NOBOX homeobox mutation causes premature ovarian failure

NOBOX (newborn ovary homeobox gene) is an oocyte-specific homeobox gene that plays a critical role in early folliculogenesis and represents a candidate gene for nonsyndromic ovarian failure. We investigated whether mutations in the NOBOX gene cause premature ovarian failure (POF). We sequenced the NOBOX gene in 96 white women with POF and discovered seven known single-nucleotide polymorphisms and four novel variations, two of which, p.Arg355His and p.Arg360Gln, cause missense mutations in the homeobox domain. Electrophoretic mobility shift assay (EMSA) confirmed that the missense mutation, p.Arg355His, disrupted NOBOX homeodomain binding to NOBOX DNA-binding element (NBE) and had a dominant negative effect on the binding of wild-type NOBOX to DNA. Our findings demonstrate that NOBOX mutations can cause POF.     

The pituitary-ovarian axis in dogs with remnant ovarian tissue

It can be difficult to confirm the presence of remnant ovarian tissue (ROT) in bitches that are presumed to be ovariohysterectomised. A GnRH stimulation test can be used to distinguish ovariectomised bitches from those in anoestrus, but it is uncertain whether the GnRH-induced changes in plasma LH and oestradiol concentrations that occur in intact bitches also occur in ROT-bitches. We report here eighteen ROT-bitches and compare the results of GnRH stimulation tests with those of six ovariectomised and six bitches in anoestrus.The basal (n = 17) and/or GnRH-stimulated (n = 18) plasma oestradiol concentration was above the detection limit of the assay, i.e., < 7 pmol/l, in all ROT-bitches but below the detection limit in all ovariectomised bitches. Basal plasma LH concentration was significantly higher in ROT-bitches (4.1 ± 0.7 μg/L) than those in anoestrus (0.64 ± 0.04 μg/L), and significantly lower than in ovariectomised bitches (20.2 ± 3.6 μg/L). Basal plasma LH concentration was relatively high in bitches in which there was a long interval between ovariectomy and appearance of oestrus. GnRH administration resulted in a significant increase in plasma LH and oestradiol concentrations in ROT-bitches. The GnRH-induced increase and subsequent decline in plasma LH concentration were significantly less in ROT-bitches than in either ovariectomised bitches or those in anoestrus. The GnRH-induced increase in plasma oestradiol concentration was significantly smaller in ROT-bitches than in those in anoestrus.In conclusion, the results of this study demonstrate that in dogs ROT is associated with noticeable changes in the pituitary-ovarian axis and suggest that a GnRH stimulation test may be used to distinguish between completely ovariectomised bitches and those with ROT.     

Familial premature ovarian failure.

Premature menopause, ovarian failure younger than 40 years of age, is relatively rare but may preclude childbearing for some women who delay attempts at fertility. We present five kindreds in which a genetic association for premature ovarian failure is strongly suggested. Transmission is either autosomal or (less likely) X-linked dominant in these examples. Chromosomal abnormalities, history of diseases, and toxic chemical or viral exposures previously associated with premature ovarian failure could not be demonstrated in these women. This suggests that these kindreds all represent familial idiopathic premature ovarian failure. These data support the need for menopausal histories on both sides of the family for women seeking to postpone reproduction, as well as for patients with ovarian failure.     

Genetic aspects of premature ovarian failure

Among the causes of premature ovarian failure (POF) two groups of factors are reported: factors which lead to decrease of follicular number and factors which stimulate follicular atresia. In the first group genetic factors are the most important whereas in the second: enzymatic autoimmunological, iatrogenic, toxins and infections are reported. In 1986 familiar POF on the background of long arm of chromosome X deletion was reported. Other chromosomes which are important for normal ovarian function are: chromosome 21 (AIRE gene), chromosome 11 (gene of beta FSH, ATM gene), chromosome 3 (gene responsible for BEPS syndrome) and chromosome 2 (genes of FSH and LH receptors). In this review the role of these genes and results of several epidemiological studies are reported.     

Somatostatin 14 affects the pituitary-ovarian axis in infant rats

The effects of multiple somatostatin (SRIH-14) treatment on the pituitary-ovarian axis were examined in infant rats. Female Wistar rats received subcutaneously two daily 20 μg/100g b.w. doses for five consecutive days (from 11 to 15 days of age). Changes in cell volume, volume density and number per unit area (mm2) of follicle-stimulating (FSH), luteinizing (LH) and somatotropic (GH) immunolabeled cells were evaluated by stereology and morphometry. Serum FSH and LH concentrations were determined by RIA. Ovaries were analyzed by simple point counting of follicles. SRIH-14 treatment significantly reduced FSH and LH cell volume, while their volume density and number per unit area were unaltered. Serum concentrations of FSH and LH were significantly reduced. Volume and volume density of GH cells was significantly decreased after SRIH-14 treatment, while their number per unit area was unaltered. In the ovary, SRIH-14 induced a significant increase in the percentage of primordial follicles followed by a significant decrease in percentage of primary follicles. The number of healthy and atretic preantral follicles was unchanged. It can be concluded that SRIH-14 treatment during the infantile period markedly inhibits pituitary FSH, LH and GH cells. In the ovary, SRIH-14 acts by inhibiting initial folliculogenesis without affecting atretic processes.     

Identification of serum biomarkers for premature ovarian failure

Premature ovarian failure (POF) is defined when a female achieves menopause before the age of 40. Although many conditions are known to be causative for POF, the most common one is idiopathic. This study was undertaken to investigate the pathogenesis of POF using proteomic tools. Two-dimensional electrophoresis (2-DE) analysis was performed to screen for proteins differentially expressed in patients with POF. Using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), we identified 11 significant proteins differentially expressed in the serum of POF patients: 5 proteins with expression increased more than two folds, 5 proteins with expression decreased more than two folds, and 1 protein expressed specifically in the serum of patients with POF. The results of the 2-DE analysis were further validated by Western blotting and ELISA analyses, which 5 reproductive system-related proteins (Ceruloplasmin, Complement C3, Fibrinogen α, Fibrinogen β, and SHBG) were selected. The different expression levels for these proteins were confirmed and demonstrated the possibility of using them as biomarkers to screen POF. These pre-clinical data provide plausible translational implications for targeting the pathogenesis of POF for each protein.     

Chemotherapy-induced premature ovarian failure: mechanisms and prevention

Significant advances have been made in the previously unexplored areas of the mechanisms involved in cyclophosphamide (CTX)-induced ovarian toxicity and the protective effects of luteinizing hormone-releasing hormone (LHRH agonists. The structure and function of granulosa cells and oocytes are affected by the chemotherapeutic agent, CTX. Results of experiments in female rats indicate that LHRH agonists may protect the ovaries from the toxic effects of chemotherapy. The protective effect may be related to the inhibition of ovarian mitotic activity during LHRH agonist administration. This inhibition is much more pronounced in female compared to male rats. This may be related to the observed better gonadal protective effects in females compared to males. Further experiments are underway to determine whether similar protective effects occur in female primates.     

Idiopathic premature ovarian failure in 63 young women

BACKGROUND: Premature ovarian failure (POF) in adolescents is defined as primary or secondary amenorrhea associated with high follicle-stimulating hormone (FSH) levels. In normal 46,XX patients, its etiology is most often unknown. We have evaluated the clinical, hormonal and ovarian phenotypes in patients with a normal karyotype who were diagnosed with POF before the age of 18. METHODS: Sixty-three patients were included in this retrospective study. RESULTS: The mean patient age was 20.4 years. The patients presented with three clinical patterns: lack of pubertal development (n = 23), primary amenorrhea with interrupted puberty (n = 18), and secondary amenorrhea with normal puberty (n = 22). Ten patients had a familial history of POF and 6 presented with hypothyroidism. The FSH, estradiol and inhibin B levels were not statistically different in the three clinical groups. Fifty percent of the patients presented small ovaries (length <2 cm) at ultrasonography. The presence of follicles was found at histology in only 7 of the 27 patients who underwent an ovarian biopsy. CONCLUSION: 46,XX patients presenting with early POF rarely presented a specific, identifiable disorder. We discuss the clinical management and different diagnosis strategies to improve our current knowledge of this syndrome.     

X-linked premature ovarian failure: a complex disease

Involvement of the X chromosome in premature ovarian failure was demonstrated by the relatively frequent chromosomal rearrangements in patients, but the requirement of two X chromosomes for ovarian function was quite unexplained until recently. Review of the data on chromosomal rearrangements suggests that several genes along the X chromosomes contribute to ovarian function. In most instances, no single X chromosome gene has a causative role in premature ovarian failure, and the phenotype is likely to derive from the additive effect of X-linked and non-X-linked factors. Recent data on a small group of balanced X-autosome translocations showed that X-linked premature ovarian failure might also be caused by a different mechanism, namely position effect of the X chromosome on non-X-linked genes, and suggest a peculiar organization of the X chromosome during oogenesis.     

CPEB3 deficiency in mice affect ovarian follicle development and causes premature ovarian insufficiency

Premature ovarian insufficiency (POI) is a heterogeneous and multifactorial disorder. In recent years, there has been an increasing interest in research on the pathogenesis and treatment of POI, owing to the implementation of the second-child policy in China. Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is an RNA-binding protein that can bind to specific RNA sequences. CPEB3 can bind to and affect the expression, cellular location, and stability of target RNAs. Cpeb3 is highly expressed in the ovary; however, its functions remain unknown. In this study, Cpeb3-mutant mice were used to characterize the physiological functions of CPEB3. Cpeb3-mutant female mice manifested signs of gradual loss of ovarian follicles, ovarian follicle development arrest, increased follicle atresia, and subfertility with a phenotype analogous to POI in women. Further analysis showed that granulosa cell proliferation was inhibited and apoptosis was markedly increased in Cpeb3-mutant ovaries. In addition, the expression of Gdf9, a potential target of CPEB3, was decreased in Cpeb3-mutant ovaries and oocytes. Altogether, these results reveal that CPEB3 is essential for ovarian follicle development and female fertility as it regulates the expression of Gdf9 in oocytes, disruption of which leads to impaired ovarian follicle development and POI.Subject terms: RNA-binding proteins, Infertility     

卵巢早衰与肠道菌群关系研究思路探讨

卵巢早衰是一种多因素影响的卵巢功能衰退的疾病,自身免疫在卵巢早衰的病因中所占比例高达10%~30%,目前研究已证实卵巢早衰与Treg、IFN-γ和Th17等多种细胞因子的调节有关。近年来肠道菌群成为国内外的研究热点,其可以影响Treg、IFN-γ、Th17等免疫细胞因子的表达。基于免疫细胞因子在两者之间的作用,笔者大胆提出以免疫细胞因子为桥梁,连接卵巢早衰与肠道菌群,探讨卵巢早衰与肠道菌群关系的设想。肠道菌群与卵巢早衰可能存在某种联系,其研究机制有待进一步探索,这将有助于我们从一个新的视角研究卵巢早衰的发病机制。其或许具有巨大的研究潜力和应用研究价值,为卵巢早衰的临床诊断和治疗提供更多帮助。     

Cytogenetic abnormalities in Tunisian women with premature ovarian failure

To identify the distribution of chromosome abnormalities among Tunisian women with premature ovarian failure (POF) referred to the department of Cytogenetic at the Pasteur Institute of Tunis (Tunisia), standard cytogenetic analysis was carried out in a total of 100 women younger than 40 affected with premature ovarian failure. We identified 18 chromosomal abnormalities, including seven X-numerical anomalies in mosaic and non-mosaic state (45,X; 47,XXX), four sex reversal, three X-structural abnormalities (terminal deletion and isochromosomes), one autosomal translocation and one supernumerary marker. The overall prevalence of chromosomal abnormalities was 18% in our cohort. X chromosome aneuploidy was the most frequent aberration. This finding confirms the essential role of X chromosome in ovarian function and underlies the importance of cytogenetic investigations in the routine management of POF.     

Counteraction of testosterone-induced suppression of the pituitary-ovarian axis in rats by flutamide.

Daily administration of 100 micrograms of testosterone to unilaterally ovariectomized rats for 18 days caused a significant decrease in compensatory ovarian hypertrophy. The number of corpora lutea was markedly reduced and many cystic follicles were noticeable. Administration of graded doses (0.5, 1 and 3 mg daily) of flutamide over the same period did not cause any significant change in the weight and histology of the ovary in untreated unilaterally ovariectomized animals. However, treatment with the same doses of flutamide prevented the changes observed in the reamining ovary of testosterone-treated animals.     

Alterations of the pituitary-ovarian axis in dogs with a functional granulosa cell tumor

Information on the pituitary-ovarian axis in dogs with a granulosa cell tumor (GCT) is lacking. Therefore, we investigated the plasma concentrations of luteinizing hormone (LH) and estradiol before and after gonadotropin-releasing hormone (GnRH) administration in seven bitches with a functional GCT (GCT-total), of which three were intact (GCT-intact) and four had remnant ovarian tissue (GCT-ROT). The results of the GnRH stimulation test were compared with those in six anestrous and six ovariectomized bitches. The most noteworthy results were as follows. The basal plasma LH concentrations of the GCT-ROT bitches were higher (P < 0.05) than those of the anestrous bitches. The increment in the plasma LH concentration after GnRH administration in the GCT-total bitches was lower (P < 0.001) than the increments in both the anestrous and ovariectomized bitches. The basal plasma estradiol concentrations in the GCT-total bitches were higher (P < 0.001) than those in the anestrous and ovariectomized bitches. In conclusion, the pituitary-ovarian axis is affected in bitches with a functional GCT and is characterized by relatively high plasma LH concentrations in GCT-ROT bitches and a subnormal LH response to GnRH stimulation in all GCT bitches compared with those in anestrous and ovariectomized bitches. The relatively high proportion of dogs with remnant ovarian tissue among the GCT bitches suggests a pathogenetic role for elevated gonadotropin secretion in the pathogenesis of GCT.     

卵巢早衰动物模型制备研究进展

卵巢早衰是一种典型异质性疾病,病因复杂多样。近年来,卵巢早衰的发病率有明显上升趋势,严重影响妇女身心健康和生活质量。建立一种理想可靠的卵巢早衰动物模型对研究卵巢早衰有着重要的临床意义。本文就国内外学者建立的卵巢早衰动物模型作一综述,讨论比较各种方法的优缺点。