment as well as 200 fertile control women. Genomic DNA was extracted from the peripheral blood. The whole exons of WEE2 were amplified by means of polymerase chain reaction and then Sanger sequencing was performed. Variants analysis of WEE2 gene. We identified five subjects that were subjected to homozygous or compound-heterozygous variants of WEE2: case 1 (from a consanguineous family) with homozygous frameshift variant: c.293_294insCTGAGACACCAGCCCAACC (p.Pro98Pro fsX2); case 2 with homozygous missense variant: c.1576T>G (p.Tyr526Asp); and three cases with compound-heterozygous variants: case 3: c.991C>A (p.His331Asn) and c.1304_1307delCCAA (p.Thr435Met fsX31); case 4: c.341_342 del AA (p.Lys114Asn fsX20) and c.864G>C (p.Gln288His); and case 5: c.1A>G (p.0?) and c.1261G>A (p.Gly421Arg). Besides c.1576T>G (from case 2) and c.864G>C (from case 4), which have been previously reported as rare single nucleotide polymorphisms (SNPs), the other six variants were novel and predicted by software to be deleterious. The parental genotypes of case 1 and case 2 indicated that the detected homozygous variants were inherited in an autosomal recessive mode. All of the detected variants were absent from the control cohort. Novel variants found in WEE2, which is autosomal-recessive inherited, may be related to recurrent pronucleus formation failure and female infertility.
2018-03-16 | A Novel FOXL2 Mutation Implying Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Type I.
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease caused by FOXL2 gene mutations, and it is clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). Functional study of novel mutations is especially critical for female patients, as it may allow the prediction of infertility and early planning of an appropriate therapy. A clinical and molecular genetic investigation was performed in all members of a Chinese family with BPES. Genomic DNA was extracted, and the FOXL2 coding region was sequenced. Subcellular localization was performed by confocal microscopy. Transactivation studies were performed by real-time PCR, dual luciferase reporter assays and electrophoretic mobility shift assays. A novel deletion mutation (C.634_641 del, CCCATGC) between the forkhead domain and the polyalanine domain was found, resulting in a frameshift mutation and a truncated protein. Functional studies showed a strong cytoplasmic mislocalization and abnormal transactivation activity, implying a type I kind mutation with a large chance of infertility. This study identifies that this mutation indicates the probability of developing into POF and shows the importance and necessity of early recognition of BPES type through mutation testing for female patients. Prompt personalized therapy and follow-up is of great clinical significance for female patients carrying this kind of mutation.
2012-01-12 | Two common polymorphisms in the peroxisome proliferator-activated receptor γ gene may improve fertilization in IVF.
Genetic factors play an important role in women's fertility and embryonic development and may also contribute to the efficacy of assisted reproduction techniques. The aim of this study was to investigate the effect of His447His and Pro12Ala peroxisome proliferator-activated receptor γ (PPARγ) gene polymorphisms on oocytes and fertilization in women undergoing IVF. Follicular fluid and blood samples were obtained from 98 IVF patients referred to Tabriz Alzahra Hospital. Samples were analysed for fatty acid content by gas-liquid chromatography and for polymorphisms of the PPARγ gene using polymerase chain reaction-restriction fragment length polymorphism-based methods. Multiple regression analyses were used to test the independence of associations between the number of mature and fertilized oocytes as outcome variables and the polymorphisms of PPARγ gene. For both polymorphisms, fertilization ratio was significantly (P<0.05) higher in carriers of the rare alleles than homozygous wild-type genotypes. The associations of His447His (P=0.003) and Pro12Ala (P=0.015) polymorphisms remained statistically significant in the multiple regression analyses. This study suggests that the two common gene polymorphisms of PPARγ may improve fertilization in vitro and, thus possibly, female fertility.
other
2022-08-02 | Biallelic variants in MOS cause large polar body in oocyte and human female infertility.
What is the genetic basis of female infertility involving abnormal oocyte morphology with the production of a large first polar body (PB1)? The homozygous missense variant (c.791C>G) and compound missense variants (c.596A>T and c.875C>T) in MOS proto-oncogene, serine/threonine kinase (MOS) (Online Mendelian Inheritance in Man (OMIM) reference: 190060; NM_005372.1) are responsible for abnormal oocyte morphology with the production of a large PB1 to cause infertility in women. MOS, an oocyte-specific gene, encodes a serine/threonine-protein kinase that directly phosphorylates mitogen-activated protein kinase (MAPK) kinase (MEK) to activate MAPK (also called extracellular-signal-regulated kinase (ERK)) signal cascade in the oocyte. Female mice lacking Mos remained viable, but infertile because of oocyte symmetric division, spontaneous parthenogenetic activation and early embryonic arrest. Recently, two independent studies demonstrated that female infertility with early embryonic arrest and fragmentation can be caused by biallelic mutations in MOS. However, so far, MOS variants have not been associated with the phenotype of large PB1 extrusion in human oocytes to contribute to female infertility. Two independent infertile families characterized by the presence of large PB1 in oocytes were recruited between December 2020 and February 2022. Genomic DNA was extracted from the peripheral blood samples of the subjects for whole-exome sequencing. Pedigree analysis was validated by Sanger sequencing. Then, the pathogenic effects of the MOS variants on MOS protein properties and ERK1/2 activation were determined in HEK293 cells and mouse oocytes. We identified three rare missense variants in MOS, including a homozygous missense variant (c.791C>G) from Patient 1 in Family 1 and two compound missense variants (c.596A>T and c.875C>T) from twin sisters in Family 2. The MOS variants followed a recessive inheritance pattern in infertile patients. All three patients displayed a high percentage of large PB1 extrusion in the oocytes. The three MOS variants could not activate MEK1/2 and ERK1/2 in oocytes and HEK293 cells. In addition, when compared with wild-type MOS, the MOS variants decreased the MOS protein level and attenuated the binding capacity with MEK1. Microinjection of wild-type human MOS complementary RNAs (cRNAs) reversed the symmetric division of oocytes after siMos treatment. In contrast, the three MOS variants demonstrated no rescuing ability. N/A. Owing to the scarcity of human oocyte samples and the associated ethical restrictions, we could not perform the rescue attempt for the study patients. Our findings expand the genetic and phenotypic spectrum of MOS variants in causing female infertility. Our study findings facilitate the early genetic diagnosis of abnormal oocyte morphology characterized as large PB1 that eventually causes infertility in women. This study was supported by the National Natural Science Foundation of China (82071640 and 82001633), Natural Science Foundation of Zhejiang Province (LD22C060001), the Key Projects Jointly Constructed by the Ministry and the Province of Zhejiang Medical and Health Science and Technology Project (WKJ-ZJ-2005), China Postdoctoral Science Foundation (2020M682575 and 2021T140198), the Changsha Municipal Natural Science Foundation (kq2007022) and Hunan Provincial Grant for Innovative Province Construction (2019SK4012). None of the authors declare any competing interests. N/A.
2022-05-30 | Obstetrical complications and outcome in patients with endometriosis.
Endometriosis is a disease that has a profound impact on the quality of life of women, due to the associated chronic pelvic pain, dysmenorrhea, dyspareunia and infertility. However, even getting long-awaited pregnancy (often after assisted reproductive technologies), patients with endometriosis have a high risk of obstetric complications, such as miscarriage, preterm birth, preeclampsia, placental abnormalities, hemorrhage in labor, birth of small for gestational age infants, stillbirth and higher cesarean section rate. In addition, during pregnancy acute complications of endometriosis may occur, such as spontaneous hemoperitoneum, which is rare but life-threatening conditions that in most cases require surgical intervention. The mechanisms of the observed complications in pregnant women with endometriosis are not fully understood. This review presents literature data and personal considerations on the effect of endometriosis on pregnancy outcome and the occurrence of complications, as well as their possible underlined mechanisms. Based on this, we proposed ways to reduce the risk of obstetric complications in pregnant women with a history of endometriosis.
2022-03-11 | Involvement of chemerin and CMKLR1 in the progesterone decrease by PCOS granulosa cells.
Polycystic ovarian syndrome (PCOS) is the main cause of infertility in women. It is frequently associated with reduced progesterone production by human luteinised granulosa cells (hlGCs). However, the molecular mechanisms involved in these steroidogenesis alterations in PCOS patients are unclear. In a dihydrotestosterone-induced PCOS mouse model, steroid production is maintained in the setting of chemokine-like receptor 1 (Cmklr1) knockout. Thus, chemerin and chemerin receptors in terms of expression and progesterone regulation could be different in control and PCOS hlGCs. We first confirmed that progesterone levels in both plasma (P < 0.0001) and follicular fluid (FF) (P < 0.0001) were significantly reduced in PCOS normal weight women compared to control women. These data were associated with a lower STAR mRNA expression in both in vivo (P < 0.0001) and in vitro (P < 0.0001) hlGCs from PCOS women. Secondly, chemerin FF levels (P < 0.0001) and RARRES2 (P < 0.05) and CMKLR1 (P < 0.0001) mRNA levels in GCs were higher in PCOS normal weight patients. Thirdly, treatment of hlGCs with a specific nanobody (the VHH CA4910) targeting the human receptor for CMKLR1 leading to its inactivation abolished chemerin-induced progesterone inhibition, suggesting the involvement of CMKLR1 in this process. Furthermore, the inhibition of progesterone secretion induced by chemerin was two-fold higher in PCOS hlGCs (P < 0.05). Moreover, the VHH CA4910 reinstated a normal progesterone secretion with lower concentrations in PCOS hlGCs, suggesting a different chemerin sensitivity between PCOS and control hlGCs. Thus, chemerin, through CMKLR1, could be involved in the steroidogenesis alterations in PCOS hlGCs.
2021-08-27 | Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause.
Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40 years of age. Known genetic causes account for 25-30% of POI cases, demonstrating the high genetic heterogeneity of POI and the necessity for further genetic explorations. Here we conducted genetic analyses using whole-exome sequencing in a Chinese non-syndromic POI family with the affected mother and at least four affected daughters. Intriguingly, a rare missense variant of BUB1B c.273A>T (p.Gln91His) was shared by all the cases in this family. Furthermore, our replication study using targeted sequencing revealed a novel stop-gain variant of BUB1B c.1509T>A (p.Cys503*) in one of 200 sporadic POI cases. Both heterozygous BUB1B variants were evaluated to be deleterious by multiple in silico tools. BUB1B encodes BUBR1, a crucial spindle assembly checkpoint component involved in cell division. BUBR1 insufficiency may induce vulnerability to oxidative stress. Therefore, we generated a mouse model with a loss-of-function mutant of Bub1b, and also employed D-galactose-induced aging assays for functional investigations. Notably, Bub1b+/- female mice presented late-onset subfertility, and they were more sensitive to oxidative stress than wild-type female controls, mimicking the clinical phenotypes of POI cases affected by deleterious BUB1B variants. Our findings in human cases and mouse models consistently suggest, for the first time, that heterozygous deleterious variants of BUB1B are involved in late-onset POI and related disorders.
2000-04-07 | The gamete fusion process is defective in eggs of Cd9-deficient mice.
The cell-surface molecule Cd9, a member of the transmembrane-4 superfamily, interacts with the integrin family and other membrane proteins. and is postulated to participate in cell migration and adhesion. Expression of Cd9 enhances membrane fusion between muscle cells and promotes viral infection in some cells. Fertilization also involves membrane fusion, between gametes. In mammals, the sperm binds to microvilli on the egg surface, and sperm-egg membrane fusion first occurs around the equatorial region of the sperm head12. The fused membrane is then disrupted, and the sperm nucleus as well as the cytoplasm is incorporated into the egg. Cd9 is expressed on the plasma membrane of the mouse egg, and an anti-Cd9 monoclonal antibody inhibits sperm-egg surface interactions. We generated Cd9 mice and found that homozygous mutant females were infertile. Sperm-egg binding was normal, but sperm-egg fusion was almost entirely inhibited in eggs from Cd9 females. Intracellular Ca2 oscillations, which signal fertilization, were absent in almost all mutant eggs; in rare cases, a response occurred after a long time period. In normal animals, Cd9 molecules were expressed on the egg microvilli and became densely concentrated at the sperm attachment site. Thus, our results show that Cd9 is important in the gamete fusion process at fertilization.
small molecules
2026-07-31 | Utility of homoeopathic medicines in management of cases of PCOS - A retrospective hospital based study
Introduction: This comprehensive study evaluates the effectiveness of Homoeopathic medicines in the management of PCOS cases through a hospital based retrospective study & identifies frequently used Homoeopathic medicines and the prominent miasm in the reported outcomes. PCOS is a multisystem disorder on the rise in the last few years. It is marked by irregular menses, Hyperandrogenism, hirsutism, acne, infertility with global prevalence of 6% to 26%.Homoeopathy is a holistic system, which helps in this endocrine disorder. Aim:To identify utility of homoeopathic medicines,the predominant miasm in cases of PCOS/PCOD through retrospective hospital based study. Materials and methods: It includes analysis of 792 female patients treated in the last 3 years (January 2021 - January 2024) of reproductive age (12 to 50 years) from a Govt. homoeo Medical College & Hospital, Rajamahendravaram, India. The data collected in specifically designed formats the master charts and details shown in the form of Tables and charts. Results: Most patients presented with irregular menses, dysmenorrhea, acne, weight gain, hirsutism, and infertility. Individualized homoeopathic medicines, mainly polycrests were frequently used with positive outcomes including menstrual regularization in over 60% of cases. Antimiasmatics and rare remedies were also applied. The predominant miasm identified through retrospective study was psoro-sycotic. Conclusion: This retrospective study data indicates individualized/constitutional homoeopathic medicines like polycrests playing a significant role in managing PCOS symptoms, particularly menstrual irregularities and infertility. The predominant miasm identified is Psorosycotic, antimiasmatics complement treatment success. It shows that polycrests are proven effective in treating PCOS. There is a requirement for well documented case formats in hospital settings, well planned, pragmatic research studies and RCTs.
2026-07-31 | Therapeutic Roles and Safety Profiles of Non-Vitamin Antioxidant Supplements in Female Infertility: A Narrative Review.
Treatment of female infertility consists different strategies including metabolic, hormonal and surgical therapeutic modalities. Non-vitamin supplements with antioxidant activity as carnitines, Inositols, Poly Unsaturated Fatty Acids (PUFAs), coenzyme Q10 and melatonin are among those with most popularity, but their prescription may confer some warnings. This review narrates the antioxidant mechanism of these supplements, beside their effect on outcomes of infertility treatment while considering side effects, warnings and ranges of doses. Carnitines are used for energy production and fat metabolism, while they have anti-aging and antioxidant effects. Supplementation with carnitines improve obesity outcomes, especially in Poly Cystic Ovarian Disease (PCOS) patients. Rare cases have shown increasing risk of seizure with levocarnitine. Coenzyme Q10 (Ubiquinone) has shown benefit in patients with PCOS or poor ovarian responders. It significantly increased live birth rate and the side effects are minimal even in higher doses. Poly Unsaturated Fatty Acids (PUFAs) have shown impact on follicular development and embryo quality. The hazard is increasing lipid low density lipoprotein (LDL) in high doses. Use of inositols in female infertility treatment is due to its metabolic effect and insulin resistance in PCOS patients resulting in decreasing use of gonadotropins. They have produced acceptable results about count of follicles and oocyte quality. Hypoglycemic effects of inositols have been reported as side effect, especially in combination with other hypoglycemic agents. Melatonin can increase the clinical pregnancy rate, and improve the outcomes about oocyte and quality of embryo via receptor- and non-receptor- action. Dizziness, drowsiness, and headache are reported in higher doses of melatonin. The attitude that all supplement can be prescribed without restriction endangers susceptible patients. Hence, increasing our knowledge about efficacy and safety profile can help individualize prescription of supplements for female infertility.
2026-06-29 | Clinical pregnancy outcomes with assisted reproduction in patients with 17α-Hydroxylase/17, 20-lyase deficiency: a single center cohort study and integrated analysis with reported cases
Background 17α-hydroxylase/17, 20-lyase deficiency (17OHD) represents a rare form of congenital adrenal hyperplasia. Affected 46, XX females typically present with sexual development abnormalities, endocrine disturbances and infertility. While assisted reproductive technology (ART) enables pregnancies in these patients, our knowledge about optimal management strategies and pregnancy outcomes remains limited. Methods We conducted a retrospective cohort study of women with 17OHD who achieved clinical pregnancy at our center between January 2009 and August 2025, followed until December 2025. Moreover, we performed a systematic review of published cases, extracting and analyzing demographic, clinical, laboratory, treatment, and outcome data. Results Among 20 female patients with 17OHD at our center, six desired fertility and three achieved clinical pregnancy with ART. Combined with 17 reported cases from 12 studies, a total of 20 pregnancies resulted in 23 live births. Median age at pregnancy preparation was 29 (range 21–42) years. The prevalence rates of hypertension and adrenal insufficiency were 25.0% (5/20) and 50.0% (10/20), respectively. Median follicular-phase progesterone was 20.8 nmol/L. Seventeen women conceived via frozen embryo transfer (FET) following ovarian stimulation, including nine with GnRH agonists (GnRHa), six with progestin-primed ovarian stimulation, one with GnRH antagonists, and one with GnRHa short protocol, respectively. Nearly 95% (18/19) participants received glucocorticoids before embryo transfer. Pregnancy complications (including gestational hypertension, diabetes, preeclampsia, and HELLP syndrome) occurred in 46.2% (6/13) cases. Only 25% (5/20) of the participants had term vaginal deliveries. All five offspring that were followed up developed normally. Conclusions For women with 17OHD, a treatment protocol combining glucocorticoid-assisted progesterone suppression with FET represents a viable strategy to achieve pregnancy. However, such patients face high risks of adverse maternal and perinatal outcomes, requiring multidisciplinary management throughout gestation.
2026-04-01 | Comment on “Farnesylation-Dependent Kinetochore Targeting of Centromere Protein F Is Essential for Oocyte Meiotic Progression and Female Fertility”
Successful cell division during meiosis is dependent on accurate chromosome segregation; the role of centromeres, kinetochores, and spindle microtubules is well characterized in mitosis, but the role of certain proteins surrounding them remains uncertain in meiosis. This is important to understand because the arrest of maturation of oocytes is a common origin of female infertility, but the mechanisms for this are largely unknown. This study was designed to assess the regulatory mechanism of the farnesylation of centromere protein F on its meiotic function as well as evaluate any association between mutations in centromere protein F and female oocyte maturation disorders. This study used oocyte microinjection, western blotting, co-immunoprecipitation, and immunofluorescence to characterize the role of centromere protein F. During mitosis, this protein assists in chromosome segregation, but it is currently unknown if its role remains the same during meiosis. This study used a mouse model to explore both genetic and pharmacologic methods of farnesylation, and to verify the mechanism of mutations in oocyte maturation. Microinjection of centromere protein F siRNA reduced maturation rates significantly, with many halting maturation at metaphase I ( P <0.05). Farnesylation likewise reduced the rate of oocyte maturation ( P <0.01), and additionally weakened the interationc between centromere protein F and Aurora kinase B, which was confirmed by co-immunoprecipitation ( P <0.01). Farnesylation also disrupted kinetochore localization, contributing to the arrest of oocyte maturation. Immunofluorescence analysis further showed that centromere protein F localized at kinetochores by metaphase I, causing arrested development. Screening human patients with infertility resulted in the identification of 4 individuals with rare heterozygous variants in the CENP-F gene that were associated with the arrest of oocyte maturation. When testing centromere protein F derived from patients who were identified to have a genetic mutation in this protein, microinjection of the patient-derived centromere protein F also caused significantly reduced maturation in mouse oocytes ( P <0.01). Two identified mutations reduced the fanesylation of centromere protein F as well as disrupted kinetochore localization and damaged the Aurora kinase B interaction. These results indicate that there is a direct association between centromere protein F mutations and infertility, specifically the arrest of oocyte maturation during meiosis. These findings contribute evidence to the controversy surrounding the influence of farnesylation on the localization of CENP- F, with some previous studies showing no effect of farneslyation and others showing a direct interaction between molecules that is dependent on farneslyation. This study emphasizes the need for further clinical research to validate the pathology of these mutations in diverse populations. Future studies should also attempt to ethically validate the results of these mouse models in human models and examine other possible mechanisms for arrested maturation of oocytes such as disruption of microtubule binding. (Summarized from Zhong O, Wang C, Zhang J, et al. Farnesylation-dependent kinetochore targeting of centromere protein F is essential for oocyte meiotic progression and female fertility. Am J Obstet Gynecol. 2026;234:116-140. doi: 10.1016/j.ajog.2025.08.031)
2026-03-25 | FEMALE GENITAL TUBERCULOSIS: A NEGLECTED CAUSE OF INFERTILITY IN DEVELOPING COUNTRIES
Background: Female genital tuberculosis (FGTB) is an important form of extrapulmonary tuberculosis and a leading, yet often under recognized, cause of infertility in women of reproductive age, particularly in developing countries. The disease is frequently asymptomatic and under diagnosed due to its nonspecific clinical presentation, contributing to delays in management and poor reproductive outcomes. Methods: This review summarizes current knowledge on the epidemiology, pathogenesis, clinical manifestations, diagnostic approaches, treatment strategies, drug resistance, and public health implications of FGTB. Data were synthesized from epidemiological studies, clinical reports, and molecular diagnostic research. Results: FGTB primarily affects the fallopian tubes (90–100%), followed by the endometrium (50–60%) and ovaries (20–30%), with rare involvement of the cervix, vagina, or vulva. Clinical presentation ranges from infertility, menstrual irregularities, and pelvic pain to asymptomatic cases. Diagnosis requires a combination of imaging (hysterosalpingography, ultrasonography, laparoscopy), histopathology, microbiological testing (Ziehl–Neelsen staining, culture), molecular methods (PCR, gene amplification, BACTEC), and immunological tests. Standard antitubercular therapy (ATT) for 6–9 months remains the cornerstone of treatment, with surgical intervention reserved for complicated cases. Drug-resistant tuberculosis, particularly multidrug-resistant TB (MDR-TB), poses a significant therapeutic challenge. FGTB causes structural and functional damage to the reproductive tract, resulting in tubal obstruction, endometrial destruction, pelvic adhesions, and ovarian dysfunction, leading to infertility in 40–80% of affected women, often necessitating assisted reproductive techniques such as in vitro fertilization. Conclusion: FGTB represents a significant reproductive health burden in endemic regions. Early detection through improved awareness, screening of infertile women, and use of molecular diagnostics is essential to prevent irreversible reproductive damage. Strengthening tuberculosis control programs and public health strategies is critical for reducing the incidence of this neglected cause of female infertility.
proteins
2026-07-30 | Hemoperitoneum after oocyte retrieval in women undergoing ART: A 2017-2022 retrospective cohort study with a historical comparison to 1996-2016.
To estimate the incidence and predictors of severity-defined hemoperitoneum after oocyte retrieval in a contemporary 2017-2022 cohort, and to place these findings in context with the center's previously published 1996-2016 experience. Retrospective cohort study including all 13,192 oocyte retrieval procedures performed at a single fertility center from January 2017 to December 2022 in 9,346 women. The primary endpoint was documented hemoperitoneum associated with hemoglobin decrease ≥ 2 g/dL and/or hospital admission, surgery or blood transfusion. The 1996-2016 cohort was retained only as an aggregate historical comparator. Predictors were estimated with robust Poisson regression clustered by patient identifier. Severity-defined hemoperitoneum was identified among 50 retrievals (0.379 %), including 46 cases with hemoglobin decrease ≥ 2 g/dL, 44 admissions, 20 surgical procedures and 12 transfusions. The contemporary primary endpoint was recorded more frequently than the historical aggregate hemorrhagic comparator (RR 1.67, 95 % CI 1.14-2.46, p = 0.010), whereas surgery did not differ significantly (RR 1.81, 95 % CI 0.97-3.36, p = 0.069). In the primary contemporary model, lower BMI (RR 0.80 per kg/m2, 95 % CI 0.73-0.88, p < 0.001), higher AMH (RR 1.08, 95 % CI 1.02-1.14, p = 0.010) and longer total retrieval time (RR 1.03 per minute, 95 % CI 1.00-1.06, p = 0.044) were associated with severity-defined hemoperitoneum. Hemoperitoneum after oocyte retrieval was rare, but associated with substantial morbidity when it occurred. Lower BMI and higher AMH were the main patient-level risk markers. Total retrieval time remained modestly associated with the risk, and should be interpreted as a marker of ovarian response and procedural complexity. The higher rate observed in the contemporary cohort should be interpreted cautiously, as surgery did not increase significantly. NCT05895227, May 31st, 2023.
2026-02-23 | The Clinico-radiological Perspective of Kartagener's Syndrome.
Kartagener's syndrome is a rare autosomal recessive genetic disorder, a subset of primary ciliary dyskinesia. It comprises the triad of situs inversus totalis, bronchiectasis, and chronic paranasal sinusitis. The incidence is 1:30,000 live births, while the male: female ratio is 1:1. Most patients of Kartagener's syndrome present in early childhood with common symptoms of frequent colds, chronic cough with excessive production of purulent sputum, and recurrent lower respiratory tract infections affecting respiratory functions. Kartagener's syndrome commonly presents as infertility in males and subfertility in females. We present the clinical and radiological findings in a patient of Kartagener's syndrome referred to us with recurrent lower respiratory tract infections.
2026-01-31 | TURNER SYNDROME: CLINICAL FEATURES AND CONTEMPORARY DIAGNOSTIC APPROACHES
Turner syndrome (TS) is a rare chromosomal disorder affecting approximately 1 in 2,500–3,000 live female births and caused by complete or partial monosomy of one X chromosome, most commonly presenting as a 45, X karyotype or mosaic forms. The syndrome is associated with a wide spectrum of clinical manifestations, including short stature, ovarian dysgenesis, delayed puberty, infertility, and congenital anomalies, particularly cardiovascular malformations such as coarctation of the aorta and bicuspid aortic valve.
2025-11-21 | Turner disease: A contemporary clinical approach
Turner syndrome (TS) is a rare genetic disorder in females caused by partial or complete loss of one X chromosome. It presents with multisystem clinical manifestations that require lifelong multidisciplinary care and monitoring. Phenotypically, TS is characterized by short stature, short neck with lateral skin folds (pterygium colli), low-set ears, and a low posterior hairline. Clinically, it is associated with cardiovascular diseases (CVD) and primary hypogonadism. The diagnosis of TS is based on clinical presentation and genetic analysis, with early prenatal detection possible. In newborns, TS should be suspected in the presence of oedema of the hands and feet. Short stature becomes evident in early childhood, while delayed puberty and primary amenorrhea are common later findings. CVDs may be congenital or acquired; coarctation of the aorta is a key diagnostic sign, whereas aortic dissection and rupture of an aortic aneurysm are life-threatening complications. Most women with TS have primary hypogonadism and high infertility rates. Spontaneous pregnancies are rare, and fertility preservation options, such as oocyte or embryo cryopreservation, should be considered early. Associated autoimmune diseases, kidney anomalies, liver disorders, and hearing loss are also common. Hormone replacement therapy is essential for pubertal induction, maintenance of general health, and prevention of long-term complications of untreated hypogonadism. Due to numerous comorbidities and variable phenotypes, an individualized multidisciplinary approach is required. With early diagnosis, appropriate management, and psychosocial support, individuals with TS can lead a good quality of life despite ongoing health risks.
2025-06-13 | Identification of Novel Genetic Variants in a Cohort of Congenital Hypogonadotropic Hypogonadism: Computational Analysis of Pathogenicity Predictions.
Congenital hypogonadotropic hypogonadism (CHH) is a rare and heterogeneous genetic disorder with variable penetrance caused by GnRH deficiency, leading to delayed puberty and infertility. In 50-60% of cases, CHH is associated with non-reproductive abnormalities, most commonly anosmia/hyposmia (Kallmann syndrome, KS). Over 60 genes have been implicated in CHH pathogenesis. We aimed to perform genetic screening in a cohort of 14 patients (10 males, 4 females; mean age 22 ± 7.72 years) with suspected or diagnosed HH/KS. Genetic analysis was conducted using next-generation sequencing (NGS) with a custom panel of 46 candidate genes. Variant interpretation followed ACMG standards and guidelines. Multiple tools were used to predict the structural effects of variants on tertiary protein structure, assessing their pathogenicity. Novel variants were functionally characterized by qRT-PCR on mRNA extracted from peripheral leukocytes. NGS identified nine rare variants and four novel variants in genes previously associated with normosmic isolated HH (nHH) and/or KS (FGFR1, PROK2, TAC3R, DCC, WDR11, IL17RD, DUSP6, KAL1, FGF8, IL17RD and DCC). The variant in TAC3R (p.Trp275Ter) was pathogenic; variants in ANOS1 (c.541+1G>A), IL17RD (c.1303_1304dup, p.Lys436ThrfsTer58), and TAC3R (p.Lys361Ter) were likely pathogenic. Nine variants were classified as variants of uncertain significance (VUS). Our study identified a possible genetic cause in 71% of the CHH/KS cohort, emphasizing the importance of genetic screening and functional characterization of genetic variants in patients with a phenotypically and genetically heterogeneous disorder like CHH.
cell therapies
2026-03-10 | Reproductive Challenges of the Ageing Female: A Comprehensive Narrative Review.
Changes in societal norms over the last few decades have resulted in novel family planning trends, notably delayed childbearing and increased maternal age at the birth of the first child. Despite advances in reproductive medicine, ageing poses significant challenges. Natural conception in women ≥ 45 years of age is rare, with high rates of pregnancy loss, and assisted reproduction using autologous oocytes yields limited success. Oocyte donation offers higher live birth rates, exceeding 50%. Elective oocyte cryopreservation could aid in family planning; nevertheless, its success depends on the age at which cryopreservation is performed. These facts highlight the correlation between advancing age and a decline in oocyte quality and quantity. An age-related decline in endometrial receptivity could pose an additional barrier, although the evidence remains controversial. Furthermore, pregnancies in older women carry high risks for both the mother and child, which should be considered before assisted conception attempts. This comprehensive narrative review examines the advancements in assisted reproductive technology that have expanded the possibilities for delayed childbearing, while underlining at the same time the major challenges in the field. Innovations such as ovarian tissue cryopreservation and stem cell-based therapies have the potential to reshape reproductive options for these women. However, thorough counselling and tailored management remain of paramount importance.
2025-12-12 | The Doing/Undoing of MRKH and the Doing of Gestational Pregnancy and Gender Through Uterus Transplants.
Women with the rare Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome are born without a uterus. Following international interviews with 34 women with MRKH and 15 surgeons and specialists, we explore how the usually invisible condition of MRKH is made visible and "done" through biomedicine. MRKH is highly medicalized, with much work undertaken to make MRKH bodies fit heteronormative standards. Some people with MRKH prefer to define themselves as intersex. Others undertake uterus transplants (UTx), to experience menstruation, gestation, and birth. UTx reconstructs their bodies to heteronormative expectations at the same time as it reinforces gendered identity as normative women, and potentially as mothers.
2025-11-26 | Endometrial Injury and Its Rescue by Mesenchymal Stem Cells Is Dependent on Estrous Cycle Phase.
Asherman Syndrome (AS) is caused by injury to the endometrium leading to uterine scarring, decreased menstruation and infertility; it typically occurs after surgical curettage of the uterus. AS is treated surgically albeit with limited success. Administration of bone marrow-derived mesenchymal stem cells (MSCs) has recently been demonstrated to restore uterine function in AS; however, there is no data available on the role of the estrous cycle phase on outcomes. Here, we describe endometrial injury during estrus or diestrus, its differential effect on fertility, and its response after bone marrow MSC treatment to reverse the infertility in a murine model. Endometrial injury in the estrus phase did not affect fertility outcomes whereas injury in the diestrus phase resulted in infertility. Bone marrow (BM)-derived MSC treatment without injury in the estrus or diestrus phase did not affect the pregnancy outcomes. BM MSC treatment following endometrial injury in the diestrus phase restored fertility. Immunofluorescence analysis revealed that vimentin or cytokeratin-positive BM-derived cells in the uterus were extremely rare. BM MSC treatment after injury increased CD45+ cells, indicating a role for immunomodulation in endometrial repair. Finally, qRT-PCR showed that Ccl3, Il-1β and Mmp3 gene expression was significantly higher in the endometrium of the injury + BM MSC group than in other groups. In summary, injury to the endometrium during the diestrus phase results in infertility that can be restored by the treatment of BM MSCs. The therapeutic effect of BM MSCs on the endometrium appears to be mediated primarily by immunomodulation rather than BM MSC engraftment.
2025-11-18 | The Danish Turner Syndrome Cryopreservation study: PROTOCOL for a prospective cohort Study on reproductive outcomes after ovarian tissue cryopreservation in girls with Turner syndrome.
BACKGROUND: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial loss of one X chromosome, resulting in a high risk of premature ovarian insufficiency (POI) and infertility. While the underlying mechanisms are not fully understood, oocyte loss is known to begin in fetal life and continue throughout childhood, often leading to ovarian failure before the onset of puberty. Ovarian tissue cryopreservation (OTC) offers a potential method to preserve fertility in girls with TS, but the procedure remains experimental in this group. To date, only three cases of autotransplantation have been reported, and no live births have occurred in women with TS. Moreover, predictors of residual ovarian function and eligibility for OTC are poorly defined, and the long-term effects of unilateral oophorectomy in girls with already limited ovarian reserve are unknown. OBJECTIVE: To investigate long-term reproductive outcomes following OTC in girls with TS. METHODS: The Danish Turner Syndrome Cryopreservation Study is a nationwide, prospective cohort study with long-term follow-up, combining observational and interventional elements. Girls with TS aged 2–17 years are invited to participate. As ovarian reserve is depleted before adulthood in most girls with TS, all participants undergo ovarian function assessment to evaluate the likelihood of remaining viable follicles. If follicles are deemed present, unilateral OTC may be offered. The primary outcome is the number of pregnancies, miscarriages, and live births following autotransplantation of cryopreserved and thawed ovarian tissue in adulthood. Secondary objectives include identifying early predictors of POI, assessing the impact of oophorectomy on ovarian function and pubertal progression, and exploring molecular mechanisms of ovarian dysgenesis through genetic and epigenetic analyses of ovarian and peripheral tissues. Recruitment began in January 2024 and is ongoing at three university hospitals across Denmark. Follow-up is expected to continue until 2050. CONCLUSION: This study addresses a critical gap in fertility preservation for girls with TS by evaluating the feasibility and long-term outcomes of OTC. The findings will improve understanding of POI progression, refine selection criteria for OTC, and support evidence-based counselling for girls with TS and their families. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05740579. Registered 13 February 2023. https//clinicaltrials.gov/study/NCT05740579.
2025-08-20 | A rare association of Craniopharyngioma and Meyer-Rokitansky-Kuster-Hauser Syndrome in a patient with primary amenorrhea and delayed puberty – A Case Report
Background: Meyer-Rokitansky-Kuster-Hauser Syndrome (MRKH) is a congenital abnormality of the uterus and the upper two-thirds of the vagina in women showing normal development of secondary sexual characteristics with a normal karyotype of 46, XY. Craniopharyngioma is a rare intracranial neoplasm found in seller/suprasellar region with two distinct histologic phenotypes – adamantinoma Tous and papillary. It has insidious onset of symptoms and presents as headache, visual impairment and hormonal imbalances secondary to compression of adjacent pituitary manifesting commonly as sexual dysfunction in adults and growth failure in children. This case report presents a 20 years female with primary amenorrhea and absence of secondary sex characteristics, headache and visual field defect who was subsequently diagnosed as adamant nous craniopharyngioma with multiple pituitary hormones deficiency with Type 1 MRKH. Patient underwent transsphenoidal resection and replacement of levothyroxine and corticosteroid with further plan of reassessing pituitary gonadal axis, creation of a neovagina, addressing puberty induction and infertility (in vitro fertilization and surrogacy). It is too early to say that there may be an association between craniopharyngioma and MRKH. Whether craniopharyngioma and MRKH share a similar etiology is unclear. With increasing genetic testing, in the future, we may get some correlation.
gene therapies
2023-11-21 | Homozygous missense variant in MEIOSIN causes premature ovarian insufficiency.
Are variants of genes involved in meiosis initiation responsible for premature ovarian insufficiency (POI)? A MEIOSIN variant participates in the pathogenesis of human POI by impairing meiosis due to insufficient transcriptional activation of essential meiotic genes. Meiosis is the key event for the establishment of the ovarian reserve, and several gene defects impairing meiotic homologous recombination have been found to contribute to the pathogenesis of POI. Although STRA8 and MEIOISN variants have been found to associate with POI in a recent study, the condition of other meiosis initiation genes is unknown and direct evidence of variants participating in the pathogenesis of POI is still lacking. This was a retrospective genetic study. An in-house whole exome sequencing (WES) database of 1030 idiopathic POI patients was screened for variations of meiosis initiation genes. Homozygous or compound heterozygous variations of genes involved in meiosis initiation were screened in the in-house WES database. The pathogenicity of the variation was verified by in vitro experiments, including protein structure prediction and dual-luciferase reporter assay. The effect of the variant on ovarian function and meiosis was demonstrated through histological analyses in a point mutation mouse model. One homozygous variant in MEIOSIN (c.1735C>T, p.R579W) and one in STRA8 (c.258 + 1G>A), which initiates meiosis via the retinoic acid-dependent pathway, were identified in a patient with idiopathic POI respectively. The STRA8 variation has been reported in the recently published work. For the MEIOSIN variation, the dual-luciferase reporter assay revealed that the variant adversely affected the transcriptional function of MEIOSIN in upregulating meiotic genes. Furthermore, knock-in mice with the homologous mutation confirmed that the variation impacted the meiotic prophase I program and accelerated oocyte depletion. Moreover, the variant p.R579W localizing in the high-mobility group (HMG) box domain disrupted the nuclear localization of the MEIOSIN protein but was dispensable for the cell-cycle switch of oocytes, suggesting a unique role of the MEIOSIN HMG box domain in meiosis initiation. Further studies are needed to explore the role of other meiosis initiation genes in the pathogenesis of POI. The MEIOSIN variant was verified to cause POI by impaired transcriptional regulation of meiotic genes and was inherited by a recessive mode. The function of HMG box domain in MEIOSIN protein was also expanded by this study. Although causative variations in meiotic initiation genes are rare in POI, our study confirmed the pathogenicity of a MEIOSIN variant and elucidated another mechanism of human infertility. This work was supported by the National Key Research & Developmental Program of China (2022YFC2703800, 2022YFC2703000), National Natural Science Foundation for Distinguished Young Scholars (82125014), National Natural Science Foundation of China (32070847, 32170867, 82071609), Basic Science Center Program of NSFC (31988101), Natural Science Foundation of Shandong Province for Grand Basic Projects (ZR2021ZD33), Natural Science Foundation of Shandong Province for Excellent Young Scholars (ZR2022YQ69), Taishan Scholars Program for Young Experts of Shandong Province (tsqn202211371), and Qilu Young Scholars Program of Shandong University. The authors declare no conflict of interest. N/A.
2019-07-15 | Novel WEE2 gene variants identified in patients with fertilization failure and female infertility.
To determine whether variants in the WEE2 (WEE1 homolog 2, also known as WEE1B) gene, which has been known to function in the formation of pronuclei during fertilization, contribute to fertilization failure. Case-control genetic study. University hospital. Ninety infertile women with repeated cycles of pronucleus formation failure undergoing in vitro fertilization and/or intracytoplasmic sperm injection treatment as well as 200 fertile control women. Genomic DNA was extracted from the peripheral blood. The whole exons of WEE2 were amplified by means of polymerase chain reaction and then Sanger sequencing was performed. Variants analysis of WEE2 gene. We identified five subjects that were subjected to homozygous or compound-heterozygous variants of WEE2: case 1 (from a consanguineous family) with homozygous frameshift variant: c.293_294insCTGAGACACCAGCCCAACC (p.Pro98Pro fsX2); case 2 with homozygous missense variant: c.1576T>G (p.Tyr526Asp); and three cases with compound-heterozygous variants: case 3: c.991C>A (p.His331Asn) and c.1304_1307delCCAA (p.Thr435Met fsX31); case 4: c.341_342 del AA (p.Lys114Asn fsX20) and c.864G>C (p.Gln288His); and case 5: c.1A>G (p.0?) and c.1261G>A (p.Gly421Arg). Besides c.1576T>G (from case 2) and c.864G>C (from case 4), which have been previously reported as rare single nucleotide polymorphisms (SNPs), the other six variants were novel and predicted by software to be deleterious. The parental genotypes of case 1 and case 2 indicated that the detected homozygous variants were inherited in an autosomal recessive mode. All of the detected variants were absent from the control cohort. Novel variants found in WEE2, which is autosomal-recessive inherited, may be related to recurrent pronucleus formation failure and female infertility.
2018-03-16 | A Novel FOXL2 Mutation Implying Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Type I.
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease caused by FOXL2 gene mutations, and it is clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). Functional study of novel mutations is especially critical for female patients, as it may allow the prediction of infertility and early planning of an appropriate therapy. A clinical and molecular genetic investigation was performed in all members of a Chinese family with BPES. Genomic DNA was extracted, and the FOXL2 coding region was sequenced. Subcellular localization was performed by confocal microscopy. Transactivation studies were performed by real-time PCR, dual luciferase reporter assays and electrophoretic mobility shift assays. A novel deletion mutation (C.634_641 del, CCCATGC) between the forkhead domain and the polyalanine domain was found, resulting in a frameshift mutation and a truncated protein. Functional studies showed a strong cytoplasmic mislocalization and abnormal transactivation activity, implying a type I kind mutation with a large chance of infertility. This study identifies that this mutation indicates the probability of developing into POF and shows the importance and necessity of early recognition of BPES type through mutation testing for female patients. Prompt personalized therapy and follow-up is of great clinical significance for female patients carrying this kind of mutation.
2012-01-12 | Two common polymorphisms in the peroxisome proliferator-activated receptor γ gene may improve fertilization in IVF.
Genetic factors play an important role in women's fertility and embryonic development and may also contribute to the efficacy of assisted reproduction techniques. The aim of this study was to investigate the effect of His447His and Pro12Ala peroxisome proliferator-activated receptor γ (PPARγ) gene polymorphisms on oocytes and fertilization in women undergoing IVF. Follicular fluid and blood samples were obtained from 98 IVF patients referred to Tabriz Alzahra Hospital. Samples were analysed for fatty acid content by gas-liquid chromatography and for polymorphisms of the PPARγ gene using polymerase chain reaction-restriction fragment length polymorphism-based methods. Multiple regression analyses were used to test the independence of associations between the number of mature and fertilized oocytes as outcome variables and the polymorphisms of PPARγ gene. For both polymorphisms, fertilization ratio was significantly (P<0.05) higher in carriers of the rare alleles than homozygous wild-type genotypes. The associations of His447His (P=0.003) and Pro12Ala (P=0.015) polymorphisms remained statistically significant in the multiple regression analyses. This study suggests that the two common gene polymorphisms of PPARγ may improve fertilization in vitro and, thus possibly, female fertility.
other
2022-08-02 | Biallelic variants in MOS cause large polar body in oocyte and human female infertility.
What is the genetic basis of female infertility involving abnormal oocyte morphology with the production of a large first polar body (PB1)? The homozygous missense variant (c.791C>G) and compound missense variants (c.596A>T and c.875C>T) in MOS proto-oncogene, serine/threonine kinase (MOS) (Online Mendelian Inheritance in Man (OMIM) reference: 190060; NM_005372.1) are responsible for abnormal oocyte morphology with the production of a large PB1 to cause infertility in women. MOS, an oocyte-specific gene, encodes a serine/threonine-protein kinase that directly phosphorylates mitogen-activated protein kinase (MAPK) kinase (MEK) to activate MAPK (also called extracellular-signal-regulated kinase (ERK)) signal cascade in the oocyte. Female mice lacking Mos remained viable, but infertile because of oocyte symmetric division, spontaneous parthenogenetic activation and early embryonic arrest. Recently, two independent studies demonstrated that female infertility with early embryonic arrest and fragmentation can be caused by biallelic mutations in MOS. However, so far, MOS variants have not been associated with the phenotype of large PB1 extrusion in human oocytes to contribute to female infertility. Two independent infertile families characterized by the presence of large PB1 in oocytes were recruited between December 2020 and February 2022. Genomic DNA was extracted from the peripheral blood samples of the subjects for whole-exome sequencing. Pedigree analysis was validated by Sanger sequencing. Then, the pathogenic effects of the MOS variants on MOS protein properties and ERK1/2 activation were determined in HEK293 cells and mouse oocytes. We identified three rare missense variants in MOS, including a homozygous missense variant (c.791C>G) from Patient 1 in Family 1 and two compound missense variants (c.596A>T and c.875C>T) from twin sisters in Family 2. The MOS variants followed a recessive inheritance pattern in infertile patients. All three patients displayed a high percentage of large PB1 extrusion in the oocytes. The three MOS variants could not activate MEK1/2 and ERK1/2 in oocytes and HEK293 cells. In addition, when compared with wild-type MOS, the MOS variants decreased the MOS protein level and attenuated the binding capacity with MEK1. Microinjection of wild-type human MOS complementary RNAs (cRNAs) reversed the symmetric division of oocytes after siMos treatment. In contrast, the three MOS variants demonstrated no rescuing ability. N/A. Owing to the scarcity of human oocyte samples and the associated ethical restrictions, we could not perform the rescue attempt for the study patients. Our findings expand the genetic and phenotypic spectrum of MOS variants in causing female infertility. Our study findings facilitate the early genetic diagnosis of abnormal oocyte morphology characterized as large PB1 that eventually causes infertility in women. This study was supported by the National Natural Science Foundation of China (82071640 and 82001633), Natural Science Foundation of Zhejiang Province (LD22C060001), the Key Projects Jointly Constructed by the Ministry and the Province of Zhejiang Medical and Health Science and Technology Project (WKJ-ZJ-2005), China Postdoctoral Science Foundation (2020M682575 and 2021T140198), the Changsha Municipal Natural Science Foundation (kq2007022) and Hunan Provincial Grant for Innovative Province Construction (2019SK4012). None of the authors declare any competing interests. N/A.
2022-05-30 | Obstetrical complications and outcome in patients with endometriosis.
Endometriosis is a disease that has a profound impact on the quality of life of women, due to the associated chronic pelvic pain, dysmenorrhea, dyspareunia and infertility. However, even getting long-awaited pregnancy (often after assisted reproductive technologies), patients with endometriosis have a high risk of obstetric complications, such as miscarriage, preterm birth, preeclampsia, placental abnormalities, hemorrhage in labor, birth of small for gestational age infants, stillbirth and higher cesarean section rate. In addition, during pregnancy acute complications of endometriosis may occur, such as spontaneous hemoperitoneum, which is rare but life-threatening conditions that in most cases require surgical intervention. The mechanisms of the observed complications in pregnant women with endometriosis are not fully understood. This review presents literature data and personal considerations on the effect of endometriosis on pregnancy outcome and the occurrence of complications, as well as their possible underlined mechanisms. Based on this, we proposed ways to reduce the risk of obstetric complications in pregnant women with a history of endometriosis.
2022-03-11 | Involvement of chemerin and CMKLR1 in the progesterone decrease by PCOS granulosa cells.
Polycystic ovarian syndrome (PCOS) is the main cause of infertility in women. It is frequently associated with reduced progesterone production by human luteinised granulosa cells (hlGCs). However, the molecular mechanisms involved in these steroidogenesis alterations in PCOS patients are unclear. In a dihydrotestosterone-induced PCOS mouse model, steroid production is maintained in the setting of chemokine-like receptor 1 (Cmklr1) knockout. Thus, chemerin and chemerin receptors in terms of expression and progesterone regulation could be different in control and PCOS hlGCs. We first confirmed that progesterone levels in both plasma (P < 0.0001) and follicular fluid (FF) (P < 0.0001) were significantly reduced in PCOS normal weight women compared to control women. These data were associated with a lower STAR mRNA expression in both in vivo (P < 0.0001) and in vitro (P < 0.0001) hlGCs from PCOS women. Secondly, chemerin FF levels (P < 0.0001) and RARRES2 (P < 0.05) and CMKLR1 (P < 0.0001) mRNA levels in GCs were higher in PCOS normal weight patients. Thirdly, treatment of hlGCs with a specific nanobody (the VHH CA4910) targeting the human receptor for CMKLR1 leading to its inactivation abolished chemerin-induced progesterone inhibition, suggesting the involvement of CMKLR1 in this process. Furthermore, the inhibition of progesterone secretion induced by chemerin was two-fold higher in PCOS hlGCs (P < 0.05). Moreover, the VHH CA4910 reinstated a normal progesterone secretion with lower concentrations in PCOS hlGCs, suggesting a different chemerin sensitivity between PCOS and control hlGCs. Thus, chemerin, through CMKLR1, could be involved in the steroidogenesis alterations in PCOS hlGCs.
2021-08-27 | Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause.
Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40 years of age. Known genetic causes account for 25-30% of POI cases, demonstrating the high genetic heterogeneity of POI and the necessity for further genetic explorations. Here we conducted genetic analyses using whole-exome sequencing in a Chinese non-syndromic POI family with the affected mother and at least four affected daughters. Intriguingly, a rare missense variant of BUB1B c.273A>T (p.Gln91His) was shared by all the cases in this family. Furthermore, our replication study using targeted sequencing revealed a novel stop-gain variant of BUB1B c.1509T>A (p.Cys503*) in one of 200 sporadic POI cases. Both heterozygous BUB1B variants were evaluated to be deleterious by multiple in silico tools. BUB1B encodes BUBR1, a crucial spindle assembly checkpoint component involved in cell division. BUBR1 insufficiency may induce vulnerability to oxidative stress. Therefore, we generated a mouse model with a loss-of-function mutant of Bub1b, and also employed D-galactose-induced aging assays for functional investigations. Notably, Bub1b+/- female mice presented late-onset subfertility, and they were more sensitive to oxidative stress than wild-type female controls, mimicking the clinical phenotypes of POI cases affected by deleterious BUB1B variants. Our findings in human cases and mouse models consistently suggest, for the first time, that heterozygous deleterious variants of BUB1B are involved in late-onset POI and related disorders.
2000-04-07 | The gamete fusion process is defective in eggs of Cd9-deficient mice.
The cell-surface molecule Cd9, a member of the transmembrane-4 superfamily, interacts with the integrin family and other membrane proteins. and is postulated to participate in cell migration and adhesion. Expression of Cd9 enhances membrane fusion between muscle cells and promotes viral infection in some cells. Fertilization also involves membrane fusion, between gametes. In mammals, the sperm binds to microvilli on the egg surface, and sperm-egg membrane fusion first occurs around the equatorial region of the sperm head12. The fused membrane is then disrupted, and the sperm nucleus as well as the cytoplasm is incorporated into the egg. Cd9 is expressed on the plasma membrane of the mouse egg, and an anti-Cd9 monoclonal antibody inhibits sperm-egg surface interactions. We generated Cd9 mice and found that homozygous mutant females were infertile. Sperm-egg binding was normal, but sperm-egg fusion was almost entirely inhibited in eggs from Cd9 females. Intracellular Ca2 oscillations, which signal fertilization, were absent in almost all mutant eggs; in rare cases, a response occurred after a long time period. In normal animals, Cd9 molecules were expressed on the egg microvilli and became densely concentrated at the sperm attachment site. Thus, our results show that Cd9 is important in the gamete fusion process at fertilization.
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Drug Discovery Landscape
1 orphan drug designation for Rare female infertility.
1 orphan drug designation for Rare female infertility.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
autologous adult bone marrow-derived and unexpanded CD133+ hematopoietic stem cells (CD133+ BMDSCs) mobilized from peripheral blood (PB) | cell therapies | FDA | 2019-02-01 | — | Asherman Therapy S.L.U. |
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