The aetiology of POI is poorly understood and clearly multifactorial. In approximately 90% of women no underlying cause will be identified (idiopathic POI).

Genetic

  • X-chromosome abnormalities

These are found more commonly in women presenting with primary amenorrhoea. The most common abnormality found is Turner syndrome (45XO) or mosaic Turner syndrome (45X/46XX).

 

  • Fragile X premutation

This is currently the most commonly identified gene mutation in women with POI. Women who carry the FMR1 gene premutation have been estimated to have a 23% risk of developing POI, furthermore they are at risk of having a child with Fragile X syndrome.

 

  • Autosomal disorders

Many other genetic mutations have been associated with POI, either occurring in isolation (e.g. mutations in FSH receptors or in gene which regulate folliculogenesis or follicular atresia) or as part of rare inherited syndromes (e.g. autoimmune polyglandular syndrome type 1 and blepharophimosis–ptosis–epicanthus inversus syndrome type 1). Isolated autosomal mutations are not frequently identified in current routine clinical practice.

 

Autoimmune

It has been estimated that approximately 5% of POI is due to autoimmunity.  This is the result of adrenal, ovarian and other steroidogenic cell autoantibodies, which can cause an autoimmune oophoritis and follicular destruction. Women with POI are also at higher risk of other autoimmune disorders including hypothyroidism and diabetes mellitus.

Infection

POI has been linked to various infections including mumps, tuberculosis, malaria, HIV and cytomegalovirus. Data is mainly restricted to case reports and, with the exception of mumps oophoritis, direct links have not yet been established. Screening for infection is therefore not recommended as part of the routine diagnostic tests in POI.

Iatrogenic

POI is commonly seen in association with treatment of malignancy as a result of surgery or chemo- or radiotherapy. The risk of developing POI after chemotherapy depends on several factors including the regimen used, the age of the patient and the type of cancer. Bone marrow transplant for other medical conditions such as B-thalassaemia may also result in POI.

POI may also occur due to surgical treatment of benign gynaecological disorders such as severe endometriosis, ovarian cysts or premenstrual syndrome.

References:

  • Nelson LM. Clinical practice. Primary ovarian insufficiency. N. Engl. J. Med. 360, 606–614 (2009).
  • Willemsen R, Levenga J, Oostra BA. CGG repeat in the FMR1 gene: size matters. Clin. Genet. 80, 214–225 (2011).
  • Persani L, Rossetti R, Cacciatore C. Genes involved in human premature ovarian failure. J. Mol. Endocrinol. 45, 257–279 (2010).
  • Silva CA, Yamakami LY, Aikawa NE, Araujo DB, Carvalho JF, Bonfa E. Autoimmune primary ovarian insufficiency. Autoimmun. Rev. 13, 427–430 (2014).
  • Green DM, Sklar CA, Boice JD Jr et al. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J. Clin.Oncol. 27, 2374–2381 (2009).