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Genetic Aspects of Premature Ovarian Failure: a Literature Review

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Genetic Aspects of Premature Ovarian Failure: a Literature Review See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/49711859 Genetic aspects of premature ovarian failure: A literature review Article in Archives of Gynecology · March 2011 DOI: 10.1007/s00404-010-1815-4 · Source: PubMed CITATIONS READS 56 185 5 authors, including: Emerson Barchi Cordts Denise Christofolini Faculdade de Medicina do ABC Faculdade de Medicina do ABC 19 PUBLICATIONS 92 CITATIONS 123 PUBLICATIONS 702 CITATIONS SEE PROFILE SEE PROFILE Bianca Bianco Caio Parente Barbosa Faculdade de Medicina do ABC Faculdade de Medicina do ABC 127 PUBLICATIONS 744 CITATIONS 121 PUBLICATIONS 625 CITATIONS SEE PROFILE SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate, Available from: Bianca Bianco letting you access and read them immediately. Retrieved on: 15 September 2016 Genetic aspects of premature ovarian failure: a literature review Archives of Gynecology and Obstetrics ISSN 0932-0067 Volume 283 Number 3 Arch Gynecol Obstet (2010) 283:635-643 DOI 10.1007/ s00404-010-1815-4 1 23 Your article is protected by copyright and all rights are held exclusively by Springer- Verlag. This e-offprint is for personal use only and shall not be self-archived in electronic repositories. If you wish to self-archive your work, please use the accepted author’s version for posting to your own website or your institution’s repository. You may further deposit the accepted author’s version on a funder’s repository at a funder’s request, provided it is not made publicly available until 12 months after publication. 1 23 Author's personal copy Arch Gynecol Obstet (2011) 283:635–643 DOI 10.1007/s00404-010-1815-4 REPRODUCTIVE MEDICINE Genetic aspects of premature ovarian failure: a literature review Emerson Barchi Cordts • Denise Maria Christofolini • Aline Amaro dos Santos • Bianca Bianco • Caio Parente Barbosa Received: 27 September 2010 / Accepted: 8 December 2010 / Published online: 29 December 2010 Ó Springer-Verlag 2010 Abstract Keywords Premature ovarian failure Á Infertility Á Background The diagnosis of premature ovarian failure Genetics Á Chromosomal abnormalities Á Polymorphism (POF) is based on the finding of amenorrhea before the age of 40 years associated with follicle-stimulating hormone levels in the menopausal range. It is a heterogeneous dis- Introduction order affecting approximately 1% of women \40 years, 1:10,000 women by age 20 years and 1:1,000 women by Premature ovarian failure (POF) (MIM—311360), or pre- age 30 years. POF is generally characterized by low levels mature ovarian insufficiency, is an early ovarian dysfunc- of gonadal hormones (estrogens and inhibins) and high tion clinically defined as the cessation of ovarian function levels of gonadotropins (LH and FSH) (hypergonadotropic with elevated gonadotrophin and low estrogen level before amenorrhea). or at the age of 40 years [1]. This condition is character- Methods Review of significant articles regarding genetic ized by the presence of primary or secondary amenorrhea causes that are associated with POF. for at least 4 months, hypoestrogenism and elevated serum Results Heterogeneity of POF is reflected by a variety of gonadotropin concentrations. The diagnosis is confirmed possible causes, including autoimmunity, toxics, drugs, as by two blood tests at least 1 month apart to measure FSH well as genetic defects. Changes at a single autosomal [2–4]. locus and many X-linked loci have been implicated in POF incidence in patients with 46, XX karyotype was women with POF. X chromosome abnormalities (e.g., estimated in around 1:1,000 women under 30 years old, Turner syndrome) represent the major cause of primary 1:250 around 35 years old and 1:100 at 40 years old [5]. amenorrhea associated with ovarian dysgenesis. Many Multiple causes of POF can be defined and result in fol- genes have been involved in POF development, among licle reduction and/or defects in the follicular development them BMP15, FMR1, FMR2, LHR, FSHR, INHA, FOXL2, stimulus mechanism [5]. Ovarian dysfunction can be sec- FOXO3, ERa, SF1, ERb and CYP19A1 genes. ondary to autoimmune diseases, infections (e.g., mumps), Conclusion Despite the description of several candidate chemotherapy and radiation treatment and metabolic dis- genes, the cause of POF remains undetermined in the vast eases (e.g., galactosemia), but for most of the cases, the majority of cases. etiology is idiopathic and probably genetic [6]. The genetic basis to the disease is supported by the occurrence of families with several affected women [3, 7–9]. Regarding the genetic causes of POF, they can be chromosomal or caused by single genes, involving the X E. B. Cordts Á D. M. Christofolini Á A. A. dos Santos Á chromosome or autosomes [10]. The X chromosome B. Bianco Á C. P. Barbosa (&) abnormalities represent 13% of the cases, followed by the Division of Human Reproduction, Department of Gynecology FMR1 premutation that represents 6% of the cases [11, and Obstetrics, Faculdade de Medicina do ABC, Avenida Prı´ncipe de Gales, 821, Santo Andre´, SP CEP 09060-650, Brazil 12]. Besides, there are many reports of mutations and e-mail: [email protected] polymorphisms in genes related to the sporadic form of 123 Author's personal copy 636 Arch Gynecol Obstet (2011) 283:635–643 the disease that will be discussed in details in this as genitourinary abnormalities, ranging from unilateral manuscript. kidney and renal dysplasia to ovarian malformations [19]. Pubertal onset and sexual development are usually normal in trisomy X; however, there have been cases of ovarian or The X chromosome defects uterine dysgenesis described in children and young adults with trisomy X [17]. Defects involving large aberrations on the X chromosome There are multiple case reports of women with trisomy have been associated with POF including complete dele- X found to have POF, with endocrine findings of hyper- tion of one X (Turner syndrome), trisomy X, partial dele- gonadotropic hypogonadism. The ages of these cases have tions or X/autosome translocations [10]. ranged from 19 to 40 years [20]. Studies on the prevalence of POF in adolescents or adults with trisomy X have not yet been performed. One study that performed genetic Turner syndrome screening on women presenting with POF identified tri- somy X in 3% of cases [21]. In trisomy X, a large per- The Turner syndrome has an incidence of 1 in 2,500 centage of the reported cases of POF have also been females and is characterized cytogenetically by X chro- associated with autoimmune diseases, including autoim- mosome monosomy (45,X). In about 60% of cases, how- mune thyroid disorder [21]. ever, in addition to the 45,X cell line, another cell line is observed that has the complete chromosome number but presents one structurally abnormal X or Y chromosome The X chromosomes rearrangements [13, 14]. Clinically, the syndrome is characterized by gonadal dysgenesis with primary amenorrhea, sexual There is a ‘‘critical region’’ for ovarian development and infantilism, webbing of the neck, cubitus valgus and short function on the long arm of the X chromosome that ranges stature in phenotypic women [14]. Ovarian failure in TS is from Xq13.3 to q27. Alternative mechanisms proposed for due to accelerated follicular atresia, usually manifesting in the explanation of the ovarian defect account for the size of childhood but sometimes later in life [15]. Infertility in the critical Xq region. They include the direct disruption of 45,X patients is caused by oocyte loss in the early stages of relevant loci or a ‘position effect’ caused by the rear- the meiotic prophase, before the pachytene meiotic stage, rangements on contiguous genes. The ‘position effect’ is a resulting in ovarian dysgenesis and streak ovaries. Ogata mechanism involving the deletion or translocation of reg- and Matsuo [16] argued that ovarian failure in X monos- ulatory domains to different position on the genome that omies could be caused by non-specific pairing errors at might cause changes in gene transcription [22]. However, it meiosis that increase the probability of germ cell atresia— has been stated that deletions of the short arm of the X the extent of ovarian failure correlates with the extent of chromosome usually result in primary amenorrhea, pairing failure. whereas deletions of the long arm of the X chromosome result in either primary or secondary ovarian failure [23]. Consequently, both the short and long arm of the X chro- Trisomy X mosome seem to contain important genes for ovarian function. Trisomy X (47,XXX) is a sex chromosome aneuploidy condition and occurs in approximately 1 in 1,000 female births; however, it is estimated that only approximately Genes involved in premature ovarian failure 10% of cases are diagnosed. Although non-mosaic 47,XXX karyotypes are the most frequent, mosaicism occurs in Many genes have been involved in POF development. approximately 10% of cases and in many combinations The genes responsible for the most number of cases such as 46,XX/47,XXX or 47,XXX/48,XXXX, or in are described on Table 1 according to chromosomal combinations including Turner syndrome cell lines such as disposition. 45,X/47,XXX or 45,X/46,XX/47,XXX [17]. Clinical characteristics include epicanthal folds, hypertelorism, BMP15 (bone morphogenetic protein 15) upslanting palpebral fissures, clinodactyly, overlapping digits, pes planus and pectus excavatum. Hypotonia and BMP15, located at Xp11.2, is a member of the large joint hyperextensibility may also be present [18]. Although superfamily of the transforming growth factor b (TGFb) major medical problems are not present in most cases, proteins involved in diverse cellular processes during some medical problems may be associated with trisomy X embryonic development and tissue formation [24]. Studies 123 Author's personal copy Arch Gynecol Obstet (2011) 283:635–643 637 Table 1 The genes involved in POF development The human mutation was shown to act as dominant nega- tive and to decrease in vitro growth of granulosa cells after Gene Chromosomelocation stimulation with wild-type BMP15.
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