Role of insulin and insulin resistance in androgen excess disorders

Table 1 Studies demonstrating cellular mechanisms of insulin resistance in women with polycystic ovary syndrome

Ref.	Objective	Method(s)	Main result(s)	Conclusion
Dunaif et al[22]	To investigate the cellular mechanisms of insulin resistance in PCOS.	Cultured skin fibroblasts from 14 women.	Increased serine phosphorylation and reduced tyrosine phosphorylation of insulin receptor.	One of the mechanisms of insulin resistance at the receptor level was demonstrated. However, 50% of women did not show this abnormality, indicating heterogeneity in the pathogenesis of insulin resistance in PCOS.
Book and Dunaif[23]	To explore the mechanisms of the paradox in metabolic and mitogenic actions of insulin.	Metabolic and mitogenic actions of insulin and IGF-1 were evaluated in cultured skin fibroblasts of 16 PCOS and 11 control women.	No difference in the number and affinity of insulin receptor in either group. Decreased glucose incorporation into glycogen in women with PCOS.Thymidine incorporation was similar between the groups.	Women with PCOS show decreased metabolic action but mitogenic action of insulin signaling was similar between the groups.
Belani et al[24]	To unravel insulin and steroidogenic signaling pathways in PCOS.	Insulin receptor beta subunit expression was investigated in luteinized granulosa cells obtained from 30 healthy women and 39 women with PCOS.	Compared to controls, 64% of cells show reduced insulin receptor beta subunit expression.Insulin-resistant women also showed decreased PI3 kinase expression.	Lower viability of luteinized granulosa cells in insulin-resistant women with PCOS.

PCOS: Polycystic ovary syndrome; IGF-1: Insulin-like growth factor-1; PI3 kinase: Phosphatidylinositol-3-kinase.

Table 2 Studies showing the effects of insulin on ovarian and adrenal hormone secretion

Ref.	Objective	Method(s)	Main result(s)	Conclusion
Cadagan et al[34]	To investigate the effects of insulin and LH on PCOS theca cell CYP17 expression and androgen secretion.	Cells were obtained from three women with PCOS and three healthy women.	PCOS theca cells exhibit increased CYP17 enzyme activity/expression and increased androgen secretion.	There is a defect of steroid biosynthesis in ovarian theca cells, which is further augmented under hyperinsulinemia and increased LH secretion.
Munir et al[35]	To define the intracellular signaling pathways that link the insulin receptor to androgen biosynthesis.	Third-passage human ovarian theca cells were used.	Insulin regulation of 17-alpha hydroxylase activity is mediated by PI3 kinase.	Insulin stimulates ovarian androgen production, which is different from the effects on glucose metabolism.
la Marca et al[36]	To test the hypothesis of the linkage of hyperinsulinemia and abnormal activity of P450CYP17.	HCG test before and one month after metformin (1500 mg/d) therapy in 11 women with PCOS	After metformin, women with PCOS had significantly lower insulin and testosterone concentrations as well as lower 17-OHP responses.	Metformin leads to a reduction in stimulated ovarian P45017-alpha hydroxylase activity.
Homburg et al[37]	To elucidate the relationship and role of IGF-1, IGFBP-1, insulin and LH in the pathogenesis of PCOS.	Serum concentrations of IGF-1, IGFBP-1, insulin and LH in women with PCOS with or without anovulation.	Similar serum IGF-1 levels were found. However, IGFBP-1 levels were decreased in anovulatory PCOS, which is negatively correlated with insulin concentrations.	Hyperinsulinemia and raised LH are independently capable of stimulating ovarian androgen production. Growth factors may have a role in PCOS pathogenesis.
Tosi et al[38]	To investigate the role of hyperinsulinemia on adrenal steroidogenesis in women with PCOS.	Hyperinsulinemic clamp and saline infusion tests were performed on separate days in 12 hyperandrogenic women. Concurrent ACTH infusion to evaluate intermediate metabolites of adrenal steroid biosynthesis.	Acute insulin elevation resulted in an increased response of 17 alpha hydroxysteroid intermediates.Increased 17-OHP/androstenedione and 17-OH pregnanolone/DHEA molar ratio suggest relative inhibition of 17-20 lyase activity by insulin.	Acute hyperinsulinemia in a range found in insulin-resistant individuals enhances adrenal response to ACTH stimulation.

PCOS: Polycystic ovary syndrome; LH: Luteinizing hormone; PI3 kinase: Phosphatidylinositol-3-kinase; P450CYP17: Cytochrome 450, 17 hydroxylase; HCG: Human chorionic gonadotropin; 17-OHP: 17-hydroxyprogesterone; IGF-1: Insulin-like growth factor-1; IGFBP-1: Insulin-like growth factor-binding protein-1; ACTH: Adrenocorticotropic hormone; DHEA: Dehydroepiandrosterone.