Mechanisms of primary ovarian insufficiency
INVITED SPEAKERS / COMUNICAÇÕES POR CONVITE
CC-01
Mechanisms of primary ovarian insufficiency
Sophie Christin-Maitre, MD, PhDI
IEndocrine Unit, AP-HP Hôpital Saint-Antoine, INSERM U933 Université Pierre et
Marie Curie, Paris, France
sophie.christin-maitre@sat.aphp.fr
Primary ovarian insufficiency (POI) affects 1-2% of the general population.
Patients have primary or secondary amenorrhea, lasting more than 4 months,
occurring before the age of 40. Their plasma gonadotropins, measured twice, are
elevated (FSH > 20 IU/L) with low estradiol levels.
In the absence of previous chemotherapy, radiotherapy and ovarian surgery,
genetic causes of POI need to be investigated. Many of them are linked to X
chromosomal abnormalities, such as Turner syndrome with 45,X karyotype or 45,X/
46,XX mosaicism. Two copies of two different regions located on Xq, named POF1
and POF2, are necessary for the maintenance of ovarian follicles. As those
regions escape X inactivation, due to their haploinsufficiency in Turner
syndrome, ovarian follicle loss is accelerated. Apart from Turner syndrome, the
patient's karyotype can reveal Xq deletions as well as X autosomal
translocations. In rare cases gene disruption is involved. However, those Xq
regions are poor in gene and a position effect on autosomal gene might be
responsible for follicle depletion. Taken together, X chromosome abnormalities
represent around 10 -15% of POI.
Mental retardation in males from the family, related to fragile X syndrome,
should be searched for, as FMR1premutations are identified in 3% and 13% of
sporadic cases and familial cases of POI, respectively. The main mechanism
involved is an increased mRNA inducing ovarian toxicity.
In patients with blepharophimosis, POI can be related to FOXL2mutations. POI
may also be linked to autoimmunity. It may rarely belong to Autoimmune
Polyendocrinopathy ECtodermal Dystrophy (APECED) due to AIREmutations. More
frequently, it is associated with type 1 diabetes, adrenal insufficiency,
hypothyroidism as well as vitiligo, lupus . As the genes involved in APS2 and
APS4 have not been identified so far, the autoimmune origin of POI is often
difficult to prove. In less than 2% of cases, POI is due to SF1mutations.
Many genetic causes of POI are non syndromic. The main one is NOBOXgene
mutations, coding for a protein expresse in the oocyte, identified in 6% of POI
cases. Other genes such as elF4ENIF1, STAG 3, HFM1, MCM8and MCM9have been
identified recently.
More than 30 candidate genes have been identified so far in POI. They can be
tested by Next Generation Sequencing. However, the cause of POI is identified
in less than 30% of cases. Studying familial cases of POI should increase our
knowledge in the near future.
Largo do Prof. Abel Salazar
4099-001 Porto
nascerecrescer@chporto.min-saude.pt
