Differential effects of progestins on the circulating IGF-I system

Objective: Circulating insulin-like growth factor-I (IGF-I) is mainly produced by the liver under GH stimulation and is influenced by nutrition and insulin. IGF-I bioavailability is regulated by interactions with specific binding proteins (IGFBPs). The objective of this paper is to review available data on modifications of the IGF-I system in menopausal women during HRT, with particular attention on the differential effects of progestins. Method: All available reports on the effects of different forms of HRT have been taken into account. Results: Available data suggest that different kinds of HRT have different effect on the IGF-I system, depending on route of administration, oestrogen dose, basal IGF-I values and type of progestin. Oestrogen administration (oestrogen replacement therapy (ERT)) reduces circulating IGF-I mainly through a hepatocellular effect. The decrease is sharper when oral ERT is used (first pass hepatic effect) and in women with higher basal IGF-I levels. The progestins endowed with androgenic effects—the 19-nortestosterone derivatives and, to a lesser extent, medroxyprogesterone acetate (MPA)—tend to reverse the IGF-I decrease induced by oral oestrogens. In contrast, progestins devoid of androgen-like hepatocellular and metabolic actions (e.g. dydrogesterone) do not interfere with the IGF-I decrease induced by oral oestrogens. Data on the effect of ERT on IGFBP-3 level are not consistent. Oral ERT, via hepatocellular actions (amplified by the first pass hepatic effect) causes a two to three-fold increase in IGFBP-1 levels. Androgenic progestins oppose the IGFBP-1 increase induced by oral oestrogens. Data on the effect of ERT and different progestins on the level of free IGF-I are scant and inconsistent. Conclusion: Even if some aspects need clarification, available data demonstrate that different progestins have differential effects on the circulating IGF-I system.