The underlying mechanisms of
polycystic ovarian syndrome (PCOS)-induced endometrial dysfunction are not fully understood, and although accumulating evidence shows that the use of
metformin has beneficial effects in PCOS patients, the precise regulatory mechanisms of
metformin on endometrial function under PCOS conditions have only been partially explored. To address these clinical challenges, this study aimed to assess the
protein expression patterns of glycolytic
enzymes,
estrogen receptor (ER), and
androgen receptor (AR) along with differences in mitochondria-dependent apoptosis in PCOS patients with and without
endometrial hyperplasia in vivo and to investigate the effects of
metformin in PCOS patients with
endometrial hyperplasia in vitro. Here, we showed that compared to non-PCOS patients and PCOS patients without
hyperplasia, the endometria from PCOS patients with
hyperplasia had a distinct
protein expression pattern of glycolytic
enzymes, including
pyruvate kinase isozyme M2
isoform (PKM2) and
pyruvate dehydrogenase (PDH), and
mitochondrial transcription factor A (TFAM). In PCOS patients with
endometrial hyperplasia, increased glandular epithelial cell secretion and infiltrated stromal cells in the glands were associated with decreased PDH immunoreactivity in the epithelial cells. Using endometrial tissues from PCOS patients with
hyperplasia, we found that in response to
metformin treatment in vitro,
hexokinase 2 (HK2) expression was decreased, whereas
phosphofructokinase (PFK), PKM2, and
lactate dehydrogenase A (LDHA) expression was increased compared to controls. Although there was no change in PDH expression,
metformin treatment increased the expression of TFAM and cleaved
caspase-3. Moreover, our in vivo study showed that while endometrial ERβ expression was no different between non-PCOS and PCOS patients regardless of whether or not
hyperplasia was present, ERα and AR
protein expression was gradually increased in women with PCOS following the onset of
endometrial hyperplasia. Our in vitro study showed that treatment with
metformin inhibited ERα expression without affecting ERβ expression. Our findings suggest that decreased glycolysis and increased mitochondrial activity might contribute to the onset of ERα-dependent
endometrial hyperplasia and that
metformin might directly reverse impaired glycolysis and normalize mitochondrial function in PCOS patients with
endometrial hyperplasia.