Cases Of Primary Ovarian Insufficiency Research Articles

Primary Ovarian Insufficiency in Children After Treatment With131I-Metaiodobenzylguanidine for Neuroblastoma: Report of the First Two Cases

Primary ovarian insufficiency (POI) is a noted late effect in childhood cancer survivors treated with alkylating agents or after radiation to a field that includes the ovaries. Gonadal failure in children with neuroblastoma (NBL) who were exposed to 131I- metaiodobenzylguanidine (MIBG) has only been reported in those who were also treated with chemotherapy. In these cases, the cause of gonadal failure was assumed to be the cytotoxic therapy. Here, we present the first two cases of POI after 131I-MIBG treatment only for NBL, indicating that 131I-MIBG treatment may have a causative role. During follow-up after treatment for NBL in childhood, elevated gonadotropins were found in a 12-year-old girl and an 11-year-old girl (FSH values, 105 and 161 U/L, respectively), indicating POI. The first patient had been diagnosed at the age of 17 months with sacrally located (intraspinal) NBL. Treatment consisted of five courses of 131I-MIBG and local resection. The second patient had been diagnosed at the age of 8 months with an abdominal (intraspinal) NBL. She had been treated with acute (neuro) surgery for decompression of her intraspinal tumor causing neurological symptoms, followed by two courses of 131I-MIBG therapy. Both girls had normal karyotypes (46, XX). No other cause for the ovarian failure was found. Estrogen suppletion was started, and patients and parents were counseled regarding fertility options. These two cases suggest that exposure to 131I-MIBG may damage the female gonads. Clinicians caring for childhood cancer survivors should be aware of the risk of POI after 131I-MIBG treatment. Prospective studies are warranted to confirm our observations.

An update on primary ovarian insufficiency

Primary ovarian insufficiency (POI) occurs in about 1% of female population under the age of 40, leading to reproductive problems, an earlier encounter with menopausal symptoms, and complicated diseases. There are three presumable mechanisms involved in the development of POI, namely apoptosis acceleration, follicular maturation blocking and premature follicle activation, through the following studied causes: (i) chromosomal abnormalities or gene mutations: mostly involve X chromosome, such as FMR1 premutation; more and more potentially causal genes have been screened recently; (ii) metabolic disorders such as classic galactosaemia and 17-OH deficiency; (iii) autoimmune mediated ovarian damage: observed alone or with some certain autoimmune disorders and syndromes; but the specificity and sensitivity of antibodies towards ovary are still questionable; (iv) iatrogenic: radiotherapy or chemotherapy used in cancer treatment, as well as pelvic surgery with potential threat to ovaries' blood supply can directly damage ovarian function; (v) virus infection such as HIV and mumps; (vi) toxins and other environmental/lifestyle factors: cigarette smoking, toxins (e.g., 4-vinylcyclohexene diepoxide), and other environmental factors are associated with the development of POI. The etiology of a majority of POI cases is not identified, and is believed to be multifactorial. Strategies to POI include hormone replacement and infertility treatment. Assisted conception with donated oocytes has been proven to achieve pregnancy in POI women. Embryo cryopreservation, ovarian tissue cryopreservation and oocyte cryopreservation have been used to preserve ovarian reserve in women undergoing cancer treatments.

Allelic reduction of Dlx5 and Dlx6 results in early follicular depletion: a new mouse model of primary ovarian insufficiency

Primary ovarian insufficiency (POI) is characterized by the loss of ovarian function before the age of 40 in humans. Although most cases of POI are idiopathic, many are familial, underlying a genetic origin of the disease. Mutations in genes involved in the control of steroidogenesis, such as NR5A1 (SF-1, Steroidogenic Factor 1), CYP17, CYP19A1 (aromatase), StAR (Steroidogenic Acute Regulatory), and the forkhead transcription factor FOXL2 have been associated with different forms of POI. In males, the homeobox transcription factors Dlx5 and Dlx6 are involved in the control of steroidogenesis through the activation of GATA4-induced-StAR transcription. Here, we analyze the potential involvement of Dlx5 and Dlx6 in female reproduction. To this end, we make use of an existing mouse model in which Dlx5 and Dlx6 are simultaneously disrupted. We show that: (i) allelic reduction of Dlx5 and Dlx6 in the mouse results in a POI-like phenotype, characterized by reduced fertility and early follicular exhaustion; (ii) in granulosa cell lines, a reciprocal regulation exists between Dlx5 and Foxl2; (iii) in the mouse ovary, allelic reduction of Dlx5/6 results in the upregulation of Foxl2. We propose that the mutual regulation between Dlx5/6 and Foxl2 and their opposite effects on StAR expression might contribute to determine the homeostatic control of steroidogenesis within the ovary. Dysregulation of this homeostatic control would result in abnormal follicular maturation and reduced fertility. Our results bring new elements to our conceptual model of follicle maturation and maintenance and provide new potential genetic targets for cases of familial POI.

Are ATPase6 polymorphisms associated with primary ovarian insufficiency?

We read with much interest the report of Venkatesh et al. [1] concerning the mitochondrial genome ATPase6 gene mutations associated with primary ovarian insufficiency (POI). Their study catalogued ATPase6 gene nucleotide polymorphisms in idiopathic cases of POI. These authors found that nucleotide changes in the ATPase6 gene were higher in the POI patients compared to a control group. They also suggested that two non-synonymous mutations, in the ATPase6 gene, 8684C[T and 9094C[T were significantly (P \ 0.005) associated with POI cases. We suggest however, that their results and conclusions are significantly weaker than they seem because they failed to examine their data thoroughly. Mitochondrial genome substitutions present in a homoplasmic fashion (haplotypes) are commonly associated in genetic lineages (mtDNA haplogroups). We reexamined the data of Venkatesh et al. [1] employing mtDNA phylogenetic tree analysis. We found that of their six mutations in the ATPase6 gene five were attributable to distinct south Asian, West Eurasian and East Asian haplogroups. Mutations 8679A[G, 8865G[A, and 9094C[T are a characteristic motif of south Asian haplogroups M39, M4b2 and U2b1, respectively [2–4]. The mutations 8684C[T and 9123G[A are defining markers for the west Eurasian haplogroups U7 and H4 [3, 5]; this mutation also occurs in the East Asian haplogroups M8a and B4a [6]. While the west Eurasian H4 and the East Asian M8a haplogroups are almost nonexistent in India, the U7 haplogroup is present in 10–15% of the population in north India [7]. Therefore, it is apparent that the substitution 8684C[T and 9123G[A scored in the POI cases actually are common mutations indicating that their carriers belong to the haplogroups U7 and B4a. The mutation 9064G[A is also a commonly occurring mutation found in four different south Asian haplogroups: M3c, M5a1a, M32, and M51 [3, 8, 9]. With the observed ATPase6 gene substitutions, cases and controls sorted into their proper mtDNA haplogroups (Table 1), we can see that of the mutations in the 20 POI study cases, 7 cases are belong to haplogroup U7, 5 individuals belong to U2b1 and B4a, and one each to haplogroups M4b2 and M39. In the control group only two participants had common haplogroup mutations and they belong to haplogroups M4b2 and B4a. This extreme difference in haplogroup distribution demonstrates clearly that the controls and POI cases were recruited from significantly different hereditary populations. Association studies produce spurious results if the cases subjects are not matched properly with control subjects [10]. It is apparent that the results in this study, for example, were misinterpreted by their authors and that the control group was not a scientifically relevant control. Once again we demonstrate the importance of examining mitochondrial mutations against the backdrop of known haplogroups, and the importance of using phylogenetic in studies of human disease. Failing to employ all data relevant to mitochondrial studies often presents a false picture of disease association, leading to incorrect conclusions and potentially inefficient and faulty new diagnostic tests. M. G. Palanichamy (&) Y.-P. Zhang Laboratory for Conservation and Utilization of Bio-resources, Yunnan University, Kunming 650 091, Yunnan, China e-mail: empalani@yahoo.com

NR5A1/SF-1 and development and function of the ovary

Primary ovarian insufficiency (POI) is defined as cessation of menstruation with associated elevation of gonadotropin levels as a result of decreased ovarian function before the age of 40. The incidence of POI is 1% in women prior to age 40, and 0.1% prior to age 30. There is evidence of a strong genetic component associated with POI. However, the gene mutations/variations influencing POI still remain uncharacterized. NR5A1, a member of the nuclear receptor superfamily, is a key transcriptional regulator of genes involved in the hypothalamic-pituitary-gonadal steroidogenic axis. Newborn mice deficient in NR5A1 lack both gonads and adrenal glands and have impaired expression of pituitary gonadotrophins. NR5A1 is also expressed in multiple cell types in the fetal, postnatal, prepubertal and mature ovary. Until 2008, 18 NR5A1 mutations were described in the human. Three of these were identified in individuals with adrenal insufficiency, two associated with 46,XY disorders of sex development (DSD) and the third a 46,XX female with conserved ovarian function. Other mutations were associated with various anomalies of testis development with no evidence of adrenal failure. We have identified further 19 mutations in NR5A1 including mutations in four familial cases having individuals with 46,XY DSD as well as POI. A further analysis of 25 sporadic cases of POI revealed two additional mutations. Functional analysis revealed that each mutant protein had altered transactivational properties on gonadal promoters. These data reveal novels insights into the role of NR5A1 in ovarian developmental and function and indicate that mutations of the NR5A1 gene may be a significant cause of human ovarian insufficiency.

Oxidative stress and ATPase6 mutation is associated with primary ovarian insufficiency

Primary ovarian insufficiency (POI) is a heterogeneous, multifactorial disorder. Though genetic anomalies, infections, autoimmune disorder and hormonal imbalance are few of the causes of POI, in the majority of patients (50-60%) no etiology has been identified. Mitochondrial bioenergetics and biogenesis play an important role in oocyte and embryo development, whereas mtDNA integrity and content are essential for the normal development of oocytes. ATPase6 helps to maintain the mt genome integrity, and mutations in ATPase6 are associated with overproduction of reactive oxygen species (ROS) in a variety of diseases; however, its role in POI has not been evaluated. Therefore, we planned to evaluate the potential role of ATPase6 gene mutations and associated oxidative stress in idiopathic cases of POI. This pilot study included: 20 cases of POI with FSH level of >40 mIU/ml; 4 cases of occult ovarian insufficiency (occult OI) with irregular menses and mean FSH levels of 16.4 mIU/ml; and 20 age-matched healthy female controls (FSH 2-5 mIU/ml). ROS levels in blood plasma were measured by luminol-dependent chemiluminescence assay and the ROS values were expressed as relative light unit per minute (RLU/min). mtDNA ATPase6 gene was amplified and sequenced from the blood lymphocyte DNA. Of all, 50% patients showed nucleotide changes in the ATPase6 gene, as compared to 10% in controls, and the majority of these mutations were non-synonymous. ATPase6 mt.8684 C>T and mt.9094 C>T were found to be significantly (P < 0.005) higher in cases as compared to controls. ROS levels were found to be significantly (P < 0.005) higher in POI and occult OI patients compared to controls and nucleotide changes were found to positively correlate with ROS levels. Moreover, ROS production was found to positively correlate (r = 0.7038, P < 0.001) with FSH levels of the patients (POI and OI) compared to controls. This pilot study clearly demonstrates for the first time ATPase6 gene nucleotide alterations and elevated ROS levels in idiopathic cases of POI. Therefore, it may be possible that OS associated with ATPase6 gene mutation may be causal in idiopathic cases of premature OI. However, larger studies with inclusion of more cases of both POI and occult OI are required to strongly establish the correlation between oxidative stress and mitochondrial nucleotide alterations in the pathogenesis of POI. Such cases with OS-induced POI may benefit immensely by early diagnosis and prompt antioxidant administration.