Endocrine Abstracts

Premature ovarian failure or primary ovarian insufficiency (POI) is characterized by amenorrhea occurring before the age of 40-year-old, with elevated gonadotropins (FSH >20 mIU/ml). It affects 1–2% of women. So far, in more than 75% of cases, its etiology remains unknown.

The obvious causes are chemotherapy, radiotherapy and ovarian surgery, mainly for bilateral ovarian endometriomas. Genetic causes of POI include rare diseases, such as blepharophimosis, galactosemia, Perrault syndrome, APECED syndrome (autoimmune polyendocrinopathy and candidosis ectodermal dystrophy) or most frequently Turner syndrome. Apart from 45X monosomy, or 46XX, 45X mosaicisms from Turner syndrome, other X chromosome abnormalities can be identified such as Xq deletions, X, autosome translocations and FRAXA premutations. In familial cases, FRAXA premutations are identified in 13% of cases. SF1 (NR5A1) mutations are rare, <2% of cases, initially described in families including 46XY DSD patients.

In the past years, new genes have been identified thanks to animal models and powerful genetic techniques such as CGH-array, GWAS and exome sequencing. For instance, disruption of Newborn Ovary Homeobox (Nobox) gene induces non syndromic ovarian failure in mouse. NOBOX mutations have been identified in 6% of cases in a large cohort of POI patients. Furthermore, familial studies have identified regions linked to POI. Recently a mutation in stromal antigen 3 (STAG3) has been found in a consanguineous family. After informed consent, a karyotype should be performed as well as a search for FRAXA premutation. Next generation sequencing is starting to test a panel of genes within a single analysis.

Hormonal replacement therapy associating estrogen and progestin is recommended in patients with POI until the age of natural menopause. POI should not be considered as premature menopause as HRT is necessary and reversibility of ovarian failure can be noticed in some cases.