Premature Ovarian Failure Cases Research Articles

7606 Partial Xp Duplication and Xq Deletion in a Patient with Premature Ovarian Failure: A Rare Case Report

Abstract Disclosure: A. Pataco: None. C.S. Moniz: None. C. Chaves: None. R. Medeiros: None. M. Ponte: None. B.D. Pereira: None. J. Anselmo: None. I. Sousa: None. Premature ovarian failure (POF) is a heterogeneous condition characterized by the cessation of ovarian function leading to amenorrhea before age 40. While the etiology of POF is diverse, the majority of cases are idiopathic, with a likely genetic basis. Xq abnormalities are commonly linked to POF, whereas Xp abnormalities are rare and infrequently reported.We describe a case of a 30-year-old woman with a personal history of depression, presenting to the Endocrinology department with an 8-month history of amenorrhea. Notably, her menstrual cycles had been irregular since menarche. Previously, a gynecological assessment led to the initiation of bromocriptine 5 mg/day for suspected microprolactinoma, indicated by symptoms of galactorrhea, elevated prolactin levels (112 ng/mL; Normal: 5.18-26.53), and a pituitary MRI showing a 3.5mm microadenoma. It is important to note her concurrent use of risperidone, sertraline, and lorazepam at that time.In the first evaluation at the Endocrinology department, the patient reported amenorrhea and denied galactorrhea. The physical examination was unremarkable with no evidence of hirsutism. The blood tests indicated hypergonadotropic hypogonadism, low levels of prolactin and Anti-Müllerian hormone: FSH 17 mIU/mL (Normal: 3.03-8.08), LH 8.30 mIU/mL (Normal: 1.80-11.78), 17-Beta Estradiol 11 pg/mL (Normal: 21-251), Total testosterone 20.1 ng/dL (Normal: 7.21-79.31), TSH 1.84 uIU/mL (Normal: 0.35-4.94), T4L 1.06 ng/dL (Normal: 0.70-1.48), PRL 1.8 ng/mL (Normal: 5.18-26.53), ACTH 21 pg/mL (Normal: 7.2-63.3), Cortisol 11.5 ug/dL (Normal: 3.7-19.4), IGF-1 130.2 ng/mL (Normal: 177-382), Anti-Müllerian hormone <0.1 ng/mL (Normal: 0.3-11.2).A diagnosis of premature ovarian failure was established. Bromocriptine was discontinued, and the hyperprolactinemia was attributed to the iatrogenic effects of her medications. A pelvic ultrasound showed no abnormalities. Cytogenetic analysis revealed an abnormal karyotype: 46 chromosomes with one X chromosome showing an anomalous configuration—partial deletion of the long arm and partial duplication of the short arm [duplication X(p22.33p11.23) with over 100 genes and deletion X(q24q28) including the FMR1 gene].The patient started hormone replacement therapy with estradiol valerate and medroxyprogesterone acetate, achieving regular menstruation thereafter. Literature review reveals that POF cases involving both partial Xp duplication and partial Xq deletion are exceedingly rare (only 6 reported cases). Genetic counseling is recommended for these patients, particularly for those considering parenthood. It is also advisable to assess the chromosomal alteration in parents to determine if the change is inherited and to evaluate the risk to other family members. Presentation: 6/2/2024

7606 Partial Xp Duplication and Xq Deletion in a Patient with Premature Ovarian Failure: A Rare Case Report

Abstract Disclosure: A. Pataco: None. C.S. Moniz: None. C. Chaves: None. R. Medeiros: None. M. Ponte: None. B.D. Pereira: None. J. Anselmo: None. I. Sousa: None. Premature ovarian failure (POF) is a heterogeneous condition characterized by the cessation of ovarian function leading to amenorrhea before age 40. While the etiology of POF is diverse, the majority of cases are idiopathic, with a likely genetic basis. Xq abnormalities are commonly linked to POF, whereas Xp abnormalities are rare and infrequently reported.We describe a case of a 30-year-old woman with a personal history of depression, presenting to the Endocrinology department with an 8-month history of amenorrhea. Notably, her menstrual cycles had been irregular since menarche. Previously, a gynecological assessment led to the initiation of bromocriptine 5 mg/day for suspected microprolactinoma, indicated by symptoms of galactorrhea, elevated prolactin levels (112 ng/mL; Normal: 5.18-26.53), and a pituitary MRI showing a 3.5mm microadenoma. It is important to note her concurrent use of risperidone, sertraline, and lorazepam at that time.In the first evaluation at the Endocrinology department, the patient reported amenorrhea and denied galactorrhea. The physical examination was unremarkable with no evidence of hirsutism. The blood tests indicated hypergonadotropic hypogonadism, low levels of prolactin and Anti-Müllerian hormone: FSH 17 mIU/mL (Normal: 3.03-8.08), LH 8.30 mIU/mL (Normal: 1.80-11.78), 17-Beta Estradiol 11 pg/mL (Normal: 21-251), Total testosterone 20.1 ng/dL (Normal: 7.21-79.31), TSH 1.84 uIU/mL (Normal: 0.35-4.94), T4L 1.06 ng/dL (Normal: 0.70-1.48), PRL 1.8 ng/mL (Normal: 5.18-26.53), ACTH 21 pg/mL (Normal: 7.2-63.3), Cortisol 11.5 ug/dL (Normal: 3.7-19.4), IGF-1 130.2 ng/mL (Normal: 177-382), Anti-Müllerian hormone <0.1 ng/mL (Normal: 0.3-11.2).A diagnosis of premature ovarian failure was established. Bromocriptine was discontinued, and the hyperprolactinemia was attributed to the iatrogenic effects of her medications. A pelvic ultrasound showed no abnormalities. Cytogenetic analysis revealed an abnormal karyotype: 46 chromosomes with one X chromosome showing an anomalous configuration—partial deletion of the long arm and partial duplication of the short arm [duplication X(p22.33p11.23) with over 100 genes and deletion X(q24q28) including the FMR1 gene].The patient started hormone replacement therapy with estradiol valerate and medroxyprogesterone acetate, achieving regular menstruation thereafter. Literature review reveals that POF cases involving both partial Xp duplication and partial Xq deletion are exceedingly rare (only 6 reported cases). Genetic counseling is recommended for these patients, particularly for those considering parenthood. It is also advisable to assess the chromosomal alteration in parents to determine if the change is inherited and to evaluate the risk to other family members. Presentation: 6/2/2024

Ayurveda management protocol for primary infertility due to premature ovarian failure: A case report

Premature Ovarian Failure (POF) is a condition associated with secondary amenorrhea, infertility, decreased ovarian reserve, reduced size of ovaries, low-level Anti-Mullerian Hormone (AMH), and elevated levels of Follicle-Stimulating Hormone (FSH). In such cases, fertility potential is greatly reduced, where in vitro fertilization with a donor’s oocyte is the possible suggestion. This is a case report of a 24-year-old female, diagnosed case of POF, who presented with secondary amenorrhea for six months and primary infertility for 14 months with symptoms of fatigue and vaginal dryness. The patient had elevated FSH (29.48 ng/mL) and reduced AMH (0.23 ng/mL) levels. The case was diagnosed as POF. Considering the symptomatology, this case was diagnosed as Dhatukshaya janya vandhya (~infertility due to excessive depletion of components of the body). Therapies such as Rasayana (~rejuvenation and revitalization therapy) to restore the natural functioning of body elements and Brimhana (~nourishing therapy) were followed in the management. After seven months of Ayurveda interventions, the AMH was increased to 0.54 ng/mL, and the FSH was reduced to 0.5 ng/mL. The management further resulted in conception and the patient delivered a female baby.

Reproductive outcomes after conservative treatment in early and advanced stage MOGCTs

BackgroundMalignant ovarian germ cell tumors usually occur in young women. The standard of care is fertility sparing surgery and comprehensive surgical staging followed by adjuvant chemotherapy with BEP (bleomycin, etoposide, cisplatin) if needed. The aim of this study was to analyze the reproductive outcomes after conservative treatment in patients diagnosed, treated and followed up in MITO (Multicenter Italian Trials in Ovarian Cancer) centers. MethodsA questionnaire concerning gynecological symptoms, reproductive outcomes and fertility treatment was administered to 164 MOGCTs survivors. Data regarding patients deceased were collected from MITO-9 database. There were 114 patients diagnosed at reproductive age between 1983 and 2019 included. Results109 patients answered the questionnaire and 5 patients decesased were included (median age 24.9 years). 78.1% were stage I,4.4% stage II, 14.9% stage III and 2.6% stage IV. 57.9% received chemotherapy, the mean number of cycles was 4.1. Median time to menstrual recovery after BEP was of 5.6 months range, only 1 case of premature ovarian failure was reported. Among the 114 patients 38 (33.3%) attempted to become pregnant, 29/38 (76.3%) got pregnant with a total of 44 conceptions. 40.9% received chemotherapy and 22.9% did not (p 0.048). Pregnancy desire was the only predictive factor associated with live births among women who attempted pregnancy after treatment. ConclusionsAs MOGCTs affect women of child-bearing age, fertility preservation represents a major treatment issue. Our results are consistent with the available evidence, confirming that adjuvant chemotherapy for MOGCT does not impact the reproductive function and fertility.

P-142 Alterations in mitochondrial DNA levels in luteal granulosa cells may affect the morphology of mature oocytes and subsequently their fertilization potential: a retrospective multicenter study

Abstract Study question Do alterations in mitochondrial DNA levels in luteal granulosa cells (LGCs) affect the quality of mature oocytes in infertile women? Summary answer Alterations in the mitochondrial DNA levels in LGCs may modify the characteristics of the first polar body in oocytes and subsequently decrease their fertilization potential. What is known already Assisted reproductive treatment outcomes are closely linked to the oocyte quality as shown in several systematic reviews and meta-analyses. Particularly, the oocyte quality is highly affected by the surrounding luteal granulosa cells (LGCs). This is mainly due to the crucial role of the mitochondria in the LGCs in fueling the metabolic processes required for oocyte maturation. Therefore, modifications in the quality of LGCs may have direct effects on the developmental competence of oocytes. However, the exact mechanisms by which this could happen are not fully understood. Study design, size, duration A retrospective multicenter study was conducted on 303 mature oocytes retrieved from 51 women undergoing intracytoplasmic sperm injection (ICSI). It was conducted in Lebanon at Al Hadi IVF center and Azoury IVF clinic, between January 2019 and January 2020. G-Power 3.1 was used to determine the sample size for Generalized Linear Mixed Models through a one-sample t-test power analysis with alpha 0.05, power 0.8, medium effect size (f2 = 0.15), and 5 predictors. Resulting sample size: 43. Participants/materials, setting, methods This study excluded cases of premature ovarian failure, severe oligozoospermia (<2 x 102/ml), or cases using frozen gametes. Mature oocytes, from young women (< 36 years old), were injected and cultured in the Embryoscope where morphometric measurements were performed. LGCs vitality and mitochondrial DNA (mtDNA) levels were analyzed using trypan blue exclusion dye and next-generation sequencing, respectively. Possible associations between these independent variables and the size and integrity of the first polar body were evaluated. Main results and the role of chance The included women presented with primary infertility. Their mean age was 29.98 ± 5.5 years old and their mean body mass index was 23.33 ± 3.32 Kg/m2. 10% of the included women had polycystic ovary syndrome, and 48% were smokers. Regarding the LGCs parameters, a statistically significant negative correlation was found between the mtDNA levels in LGCs and their vitality percentage (r = −0.313, p = 0.029). Interestingly, the average size of the first polar body (PBI) was 346.67 µm. Here we found that the PBI size decreased by 15.05 units when the mtDNA level in LGCs increased by one unit above its average. In parallel, the median percentage of oocytes having a fragmented PBI was 33.33 (0-100). This percentage increased by 4.26% for every one unit increase in the mtDNA level in LGCs (p < 0.0001). In contrast, this percentage decreased by 0.86% for every unit increase in the percentage of LGCs vitality (p < 0.0001). Moreover, the mean percentage of fertilization rate was found to be 70.19 ± 26.7. A higher percentage of fragmented PBI (38.3%) was found among oocytes that did not fertilize compared to those that did successfully fertilize (24%) (p = 0.019). Limitations, reasons for caution This study only analyzed the effects of alterations in mtDNA levels in LGCs on oocytes. It would be worthwhile to also analyze the effects on foetal development and offspring health. Furthermore, it would be interesting to study the relationship between alterations in LGCs and oocyte quality within individual follicles. Wider implications of the findings Several studies have suggested that abnormal size and fragmentation of the PBI may impair embryo development. Therefore, treating factors that affect LGCs, such as obesity and polycystic ovary syndrome, may benefit infertile women. This highlights the need for new clinical trials in this context. Trial registration number Not applicable

Umbilical Cord-Derived Mesenchymal Stem Cells for the Treatment of Infertility Due to Premature Ovarian Failure.

Females belonging to the reproductive age group may face challenges regarding infertility or miscarriage due to conditions such as premature ovarian failure (POF). It is the conditionthat happens when a female's ovaries stop working before she is 40. The majority of the causes of POF cases are idiopathic. Other reasons includegenetic disorders (Turner's syndrome, bone morphogenetic protein 15 (BMP15) mutation, galactosemia, mutation of forkhead box protein L2 (FOXL2), growth differentiation factor-9 (GDF9), mutation of luteinizing hormone (LH) and follicle-stimulating hormonereceptors (FSHR), etc.), enzymatic mutation such as aromatase, autoimmune disorders (Addison's disease, vitiligo, systemic lupus erythematosus, myasthenia gravis, autoimmune thyroiditis, autoimmune polyglandular syndrome, etc.), vaccination, and environmental factors (cigarette smoking, toxins, and infections). Manyattempts have been made to treat POF by various methods. Some of the methods of treatment include hormone replacement therapy (HRT), melatonin therapy, dehydroepiandrosterone (DHEA) therapy, and stem cell therapy. Stem cell therapy has proven to be the most efficient form for treating POF as compared to all other options. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) are the best among the other sources of mesenchymal stem cells (MSCs) for the treatment of POF as they have a painless extraction procedure. They have a tremendous capacity for self-repair and regeneration, which helps them in restoring degenerated ovaries. This review includes informationon the causes of POF, its efficacious therapeutic approaches, and the impact of transplantation of human umbilical cord mesenchymal stem cells (hUCMSCs) as an option for the therapy of POF. Numerous studies conducted on stem cell therapy provethat it is an effective approach for the treatment of sterility.

Impact of Violence against Women on Sexual and Reproductive Health: Research Protocol and Results from a Pilot Study

Objectives: Violence against women (VAW) is associated with a deterioration of endocrine function with consequences similar to those of premature ovarian failure in women. The main objective of this study is to evaluate the hormonal repercussions of VAW and, secondly, to analyse the cardio-metabolic, bone, cognitive, psychological, and psychosexual consequences of hypoestrogenism secondary to VAW. Materials and Methods: A cross-sectional study will be conducted on women of any age who have suffered VAW at some point in their lifespan, whether psychological, sexual, or physical. Clinical, hormonal, cardio-metabolic, bone, psychological, and psychosexual parameters will be analysed. Results: The pilot study from the first 23 women show that all of them are suffering from severe sexual dysfunction. In addition, all women reported menstrual irregularity and hypoestrogenism (including two cases of premature ovarian failure) since the VAW episode. Conclusions: VAW is a pandemic that affects all women equally, regardless of their age, status, social background, or education. Despite the claims made by certain groups, VAW does not depend on women, but rather it affects women and is clearly harmful to their sexual, reproductive, and general health.

Urinary levels of phthalate metabolites in women associated with risk of premature ovarian failure and reproductive hormones.

Phthalates, a class of high production-volume chemicals widely used as plasticizers, have been shown to impair ovarian functions in female animals, but epidemiological evidence is very limited. In this case-control study, the associations between phthalate exposure and premature ovarian failure (POF) in women were assessed. A total of 173 POF cases and 246 control women were recruited in Zhejiang, China. The urinary concentrations of 8 phthalate metabolites and the serum levels of ovary-related hormones were determined. Mono-isobutyl phthalate (MiBP) was the metabolite with the highest median concentration of 27.23 μg/g of creatinine in the whole group. Compared with the lowest quartile, higher urinary concentrations of MiBP were significantly associated with increased odds of POF (OR = 1.38, 95% CI: 0.73-2.61 for the fourth quartile; p for trend = 0.01). The estradiol/FSH ratio, a marker of ovarian function, in control women was significantly negatively associated with the urinary concentrations of most tested phthalate metabolites. Our results suggest that exposure to some phthalates may impair ovarian function and increase the odds of POF in women.

Generation of induced pluripotent stem cell line-NTUHi001-A from a premature ovarian failure patient with Turner's syndrome mosaicism

Turner's syndrome (TS) is one of the main causes of premature ovarian failure (POF). However, the mechanisms underlying POF are difficult to study due to the lack of suitable disease models. Herein, we have generated a human induced pluripotent stem cell (hiPSC) line derived from the peripheral blood mononuclear cells of a female patient with Turner's syndrome mosaicism via integration-free Sendai-virus system. The hiPSCs were confirmed with a 45, X karyotype and the acquisition of pluripotency. It's likely that hiPSCs can serve as a feasible cellular model for further pathophysiological studies of POF cases, especially for those originating in TS.

Association between cadmium and anti-Mullerian hormone in premenopausal women at particular ages

BackgroundAnti-Mullerian hormone (AMH) in women is secreted by granulosa cells of antral follicles. AMH appears to be a very stable marker for ovarian function. It may be used to diagnosis cases of premature ovarian failure, polycystic ovary syndrome (PCOS), and ovarian tumors. It has been suggested that cadmium exposure can reduce female fecundity. The purpose of this study was to investigate whether environmental exposure to cadmium was associated with alterations in AMH with regards to age.MethodsIn a cross-sectional study, the data of premenopausal women living in Seoul, ranging from 30 to 45 of age was collected. The study included a total of 283 women who completed serum AMH and whole blood cadmium assessments. Linear regression analyses were used in order to examine the association between cadmium and AMH. Given that age was the strongest confounder in both cadmium and AMH concentrations, we stratified subjects by 5 years old and analyzed their data.ResultsGeometric mean concentrations of blood cadmium and AMH were 0.97 μg/L and 3.02 ng/ml, respectively. Total association between cadmium and AMH was statistically significant (adjusted coefficient = − 0.34 (0.15), p = 0.02). After stratification, the only age group with a negative association between cadmium and AMH were the women raging between 30 and 35 years (adjusted coefficient = − 0.43 (0.18), p = 0.01).ConclusionsThe results of this study suggest that environmental exposure to cadmium may alter the AMH level of premenopausal women, depending on their age group.

Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases.

STUDY QUESTIONCan spontaneous premature ovarian failure (POF) patients derived from population-based biobanks reveal the association between copy number variations (CNVs) and POF?SUMMARY ANSWERCNVs can hamper the functional capacity of ovaries by disrupting key genes and pathways essential for proper ovarian function.WHAT IS KNOWN ALREADYPOF is defined as the cessation of ovarian function before the age of 40 years. POF is a major reason for female infertility, although its cause remains largely unknown.STUDY DESIGN, SIZE, DURATIONThe current retrospective CNV study included 301 spontaneous POF patients and 3188 control individuals registered between 2003 and 2014 at Estonian Genome Center at the University of Tartu (EGCUT) biobank.PARTICIPANTS/MATERIALS, SETTING, METHODSDNA samples from 301 spontaneous POF patients were genotyped by Illumina HumanCoreExome (258 samples) and HumanOmniExpress (43 samples) BeadChip arrays. Genotype and phenotype information was drawn from the EGCUT for the 3188 control population samples, previously genotyped with HumanCNV370 and HumanOmniExpress BeadChip arrays. All identified CNVs were subjected to functional enrichment studies for highlighting the POF pathogenesis. Real-time quantitative PCR was used to validate a subset of CNVs. Whole-exome sequencing was performed on six patients carrying hemizygous deletions that encompass genes essential for meiosis or folliculogenesis.MAIN RESULTS AND THE ROLE OF CHANCEEleven novel microdeletions and microduplications that encompass genes relevant to POF were identified. For example, FMN2 (1q43) and SGOL2 (2q33.1) are essential for meiotic progression, while TBP (6q27), SCARB1 (12q24.31), BNC1 (15q25) and ARFGAP3 (22q13.2) are involved in follicular growth and oocyte maturation. The importance of recently discovered hemizygous microdeletions of meiotic genes SYCE1 (10q26.3) and CPEB1 (15q25.2) in POF patients was also corroborated.LIMITATIONS, REASONS FOR CAUTIONThis is a descriptive analysis and no functional studies were performed. Anamnestic data obtained from population-based biobank lacked clinical, biological (hormone levels) or ultrasonographical data, and spontaneous POF was predicted retrospectively by excluding known extraovarian causes for premature menopause.WIDER IMPLICATIONS OF THE FINDINGSThe present study, with high number of spontaneous POF cases, provides novel data on associations between the genomic aberrations and premature menopause of ovarian cause and demonstrates that population-based biobanks are powerful source of biological samples and clinical data to reveal novel genetic lesions associated with human reproductive health and disease, including POF.STUDY FUNDING/COMPETING INTERESTThis study was supported by the Estonian Ministry of Education and Research (IUT20-43, IUT20-60, IUT34-16, SF0180027s10 and 9205), Enterprise Estonia (EU30020 and EU48695), Eureka's EUROSTARS programme (NOTED, EU41564), grants from European Union's FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, SARM, |EU324509) and Horizon 2020 innovation programme (WIDENLIFE, 692065), Academy of Finland and the Sigrid Juselius Foundation.

Autologous stem cells therapy, The first baby of idiopathic premature ovarian failure

Introduction: Stem cells (sc) are the foundation cells for every organ, tissue and cell in the body. They are self sustaining and can replicate themselves for long periods of time. Stem cells can differentiate into different types of cells. Women below the age of forty and showing ovarian function loss are defined to have premature ovarian failure (POF). It is associated with sex steroid deficiency, amenorrhea, infertility, and elevated serum gonadotropins. Aim: To evaluate the therapeutic potential of autologous Mesenchymal sc (MSC) transplantation in women suffering from POF. Out of 112 high risk patients for POF(cases with amenorrhoea befor the age of forty), diagnosis was confirmed in10 cases. The ten POF patients were scheduled for MSC transplantation at Al- Azhar University Hospitals. MSC preparation from the bone marrow of the iliac crest was laparoscopically injected into the ovaries. Endometrial fractional biopsy was histopathologicaly (HP) and Immunohistochemically (IH) stained and evaluated according to Edessy stem cells score (ESS). Ovarian reserve was evaluated according to Edessy ovarian reserve score (EORS). Results: Showed that after transplantation two cases (20%) (ESS = 5 and 6) resumed menstruation after 3 months, one of them (10%) (Case no 5) (ESS = 6) got pregnancy after 11 months and delivered a healthy full term baby (Zeinab).Ten months after transplantation EORS of patient who developed pregnancy (case no 6) was found to be 7 after being 0 before therapy. EORS of the other menstruating case (case no 10) was 5 after being 0. The 2 menstruating cases showed focal secretory changes after being atrophic endometrium in case 5 and distorted proliferative endometrium in case 10. Conclusion: Stem cell transplantation is a good procedure and regarded as a real and hope to get healthy pregnancy and baby for cases of POF. It showed good clinical, HP and IH outcome.

Mutations Analysis of the Growth Differentiation Factor 9 Gene in Syrian Women with Ovarian Failure

Premature ovarian failure (POF) is a primary ovarian defect characterized by absent menarche or premature depletion of ovarian follicles. Growth differentiation factor 9 (GDF9) plays an important role in normal growth, differentiation, and proliferation of granulosa cells surrounding the oocyte in the ovary. The present study was to verify the involvement of GDF9 variations in a POF woman in Syrian. POF cases (n= 80) consist of (primary amenorrhea PA n=55) and (secondary amenorrhea SA n=25) compared with 200 controls. All cases with POF had a normal karyotype analysis (46XX). Genetic analysis of the GDF9 gene were showed, four variants in 23 patients. Two of novel variants were observed in two patients, the first was (c.1231G T) was observed in 17 patients and 15 controls. But the variant (c.546G>A) was showed in one patient and in one control. The variant (c.447C>T) appeared associated with the variant (c.546G>A) in 3 patients (c.447C>T)+(c.546G>A) (compound heterozygous genotype). this compound variant didn't detect in the controls. The researchers' findings are consistent with the critical role played by GDF9 in human folliculogenesis. The presence of these variants might indicate a higher risk for POF,.

The genetics of premature ovarian failure: current perspectives.

Premature ovarian failure (POF) is a common cause of infertility in women, characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40. Many genes have been identified over the past few years that contribute to the development of POF. However, few genes have been identified that can explain a substantial proportion of cases of POF. The unbiased approaches of genome-wide association studies and next-generation sequencing technologies have identified several novel genes implicated in POF. As only a small proportion of genes influencing idiopathic POF have been identified thus far, it remains to be determined how many genes and molecular pathways may influence idiopathic POF development. However, owing to POF’s diverse etiology and genetic heterogeneity, we expect to see the contribution of several new and novel molecular pathways that will greatly enhance our understanding of the regulation of ovarian function. Future genetic studies in large cohorts of well-defined, unrelated, idiopathic POF patients will provide a great opportunity to identify the missing heritability of idiopathic POF. The identification of several causative genes may allow for early detection and would provide better opportunity for early intervention, and furthermore, the identification of specific gene defects will help direct potential targets for future treatment.

Mutations Analysis of the Growth Differentiation Factor 9 Gene in Syrian Women with Ovarian Failure

Premature ovarian failure (POF) is a primary ovarian defect characterized by absent menarche or premature depletion of ovarian follicles. Growth differentiation factor 9 (GDF9) plays an important role in normal growth, differentiation, and proliferation of granulosa cells surrounding the oocyte in the ovary. The present study was to verify the involvement of GDF9 variations in a POF woman in Syrian. POF cases (n= 80) consist of (primary amenorrhea PA n=55) and (secondary amenorrhea SA n=25) compared with 200 controls. All cases with POF had a normal karyotype analysis (46XX). Genetic analysis of the GDF9 gene were showed, four variants in 23 patients. Two of novel variants were observed in two patients, the first was (c.1231G T) was observed in 17 patients and 15 controls. But the variant (c.546G>A) was showed in one patient and in one control. The variant (c.447C>T) appeared associated with the variant (c.546G>A) in 3 patients (c.447C>T)+(c.546G>A) (compound heterozygous genotype). this compound variant didn't detect in the controls. The researchers' findings are consistent with the critical role played by GDF9 in human folliculogenesis. The presence of these variants might indicate a higher risk for POF,.

Mutational analysis of the FIGLA gene in women with idiopathic premature ovarian failure.

The aim of our study was to identify the association of FIGLA (factor in the germ line α) gene variants with premature ovarian failure (POF) in the Indian population. Two hundred nineteen women with idiopathic POF and 230 healthy controls were recruited for this study. All exons, intron-exon boundaries, and untranslated regions of the FIGLA gene were analyzed by polymerase chain reaction and sequencing. All FIGLA variants were analyzed in silico, using PolyPhen, SIFT, MutationTaster, PMUT, I-Mutant, Mupro, Align-GVGD, PROVEAN, and HOPE software, to predict pathogenicity and changes in protein stability. Seven different FIGLA variants were detected among women with POF. Two exon 3 variants, c.427G → C and c.557C → T, showed strong association between cases and controls (P = 0.02 and P = 0.02, respectively). Significant differences in both of these variants were observed between cases and controls in genotype and dominant models. No significant difference between controls and women with POF was found on haplotype analysis. A nonsynonymous variant, p.(Arg83Cys), was found only in POF cases. Variant p.(Arg83Cys) lies in the functional domain of the FIGLA gene (basic helix-loop-helix), and protein alignments reveal that it is highly conserved among mammals. In silico analysis suggests the functional involvement of p.(Arg83Cys) and p.(Ser141Thr) variants in POF pathogenesis. We have established a strong association between FIGLA gene variants and POF in Indian women, which may be a potential genetic risk factor in the development of idiopathic POF. However, further independent genetic and functional studies are necessary to confirm our findings.

Bone marrow derived mesenchymal stem cell restore ovarian activity in cases of premature ovarian failure

Introduction: Approximately 1-5% of women worldwide experience cessation of their menstrual cycle prior to age 40, a condition known as POF.The incidence of POF has increased in recent years. As yet, POF cannot be reversed and though some treatments are currently available, improved treatment strategies are urgently required. Regenerative medicine research suggests that stem cells could be used to treat various human diseases, due to their selfrenewal capacity and multiplex differentiation potential. Mesenchymal stem cells (MSCs) are ideal candidates for this purpose. Aim of Work: The purpose of this study is to assess whether bone marrow stem cells (BMSCs) could enter into ovarian niche and differentiate in to oocytes in a mouse model of ovarian failure. Secondly, to explore the therapeutic potency of autologous bone marrow MSC transplantation for primary and chemotherapy-induced ovarian damage and restoration of ovarian function in a pilot human clinical trial. Study Plan: I. Animal study: 18 adult female rats were subjected to cyclophosphamide injection until induction of ovarian failure. 9 mice were injected by 2x106 MSC/Kg . Hormonal and histologic evaluation was done for evidence of regeneration. II. Pilot human trial: 20 cases of premature ovarian failure were enrolled. Autologous bone marrow derived MSC were injected in to the ovaries laparoscopically. Followup was done by measuring serum FSH& follicle counting by ultrasound. Results and Conclusions: All mice of the stem cell treatment group showed positive ovulation with more than 4 ova/low power field. Human subjects showed nomalization of FSH and E2 with sonographic evidence of ovulation in 5 out of 20 patients. These patients were referred to IVF centers.

Association study of TGFBR2 and miR-518 gene polymorphisms with age at natural menopause, premature ovarian failure, and early menopause among Chinese Han women.

Age at natural menopause (ANM), a highly heritable phenotype, has been identified to be closely associated with major hormone-related diseases, including breast cancer and gynecological cancers. We previously identified an important role for the transforming growth factor, β receptor II (TGFBR2) gene polymorphisms in breast cancer susceptibility among Asian women. Considering the important role of ANM in breast carcinogenesis, we hypothesized that TGFBR2 signals were involved in the formation of natural menopause.In a population-based study of 1844 Chinese women, we evaluated the effect of the genetic polymorphisms of TGFBR2 and miR-518 to determine if they are associated with ANM, premature ovarian failure (POF), and early menopause (EM) risk.No significant differences in the distribution of body mass index, education levels, smoking, drinking, and hypertension were detected between POF and EM cases and controls except for POF cases that were older (P = 0.015) than controls and more likely to have dyslipidemia (P = 0.002). The results showed that miR-518 rs7256241 was significantly associated with ANM. The carriers of minor allele G of rs7256241 have significantly higher ANM than those of the major allele homozygotes TT (β = 0.385, P = 0.035). TGFBR2 rs3773661 was significantly associated with POF, with odds ratio (OR) (95% confidence intervals [CIs]) of 0.66 (0.47-0.94) associated with per minor allele C (P = 0.023). The quartiles of genetic risk score were significantly associated with POF (OR, 1.27; 95% CI, 1.02-1.58; Ptrend = 0.034). Sensitivity analyses confirmed the robustness of these findings and no significant interactions were detected.This study provides evidence to implicate TGFBR2 and miR-518 gene polymorphisms as novel susceptibility factors for ANM, POF, and EM in Asians. Further research on these genetic regions will enhance our understanding of the genetic basis of natural menopause.

Impact of Premature Ovarian Failure on Mortality and Morbidity among Chinese Women

ObjectiveTo evaluate associations of premature ovarian failure (POF) with mortality and morbidity in Asian populations.MethodsWe identified 1,003 cases of POF among 36,402 postmenopausal women who participated in the Shanghai Women's Health Study, a population-based cohort study. Cox regression and logistic regression models were applied in data analysis.ResultsAfter adjustment for potential confounding factors, we found that POF increased the risk of total and cancer-specific mortality (HR (95%CIs): 1.29 (1.08–1.54) and 1.38 (1.05–1.81), respectively). POF was also associated with high prevalence of autoimmune disease (OR (95%CI): 1.56 (1.04–2.35)) but decreased incidence of breast cancer (OR (95%CI): 0.59 (0.38–0.91)). Similar results were observed when hormone replacement therapy users were excluded from the analysis. POF is associated with high waist-to-hip ratio.ConclusionsOur results suggest that women with POF experience increased mortality and that these women may benefit from heightened surveillance and appropriate interventions.

Novel variants in the SOHLH2 gene are implicated in human premature ovarian failure

To determine whether variants in the SOHLH2 gene contribute to human premature ovarian failure (POF) in different ethnicities. Case-control genetic study. University hospitals. Chinese (364 cases) and Serbian (197 cases) women with nonsyndromic POF and ethnically matched controls. None. Variation analysis of the SOHLH2 gene. Eleven novel heterozygous variants were identified in cohorts of POF but were absent in matched controls. These included the nonsynonymous variants p.Glu79Lys (n = 2 cases), p.Glu105Gly, and p.Thr321Pro, which were found among four Chinese POF cases, and p.Leu120Phe (n = 3 cases) and p.Leu204Phe, which were found among four Serbian women. Protein alignments reveal that p.Glu79Lys and p.Glu105Gly involve amino acids highly conserved among mammals, both of which are predicted to be deleterious. The c.-210G>T found in the Chinese POF cohort lies in the core promoter region, which is enriched with transcription factor binding sites and CpG islands. In the Serbian cohort, the variant most likely to have a deleterious effect is c.530+6T>G, which is predicted to affect RNA splicing and result in nonsense mediated decay of transcripts. The other variants are less likely to be deleterious. Disturbing the expression, transactivation or homo-/ heterodimerization of the SOHLH2 protein could result in ovarian failure. Overall, four of the 11 novel variants seem plausible explanations for POF; the other seven variants are less likely but cannot be categorically excluded. Our identification of novel variants in the SOHLH2 gene, in women with POF of both Chinese and Serbian origin, strongly suggests an important role for SOHLH2 in human POF etiology.