Alpha-ketoglutarate ameliorates induced premature ovarian insufficiency in rats by inhibiting apoptosis and upregulating glycolysis

Abstract

Research questionWhat are the effects of alpha-ketoglutarate (α-KG) treatment on the ovarian morphology and ovarian reserve function of rats with cyclophosphamide (CTX)-induced premature ovarian insufficiency (POI)? DesignThirty female Sprague Dawley rats were randomly allocated to a control group (n = 10) and a POI group (n = 20). Cyclophosphamide was administered for 2 weeks to induce POI. The POI group was then divided into two groups: a CTX-POI group (n = 10), administered normal saline, and a CTX-POI + α-KG group (n = 10), administered α-KG 250 mg/kg per day for 21 days. Body mass and fertility was assessed at the end of the study. Serum samples were collected for hormone concentration measurement, and biochemical, histopathological, TUNEL, immunohistochemical and glycolytic pathway analyses were conducted for each group. ResultsThe α-KG treatment increased body mass and ovarian index of rats, partially normalized their disrupted estrous cycles, prevented follicular loss, restored ovarian reserve, and increased pregnancy rate and litter sizes of rats with POI. It significantly reduced serum concentration of FSH (P < 0.001), increased that of oestradiol (P<0.001) and reduced apoptosis of granulosa cells (P = 0.0003). Moreover, α-KG increased concentrations of lactate (P = 0.015) and ATP (P = 0.025), reduced that of pyruvate (P<0.001) and increased expression of rate-limiting enzymes of glycolysis in the ovary. Conclusionsα-KG treatment ameliorates the deleterious effects of CTX on the fertility of female rats, possibly by reducing the apoptosis of ovarian granulosa cells and restoring glycolysis.