Etiology
Although the cause remains unidentified in most of the cases with primary ovarian failure, the disorder develops through two mechanisms: follicle dysfunction and follicle absence. In follicle dysfunction, ovaries do contain follicles but these do not function normally as a result of diverse pathologic events. Follicle absence, on the other hand, is associated with insufficient intrauterine primordial follicle count or rapid depletion of follicles due to several genetic and environmental factors (8-11). Table 1 lists POF causes by these mechanisms.
A single X chromosome is sufficient for ovarian differentiation (12). However, in cases without two intact X chromosome as in individuals with Turner’s syndrome (45,X0), ovarian follicles degenerate with delivery. The second X chromosome ensures continued ovary functioning (13). Absence of a second X chromosome leads to ovarian dysgenesis in almost all cases and to primary amenorrhea and, rarely, secondary amenorrhea (14). The most common chromosome abnormality leading to POF is the absence of X chromosome (15). Menstruation may continue for a couple of years in mosaic cases of Turner’s syndrome (45,X/46,XX) (16).
Fragile X syndrome is a clinical condition resulting from increased repeated formation of triple nucleotide sequences at the first exon of the FMR1 gene (Xq27.3). Fragile X syndrome occurs when the number of repeated triple nucleotide sequences exceeds 200 and no transcription occurs at the FMR1 gene and, as a consequence, no FMR1 protein is expressed (17). Healthy individuals have less than 60 repeated sequences of this gene loculation. Fragile X premutation develops when the number of repeated sequence is between 60 and 200 and is a FMR1 protein-expressing condition (18). Individuals who are carriers of premutation have less than expected oocytes in the ovaries at the time of birth (19). Women who develop premature ovarian failure are 10-fold more likely to carry fragile X premutation compared to the overall population. A woman with sporadic POF is 2-5% more likely to have fragile X premutation. It is identified in 13-15% of individuals with familial POF (19-21).
Mutations in autosomal gene have also been found to be associated with POF. Studies on mutations in receptors and gonadotropins have revealed that these very rare conditions could also lead to POF. Point mutation, which causes inactivation at the FSH receptor, has autosomal recessive contribution and is responsible for the POF cases first identified in Finland (22). Mutation at the short arm of the second chromosome results in the synthesis of alanine instead of valine amino acid. In individuals with this mutation, the ovaries are hypoplasic and contain less primordial follicles histologically, whereas complete ovarian dysgenesis and streak ovary syndrome are never observed. In individuals with FSH receptor mutation, secondary amenorrhea develops over the years following normal puberty (23).
Autocrine- and paracrine-regulating mechanisms at follicular microenvironments such as the hypothalamic-pituitary-ovarian system are also known to be involved during the continued folliculogenesis. Most of the regulating factors released from the oocyte and granulosa cells belong to the Transforming Growth Factor (TGF) super-family (24). This family includes activin/inhibin, Bone Morphogenetic Protein (BMP) and Growth Differentiation Factor subgroups. By controlling FSH via the negative feedback mechanism, inhibin ensures completion of folliculogenesis. In premenopausal women, serum inhibin levels start to elevate before the onset of menopausal symptoms. Inhibin, which reflects the decreased ovarian follicle capacity, is therefore a good indicator (25). In a study with 43 POF cases, gene mutation of inhibin, a glycoprotein, at the alpha subunit was shown in 3 women (7%), but in only one woman (0.7%) in the control group of 150 subjects (26).
Cases of spontaneous 46,XX POF may by the component of a syndrome. Mutation at the ATM gene (ataxia-telangiectasia mutated), which is responsible for ataxia- telangiectasias syndrome characterized by cerebellar ataxia, telangiectasias, immune defects, cancer predisposition and premature ageing, may result in ovarian failure (2).
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) develops as a result of mutation at the type 1 FOXL2 (forkhead box L2) gene and may be a cause of POF (27). FOXL2 gene has an important role in early ovarian differentiation and in maintaining ovarian function (28).
Galactosemia affects one in every 60000 neonates and exhibits autosomal recessive involvement. With a clinically heterogeneous presentation, galactosemia results from complete or partial deficiency of galactose 1-phosphate uridyl transferase (GALT). Excessive amounts of galactose 1-phosphate (Gal 1-P) accumulate in the plasma of such individuals. Although the mechanism that leads to POF in galactosemia in not known, apoptosis secondary to accumulation of Gal 1-P or other galactose metabolites at the oocyte or ovarian stromal cells may be the underlying cause (29).
Primary ovarian failure polyglandular syndrome (hypothyroidism, adrenal insufficiency and hypoparathyroidism) may co-exist with autoimmune conditions including dry eye syndrome, myastenia gravis, rheumatoid arthritis, diabetes mellitus or systemic lupus erythematosus (8,30,31). The incidence of anti-ovarian antibodies differs significantly among patients with primary ovarian failure (0-67%). Establishing their roles and clinical relevance is challenging due to very variable ELISA tests and because anti-ovarian antibodies may be present only temporarily, and there is a weak correlation between antibody values and the severity of the condition. IgG-type steroid cell antibodies have been found as bound to the hilar, granulosa and theca cells of the ovary. These antibodies, however, are present in Addison’s disease rather than isolated POF patients. Development of POF in 10-15 years has been reported in 42.8% of Addison’s disease patients who were carriers of steroid cell antibodies (32). Anti-ovarian antibody measurement is not recommended in patients with POF due to the poor specificity of the assay (33).
Primary ovarian failure ovarian may develop as a result of surgical interventions, viral infections or exposure to environmental toxic agents, although the leading causes of acquired conditions are chemotherapy and radiotherapy. Agents used to treat autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis and those that are used to prevent rejection after organ transplantation result in gonadal damage. The type of cancer, intensity of treatment and patient’s age during treatment determine the risk of (34).
Chemotherapy-associated ovarian damage occurs due to disturbed follicular maturation or primordial follicle depletion or both (35,36). Alkylating agents used for the treatment of Hodgkin’s disease or autoimmune diseases are the chemotherapeutics which are most commonly associated with gonadal damage (35,37,38). These agents do not need cell proliferation to exert cytotoxic effect and may destroy resting oocyte and primordial follicle’s pregranulosa cells (36). Anti-metabolites used for the treatment of breast cancer exert their activity on split cells and thus cause less damage on the ovaries. Methotrexate is used at high doses for the treatment of osteosarcoma and has recently found increasing use in ectopic pregnancies. Although there is some evidence suggesting that methotrexate affects gonadal functions, the agent is considered to have no effect on ovary functions (39). While there are studies indicating that gonadotropin-releasing hormone agonists co-administered with chemotherapy may protect oocyte functions (40-42), this treatment needs to be investigated by extensive randomized studies.
Ovaries are highly susceptible to radiation. Patient age, the extent, dose and type of the radiotherapy administered are important prognostic factors in POF development. Single-dose radiotherapy causes more damage on the oocytes than radiotherapy in divided doses. While abdominal and pelvic irradiation present the highest risk for the ovaries, even scattered radiation in therapies where the ovaries are out of the radiation scope may result in significant ovarian damage (37).
