The cause of premature menopause (PM) is unknown in the majority of women (occurring in up to 60% cases in one series) and is classified as karyotypically normal spontaneous premature ovarian failure. Other causes of premature menopause include genetic abnormalities, metabolic or autoimmune disorders and medically induced PM (see Table: Causes of Premature Menopause).

Genetic disorders account for approximately 10% of cases of premature ovarian failure (POF) / premature menopause. The majority involve the X chromosome, although autosomal abnormalities have also been identified. A number of candidate genes have been identified; however, none is suitable at present as a genetic marker for PM. It has become apparent that two functioning X chromosomes are necessary for normal ovarian function. X chromosome defects may involve numerical defects, such as Turner's syndrome and trisomy X, as well as partial defects including deletions, isochromosomes and translocations. The most common identified genetic abnormality (associated with a normal karyotype) is the premutation for fragile X syndrome (FRAXA) with 13% of familial cases and 3% of sporadic cases of POF showing this mutation in one series. A questionnaire study of 205 FRAXA carriers reported menopause occurring 6-8 years earlier than women in the general population and 28% of women experienced POF. Two loci have been identified within a "critical region" for normal ovarian function on the long arm of the X chromosome and designated POF1 and POF2. POF occurring at ages 24-39 are associated with deletions involving POF1 whereas translocations involving POF2 result in earlier onset POF, occurring at ages 16-21 years. POF can occur as part of the phenotype of rare autosomal gene mutations including the gonadotrophin receptor genes, genes coding for gonadotrophin subunits or inhibin, AIRE gene (responsible for autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy syndrome) and the FOXL2 gene (associated with blepharophimosis-ptosis-epicanthus inversus type 1 syndrome). Normal ovarian function is dependent upon an intact hypothalamo-pituitary- ovarian axis and disruption of any of the components (hormone or receptor) may lead to POF / PM.

Bilateral oophorectomy will obviously result in premature menopause. However, any pelvic surgery has the potential to cause ovarian failure via disruption of ovarian blood supply or precipitating inflammation. An increased risk of premature menopause is observed in women with single oophorectomy and/or hysterectomy although the magnitude of this increased risk remains unclear. An earlier menopause was reported in cervical cancer patients treated with ovarian transposition and radical hysterectomy. Uterine artery embolisation, a recent development in the treatment of uterine fibroids, has been associated with the loss of ovarian function in up to14% cases; with the majority of cases reported in women aged > 40 years. Recurrent ovarian surgery for cysts or endometriosis leading to reduced functional ovarian tissue also increases the risk of premature menopause.

The rate of chemotherapy-induced premature menopause depends on age, cumulative dose, duration of therapy and agent involved. An increased risk of premature menopause is observed in women older than 35 years, with higher dose chemotherapy, longer duration of treatment (after 6 courses) and when using alkylating agents such as cyclophosphamide. Stage of the menstrual cycle and genotype have also been implicated; an increased risk of amenorrhoea was observed when chemotherapy was given during the follicular phase and women with a specific P450 genotype were less likely to develop cyclophosphamide-induced premature menopause during treatment for lupus nephritis. Ovarian failure may occur abruptly or may develop insidiously.

Radiation exposure to the ovaries can occur with total body, craniospinal axis, whole abdominal and pelvic irradiation. The risk of premature menopause associated with radiotherapy increases with irradiation below the diaphragm, higher doses and increasing age. This risk is further increased with combined chemotherapy / radiotherapy or radiotherapy / ovarian transposition / hysterectomy. In one study of 1067 cancer survivors age 21 years compared with 1599 control women, a 4-fold increased risk of menopause was observed between the ages 21-25 years. Radiotherapy alone was associated with a relative risk (RR) of 3.7, use of alkylating agent alone RR 9.7, and combined therapy RR 27. By age 31, 42% of women had reached menopause compared with only 55 control women.

*putative risk factors only at present

POF associated with autoimmune disease ranges from 20%- 40% cases, with both endocrine and non-endocrine disorders involved. Clinical or sub-clinical (detection of auto-antibodies only) manifestations of the autoimmune disease may be present. Autoimmune thyroid disease is the most common association, reported in 27% of women in one prospective study. Adrenal autoimmunity is observed in 2-10% cases of POF. Importantly, POF may precede Addison's disease by 8-14 years. The autoimmune polyglandular failure syndromes (APS) types 1 and II are observed in 3% of patients with POF. POF manifesting as primary amenorrhoea occurs in 60% of affected females in the autosomal recessive APS Type I. Polygenic APS type II is associated with POF, occurring in the third to fourth decade, in up to 10% cases. Ovarian auto-antibodies and altered cellular immunity have been variably detected in women with POF; however their specificity and pathogenic role remains unclear.

Metabolic disorders are rare causes of premature menopause. Galctosaemia, an autosomal recessive disorder secondary to GALT gene deficiency, is associated with POF in 60-70% cases. Although usually due to hypopituitarism, ovarian failure secondary to iron overload associated with haemochromatosis or the treatment of Thalassemia major has been reported. Deficiency of 17a-hydroxylase results in ovarian failure secondary to impaired oestrogen and adrenal hormone synthesis. Ovarian failure has also been reported in association with aromatase deficiency.

Viral infections, such as mumps oophoritis, are thought to cause POF. The role of environmental factors and toxins in the pathogenesis of ovarian failure is unknown.

Content Updated November 20, 2007