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Background The protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates early follicular activation and follicular pool maintenance in female germline cells. Fragile X mental retardation 1 ( FMR1 ) regulates folliculogenesis and it is variably expressed in patients with Premature Ovary Insufficiency.  FMR1  expression is supposed to be linked to AKT/mTOR signaling in an ovarian response dependent manner as demonstrated in recent  in  vitro  and  in  vivo  studies in the female germline  in  vitro  and  in  vivo . Methods We evaluated changes in the expression of AKT/mTOR signaling pathway genes by real time PCR in the peripheral blood of 74 patients with Premature Ovarian Insufficiency and 56 fertile controls and correlated their expression with  FMR1  expression. Results Expression of the genes  AKT1 ,  TSC2, mTOR , and  S6K  was significantly more abundant in patients with POI than in the controls. For  AKT1 ,  TSC2  and  mTOR,  gene expression was not affected by  FMR1 -CGG repeat number in the 5´-untranslated region.  FMR1  and  S6K  expression levels ,  however, were significantly upregulated in patients with POI and an  FMR1  premutation. Independent of a premutation, expression of  mTOR ,  S6K , and  TSC2  was significantly correlated with that of  FMR1  in all patients. Furthermore, when grouped according to ovarian reserve, this effect remained significant only for  mTOR  and  S6K , with higher significance note in patients with Premature Ovarian Insufficiency than in the controls. Conclusions In Premature ovarian insufficiency patients, activation of AKT/mTOR signaling pathway is remarkable and putatively pathognomonic. Additionally, it seems to be triggered by an  FMR1 / mTOR / S6K  linkage mechanism, most relevant in premutation carriers.

reproductive biology and endocrinology

Activation of AKT/mammalian target of rapamycin signaling in the peripheral blood of women with premature ovarian insufficiency and its correlation with FMR1 expression