Premature Ovarian Failure 1

A number sign (#) is used with this entry because premature ovarian failure-1 (POF1) is associated with premutations in the FMR1 gene (309550) on chromosome Xq27.3, within a region defined as POF1 (Xq26-q28).

Description

Premature ovarian failure is clearly a heterogeneous disorder. The terms 'hypergonadotropic ovarian failure' and 'hypergonadotropic ovarian dysgenesis' (see ODG1, 233300) have been used to indicate a group of disorders in which amenorrhea associated with elevated levels of serum gonadotropins occurs long before the age of 40 years (Coulam, 1982). Cytogenetic studies of X-chromosome aberrations have suggested that it is mainly the long arm of the X chromosome that is involved in defects of ovulation (Bione et al., 1998).

Reviews

Rossetti et al. (2017) reviewed the genetics of primary ovarian insufficiency, noting that the significance of this disorder was increasing because of the increasing number of women desiring conception beyond 30 years of age, at which point POF prevalence is more than 1%.

Genetic Heterogeneity of Premature Ovarian Failure

Mutations in genes identified within a region defined as POF2 (Xq13.3-q21.1) have been found to cause other forms of POF: POF2A (300511) by mutation in the DIAPH2 gene (300108) and POF2B (300604) by mutation in the POF1B gene (300603). See also POF3 (608996), caused by mutation in the FOXL2 gene (605597) on chromosome 3q22; POF4 (see 300510), caused by mutation in the BMP15 gene (300247) on chromosome Xp11; POF5 (611548), caused by mutation in the NOBOX gene (610934) on chromosome 7q35; POF6 (612310), caused by mutation in the FIGLA gene (608697) on chromosome 2p13; POF7 (612964), caused by mutation in the NR5A1 gene (184757) on chromosome 9q33; POF8 (615723), caused by mutation in the STAG3 gene (608489) on chromosome 7q22; POF9 (615724), caused by mutation in the HFM1 gene (615684) on chromosome 1p22; POF10 (612885), caused by mutation in the MCM8 gene (608187) on chromosome 20p12; POF11 (616946), caused by mutation in the ERCC6 gene (609413) on chromosome 10q11; POF12 (616947), caused by mutation in the SYCE1 gene (611486) on chromosome 10q26; POF13 (617442), caused by mutation in the MSH5 gene (603382) on chromosome 6p21; and POF14 (618014), caused by mutation in the GDF9 gene (601918) on chromosome 5q31.

In 100 patients with primary or secondary amenorrhea before the age of 40 years, who also exhibited elevated FSH, Bouilly et al. (2016) screened for variants in 19 POF-associated or candidate genes. The authors noted that 8 of the 19 mutation-positive patients carried a genetic defect in more than 1 gene, and that patients with 2 or more variants tended to have a younger age of onset and were more likely have primary rather than secondary amenorrhea. Bouilly et al. (2016) suggested that digenicity and possibly oligogenicity may contribute to POF, noting that this might account for the phenotypic variability and incomplete penetrance that have been observed in patients with POF.

Clinical Features

Although the average age of menarche decreased during the 20th century, the mean age of menopause appears to be invariant with time and race and occurs at approximately 50 years. Premature ovarian failure can be defined as secondary amenorrhea with elevated gonadotropins occurring before age 40. Depletion of ova is usually the basis although an ovary no longer sensitive to gonadotropins can masquerade as true failure (Jones and De Moraes-Ruehsen, 1969; Maxson and Wentz, 1983). Premature ovarian failure is usually idiopathic but occasionally can be due to a genetic disorder that is associated with rapid atresia of follicles, such as Turner variants (Fitch et al., 1982), or with formation of a small number of follicles, as in galactosemia (230400) (Kaufman et al., 1981). Destruction of germ cells in pre- or postpubertal stages by viral infections, drugs (cigarette smoking, antitumor drugs), or radiation can also be responsible. Autoimmunity appears to be the basis of POF in patients with antiovarian antibodies, in Addison disease (240200) and in myasthenia gravis (254200). The role of familial factors was suggested by de Moraes-Ruehsen and Jones (1967) and by Smith et al. (1979). On the basis of 5 kindreds, Mattison et al. (1984) proposed that POF can be a mendelian disorder, inherited either paternally or maternally, as an autosomal or X-linked dominant.

Smith et al. (2004) studied 65 patients with POF and 36 age-matched healthy controls. They found that women with POF were more likely to exhibit ocular surface damage and symptoms of dry eye than age-matched controls, but were not more likely to have reduced tear production.

Eggermann et al. (2005) described a 33-year-old German woman with POF and her mother, who both showed mild Turner stigmata including a low-set hairline, moderately high-arched palate, short and mildly webbed neck, and hypoplastic and/or upturned fingernails and toenails. The daughter also had sparse hair and an asymmetric right hypoplastic breast.

Cytogenetics

Krauss et al. (1987) described a family in which 4 and perhaps 5 women in 3 generations had menstrual irregularities. Four of the 5 were demonstrated to have a partial deletion of the long arm of the X chromosome: 46,XX,del(X)(pter-q21.3::q27-qter). Ovarian function ceased prematurely with demonstrated estrogen deficiency and elevation of serum gonadotropin levels before the age of 40. In 3 of the 4 women, ovarian failure occurred at ages 24 to 37 years. Similar familial premature ovarian failure was reported by Coulam et al. (1983) and by Mattison et al. (1984). Premature menopause due to a small deletion in the long arm of the X chromosome was described by Fitch et al. (1982). Skibsted et al. (1984) suggested that the 'critical region' essential for normal ovarian function is Xq26-q28. The observations of Krauss et al. (1987) may indicate the presence in this region of a gene essential to ovarian function which in some nondeletion cases may be mutant, leading to the same clinical picture of premature ovarian failure.

In 2 sisters with POF, previously reported by Fitch et al. (1982), Schwartz et al. (1987) used polymorphic DNA probes to define further the small deletion of the long arm of 1 of their X chromosomes. The deleted chromosome retained the factor IX locus (F9; 300746) and 2 loci proximal to F9, but the factor VIII locus (F8; 300841) and 2 loci tightly linked to it were not present. BrdU incorporation confirmed that the deleted chromosome was always the inactive one. Schwartz et al. (1987) designated the patients' deletion del(X)(pter-q26.3:). One sister had entered menopause at age 21; the other, who had 1 child, had very irregular menstrual periods before age 40. Their mother, who was deceased, was said to have had onset of menopause at age 35. The women were of normal intelligence and in good health; none had stigmata of the Turner syndrome.

To establish the prevalence of X chromosome deletions in women with premature ovarian failure, Davison et al. (1998) performed cytogenetic analyses on 79 women with primary or secondary amenorrhea. A normal karyotype was found in 77 women. One woman with primary amenorrhea had an XY karyotype and a woman with secondary amenorrhea had a deletion at Xq26.1. This second woman had a family history of premature ovarian failure; her mother, who underwent premature ovarian failure at 28 years, shared the deletion. The early diagnosis of familial X deletions causing POF allowed for the prediction of impending menopause and the implementation of maneuvers to advance conception.

Marozzi et al. (2000) performed high-resolution cytogenetic analysis of a large number of women with POF and identified 6 patients carrying different Xq chromosome rearrangements. The patients (1 familial and 5 sporadic cases) were negative for Turner stigmata and experienced a variable onset of menopause. All of the patients had an Xq deletion as the common chromosome abnormality, which was the only event in 3 patients and was associated with partial Xp or 9p trisomies in the remaining 3. Two of these, carrying X;X and X;9 unbalanced translocations, respectively, showed terminal deletions with the breakpoint at Xq22 within the DIAPH2 gene (300108). Marozzi et al. (2000) concluded that the restricted Xq region involved in the POF phenotype extends from approximately Xq26.2 to Xq28 and covers approximately 22 Mb of DNA.

In 2 sisters with POF and their mother, originally described by Maraschio et al. (1996), Rossetti et al. (2004) reported the fine mapping of an interstitial deletion of the X chromosome. The 2 daughters had secondary amenorrhea at 17 and 22 years of age, respectively, whereas their mother was fertile, had 4 children, and underwent premature menopause at 43 years of age. The proximal breakpoint was mapped to Xq27.3 and the distal breakpoint was localized within the OPN (see 300821)/CXORF2 (see 300092) gene cluster on Xq28. Rossetti et al. (2004) compared the deletion in these 3 women with that in a family identified from a male proband with X-linked mental retardation in which the mother had undergone menopause at age 47 years (Wolff et al., 1997), indicating that the deletion in the second family did not include a gene for POF. The 2 deletions were found to partly overlap in their proximal region, thus reducing the POF susceptibility region to a 4.5-Mb interval between the iduronate 2-sulfatase gene (IDS; 300823) and the OPN gene cluster. Because the deletion breakpoints were identical in the 3 women, Rossetti et al. (2004) concluded that the phenotypic differences in this family must have been due to other genetic or environmental factors.

In a 33-year-old German woman with POF and her mother, Eggermann et al. (2005) identified a small terminal Xq deletion; typing of microsatellite markers narrowed the deletion to a 10.5-Mb region, Xq27.2/Xq27.3-q28.

Heterogeneity

Findings derived from investigation of X/autosome balanced translocations and Xq terminal deletions allowed identification of 2 independent regions within the Xq arm that seemed to be involved in ovarian function (Marozzi et al., 2000). These regions are located at Xq26-q28 (Tharapel et al., 1993) and Xq13.3-q22.

Schlessinger et al. (2002) reviewed genes and translocations involved in POF. Sporadic X;autosomal translocations showed breakpoints distributed at many points on the X chromosome, but concentrated in a critical region on Xq. They suggested that many of the translocations, like X monosomy (Turner syndrome), lead to POF not by interrupting specific genes important in ovarian development, but by causing aberrations in pairing or X inactivation during folliculogenesis. The authors noted that the critical region has unusual features, neighboring the X-inactivation center and including an 18-Mb region of very low recombination. Schlessinger et al. (2002) concluded that chromosome dynamics in the region may be sensitive to structural changes, and when modified by translocations may provoke apoptosis at meiotic checkpoints.

Rizzolio et al. (2007) analyzed the breakpoints of 4 POF cases with Xq chromosomal rearrangements and found that while the X-chromosome breakpoints interrupted a gene-poor region on Xq21 containing no ovary-expressed candidate genes, ovary-expressed genes flanked the autosomal breakpoints in all 4 cases. In another case involving an X;autosome balanced translocation and normal fertility, the X-chromosome breakpoint was flanked by 2 POF-associated breakpoints, whereas the autosomal breakpoint mapped to an rDNA cluster on chromosome 22p. Microarray expression data showed that global downregulation in the oocyte and upregulation in the ovary of X-linked genes compared to autosomal genes was primarily due to genes in the POF 'critical region.' Rizzolio et al. (2007) suggested that POF associated with X;autosome balanced translocations may be caused by an oocyte-specific position effect on autosomal genes in some cases.

Other Associations

POF has an autoimmune pathogenesis in a significant proportion of cases. Autoantibodies to 3-beta-HSD (613890) are present in one-fifth of patients and may identify an autoimmune subgroup. Arif et al. (1999) showed that POF patients with 3-beta-HSD autoantibodies have a higher frequency of DQB1 (604305) alleles that encode aspartate at codon 57 on the DQ-beta chain, although levels of significance were not maintained after correction for multiple analyses.

Molecular Genetics

Nomenclature of Expanded Trinucleotide Repeats

The repeat in the FMR1 gene that is involved in the fragile X syndrome (300624) and is also associated with premature ovarian failure is variously referred to here as (CGG)n or (CCG)n. The identical repeat found in the cloned FRAXE gene (309548) was referred to as (GCC)n by Knight et al. (1993). There are only 10 different trinucleotide repeats, but each can be written in a number of ways. Sutherland (1993) favored the convention that lists the motif in alphabetical order in the 5-prime to 3-prime direction. Consistent with this, he uses the (CCG)n designation. He preferred, furthermore, the designation (AGC)n for the other clinically significant dinucleotide repeat found in myotonic dystrophy (DM1; 160900), Huntington disease (143100), Kennedy disease (SMAX1; 313200), and SCA1 (164400); (CAG)n is the designation most often used. Sutherland (1993) suggested that the same convention can apply to dinucleotides. He wrote: 'It must be very confusing for newcomers to the literature to find (AC)n, (CA)n, (GT)n, and (TG)n repeats, when the cognoscenti know these are synonyms.'

Premature Ovarian Failure 1

Murray et al. (1998) screened 147 women with idiopathic premature ovarian failure, defined as cessation of menses before 40 years of age with no known cause, and found a significant association with premutations in the FMR1 gene (309550.0004). Of the 6 women with FRAXA premutations, 4 were familial cases; analysis of 3 affected female relatives demonstrated that they also carried FRAXA premutations. None of the women had full mutations in the FMR1 gene. The authors concluded that FRAXA premutation alleles can affect ovarian development or function or both.

Murray et al. (1999) screened a cohort of 209 women with POF for FMR1 premutations and found that 9 had greater than 50 trinucleotide repeats (309550.0004).

In an international collaborative study of 760 women from fragile X families, Allingham-Hawkins et al. (1999) found that 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. In 63 (16%) of the premutation carriers, menopause occurred before the age of 40, compared with none of the full-mutation carriers and 1 (0.4%) of the controls, indicating a significant association between premature menopause and premutation carrier status.

Among 109 female premutation carriers, Hundscheid et al. (2000) found that POF had occurred in 23 (28%) of 82 with paternal inheritance and only 1 (3.7%) of 23 with maternal inheritance. Kaplan-Meier analysis of a larger group of 148 premutation carriers showed that the age at menopause was significantly lower in the women with paternal inheritance compared to those with maternal inheritance (p = 0.003 with Breslow test in Kaplan-Meier analysis). Hundscheid et al. (2000) hypothesized a paternal imprinting effect on POF in fragile X premutation carriers. Expression of the FMR1 gene and other X-linked genes is nonfunctional during normal spermatogenesis, when the X chromosome becomes condensed and transcriptionally inactive. Most genes are reactivated during the first few cell divisions after fertilization, whereas 2 X chromosomes are active in the female morula. However, when a paternal gene is imprinted, there may be a delay in reactivation of the inactive paternal X chromosome during early embryonic development; thus, only the maternal allele would be expressed at this critical developmental stage. Although there was no direct evidence that abnormal FMR1 protein production in oocytes leads to a smaller oocyte pool, it was considered possible that FMR1 protein plays a role in oogenesis, because FMR1 is highly expressed when oogenesis occurs. Murray et al. (2000) and Vianna-Morgante and Costa (2000) were unable to confirm a parent-of-origin effect on premature ovarian failure in fragile X premutation carriers. The reason for the discrepancy with the findings of Hundscheid et al. (2000) was discussed by Hundscheid et al. (2000) and Sherman (2000).

Machado-Ferreira Mdo et al. (2004) studied 58 women from 24 families with fragile X syndrome. Using Southern blotting for direct DNA analysis, they identified 19 normal individuals, 33 premutation carriers, and 6 fully mutated individuals; the results included 4 cases of somatic mosaicism showing premutated and fully mutated alleles. Among the premutated women, 11 (including 1 case of somatic mosaicism) experienced menopause before the age of 40 (POF), while none of the normal women identified in these families experienced POF. The data corroborated the notion that females carrying alleles in the premutation range are at high risk of experiencing POF.

Among 53 unrelated women with POF, Bretherick et al. (2005) found a significant increase in the number of FMR1 alleles (14.2%) in the intermediate or high-normal zones (35 to 54 CGG repeats) compared to 161 controls (6.5%) and 21 women with proven fertility at an advanced age (4.8%). Two individuals with premature ovarian failure had premutation alleles (62 and 80 repeats, respectively), 1 control individual had a premutation allele (70 repeats), and 1 control had a full mutation allele.

Murray et al. (2014) studied FMR1 CGG repeat number in more than 2,000 women from the Breakthrough Generations Study who underwent menopause before the age of 46. The authors determined the prevalence of premutation FMR1 alleles (55-200 CGG repeats) and intermediate (45-54 CGG repeats) alleles in 254 women with primary ovarian failure, defined as menopause prior to the age of 40, and 1,881 with early menopause, defined as menopause between the ages of 40 and 45. The prevalence of the premutation was 2.0% in primary ovarian failure and 0.7% in early menopause compared with 0.4% in controls, corresponding to odds ratios of 5.4 (95% CI = 1.7-17.4; p = 0.004) for primary ovarian failure and 2.0 (95% CI = 0.8-5.1; p = 0.12) for early menopause. Intermediate alleles were not significant risk factors for either early menopause or primary ovarian failure.

Associations Pending Confirmation

In a cohort of 200 women with POF who did not carry a FRAXA premutation, Murray et al. (1999) screened for mutations in the FMR2 gene (AFF2; 300806) and found an excess of FMR2 alleles with fewer than 11 repeats. Sequence analysis of these alleles showed that the excess was caused by 3 individuals carrying cryptic deletions in FMR2, the gene associated with FRAXE. Murray et al. (1999) proposed that microdeletions in FMR2 may be a significant cause of POF, being found in 1.5% of the population with POF, but in only 0.04% of the general population.

For discussion of a possible association between POF and variation in the INHA gene, see 147380.0001.

For discussion of a possible association between POF and variation in the DMC1 gene, see 602721.0001.

Animal Model

Shiina et al. (2006) observed that female Ar (313700)-null mice appeared normal but developed premature ovarian failure with aberrant ovarian gene expression. Eight-week-old Ar -/- females were fertile, but had lower follicle numbers and impaired mammary development, and produced only half of the normal number of pups per litter. Forty-week-old Ar -/- females were infertile due to complete loss of follicles. Genomewide microarray analysis of mRNA from Ar -/- ovaries revealed that a number of major regulators of folliculogenesis were under transcriptional control by Ar. Shiina et al. (2006) suggested that AR function is required for normal female reproduction, particularly folliculogenesis.