Human Granulosa Cells: Insulin and Insulin-Like Growth Factor-1 Receptors and Aromatase Expression Modulation by Metformin

Abstract

Background/Aim: Granulosa cells are the source of the most important ovarian steroids. Even in patients without significant improvement in metabolic parameters, metformin has apparently an important effect on the ovary. The aim of this study was to evaluate gene and protein expression of an insulin receptor (IR), insulin-like growth factor-1 (IGF1) receptor (IGF1R) and aromatase in granulosa cells treated with metformin and insulin. Methods: Luteinized granulosa cells were collected from 27 patients during in vitro fertilization procedures. Cells were isolated, stored in culture for 24 h and divided into four groups: control; metformin for 30 min, and metformin for 30 min plus insulin for 30 or 60 min. Results: IR and IGF1R mRNA expression was significantly enhanced by metformin but was not affected by insulin. Aromatase mRNA expression was significantly reduced in metformin-incubated cells following stimulation with insulin for 30 min. No statistical differences were found in IGF1R and aromatase protein expression, and IR expression was not detected. Conclusion: A direct effect of metformin on the gene expression of IGF1R, IR and aromatase was observed. Further studies should investigate the role of IGF1R, IR and aromatase in ovarian physiology for a better understanding of the effect of metformin.

Ovarian hyperstimulation syndrome: pathophysiology, staging, prediction and prevention

“…One of these target tissues is the granulosa cells in the ovaries. Metformin changes the insulin‐dependent metabolism of glucose in granulosa cells, and decreases ovarian sensitivity to FSH, possibly ameliorating the response to COS.…”

Modulation of gonadotrophin induced steroidogenic enzymes in granulosa cells by d-chiroinositol

“…The PCOS is characterized by elevated levels of insulin and IGF-1R [42] and it has been hypothesized that this could influence the pathogenesis of the syndrome and the alterations of sexual steroids commonly frequent in patients affected by PCOS. IGF-1R is present on the cellular membrane of hGCs [43] and it has been demonstrated that different insulin sensitizer drugs such metformin are able to modulate gene expression [20, 44]. …”

“…Insulin has been reported to be able to interact with steroidogenic enzymes in granulosa and luteinic cells of the ovaries [16–20]. Specifically insulin seems to potentiate the FSH and luteinizing hormone (LH) induction of cytochrome P450 family 19 subfamily A member 1 ( CYP19A1 ) aromatase and this effect has been shown to be so evident that insulin is considered by many as a co-gonadotrophin [17–19, 21].…”

Metformin in Reproductive Biology

“…Culture of luteinized granulosa cells exposed to the pre-ovulatory LH surge and with metformin lowers progesterone and estradiol syntheses in the same manner as non-luteinized granulosa cells exposed to either FSH or insulin ( 85 ). Rice et al and Fuhrmeister et al have demonstrated, that metformin induces a decrease in estradiol synthesis via the inhibition of aromatase expression by the MAPK signaling pathway ( 86 , 87 ). However, metformin also induces activation of insulin-dependent AMPK pathways involved in lactate production by human granulosa cells ( 88 , 89 ).…”