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1.  Premature ovarian failure 
Premature ovarian failure (POF) is a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 years (secondary amenorrhea). It is a heterogeneous disorder affecting approximately 1% of women <40 years, 1:10,000 women by age 20 and 1:1,000 women by age 30. The most severe forms present with absent pubertal development and primary amenorrhea (50% of these cases due to ovarian dysgenesis), whereas forms with post-pubertal onset are characterized by disappearance of menstrual cycles (secondary amenorrhea) associated with premature follicular depletion. As in the case of physiological menopause, POF presents by typical manifestations of climacterium: infertility associated with palpitations, heat intolerance, flushes, anxiety, depression, fatigue. POF is biochemically characterized by low levels of gonadal hormones (estrogens and inhibins) and high levels of gonadotropins (LH and FSH) (hypergonadotropic amenorrhea). Beyond infertility, hormone defects may cause severe neurological, metabolic or cardiovascular consequences and lead to the early onset of osteoporosis. Heterogeneity of POF is also reflected by the variety of possible causes, including autoimmunity, toxics, drugs, as well as genetic defects. POF has a strong genetic component. X chromosome abnormalities (e.g. Turner syndrome) represent the major cause of primary amenorrhea associated with ovarian dysgenesis. Despite the description of several candidate genes, the cause of POF remains undetermined in the vast majority of the cases. Management includes substitution of the hormone defect by estrogen/progestin preparations. The only solution presently available for the fertility defect in women with absent follicular reserve is ovum donation.
doi:10.1186/1750-1172-1-9
PMCID: PMC1502130  PMID: 16722528
2.  Premature Ovarian Failure: A Critical Condition in The Reproductive Potential with Various Genetic Causes 
Premature ovarian failure (POF) is identified as a heterogeneous disorder leading to amenorrhea and ovarian failure before the age of 40 years. The first known symptom of the disease is having irregular menstrual periods. The phenotype appearance of POF depends significantly on the variations in hormones. Low levels of gonadal hormones (estrogens and inhibins) and increased level of gonadotropins [luteinizing hormone (LH) and Follicle stimulating hormone (FSH)] (hypergonadotropic amenorrhea) are well documented as causes of POF. There is an association between the failure of germ cell development and complete ovarian failure, and consistently decreased number of germ cells is more likely associated with partial ovarian failure resulting in secondary amenorrhea. A literature review on recent findings about POF and its association with genomic alterations in terms of genes and chromosomes. POF is a complex heterogeneous disorder. Some of POF cases are carriers of a single gene mutation inherited in an autosomal or X-linked manner while a number of patients suffer from a chromosome abnormality like Turner syndrome in mosaic form and manifest secondary amenorrhea associated with ovarian dysgenesis. Among many of the known involved genes in POF development, several are prove to be positively associated to the disease development in different populations. While there is a promising association between X chromosome anomalies and specific gene mutations with POF, genome-wide analysis could prove a powerful tool for identifying the most important candidate genes that influence POF manifestation.
PMCID: PMC3973172  PMID: 24696764
Premature Ovarian Failure; Infertility; Amenorrhea
3.  Analysis of X chromosome genomic DNA sequence copy number variation associated with premature ovarian failure (POF) 
Human reproduction (Oxford, England)  2010;25(8):10.1093/humrep/deq158.
BACKGROUND
Premature ovarian failure (POF) is a heterogeneous disease defined as amenorrhoea for >6 months before age 40, with an FSH serum level >40 mIU/ml (menopausal levels). While there is a strong genetic association with POF, familial studies have also indicated that idiopathic POF may also be genetically linked. Conventional cytogenetic analyses have identified regions of the X chromosome that are strongly associated with ovarian function, as well as several POF candidate genes. Cryptic chromosome abnormalities that have been missed might be detected by array comparative genomic hybridization.
METHODS
In this study, samples from 42 idiopathic POF patients were subjected to a complete end-to-end X/Y chromosome tiling path array to achieve a detailed copy number variation (CNV) analysis of X chromosome involvement in POF. The arrays also contained a 1 Mb autosomal tiling path as a reference control. Quantitative PCR for selected genes contained within the CNVs was used to confirm the majority of the changes detected. The expression pattern of some of these genes in human tissue RNA was examined by reverse transcription (RT)–PCR.
RESULTS
A number of CNVs were identified on both Xp and Xq, with several being shared among the POF cases. Some CNVs fall within known polymorphic CNV regions, and others span previously identified POF candidate regions and genes.
CONCLUSIONS
The new data reported in this study reveal further discrete X chromosome intervals not previously associated with the disease and therefore implicate new clusters of candidate genes. Further studies will be required to elucidate their involvement in POF.
doi:10.1093/humrep/deq158
PMCID: PMC3836253  PMID: 20570974
ovarian failure; X chromosome; CNV; female infertility; Q-PCR
4.  A de novo Reciprocal X; 9 Translocation in A Patient with Premature Ovarian Failure 
Premature ovarian failure (POF) causes hypergonadotrophic amenorrhea in 1-3% of females, occurring before the age of 40 among women with chromosomal rearrangements in the long arm of the X chromosome 'critical region'. In this article, we report a case of POF and primary amenorrheain a girl with a de novo reciprocal translocation between chromosomes X and 9. The proband was a 17 years old girl with a history of irregular menstruation and high level of follicle-stimulating hormone (FSH) (151 mlU/mL) and luteinizing hormone (LH) (56 mlU/mL). In ultrasound examination, left ovarian gonad was atrophic without any follicles. Right ovarian gonad was not seen. Cytogenetical analysis was performed on the patient and her parents. Her karyotype results was 46, X, rcp (X; 9) (q24; q13) dn. Her parents had normal karyotype. This reciprocal translocation between chromosome X and 9 and observed POF in the patient suggest either the disruption of a critical gene expression due to 'position effect' or deletion of one or more POF-related genes in the disrupted long arm of the affected X chromosome.
PMCID: PMC3850340  PMID: 24520475
Premature Ovarian Failure; Translocation; Amenorrhea
5.  Chromosomal abnormalities & oxidative stress in women with premature ovarian failure (POF) 
Background & objectives:
Premature ovarian failure (POF) is defined as the cessation of ovarian function under the age of 40 yr and is characterized by amenorrhoea, hypoestrogenism and elevated serum gonadotrophin levels. The cause of POF remains undetermined in majority of the cases. This study was aimed to investigate the type and frequency of cytogenetic abnormalities in patients with idiopathic POF and also to study the role of oxidative stress in such cases.
Methods:
Seventy five women with idiopathic POF were included in this study. Chromosome analysis was done in peripheral blood lymphocytes by conventional GTG banding to identify numerical or structural abnormalities. Cytogenetically normal cases were investigated for reactive oxygen species (ROS) levels in their blood by luminol-chemiluminescence assay.
Results:
Eighteen chromosomal anomalies were identified in POF patients (24%). Majority of the cases were found to have X-chromosome abnormalities (28%). Overall median ROS range was found to be significantly higher (P<0.01) in POF patients [50480 (120,132966) RLU/min] compared to controls [340 (120,5094) RLU/min]. Among these, 50 per cent of the POF patients had higher ROS levels, 20 per cent had medium elevation and 30 per cent were found to have normal values comparable to controls.
Interpretation & conclusions:
X-chromosome anomalies were found to be the major contributor of POF. Oxidative stress may be the underlying aetiology in idiopathic premature ovarian failure. Thus the results of this study highlight the role of cytogenetic abnormalities and supraphysiological levels of ROS in causation of idiopathic POF. But the role of oxidative stress needs to be confirmed by other studies on patients from different geographical areas and from different ethnicities.
doi:10.4103/0971-5916.93430
PMCID: PMC3307192  PMID: 22382189
Cytogenetic; female infertility; premature ovarian failure; reactive oxygen species
6.  X-chromosome terminal deletion in a female with premature ovarian failure: Haploinsufficiency of X-linked genes as a possible explanation 
Background
Premature ovarian failure (POF) has repeatedly been associated to X-chromosome deletions. FMR1 gene premutation allele's carrier women have an increased risk for POF. We intent to determine the cause of POF in a 29 year old female, evaluating both of these situations.
Methods
Concomitant analysis of FMR1 gene CGG repeat number and karyotype revealed an X-chromosome terminal deletion. Fluorescence in situ further characterized the breakpoint. A methylation assay for FMR1 gene allowed to determine its methylation status, and hence, the methylation status of the normal X-chromosome.
Results
We report a POF patient with a 46,X,del(X)(q26) karyotype and with skewed X-chromosome inactivation of the structural abnormal X-chromosome.
Conclusions
Despite the hemizygosity of FMR1 gene, the patient does not present Fragile X syndrome features, since the normal X-chromosome is not subject to methylation. The described deletion supports the hypothesis that haploinsufficiency of X-linked genes can be on the basis of POF, and special attention should be paid to X-linked genes in region Xq28 since they escape inactivation and might have a role in this disorder. A full clinical and cytogenetic characterization of all POF cases is important to highlight a pattern and help to understand which genes are crucial for normal ovarian development.
doi:10.1186/1755-8166-3-14
PMCID: PMC2916005  PMID: 20646274
7.  Investigating the role of X chromosome breakpoints in premature ovarian failure 
The importance of the genetic factor in the aetiology of premature ovarian failure (POF) is emphasized by the high percentage of familial cases and X chromosome abnormalities account for 10% of chromosomal aberrations. In this study, we report the detailed analysis of 4 chromosomal abnormalities involving the X chromosome and associated with POF that were detected during a screening of 269 affected women. Conventional and molecular cytogenetics were valuable tools for locating the breakpoint regions and thus the following karyotypes were defined: 46,X,der(X)t(X;19)(p21.1;q13.42)mat, 46,X,t(X;2)(q21.33;q14.3)dn, 46,X,der(X)t(X;Y)(q26.2;q11.223)mat and 46,X,t(X;13)(q13.3;q31)dn. A bioinformatic analysis of the breakpoint regions identified putative candidate genes for ovarian failure near the breakpoint regions on the X chromosome or on autosomes that were involved in the translocation event. HS6ST1, HS6ST2 and MATER genes were identified and their functions and a literature review revealed an interesting connection to the POF phenotype. Moreover, the 19q13.32 locus is associated with the age of onset of the natural menopause. These results support the position effect of the breakpoint on flanking genes, and cytogenetic techniques, in combination with bioinformatic analysis, may help to improve what is known about this puzzling disorder and its diagnostic potential.
doi:10.1186/1755-8166-5-32
PMCID: PMC3443441  PMID: 22794123
Breakpoint definition; Premature ovarian failure; X chromosome structural aberrations
8.  Prognostic models for high and low ovarian responses in controlled ovarian stimulation using a GnRH antagonist protocol 
Human Reproduction (Oxford, England)  2014;29(8):1688-1697.
STUDY QUESTION
Can predictors of low and high ovarian responses be identified in patients undergoing controlled ovarian stimulation (COS) in a GnRH antagonist protocol?
SUMMARY ANSWER
Common prognostic factors for high and low ovarian responses were female age, antral follicle count (AFC) and basal serum FSH and LH.
WHAT IS KNOWN ALREADY
Predictors of ovarian response have been identified in GnRH agonist protocols. With the introduction of GnRH antagonists to prevent premature LH rises during COS, and the gradual shift in use of long GnRH agonist to short GnRH antagonist protocols, there is a need for data on the predictability of ovarian response in GnRH antagonist cycles.
STUDY DESIGN, SIZE, DURATION
A retrospective analysis of data from the Engage trial and validation with the Xpect trial. Prognostic models were constructed for high (>18 oocytes retrieved) and low (<6 oocytes retrieved) ovarian response. Model building was based on the recombinant FSH (rFSH) arm (n = 747) of the Engage trial. Multivariable logistic regression models were constructed in a stepwise fashion (P < 0.15 for entry). Validation based on calibration was performed in patients with equivalent treatment (n = 199) in the Xpect trial.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Infertile women with an indication for COS prior to IVF. The Engage and Xpect trials included patients of similar ethnic origins from North America and Europe who had regular menstrual cycles. The main causes of infertility were male factor, tubal factor and endometriosis.
MAIN RESULTS AND THE ROLE OF CHANCE
In the Engage trial, 18.3% of patients had a high and 12.7% had a low ovarian response. Age, AFC, serum FSH and serum LH at stimulation Day 1 were prognostic for both high and low ovarian responses. Higher AFC and LH were associated with an increased chance of high ovarian response. Older age and higher FSH correlated with an increased chance of low ovarian response. Region (North America/Europe) and BMI were prognostic for high ovarian response, and serum estradiol at stimulation Day 1 was associated with low ovarian response. The area under the receiver operating characteristic (ROC) curve (AUC) for the model for a high ovarian response was 0.82. Sensitivity and specificity were 0.82 and 0.73; positive and negative predictive values were 0.40 and 0.95, respectively. The AUC for the model for a low ovarian response was 0.80. Sensitivity and specificity were 0.77 and 0.73, respectively; positive and negative predictive values were 0.29 and 0.96, respectively. In Xpect, 19.1% of patients were high ovarian responders and 16.1% were low ovarian responders. The slope of the calibration line was 0.81 and 1.35 for high and low ovarian responses, respectively, both not statistically different from 1.0. In summary, common prognostic factors for high and low ovarian responses were female age, AFC and basal serum FSH and LH. Simple multivariable models are presented that are able to predict both a too low or too high ovarian response in patients treated with a GnRH antagonist protocol and daily rFSH.
LIMITATIONS, REASONS FOR CAUTION
Anti-Müllerian hormone was not included in the prediction modelling.
WIDER IMPLICATIONS OF THE FINDINGS
The findings will help with the identification of patients at risk of a too high or too low ovarian response and individualization of COS treatment.
STUDY FUNDING/COMPETING INTERESTS
Financial support for this study and the editorial work was provided by Merck, Sharp & Dohme Corp. (MSD), a subsidiary of Merck & Co. Inc., Whitehouse Station, NJ, USA. F.J.B. received a grant from CVZ to his institution; P.J.M.V. and H.W. are employees of MSD, and B.M.J.L.M. was an employee of MSD at the time of development of this manuscript.
TRIAL REGISTRATION NUMBERS
NCT 00696800 and NCT00778999.
doi:10.1093/humrep/deu090
PMCID: PMC4093990  PMID: 24903202
predictive modelling; ovarian response; recombinant FSH; GnRH antagonist
9.  Molecular cytogenetic analysis of Xq critical regions in premature ovarian failure 
Background
One of the frequent reasons for unsuccessful conception is premature ovarian failure/primary ovarian insufficiency (POF/POI) that is defined as the loss of functional follicles below the age of 40 years. Among the genetic causes the most common one involves the X chromosome, as in Turner syndrome, partial X deletion and X-autosome translocations. Here we report a case of a 27-year-old female patient referred to genetic counselling because of premature ovarian failure. The aim of this case study to perform molecular genetic and cytogenetic analyses in order to identify the exact genetic background of the pathogenic phenotype.
Results
For premature ovarian failure disease diagnostics we performed the Fragile mental retardation 1 gene analysis using Southern blot technique and Repeat Primed PCR in order to identify the relationship between the Fragile mental retardation 1 gene premutation status and the premature ovarion failure disease. At this early onset, the premature ovarian failure affected patient we detected one normal allele of Fragile mental retardation 1 gene and we couldn’t verify the methylated allele, therefore we performed the cytogenetic analyses using G-banding and fluorescent in situ hybridization methods and a high resolution molecular cytogenetic method, the array comparative genomic hybridization technique. For this patient applying the G-banding, we identified a large deletion on the X chromosome at the critical region (ChrX q21.31-q28) which is associated with the premature ovarian failure phenotype. In order to detect the exact breakpoints, we used a special cytogenetic array ISCA plus CGH array and we verified a 67.355 Mb size loss at the critical region which include total 795 genes.
Conclusions
We conclude for this case study that the karyotyping is definitely helpful in the evaluation of premature ovarian failure patients, to identify the non submicroscopic chromosomal rearrangement, and using the array CGH technique we can contribute to the most efficient detection and mapping of exact deletion breakpoints of the deleted Xq region.
doi:10.1186/1755-8166-6-62
PMCID: PMC3914679  PMID: 24359613
Sterility; Premature premature ovarian failure (POF); Primary ovarian insufficiency (POI); FMR1 gene analysis; Array–comparative genomic hybridization (aCGH); X chromosome deletion; Repeat primed PCR; G-banding; Deletion breakpoint; Turner syndrome
10.  Immunoregulation of follicular renewal, selection, POF, and menopause in vivo, vs. neo-oogenesis in vitro, POF and ovarian infertility treatment, and a clinical trial 
The immune system plays an important role in the regulation of tissue homeostasis ("tissue immune physiology"). Function of distinct tissues during adulthood, including the ovary, requires (1) Renewal from stem cells, (2) Preservation of tissue-specific cells in a proper differentiated state, which differs among distinct tissues, and (3) Regulation of tissue quantity. Such morphostasis can be executed by the tissue control system, consisting of immune system-related components, vascular pericytes, and autonomic innervation. Morphostasis is established epigenetically, during morphogenetic (developmental) immune adaptation, i.e., during the critical developmental period. Subsequently, the tissues are maintained in a state of differentiation reached during the adaptation by a “stop effect” of resident and self renewing monocyte-derived cells. The later normal tissue is programmed to emerge (e.g., late emergence of ovarian granulosa cells), the earlier its function ceases. Alteration of certain tissue differentiation during the critical developmental period causes persistent alteration of that tissue function, including premature ovarian failure (POF) and primary amenorrhea. In fetal and adult human ovaries the ovarian surface epithelium cells called ovarian stem cells (OSC) are bipotent stem cells for the formation of ovarian germ and granulosa cells. Recently termed oogonial stem cells are, in reality, not stem but already germ cells which have the ability to divide. Immune system-related cells and molecules accompany asymmetric division of OSC resulting in the emergence of secondary germ cells, symmetric division, and migration of secondary germ cells, formation of new granulosa cells and fetal and adult primordial follicles (follicular renewal), and selection and growth of primary/preantral, and dominant follicles. The number of selected follicles during each ovarian cycle is determined by autonomic innervation. Morphostasis is altered with advancing age, due to degenerative changes of the immune system. This causes cessation of oocyte and follicular renewal at 38 +/-2 years of age due to the lack of formation of new granulosa cells. Oocytes in primordial follicles persisting after the end of the prime reproductive period accumulate genetic alterations resulting in an exponentially growing incidence of fetal trisomies and other genetic abnormalities with advanced maternal age. The secondary germ cells also develop in the OSC cultures derived from POF and aging ovaries. In vitro conditions are free of immune mechanisms, which prevent neo-oogenesis in vivo. Such germ cells are capable of differentiating in vitro into functional oocytes. This may provide fresh oocytes and genetically related children to women lacking the ability to produce their own follicular oocytes. Further study of "immune physiology" may help us to better understand ovarian physiology and pathology, including ovarian infertility caused by POF or by a lack of ovarian follicles with functional oocytes in aging ovaries. The observations indicating involvement of immunoregulation in physiological neo-oogenesis and follicular renewal from OSC during the fetal and prime reproductive periods are reviewed as well as immune system and age-independent neo-oogenesis and oocyte maturation in OSC cultures, perimenopausal alteration of homeostasis causing disorders of many tissues, and the first OSC culture clinical trial.
doi:10.1186/1477-7827-10-97
PMCID: PMC3551781  PMID: 23176151
Fetal neo-oogenesis; Follicular renewal in mammals; Follicular selection; Granulosa cell renewal; Immune physiology; Neo-oogensis during the prime reproductive period; Neo-oogenesis in vitro; Ovarian function; Ovary; Tissue homeostasis
11.  The clinical analysis of poor ovarian response in in-vitro-fertilization embryo-transfer among Chinese couples 
Purpose
To explore the prevalence, predictor of clinical pregnancy and possible aetiology of poor ovarian response (POR) in in vitro fertilization–embryo transfer (IVF–ET) in Chinese.
Methods
A total of 4,600 retrieval oocyte cycles were finished between July 1, 2004 and April 30, 2006. Poor ovarian responses were observed in 426 patients of 472 cycles undergoing IVF, which were selected on the same retrieve oocyte day as the control group. The outcome of IVF–ET and the common markers of ovarian reserve were compared.
Results
The patients had previous ovarian surgery in 64 cycles of 472 poor ovarian response cycles. The group with poor ovarian response has significant differences in comparison with the control group in age (36.6 ± 4.2 vs 33.3 ± 4.04), ovarian surgeries (13.6 vs 2.8%), dose of gonadotrophin (58.5 ± 15.8 vs 40.6 ± 17.0), fertilization rate (71.5 vs 86%) and pregnancy rate (14.8 vs 36.7%). In the group with poor ovarian responses, clinical pregnancy rate declined significantly in women aged >40 years than in those aged ≤40 years (2.8 vs 18.5%, P < 0.001). The age, basal serum follicle stimulating hormone (FSH), basal serum luteinizing hormone (LH), basal oestradiol (E2) concentrations, FSH to LH ratio and the antral follicle count (AFC) are the common markers of ovarian reserve in our center. We found that there were significant differences in age, basal FSH, FSH-to-LH ratio and the antral follicle count. But no statistical significant differences were observed in basal oestradiol concentration and basal serum LH when comparing the two groups. Binary logistic regression analysis was used to study the relation among age, FSH, LH, E2, AFC and clinical pregnancy, and the age (odds ratio, 0.863; 95% confidence interval, 0.805–0.925; p = 0.000) was the only variable selected.
Conclusion
Our data show that the prevalence of poor ovarian response in Chinese is 11.9%. Previous ovarian surgery is associated with poor ovarian responses. The pregnancy rate of women with poor ovarian response is low in IVF–ET, especially the decline in clinical pregnancy rate of women aged >40 years became accelerated. Correct identification of those who are at risk for POR prior to stimulation is helpful in tailoring the best stimulation protocol to individual patients. Chronological age significantly improved the prediction of clinical pregnancy of poor ovarian responders.
doi:10.1007/s10815-007-9187-9
PMCID: PMC2582105  PMID: 18202912
In vitro fertilization–embryos transfer; Poor ovarian response; Pregnancy outcome; Predictor
12.  Simple tools for assessment of ovarian reserve (OR): Individual ovarian dimensions are reliable predictors of OR 
Fertility and sterility  2007;88(2):390-395.
Objective
To determine the association between individual ovarian dimensions, advancing age and declining ovarian reserve in an infertile population.
Design
An ongoing prospective observational study.
Setting
Academic infertility practice.
Patients
69 premenopausal women presenting for the evaluation and management of infertility.
Interventions
Transvaginal ultrasound assessment of the ovarian dimensions (length, width and overall diameter in mm) and evaluation of the ovarian reserve status by measuring serum levels of follicle stimulating hormone and estradiol in the early follicular phase of the menstrual cycle.
Main Outcomes
Relationship between the individual ovarian dimensions with age (years) and ovarian reserve-OR (reflected by historical maximal FSH levels).
Results
A statistically significant decrease in ovarian size parameters accompanied advancing age (ovarian width, r= − 0.30, p= 0.01, ovarian length, r = − 0.24, p= 0.04, and the mean overall diameter, r= − 0.30, p= 0.01). FSH levels demonstrated a significant and linear correlation with age (r=0.39, p<0.01). Increasing levels of FSH (and hence declining OR) were associated with a significant decline in the mean ovarian width (r= − 0.39, p<0.01), the length (r= −0.38, p<0.01) and the overall mean ovarian diameter (− 0.42, p<0.01), Patients with a known diagnosis of diminished ovarian reserve demonstrated significantly reduced ovarian dimensions compared to patients with other infertility etiologies. Multivariate linear regression analysis confirmed individual ovarian measurements (width, length and overall diameter) as independent predictors of OR (FSH levels) after adjusting for parameters that are known to influence ovarian size, i.e. age, smoking status, BMI and anovulation history. Ovarian width emerged as the strongest predictor of OR (largest β coefficient and hence the strongest association with OR status) compared to ovarian length and the mean ovarian diameter.
Conclusion
Single ovarian dimensions are reliable predictors of advancing age and declining OR status in premenopausal infertile women. The magnitude of this association is most robust for the ovarian width.
doi:10.1016/j.fertnstert.2006.11.175
PMCID: PMC2000481  PMID: 17412332
Ovarian reserve; infertility; Ovarian diameter; Ovarian size; FSH
13.  Isochromosome Yp and jumping translocation of Yq resulting in five cell lines in an infertile male: a case report and review of the literature 
Background
Jumping translocations are a rare type of mosaicism in which the same portion of one donor chromosome is translocated to several recipient chromosomes. Constitutional forms of jumping translocations are rare, and the 48 cases reported to date have been associated with both normal and abnormal phenotypes. Concurrence of isochromosome (i) of one arm and translocation of the other is also rare, with seven reported cases. We describe a unique case involving concurrence of i(Yp) and a jumping translocation of Yq to the telomere of chromosomes 12q and 17q, which resulted in five cell lines.
Case presentation
The patient, an otherwise healthy 35-year-old man, was referred for cytogenetic studies because of absolute azoospermia. He had elevated levels of follicle stimulating hormone and luteinizing hormone, consistent with abnormal spermatogenesis, and decreased levels of free testosterone and inhibin B. G-banded chromosome analysis revealed a mosaic male karyotype involving five abnormal cell lines. One of the cell lines showed loss of chromosome Y and presence of i(Yp) as the sole abnormality. Three cell lines exhibited jumping translocation: two involved 17qter, and the other involved 12qter as the recipient and Yq as the common donor chromosome. One of the cell lines with der(17) additionally showed i(Yp). The other der(17) and der(12) cell lines had a missing Y chromosome. All five cell lines were confirmed by FISH. Subtelomric FISH study demonstrated no loss of chromosome material from the recipient chromosomes at the translocation junctions.
Conclusions
We postulate that a postzygotic pericentromeric break of the Y chromosome led to formation of isochromosome Yp, whereas Yq formed a jumping translocation through recombination between its internal telomere repeats and telomeric repeats of recipient chromosomes. This in turn led to either pairing or an exchange at the complimentary sequences. Such translocation junctions appear to be unstable and to result in a jumping translocation. Cryptic deletion or disruption of AZF (azoospermic factor) genes at Yq11 during translocation or defective pairing of X and Y chromosomes during meiosis, with abnormal sex vesicle formation and consequent spermatogenetic arrest, might be the main cause of the azoospermia in our patient.
doi:10.1186/1755-8166-6-36
PMCID: PMC3848363  PMID: 24020961
Isochromosome Yp; Jumping translocation Yq
14.  AUTOANTIBODIES TO MESOTHELIN IN INFERTILITYa,b,c 
Background
According to extensive epidemiological data, infertility is associated with increased ovarian cancer risk. Previous studies showed that both women with infertility and those with ovarian cancer have autoantibodies to ovarian antigens. The objective was to determine if women with infertility have antibodies to mesothelin, a well characterized ovarian cancer antigen.
Methods
Sera were obtained from women with infertility (n=109), ovarian cancer (n=28), benign ovarian tumors or cysts (n=24) and from healthy women (n=152). Infertility included those with a risk for ovarian cancer; endometriosis (n=23), ovulatory dysfunction (n=17), premature ovarian failure (n=25) and unexplained infertility (n=44). Sera were assayed for mesothelin antibodies and for circulating mesothelin antigen by immunoassay and compared to assay control sera (n=16) to determine a positive result.
Results
Mesothelin antibodies were significantly more frequent in women with prematurely reduced ovarian function including ovulatory dysfunction (59%), ovarian failure (POF) (44%) and unexplained infertility (25%) compared to controls. In contrast, women with endometriosis, who also have a high risk for ovarian cancer, did not have mesothelin antibodies. Serum levels of mesothelin were rarely elevated in women with infertility but were high in most patients with ovarian cancer.
Conclusions and Significance
We show for the first time that antibodies to mesothelin, a well characterized ovarian cancer antigen, occur in some women with epidemiologic risk for ovarian cancer. The results suggest it may be possible to identify which women with infertility have ovarian cancer risk.
doi:10.1158/1055-9965.EPI-11-0139
PMCID: PMC3304582  PMID: 21846819
Autoantibodies; Mesothelin; Infertility; Ovarian Cancer
15.  Trisomic pregnancy and elevated FSH: implications for the oocyte pool hypothesis 
Human Reproduction (Oxford, England)  2011;26(6):1537-1550.
BACKGROUND
Some studies, but not all, support the hypothesis that trisomy frequency is related to the size of the oocyte pool, with the risk increased for women with fewer oocytes (older ovarian age). We tested this hypothesis by comparing hormonal indicators of ovarian age among women who had trisomic pregnancy losses with indicators among women with non-trisomic losses or chromosomally normal births. The three primary indicators of advanced ovarian age were low level of anti-Müllerian hormone (AMH), high level of follicle-stimulating hormone (FSH) and low level of inhibin B.
METHODS
The analysis drew on data from two hospital-based case–control studies. Data were analyzed separately and the evidence from the two sites was combined. We compared 159 women with trisomic pregnancy losses to three comparison groups: 60 women with other chromosomally abnormal losses, 79 women with chromosomally normal losses and 344 women with live births (LBs) age-matched to women with losses. We analyzed the hormone measures as continuous and as categorical variables. All analyses adjust for age in single years, day of blood draw, interval in storage and site.
RESULTS
AMH and inhibin B did not differ between women with trisomic losses and any of the three comparison groups. Mean ln(FSH) was 0.137 units (95% confidence interval (CI): 0.055, 0.219) higher for trisomy cases compared with LB controls; it was also higher, though not significantly so, for trisomy cases compared with women with other chromosomally abnormal losses or chromosomally normal losses. The adjusted odds ratio in relation to high FSH (≥10 mIU/ml) was significantly increased for trisomy cases versus LB controls (adjusted odds ratio (OR): 3.8, 95% CI: 1.6, 8.9).
CONCLUSIONS
The association of trisomy with elevated FSH is compatible with the oocyte pool hypothesis, whereas the absence of an association with AMH is not. Alternative interpretations are considered, including the possibility that elevated FSH may disrupt meiotic processes or allow recruitment of abnormal follicles.
doi:10.1093/humrep/der091
PMCID: PMC3140264  PMID: 21467203
epidemiology; aneuploidy; FSH; Müllerian inhibiting substance
16.  The significance of FSH elevation in young women with disorders of ovulation. 
British Medical Journal  1980;281(6253):1447-1450.
High serum follicle stimulating hormone (FSH) values are consistent with ovarian failure. We studied the progress of 67 women aged under 35 years with oligomenorrhoea or secondary amenorrhoea in whom the serum FSH value was greater than 20 U/1. Twenty-four patients remained amenorrhoeic, but 17 ovulated and six conceived, two on two occasions. Coincident mean serum luteinising hormone (LH) concentrations were significantly lower and mean total urinary oestrogen concentrations were significantly higher in patients who subsequently ovulated, but the degree of increase in FSH did not correlate well with later ovarian function. Treatment with oestrogens, clomiphene citrate, human pituitary gonadotrophin, and bromocriptine was of no benefit in inducing an ovarian response while FSH concentrations remained raised. Our results suggest that a considerable proportion of younger women with ovulatory disorders associated with FSH values in the menopausal range will spontaneously resume ovulation and some will conceive.
PMCID: PMC1714809  PMID: 6777022
17.  Female infertility 
Clinical Evidence  2005;2005:0819.
Introduction
About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis, or a low sperm count. In resource-rich countries, 80-90% of couples attempting to conceive are successful after 1 year and 95% after 2 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for infertility caused by ovulation disorders? What are the effects of treatments for tubal infertility? What are the effects of treatments for infertility associated with endometriosis? We searched: Medline, Embase, The Cochrane Library and other important databases up to April 2004 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 56 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: clomifene; cyclofenil; drug-induced ovarian suppression; gonadotrophin priming of oocytes before in vitro maturation; gonadotrophins; gonadotrophin-releasing hormone agonists plus gonadotrophins; gonadotrophin-releasing hormone antagonists; in vitro fertilisation; intrauterine insemination plus controlled ovarian stimulation; intrauterine insemination plus gonadotrophins; laparoscopic ablation of endometrial deposits; laparoscopic ovarian drilling; metformin; ovarian wedge biopsy; pulsatile gonadotrophin-releasing hormone; selective salpingography plus tubal catheterisation; tamoxifen; tubal flushing with oil-soluble media or with water-soluble media; tubal surgery before in vitro fertilisation.
Key Points
About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis or a low sperm count.
In women with infertility, in vitro fertilisation may be as likely to lead to pregnancy as intracytoplasmic sperm injection, but increases the risks of multiple pregnancy. Gonadotrophin releasing hormone agonists also increase pregnancy rates, but gonadotrophin releasing hormone antagonists may be less effective. Intrauterine insemination plus controlled ovarian stimulation is considered to be beneficial in women with unexplained infertility or cervical hostility.
In women with ovulatory disorders, clomifene and tamoxifen increase ovulation and pregnancy rates, and metformin increases ovulation rates. Gonadotrophins may increase pregnancy rates but may increase the risk of ovarian cancer, ovarian hyperstimulation syndrome and multiple pregnancy. Laparoscopic ovarian drilling may be as effective as gonadotrophins.We don't know whether cyclofenil, pulsed gonadotrophin releasing hormone, gonadotrophin priming of oocytes before in vitro maturation, or ovarian wedge biopsy increase pregnancy rates compared with no treatment.
In women with tubal infertility, tubal flushing increases pregnancy rates, with oil soluble media possibly more effective than water soluble media. Tubal surgery before in vitro fertilisation may increase pregnancy rates compared with no treatment in women with hydrosalpinges, but we don't know whether selective salpingography plus tubal catheterisation is beneficial.
In women with endometriosis, adding gonadotrophins to intrauterine insemination increases live birth rates compared with intrauterine insemination alone. Laparoscopic ablation of endometrial deposits may increase live birth rates compared with diagnostic laparoscopy.Drugs to induce ovarian suppression may not increase pregnancy rates.
PMCID: PMC2907557
18.  Fibrin promotes development and function of macaque primary follicles during encapsulated three-dimensional culture 
Human Reproduction (Oxford, England)  2013;28(8):2187-2200.
STUDY QUESTION
Does fibrin introduced into the extracellular matrix affect the growth and maturation of individual primate follicles during encapsulated three-dimensional (3D) culture?
SUMMARY ANSWER
While not altering follicle survival, fibrin–alginate (FIBRIN) improves macaque primary, but not secondary, follicle development during encapsulated 3D culture in terms of growth, steroidogenesis, anti-Müllerian hormone (AMH)/vascular endothelial growth factor (VEGF) production and oocyte maturation.
WHAT IS KNOWN ALREADY
Efforts to grow non-human primate ovarian follicles from the secondary to the antral stage during encapsulated 3D culture have been successful. However, the growth and maturation of primary follicles in vitro has not been reported in primates, especially in chemically defined conditions.
STUDY DESIGN, SIZE, DURATION
In vitro follicle maturation was investigated using the rhesus macaque (Macaca mulatta). Ovaries (n = 7 pairs) were obtained during the early follicular phase of the menstrual cycle (cycle day 1–4). Primary (80–120 µm diameter) and secondary (125–225 µm diameter) follicles were isolated mechanically, randomly assigned to experimental groups, encapsulated into alginate (0.25% w/v) or FIBRIN (25 mg/ml fibrinogen–0.25% alginate) and cultured for 13 and 5 weeks, respectively.
MATERIALS, SETTING, METHODS
Individual follicles were cultured in alpha minimum essential medium supplemented with FSH. Follicle survival and growth were assessed by microscopy. Follicles that reached the antral stage were treated with recombinant hCG. Metaphase II (MII) oocytes were inseminated via ICSI. Follicle morphology was evaluated by hematoxylin and eosin (H&E) staining. Immunohistochemistry was performed for cytochrome P450 family 17 subfamily A polypeptide 1 (CYP17A1) and 19 subfamily A polypeptide 1 (CYP19A1). Culture medium was analyzed for estradiol (E2) and progesterone by chemiluminescence, androstenedione (A4) by radioimmunoassay, as well as anti-Müllerian hormone (AMH) and vascular endothelial growth factor (VEGF) by enzyme-linked immunosorbent assay.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 105 primary and 133 secondary follicles were collected. The presence of fibrin in the alginate matrix had no effect on either primary or secondary follicle survival. Growing primary and secondary follicles formed an antrum at Weeks 9 and 3, respectively. The percentage of growing follicles was higher (P < 0.05) for primary follicles cultured in FIBRIN than alginate at Week 13. The diameters were larger for the growing secondary follicles cultured in alginate than FIBRIN at Week 5 (P < 0.05). H&E staining revealed the typical morphology for small antral follicles. CPY17A1 immunostaining was detected in theca cells, while CYP19A1 was observed in granulosa cells. E2 increased (P < 0.05) during antrum formation in growing follicles at Week 9 for primary and Week 3 for secondary follicles. AMH levels in medium from growing primary follicles increased (P < 0.05) after Week 4 with peak levels at Weeks 9–11. AMH increased (P < 0.05) in growing secondary follicles at Weeks 3–5. VEGF levels in medium were elevated (P < 0.05) in growing primary follicles at Week 9. VEGF increased (P < 0.05) in medium from growing secondary follicles at Weeks 3–5. E2, AMH and VEGF production was higher (P < 0.05) in primary follicle culture with FIBRIN than alginate alone. One primary follicle cultured in FIBRIN (1 of 5 follicles harvested) and a secondary follicle cultured in alginate alone (1 of 15 follicles harvested) yielded an MII oocyte. The fertilized oocyte from primary follicle culture arrested without cell division after fertilization, while the oocyte from secondary follicle culture cleaved and reached the morula stage.
LIMITATIONS, REASONS FOR CAUTION
The study reports on in vitro development and function of individual macaque follicles, that is limited to the interval from the primary and secondary stage to the small antral stage. The findings await translation to human ovarian follicles.
WIDER IMPLICATIONS OF THE FINDINGS
The 3D model for primate follicle development offers a unique opportunity to investigate the growth and regulation of primate primary, as well as secondary follicles, and their enclosed oocytes, as they grow to the antral stage by monitoring and manipulating factors or signaling pathways in vitro. Since primate primary follicles, in addition to secondary follicles, can be cultured to the antral stage to provide mature oocytes, they represent an additional source of pre-antral follicles for in vitro follicle maturation with the potential to provide gametes for assisted reproductive technology as an option for fertility preservation in women, including patients with cancer.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by The Oncofertility Consortium (NIH U54 RR024347-HD058294, PL1-EB008542), NIH U54-HD18185 (Eunice Kennedy Shriver Specialized Cooperative Centers Program in Reproduction and Infertility Research), NIH ORWH/NICHD 2K12HD043488 (BIRCWH), Oregon National Primate Research Center 8P51OD011092. There are no conflicts of interest.
doi:10.1093/humrep/det093
PMCID: PMC3712659  PMID: 23608357
macaque; follicle culture; primary follicle; secondary follicle; fibrin
19.  The forkhead transcription factor FOXL2 is expressed in somatic cells of the human ovary prior to follicle formation 
Molecular Human Reproduction  2009;15(12):771-777.
Interactions between germ cells and surrounding somatic cells are central to ovarian development as well as later function. Disruption of these interactions arising from abnormalities in either cell type can lead to premature ovarian failure (POF). The forkhead transcription factor FOXL2 is a candidate POF factor, and mutations in the FOXL2 gene are associated with syndromic and non-syndromic ovarian failure. Foxl2-deficient mice display major defects in primordial follicle activation with consequent follicle loss, and earlier roles in gonadal development and sex determination have also been suggested. However, despite its importance no data presently exist on its expression in the developing human ovary. Expression of FOXL2 mRNA was demonstrated in the human fetal ovary between 8 and 19 weeks gestation, thus from soon after sex determination to primordial follicle development. Expression in the ovary was higher after 14 weeks than at earlier gestation weeks and was very low in the fetal testis at all ages examined. Immunolocalization revealed FOXL2 expression to be confined to somatic cells, both adjacent to germ cells and those located in the developing ovarian stroma. These cells are the site of action of oocyte-derived activin signalling, but in vitro treatment of human fetal ovaries with activin failed to reveal any regulation of FOXL2 transcription by this pathway. In summary, the expression of FOXL2 in somatic cells of the developing human ovary before and during follicle formation supports a conserved and continuing role for this factor in somatic/germ cell interactions from the earliest stages of human ovarian development.
doi:10.1093/molehr/gap065
PMCID: PMC2776473  PMID: 19706741
fetal ovary; forkhead; germ cell; primordial follicle; transcription factor
20.  Female infertility 
Clinical Evidence  2010;2010:0819.
Introduction
About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis, or a low sperm count. In developed countries, 80% to 90% of couples attempting to conceive are successful after 1 year and 95% after 2 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for infertility caused by ovulation disorders? What are the effects of treatments for tubal infertility? What are the effects of treatments for infertility associated with endometriosis? What are the effects of treatments for unexplained infertility? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 55 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: clomifene; drug-induced ovarian suppression; gonadotrophin priming of oocytes before in vitro maturation; gonadotrophins; gonadotrophin-releasing hormone agonists plus gonadotrophins; gonadotrophin-releasing hormone antagonists; in vitro fertilisation; intrauterine insemination alone, or combined with gonadotrophins or clomifene; laparoscopic ablation of endometrial deposits; laparoscopic ovarian drilling; laparoscopic removal; metformin; ovarian wedge biopsy; pulsatile gonadotrophin-releasing hormone; selective salpingography plus tubal catheterisation; tamoxifen; tubal flushing; and tubal surgery before in vitro fertilisation.
Key Points
About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis, or a low sperm count.
In women with ovulatory disorders, clomifene and metformin increase ovulation and pregnancy rates. There is some evidence that tamoxifen may have similar efficacy to clomifene, but we found no RCTs of sufficient quality comparing tamoxifen with placebo, and it is rarely used nowadays. Gonadotrophins may increase pregnancy rates but may increase ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. Laparoscopic ovarian drilling may be as effective as gonadotrophins. We don't know whether pulsed gonadotrophin-releasing hormone (GnRH), or gonadotrophin priming of oocytes before in vitro maturation increase pregnancy rates.Consensus suggests that in vitro fertilisation may lead to pregnancy, but increases the risks of multiple pregnancy unless single embryo replacement is practised.We don't know whether GnRH agonists plus gonadotrophins increase pregnancy rates compared with gonadotrophins alone but the combination treatment may be associated with an increased risk of OHSS. We don't know how effective GnRH antagonists are because we found few trials.We don't know whether intrauterine insemination alone, or combined with gonadotrophins or clomifene is effective for infertility caused by ovulation disorders.
In women with tubal infertility, tubal flushing may increase pregnancy rates, with oil soluble media possibly more effective than water soluble media; however, we found few trials solely in women with tubal infertility. Tubal surgery before in vitro fertilisation may increase pregnancy rates compared with no treatment in women with hydrosalpinges, but we don't know whether selective salpingography plus tubal catheterisation is beneficial.Consensus suggests that in vitro fertilisation is beneficial.
In women with endometriosis, adding gonadotrophins to intrauterine insemination increases live birth rates compared with no treatment and increases pregnancy rates compared with intrauterine insemination alone. Laparoscopic ablation of endometrial deposits may increase live birth rates compared with diagnostic laparoscopy.Drugs to induce ovarian suppression may not increase pregnancy rates.Consensus suggests that in vitro fertilisation may be beneficial.Tubal flushing with oil-based media may increase live birth rates and pregnancy rates in women with minimal or mild endometriosis.
In women with unexplained infertility, clomifene does not increase live birth rates. It is not better than expectant management. Intrauterine insemination without ovarian stimulation does not result in a significant increase in live birth rates. Intrauterine insemination plus controlled ovarian stimulation may increase pregnancy rates but may increase OHSS and multiple pregnancy. In vitro fertilisation may be beneficial, however, evidence is insufficient to make any conclusions.
PMCID: PMC3217752  PMID: 21406133
21.  The FMR1 gene, infertility, and reproductive decision-making: a review 
Frontiers in Genetics  2014;5:195.
The strongest association between FMR1 and the ovary in humans is the increased risk of premature ovarian failure (POF) in women who carry the premutation level of CGG repeats (55–199 CGGs). Research on the FMR1 gene has extended to other endpoints of relevance in the OB/GYN setting for women, including infertility and ovarian hormones. After reviewing the nomenclature changes that have occurred in recent years, this article reviews the evidence linking the length of the FMR1 repeat length to fertility and ovarian hormones (follicle stimulating hormone and anti-mullerian hormone as the primary methods to assess ovarian reserve in clinical settings). The literature is inconsistent on the association between the FMR1 trinucleotide repeat length and infertility. Elevated levels of follicle stimulating hormone have been found in women who carry the premutation; however the literature on the relationship between anti-mullerian hormone and the CGG repeat length are too disparate in design to make a summary statement. This article considers the implications of two transgenic mouse models (FXPM 130R and YAC90R) for theories on pathogenesis related to ovarian endpoints. Given the current screening/testing recommendations for reproductive age females and the variability of screening protocols in clinics, future research is recommended on pretest and posttest genetic counseling needs. Future research is also needed on ovarian health measurements across a range of CGG repeat lengths in order to interpret FMR1 test results in reproductive age women; the inconsistencies in the literature make it quite challenging to advise women on their risks related to FMR1 repeat length.
doi:10.3389/fgene.2014.00195
PMCID: PMC4083559  PMID: 25071825
FMR1; female infertility; primary ovarian insufficiency; mouse models; diminished ovarian reserve; follicle stimulating hormone; anti-mullerian hormone; genetic counseling
22.  AUTOANTIGENS IN OVARIAN AUTOIMMUNITY ASSOCIATED WITH UNEXPLAINED INFERTILITY AND PREMATURE OVARIAN FAILURE 
Fertility and sterility  2010;94(7):2636-2641.
Study Objective
To identify ovarian autoantigens associated with ovarian autoantibodies.
Design
Hypothesis generating prospective study.
Setting
Urban infertility referral centers and academic research institution.
Patients
74 patients with infertility, 19 patients with premature ovarian failure, 16 healthy control women.
Interventions
None.
Main outcome measures
Identification of autoantigens.
Results
In order to identify major antigens for ovarian autoimmunity, 74 sera from women with unexplained infertility were screened for ovarian autoantibodies (AOA) by immunoassay and one-dimensional Western blot. The majority of sera had immuno-reactions at 50-56kDa. Six representative positive infertility sera were used to identify antigens between 40-60kD by two-dimensional Western blot and mass spectrometry. Antigens included aldehyde (retinal) dehydrogenases (ALDH1A1, ALDH1A2, ALDH7A1), protein disulfide-isomerase A3 (PDIA3), vimentin (VIME), α-enolase (ENO1), phosphoglycerate dehydrogenase and selenium binding protein 1 (SBP1). 60% (n=24/40) of infertility and POF sera were positive for recombinant ALDH1A1, SBP1 or enolase. 80.7% (n=21/26) of AOA positive sera had antibodies to one or more of the three antigens, while only 7% (n=1/14) of AOA negative sera had antibodies to recombinant proteins.
Conclusion
ALDH1A1 and SBP1 are unique to ovarian autoimmunity associated with infertility and POF, and may provide the basis for specific tests to identify patients with ovarian autoimmunity.
doi:10.1016/j.fertnstert.2010.04.012
PMCID: PMC2948062  PMID: 20522323
ovary; autoantigens; autoimmune; infertility; POF
23.  Disruption of CCTβ2 Expression Leads to Gonadal Dysfunction 
Molecular and Cellular Biology  2004;24(11):4720-4733.
There are two mammalian genes that encode isoforms of CTP:phosphocholine cytidylyltransferase (CCT), a key rate-controlling step in membrane phospholipid biogenesis. Quantitative determination of the CCT transcripts reveals that CCTα is ubiquitously expressed and is found at the highest levels in the testis and lung, with lower levels in the liver and ovary. CCTβ2 is a very minor isoform in most tissues but is significantly expressed in the brain, lung, and gonads. CCTβ3 is the third isoform recently discovered in mice and is expressed in the same tissues as CCTβ2, with its highest level in testes. We investigated the role(s) of CCTβ2 by generating knockout mice. The brains and lungs of mice lacking CCTβ2 expression did not exhibit any overt defects. On the other hand, a large percentage of the CCTβ2−/− females were sterile and their ovaries exhibited defective ovarian follicle development. The proportion of female CCTβ2−/− mice with defective ovaries increased as the animals aged. The rare litters born from CCTβ2−/− × CCTβ2−/0 matings had the normal number of pups. The abnormal ovarian histopathology was characterized by disorganization of the tissue in young adult mice and absence of follicles and ova in older mice, along with interstitial stromal cell hyperplasia which culminated in the emergence of tubulostromal ovarian tumors by 16 months of age. Grossly defective CCTβ2−/− ovaries were associated with high follicle-stimulating (FSH) and luteinizing (LH) hormone levels. Male CCTβ2−/0 mice exhibited progressive multifocal testicular degeneration and reduced fertility but had normal FSH and LH levels. Thus, the most notable phenotype of CCTβ2 knockout mice was gonad degeneration and reproductive deficiency. The results indicate that although CCTβ2 is expressed at very low levels compared to the α-isoform, loss of CCTβ2 expression causes a breakdown in the gonadal response to hormonal stimulation.
doi:10.1128/MCB.24.11.4720-4733.2004
PMCID: PMC416414  PMID: 15143167
24.  Gonadotropin-regulated Lymphangiogenesis in Ovarian Cancer is mediated by LEDGF induced expression of VEGF-C 
Cancer research  2009;69(24):9306-9314.
The risk and severity of ovarian carcinoma, the leading cause of gynecological malignancy death, are significantly elevated in postmenopausal women. Ovarian failure at menopause, associated with a reduction in estrogen secretion, results in rise of the gonadotropic luteinizing and follicle stimulating hormones (LH and FSH), suggesting a role for these hormones in facilitating the progression of ovarian carcinoma. The current study examined the influence of hormonal stimulation on lymphangiogenesis in ovarian cancer cells. In vitro stimulation of ES2 ovarian carcinoma cells with LH and FSH induced expression of VEGF-C. In vivo, ovariectomy of mice resulted in activation of the VEGF-C promoter in ovarian carcinoma xenografts, increased VEGF-C mRNA level, and enhanced tumor lymphangiogenesis and angiogenesis. Seeking for the molecular mechanism, we examined the role of lens epithelial derived growth factor (LEDGF/p75), and the possible contribution of its putative target, a conserved stress response element (STRE) identified in silico in the VEGF-C promoter. Using chromatin immunoprecipitation we showed that LEDGF/p75 indeed binds the VEGF-C promoter, and binding is augmented by FSH. A corresponding hormonally regulated increase in the LEDGF/p75 mRNA and protein levels was observed. Suppression of LEDGF/p75 expression using siRNA, suppression of LH and FSH production using the gonadotropin-releasing hormone antagonist cetrorelix, or mutation of the conserved STRE suppressed the hormonally induced expression of VEGF-C. Overall our data suggests a possible role for elevated gonadotropins in augmenting ovarian tumor lymphangiogenesis in postmenopausal women.
doi:10.1158/0008-5472.CAN-09-1213
PMCID: PMC2794933  PMID: 19934313
Menopause; Gonadotropins; VEGF-C; LEDGF/p75; lymphangiogenesis
25.  Blood Cell Mitochondrial DNA Content and Premature Ovarian Aging 
PLoS ONE  2012;7(8):e42423.
Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction.
doi:10.1371/journal.pone.0042423
PMCID: PMC3411770  PMID: 22879975

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