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.
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.
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.
Cytogenetic; female infertility; premature ovarian failure; reactive oxygen species
The importance of X chromosome in the aetiology of premature ovarian failure (POF) is well-known but in many cases POF still remains idiopathic. Chromosome aneuploidy increase is a physiological phenomenon related to aging, but the role of low-level sex chromosome mosaicism in ovarian function is still undiscovered. Standard cytogenetic analysis was carried out in a total of 269 patients affected by POF: 27 chromosomal abnormalities were identified, including X chromosome and autosomal structural and numerical abnormalities. In 47 patients with 46,XX karyotype we performed interphase FISH using X alpha-satellite probe in order to identify X chromosome mosaicism rate. Aneuploidy rate in the patient group was significantly higher than the general population group. These findings underline the importance of X chromosome in the aetiology of POF and highlight the potential role of low-level sex chromosome mosaicism in ovarian aging that may lead to a premature onset of menopause.
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.
A luteinizing hormone/follicle-stimulating hormone-releasing hormone (LH/FSH-RH) test was performed in 70 women with amenorrhoea or anovulatory infertility, or both, and a clomiphene stimulation test was also performed in 24 of these patients. Most patients responded to LH/FSH-RH with significant increases in LH and FSH. In women with gonadal dysgenesis or premature ovarian failure exaggerated responses were observed after LH/FSH-RH and there was no change in high basal LH levels after clomiphene. Patients with absent or impaired responses to LH/FSH-RH failed to respond to clomiphene. All patients with anovulatory menstrual cycles responded to both LH/FSH-RH and clomiphene, while seven out of 13 amenorrhoeic patients with a normal LH/FSH-RH response showed an early LH rise during clomiphene treatment and six were unresponsive. These results suggest a difference between the two groups at hypothalamic level with consequent therapeutic implications.
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.
Breakpoint definition; Premature ovarian failure; X chromosome structural aberrations
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.
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.
fetal ovary; forkhead; germ cell; primordial follicle; transcription factor
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.
Menopause; Gonadotropins; VEGF-C; LEDGF/p75; lymphangiogenesis
Premature Ovarian Failure (POF) is an important cause of amenorrhoea and infertility. However some women may spontaneously ovulate and conceive. Primary ovarian insufficiency (POI) is thus the preferred term. POF / POI is multifactorial in etiology. Autoimmunity is an important mechanism for accelerated destruction of ovarian follicles. The present review focuses on the role of autoimmunity in the pathophysiology of POI. Antibodies to multiple ovarian antigens have been proposed as markers of ovarian autoimmunity. However, there has been lack of clinically proven sensitive and specific serum tests to confirm autoimmune involvement in POI. The review details recently developed specific test for antiovarian antibodies (AOA) that has enabeled identification of different molecular antigenic targets in the ovary. The application of this specific test for AOA has brought to light the need for screening for autoimmunity prior to patients undergoing IVF technique.
Premature ovarian insufficiency; ovarian autoimmunity; amenorrhoea
Premature ovarian failure is defined as the cessation of ovarian activity before the age of 40 years. It is biochemically characterized by low levels of gonadal hormones (estrogens and inhibins) and high levels of gonadotropins (luteinizing hormone and follicle-stimulating hormone).
Our patient, a 22-year-old Caucasian woman under evaluation for infertility, had experienced secondary amenorrhea from the age of 18. No positive family history was noted regarding premature menopause. An examination of our patient’s karyotype showed the presence of a reciprocal translocation, apparently balanced, which had the X chromosome long arm (q13) and the 14 chromosome short arm (p12) with consequent karyotype: 46, X, t(X; 14)(q13;p12).
Our study has underlined that karyotyping is one of the fundamental investigations in the evaluation of amenorrhea. It highlighted a genetic etiology, in the form of a chromosomal abnormality, as the causal factor in amenorrhea.
Premature ovarian failure (POF) is a secondary hypergonadotrophic amenorrhea occurring before the age of 40 and affecting 1-3% of females. Chromosome anomalies account for 6-8% of POF cases, but only few cases are associated with translocations involving X and Y chromosomes.
This study shows the cytogenetic and molecular analysis of a POF patient came to our attention as she developed a left ovary choriocarcinoma at the age of 10 and at 14 years of age she presented secondary amenorrhea with elevated levels of gonadotropins.
Breakpoint position on X and Y chromosomes was investigated using Fluorescent In Situ Hybridisation (FISH) with a panel of specific BAC probes, microsatellite analysis and evaluation of copy number changes and loss of heterozigosity by Affymetrix® GeneChip platform (Santa Clara, CA, USA). Patient's karyotype resulted 46, X, der(Y)t(X;Y)(q13.1;q11.223). X inactivation study was assessed by RBA banding and showed preferential inactivation of derivative chromosome. The reciprocal spatial disposition of sexual chromosome territories was investigated using whole chromosome painting and centromeres probes: patient's results didn't show a significant difference in comparison to normal controls.
The peculiar clinical case come to our attention highlighted the complexity of POF aetiology and of the translocation event, even if our results seem to exclude any effect on nuclear organisation. POF phenotype could be partially explained by skewed X chromosome inactivation that influences gene expression.
To understand the mechanism of premature ovarian failure (POF).
The ultrastructural (electron microscopy) analysis of primordial ovarian follicles in Nobox deficient mice.
We studied, for the first time, the fate of oogonia in embryonic (prenatal) mouse ovaries and showed that the abolishment of the transition from germ cell cysts to primordial follicles in the ovaries of Nobox deficient mice is caused by defects in germ cell cyst breakdown, leading to the formation of syncytial follicles instead of primordial follicles.
These results indicate that POF syndrome in Nobox deficient mice results from the faulty signaling between somatic and germ line components during embryonic development. In addition, the extremely unusual and abnormal presence of adherens junctions between unseparated oocytes within syncytial follicles indicates that faulty communication between somatic and germ cells is involved in, or leads to, abnormalities in the cell adhesion program.
Premature ovarian failure; Nobox; Homeobox; Ovary; Germ cells
To prospectively estimate the risk for earlier ovarian failure among women undergoing hysterectomy with ovarian preservation, as compared to women of similar age without hysterectomy.
A prospective cohort study was conducted among women aged 30 to 47 years undergoing hysterectomy without bilateral oophorectomy (n=406) and women with intact uteri (n=465). Blood samples and questionnaire data were obtained at baseline and annually for up to 5 years. Hazard ratios (HR) for ovarian failure, defined as follicle-stimulating hormone (FSH) levels 40 IU/L or higher, were calculated using Cox proportional hazards models.
Ovarian failure occurred among 60 of the women with hysterectomy and 46 of the control women. Women undergoing hysterectomy were at nearly a twofold increased risk for ovarian failure as compared to women with intact uteri (HR=1.92, 95% confidence interval (CI) 1.29 – 2.86). The proportional hazards model further estimated that 14.8% of women with hysterectomy experienced ovarian failure after four years of follow-up compared to 8.0% of the control women. Risk for ovarian failure was greater for women who had a unilateral oophorectomy along with their hysterectomy (HR=2.93, 95% CI 1.57 – 5.49), but also was significantly increased for women who retained both ovaries (HR=1.74, 95% CI 1.14 – 2.65).
Increased risk of earlier ovarian failure is a possible consequence of premenopausal hysterectomy. While it is unresolved whether it is the surgery itself or the underlying condition leading to hysterectomy that is the cause of earlier ovarian failure, physicians and patients should take into account this possible sequela when considering options for treatment of benign conditions of the uterus.
(a) To establish the cut-off levels for anti-Mullerian hormone (AMH) in a population of Indian women that would determine poor response. (b) To determine which among the three ie.,: age, follicle stimulating hormone (FSH), or AMH, is the better determinant of ovarian reserve.
Prospective observational study.
In vitro fertilization (IVF) unit of a tertiary hospital.
MATERIALS AND METHODS:
The inclusion criterion was all women who presented to the center for in-vitro fertilization/Intracytoplasmic sperm injection (IVF/ICSI). The exclusion criteria were age >45 years, major medical illnesses precluding IVF or pregnancy, FSH more than 20 IU/L, and failure to obtain consent. The interventions including baseline pelvic scan, day 2/3 FSH, luteinizing hormone (LH), estradiol estimations, and AMH measurement on any random day of cycle were done. Subjects underwent IVF according to long agonist or antagonist protocol regimen. Oocyte recovery was correlated with studied variables. The primary outcome measure was the number of oocytes aspirated (OCR). Three categories of ovarian response were defined: poor response, OCR ≤ 3; average response, OCR between 4 and 15; hyperresponse, OCR > 15.
Of the 198 patients enrolled, poor, average, and hyperresponse were observed in 23%, 63%, and 14% respectively. Correlation coefficient for AMH with ovarian response was r = 0.591. Area under the curve (AUCs) for poor response for AMH, subject's age, and FSH were 0.768, 0.624, and 0.635, respectively. The discriminatory level of AMH for prediction of absolute poor response was 2 pmoL/l, with 98% specificity and 20% sensitivity.
AMH fares better than age and FSH in predicting the overall ovarian response and poor response, though it cannot be the absolute predictor of non-responder status. A level of 2 pmol/l is discriminatory for poor response.
Age; anti-Mullerian hormone; follicle stimulating hormone; poor ovarian response
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.
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.
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.
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.
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.
FRAXA premutations have been associated with premature ovarian failure (POF) or menopause before the age of 40. We have studied women in families ascertained because of a mentally retarded full mutation relative and determined their age of menopause, serum hormone levels in premenopausal individuals and the outcome of any pregnancies. Survival analysis was used as a measure of menopause and demonstrated a significant decrease in age of menopause in premutation carriers compared with their full mutation carrier and normal relatives. Serum FSH was also raised in premutation carriers, although oestradiol, inhibin A and inhibin B were not significantly different. However, we did not find an excess of dizygous twins or pregnancy loss/trisomies, both of which are associated with aging ovaries. Thus premutation carriers as a group have an earlier menopause and raised serum FSH but do not appear to manifest other features of an aging ovary.
Fragile X; premutation; premature ovarian failure
Follicle stimulating hormone (FSH) and anti-Müllerian hormone (AMH) represent the two most frequently utilized laboratory tests in determining ovarian reserve (OR). This study determined the clinical significance of their concordance and discordance in female infertility patients.
We investigated 366 consecutive infertility patients (350 reached IVF), excluding women with polycystic ovarian syndrome (PCOS). They were considered to have normal FSH and AMH if values fell within age-specific (as-) 95% confidence intervals (CI), and to suffer from diminished ovarian reserve (DOR) if FSH exceeded and/or AMH fell below those. The two hormones, thus, could be concordant (Group I), both normal (IA) or abnormal (IB), show normal AMH/abnormal FSH (Group II) or normal FSH/abnormal AMH (Group III). Oocyte yields, stratified for age categories, were then studied in each group as reflection of OR.
Oocyte yields significantly decreased from groups IA to II to III and IB. Predictive values of as-FSH/AMH patterns changed, however, at different ages. Except at very young and very old ages, normal as-AMH better predicted higher oocytes yields than normal as-FSH, though above age 42 years normal as-FSH predicts good oocyte yields even with abnormally low AMH. Under age 42 discrepancies between as- FSH and as-AMH remain similarly predictive of oocyte yields at all ages.
Concordances and discordances between as-FSH and as-AMH improve OR assessments and predictability of oocyte yields in IVF.
Ovarian function was studied in 18 female patients treated for abdominal tumours during childhood. All received abdominal radiotherapy as part of their treatment and were studied between 1 and 26 years after irradiation. The serum gonadotrophins and oestradiol levels were consistent with ovarian failure in each case but there was a disproportionate elevation in serum follicle stimulating hormone (FSH) when compared to serum luteinizing hormone (LH) in 16. In 2 patients, the radiotherapeutic field extended downwards only as far as the sacral promontory. However, these 2 girls show similar evidence of ovarian failure to that in the other 16.
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.
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.
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).
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.
epidemiology; aneuploidy; FSH; Müllerian inhibiting substance
The diagnostic value of measurements of plasma and urinary luteinizing hormone (LH) has been studied in 209 patients with endocrine disease. In 44 patients puberty was either delayed or had failed to occur. In those with chromosomal abnormalities the LH levels were often within the normal range, whereas those with a pituitary cause usually had low levels. In boys with delayed puberty plasma LH levels rose before physical changes occurred and had prognostic value. In patients with later gonadal failure, men with impotence or infertility, and women with secondary amenorrhoea LH assays proved of little value, although in one case a premature menopause was suspected and six patients with anorexia nervosa had low LH levels.
Sixty patients with disorders of the hypothalamicpituitary area were studied. Levels of LH were measured and considered in relation to the other anterior pituitary hormones. Impairment of LH secretion was one of the first effects on hormone production of disease affecting this area, and this was, of course, most readily detected in postmenopausal women.
The normal ranges of both plasma and urine LH are wide and there seems to be considerable day-to-day variation, especially of urinary output. Several samples should, therefore, be measured if therapeutic decisions are involved.
The premature ovarian failures with underlying chromosomal abnormalities are normally X-linked, although their associations with the autosomal and the Robertsonian translocations are also possible. Here, we are reporting a case of premature ovarian failure which was associated with a translocation between the long arm of chromosome 7 at q11.23 and the short arm of chromosome 5 at p15.3. The proband was a 26-year-old Malay woman who presented with premature ovarian failure, who was referred for cytogenetic testing due to the suspicion of a chromosomal anomaly. Her physical examination revealed that she had no abdominal or pelvic masses and that she had normal secondary sexual characteristics. Her medical history as well, revealed no points for concern. However, a consanguineous relationship existed, as the patient’s paternal grandmother and maternal grandfather were biological cousins. Our present case indicated that region p15.3 of chromosome 5 and region q11.23 of chromosome 7 possibly carried essential genes for the ovarian function and that they postulated a link between the consanguinity and the chromosomal abnormalities.
Premature ovarian failure; Chromosomal abnormality; Consanguinity; Translocation; Cytogenetic test
The increased survival of patients with breast cancer has given rise to other problems associated with the complications of chemotherapy. One major complication is premature ovarian failure, an especially harmful outcome for women of reproductive age. This study was performed to evaluate the efficacy of GnRH agonist (GnRHa) treatment on protecting ovarian function in young breast cancer patients (30.59±5.1 yr) receiving chemotherapy after surgery. Twenty-two women were enrolled and given subcutaneous injections of leuprolide acetate (3.75 mg) every 4 weeks during chemotherapy. Follow-up laboratory tests (luteinizing hormone [LH], follicle stimulating hormone [FSH], and estradiol) were performed 1, 3, and 6 months after chemotherapy. Menstruation patterns and clinical symptoms were followed up for a mean duration of 35.6±1.7 months. FSH and LH levels were normal in all patients 6 months after completing chemotherapy (8.0±5.3, 4.4±2.7 mIU/mL, respectively). During follow-up, none of the patients complained of menopausal symptoms and 81.8% experienced recovery of menstruation. This report is the first trial of GnRHa as a treatment modality to protect ovarian function during adjuvant chemotherapy in young Korean breast cancer patients.
Ovarian function; Drug Therapy; GnRH agonist; Breast Neoplasms
Follicle-stimulating hormone (FSH)-secreting pituitary adenoma is usually a nonfunctioning tumor, but in rare cases it may develop into ovarian hyperstimulation. Several reports have revealed that serum FSH levels are normal to slightly high in patients with combined FSH-secreting pituitary adenoma with ovarian hyperstimulation. This finding is different from iatrogenic ovarian hyperstimulation syndrome (OHSS), which is associated with extremely high levels of FSH.
To describe the clinical course of two patients who developed OHSS from FSH-secreting pituitary adenoma.
Endocrine studies of the two cases revealed that FSH levels were normal or slightly increased, but luteinizing hormone levels were low to undetectable. Their estradiol (E2) levels were intriguing: levels fluctuated drastically over 6 weeks in Case 1, but stayed flat in Case 2. Ultrasonographic examinations showed bilaterally enlarged multicystic ovaries, and magnetic resonance imaging indicated pituitary tumors. Transsephenoidal resection of the tumors ameliorated the symptoms and pathological diagnosis revealed FSH-secreting pituitary adenomas.
As is not the case in iatrogenic OHSS, even a small to moderate amount of FSH stimulation, which is continuously secreted by a pituitary adenoma, can cause ovarian hyperstimulation. Although FSH-secreting pituitary adenoma can cause ovarian hyperstimulation, an extremely high amount of E2 biosynthesis from granulosa cells seldom occurs.
pituitary adenoma; OHSS; FSH; estradiol; luteinizing hormone
To determine whether premature ovarian insufficiency (POI) associated with classic galactosemia results from a true deficiency of ovarian function or from aberrant follicle stimulating hormone (FSH).
University research laboratory
Patients or other participants
Study subjects included 35 girls and women with galactosemia and 43 control girls and women between the ages of <1 yrs to 51 yrs.
Blood sampling and medical and reproductive histories were obtained.
Main outcome measures
We determined FSH and anti-Müllerian hormone (AMH) levels in subjects with and without classic galactosemia. FSH bioactivity was measured in a subset of girls and women with and without galactosemia who were not on hormone therapy.
FSH levels were significantly higher and AMH levels were significantly lower in our galactosemic cases relative to controls. FSH bioactivity did not significantly differ between cases and controls.
Close to 90% of girls and women with classic galactosemia have a profound absence of ovarian function, a deficit which is evident shortly after birth, if not before. These patients have no evidence of abnormally functioning FSH. AMH levels can be assessed prior to menarche or after initiation of hormone therapy and may supplement FSH as a useful blood biomarker of ovarian function for patients with classic galactosemia.
galactosemia; ovarian insufficiency; AMH; FSH; FSH bioactivity