Regulation of the aromatase activity of human placental cytotrophoblasts by insulin, insulin-like growth factor-I, and -II.
Studies to be reviewed were stimulated by the clinical observation, albeit controversial, that diabetic pregnancy may be associated with lower serum oestrogen levels than nondiabetic pregnancy. Pregnant diabetic women are usually intensively treated with insulin to maintain euglycemia, frequently resulting in peripheral hyperinsulinemia. The placenta, which is the primary source of oestrogens during pregnancy, would be exposed to this elevation in circulating insulin levels. Similarly, insulin-like growth factors (IGFs), which are synthesized and secreted by placental tissues and could influence placental function in an autocrine or paracrine fashion, may be elevated in diabetic pregnancy. We will review studies, which show that (i) insulin, insulin-like growth factor-I (IGF-I), and -II inhibit the aromatase activity of human cytotrophoblasts, (ii) these peptides can inhibit aromatase by activation of their respective receptors, and (iii) the potency of IGF-II in suppressing aromatase greatly exceeds that of either insulin or IGF-I. Finally, evidence will be reviewed, which suggests that inositol-glycan mediators ('second messengers') serve as the signal transduction system for insulin's inhibition of aromatase activity. Hence, placental exposure to increased concentrations of insulin and/or IGFs in the pregnant diabetic woman may result in inhibition of aromatase activity and decreased serum oestrogen levels.
Nestler
J E
JE
Division of Endocrinology and Metabolism, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298.
D000735:Androstenedione / Q000378:metabolism; D001141:Aromatase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D007700:Kinetics; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D014327:Trophoblasts / Q000187:drug effects / Q000201:enzymology*
D004967:Estrogens; D007328:Insulin; D000735:Androstenedione; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D001141:Aromatase