The cause of spontaneous premature ovarian failure (POF) is unknown in the majority of women (occurring in up to 90% cases in one series) and is classified as karyotypically normal spontaneous premature ovarian failure (POF). Other causes of premature menopause (PM) include genetic abnormalities, metabolic or autoimmune disorders and medically induced PM (see Early Menopause Website Table: Causes of Premature Menopause).

Genetic

The majority of genetic disorders involve the X chromosome; however, autosomal abnormalities have also been identified. Although a number of candidate genes (for example,  POF 1 and 2 gene loci) have been identified, it is likely that POF is a heterogenous disorder and no specific locus is suitable as a genetic marker for PM at present. 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 commonly identified genetic abnormality associated with a normal karyotype is the FMR-1 gene premutation for fragile X syndrome which is associated with POF in up to 28% cases.

Medically induced

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, uterine artery embolisation and recurrent ovarian surgery. The rate of chemotherapy-induced premature menopause depends on age, cumulative dose, duration of therapy and agent involved. (see Epidemiology). 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 (see Epidemiology) This risk is further increased with combined chemotherapy / radiotherapy or radiotherapy / ovarian transposition / hysterectomy.

Autoimmune disorders

POF associated with autoimmune disease ranges from 20%- 40% cases, with both endocrine and non-endocrine disorders involved (see Early Menopause Website Table: Autoimmune disorders associated with POF). 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 insufficiency (occurring 8-14 years after the diagnosis of menopause) has been reported in 50% of women with positive adrenal antibodies and POF.

Metabolic Disorders

Metabolic disorders are rare causes of premature menopause. Galactosaemia, an autosomal recessive disorder secondary to galactose 1-phosphate uridyltransferase gene deficiency, is associated with POF in 60-70% cases. 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.

Other

Viral infections such as mumps oophoritis may cause POF with a reported incidence of 3-7%. The role of environmental factors and toxins in the pathogenesis of ovarian failure is unclear: however, polycyclic hydrocarbons are postulated to be the gonadotoxic factor in tobacco smoke.

References

• Hickey M, Peate M et al., Breast cancer in young women and its impact on reproductive function. Hum Reprod Update (2009) 15:323-339.
• Nippita TA and Baber RJ. Premature ovarian failure: a review. Climacteric (2007); 10:11-22.
• Sklar CA, Mertens AC et al., Premature menopause in survivors of childhood cancer: A report from the childhood cancer survivor study. J Natl Cancer Inst (2006) 98: 890-896.

7. Clinical Presentation

Content updated December 2010