Premature Ovarian Failure: A Critical Condition in The Reproductive Potential with Various Genetic Causes

In different reports, chromosomal abnormalities have been recognized as the most common causes of POF disease (12-17, 20), confirming the importance of cytogenetic analysis in reproductive management and genetic counseling for this disease. Investigations in this regard show the association of POF with chromosome abnormalities, particularly those of X chromosome such as structural anomalies, translocation of X with autosomes, isochromosomes and the related aneuploidies (21-25). Also, translocation of Y chromosome heterochromatic regions on derivative X chromosome which affected the X chromosome inactivation was reported (26). Presence of a Y chromosome in a woman’s genome is a clear sign of chromosome abnormality which mostly causes tumor formation in mosaic karyotypes. Pouresmaeili et al. reported a patient with POF who carried aneuploidy of this kind (27). Unknown X-linked gene imbalance is an expected cause of POF in these patients.

A critical region from Xq13.3 to Xq27 has been characterized for ovarian development and function (28). Studies have shown that deletion of the short arm and the long arm of the X chromosome result in either early primary or secondary amenorrhea (29). These observations suggested that important genes for normal ovarian function are located on both arms of the X chromosome (30).

Translocational studies between X chromosome and autosomes have been significant in determining the involvement of autosomal as well as X chromosomal genes in the development of POF disease. For example, the association of HS6ST1, HS6ST2, MATER and CHM genes with POF were identified following to the analysis of the POF patients with karyotypes 46, X, der (X) t (X; 19) (p21; q13), 46, X, t (X; 2) (q21; q14), 46, X, der (X)t (X; Y) (q25-26; q11.22), 46, X, t (X; 4) (q21.2; p16.3) respectively (31, 32). One possible explanation for the disease occurrence in these cases was attributed to the positional effect of an autosome- X chromosome translocation. In fact, transferred genes to the highly heterochromatic region of the X chromosome tolerate epigenetic effects after a rearrangement which changes their chromatin structure and consequently result in lower expression of genes associated with ovarian function and fertility (33).

Moreover, some studies have reported a Robertsonian translocation (13, 14) in some women with sporadic POF. It was also suggested that the functional changes and interruptions in some critical genes for ovarian function on acrocentric chromosomes, due to translocation, could be a possible reason of the disease etiology in this group of patients (20, 34, 35).

Also, there are POF patients with trisomy X who were diagnosed after showing an endocrine disorder, hypergonadotropic hypogonadism (36). It is suggested that the genes located on the X chromosome escaping inactivation could be overexpressed in 47, XXX patients, resulting in the disorder revelation (37). It is identified that complete

absence or a segmental deletion of one X chromosome (TS) causes abnormalities throughout the reproductive system. Using fluorescent in situ hybridization (FISH) and several specific markers to the short arm of X chromosome including DXS1058, DXS6810, DXS1302 and ZXDB, deletion of Xp11.2-p22.1 was introduced as a critical area related to TS and POF (38). Therefore, we understand that the presence of two intact X chromosomes is indigence vital for normal ovarian function (8, 39-41) and prevents follicle apoptosis and atresia (41). This hypothesis is supportive for the POF etiology when there is a significant difference between the highest and lowest follicle numbers in mosaic Turner syndrome and subjects with 45, X karyotype (42).

Chromosome aneuploidy leading to trisomy X is known as one of the genetic reasons of POF which causes elevated endocrine gonadotropine hormone (FSH) with an incidence rate of 1:1000 female live births. Although the ovarian function is normal in most of trisomy X patients, but the ovarian dysfunction in some 47, XXX might manifest as early menopause, secondary amenorrhea and oligomenorrhea (36).

Mosaic types of the syndrome include 10% of the cases with various karyotypes such as 46, XX/47, XXX or 45, X/47, XXX. The mosaic trisomy X might be the result of a post-zygotic nondisjunction event or post-zygotic trisomy rescue. The manifestation of symptoms depends on the time at which the causing events occurred.

The cytogenetic analysis done on POF patients indicated that trisomy X (regardless of mosaic or non-mosaic) have low frequency in individuals with POF (30, 37, 43).

The patients carried different symptoms with abnormalities in genitourinary tract which could be associated with the trisomy status (44). Although some of the cases showed uterine dysgenesis, other cases had no defects in the reproductive system and sexual development (37).

Investigations have shown that the autoimmune thyroid disease is related to many POF cases with trisomy X (45). The ovarian failure in 47, XXX patients (either mosaic or non-mosiac) could be the result of meiotic disorganization of three X chromosomes (20). However, more studies on 47, XXX patients with POF are required.

Numerous studies have identified different genes whose functions were significant in ovarian development and also play a role in POF progression. However, inconsistent results have been observed in different studies which are presumably the result of genetic variability between studied ethnic groups (46-48). Table 1 describes several candidate genes with possible involvement in ovarian function and POF genesis. All the introduced genic variation as mutations and polymorphisms are thought to affect POF (30).

The FMR1 premutation of CGG repeats with incidence of 1:800 in males and 1:100-200 in women is recognized as the most important gene associated with POF (49-51). The authors mention that carrier women of the premutation are predisposed to POF disease. Expression study on fragile X mental retardation protein has demonstrated that the variation in the level of the gene product (FMRP) could be utilized as a candidate biomarker to evaluate a person with folliculogenesis disruption, heavy follicle atresia and eventual POF. In this study immunocytochemistry was applied on ovarian sections to show different FMRP1 signals in tissues with different CGG repeats. These expression studies showed that the elevated amount of the expressed gene in fetus germ line cells have a negative effect on the number of oocytes and their development (52, 53). The incidence of the disease is about 0.1-1% in normal individuals but 20-28% in the carriers of premutation FMR1, 13 times more than controls, respectively (54-58). Some studies indicated that the intermediate alleles of FMR1 CGG repeats could also increase the risk of POF development (57, 59-66).

SF1, a nuclear receptor which is expressed in various cell types in fetus and adult, regulates different genes involved in development of the reproductive system, hypothalamic-pituitary-steroidogenesis and familial or isolated POF. The gene polymorphism Gly146Ala resulted from GGG to GCG sequence is known to be associated with POF in either familial or isolated form. Carriers of the 146Ala allele showed a significant decline in plasma stradiol. Therefore, this polymorphism could be a risk marker for POF is some women (67-72).

Inhibins are of other POF candidate genes predominantly produced in the ovary at different times of the menstrual cycle and play a regulatory role in folliculogenesis (73, 74). Among these proteins, Inhibin alpha (INHA) gene polymorphisms have been shown to have a significant association with risk of POF in certain ethnic populations (74-77).

The luteinizing hormone (LH) through luteiniz- ing hormone receptor (LHR) plays an important role in the follicular growth and oocyte maturation. Women carrying LHR mutations showed anovula- tion and primary amenorrhea (78-81).

FSH receptor (FSHR) is expressed in the granulosa cells of the ovary and has an important function in follicular development (82, 83). In different studies on Chinese, Argentinian and British women, it has been revealed that FSH receptor gene mutations are seldom identified in POF patients. First, mutations of FSHR and later sentences are talking about them FSHR gene polymorphisms which are different terms (84-88).

FOXL2 was found in undifferentiated granulosa cells of the ovary which are involved in ovarian follicle development (89-92). The studies have indicated that FOXL2 mutations are rarely associated with POF disease (93-95).

The FOX3a is also expressed in the ovary with a regulatory role in the follicular activation (96). Although some mutations of the encoding gene have been reported in women with POF, it seems that FOX3a mutations could not be counted as a common cause (97-99).

Estrogen stimulates gonadotropins releasing at the hypothalamus-hypophysis-ovarian axis by acting on estrogen receptor-α (ESR1) which enhances folliculogenesis (100). It has been reported that several single nucleotide polymorphisms (SNPs) such as rs2234693, rs9340799 and rs2234693 of ESR1 are associated with the increased risk of POF (101-104). Some studies have suggested an association between Estrogen receptor alpha gene polymorphism, PvuII and XbaI restriction fragment length polymorphisms (RFLPs) and low bone mineral density (BMD) (105), while others observed no significant correlation between these polymorphisms with age, menopausal status and BMD (106). Nevertheless, it has been revealed that baseline BMD and change in menstrual status contributed more to the magnitude of the difference in bone change (107).

The CYP19A1 gene encodes aromatase, the key enzyme in biosynthesis of estrogens. High expression of aromatase during the ovary differentiation has been reported previously (108, 109). Investigations on Korean patients with POF have shown a significant association between 3’ UTR SNPs "rs10046" and "rs4646" of CYP19A1 with the disease (110).

It has been demonstrated that CXCL12 through its receptor acts on migration and survival of primordial germ cells (PGCs) (111-115). The association between CXCL12 polymorphisms and POF has been observed in the studied populations (116, 117).

The FMR2 gene is another candidate gene for POF manifestation. Microdeletions within FMR2 have been found in some individuals with POF disease. However, the function of FMR2 in oocyte development is still unclear (30, 118).

The newborn ovary homeobox gene (NOBOX) functions as an oocyte-specific gene in early folliculogenesis (119). However, the mutation analysis of NOBOX indicated that NOBOX mutations are an uncommon cause of POF (120-122).

In some POF patients, deletions within DIAPH2 have been found along with the breakpoints at Xq22 (123). Researchers believe that the human DIAPH2 influences the ovarian follicular development (124, 125) and that the gene is a potential candidate for POF manifestation (126).

The variants of methylenetetrahydrofolate reductase (MTHFR) gene are evidenced to be associated with folliculogenesis (127). The MTHFR C677T and A1298C polymorphisms are significantly associated with the elevated risk of POF in different studied populations (128, 129).

Laminin is one of the most abundant components of the basal lamina. It has been demonstrated that the LAMC1 expression increases during follicular development (130, 131). LAMC1 variations presented a significantly association with susceptibility to POF (132).

Other genetic variations associated to POF in addition to the discussed genes in table 1, is much evidence confirming the involvement of other genes coding for small RNAs (like miRNA) during folliculogenesis (133-137). The exact function of these miRNAs is not clear yet, but germ cell development and maturation is influenced by several small RNAs such as piRNA, and siRNA that are supposed to be effective in oocyte maturation (138). The experiments indicated that the mutations or alterations of the involved genes in miRNA processing, biosynthe- sis or miRNA targets could result in increased susceptibility to sex reversal or infertility (139- 143). This effectiveness depends on the gonad- otropin hormone surge (like LH and FSH) and the pathway where a gene is able to diminish or elevate another specific activity of a gene in a certain developmental time and in a specific gonad or specific tissue during embryogenesis or ovarian development (144, 145).

In the recent years, copy number variation array (CNV array) has been an effective tool to assess the numerical variation (micro-deletion and micro-duplication) of important genes in early menopause (146). It is believed that chromosomal alterations could negatively affect germ cell apoptosis through meiotic DNA repair disruption (147).

SNPs are genetic variations which in interaction with other genes are thought to increase the risk for premature ovarian failure (148). The association data obtained from analysis of TGFR3, HSD17B4, LAMC1, ESR1, HK3 and BRSK1 are of the recent studies explaining how gene variants could be correlated to the etiology of premature ovarian failure (117, 132, 149).

A woman is diagnosed for POF if she has lost her regular menstrual periods for at least 4 months before the age 40. The reduction of antral follicle in POF patients could be examined by Pelvic ultrasonography (150). A new diagnostic method is the measurement of anti- Mullerian hormone (AMH) produced by antral follicles. The AMH secretion is decreased in POF patients (151, 152). The measurement of anti-adrenal, anti-ovarian and anti-thyroid autoantibodies could be useful in the diagnosis of the immune system deficiency leading to POF (150, 153). After confirming the diagnosis of POF, karyotyping and analysis of FMR1 premutation should be done to exclude major genetic causes (150). The hormone replacement therapy (HRT) is the accepted management for POF patients. Estrogen replacement is recommended to decrease the risk of osteoporosis and cardiovascular disease (154). Anxiety and depression increases in women with POF, thus, psychological support could be useful in the management of the disease (155, 156). POF is associated with complete follicular depletion and infertility. Infertility in patients with POF could be resolved by ovum donation (157). Recent studies have focused on stem cell therapy of POF. One of these investigations used CD44+/CD105+ HuAFCs (human amniotic fluid cells) to treat POF in mice and demonstrated that the cells were valid candidates for stem cell transplantation of POF due to their long half-life in vitro and mesenchymal potential (158).