Modulation by progestogens of the effects of oestrogen on hepatic endocrine function in postmenopausal women

OBJECTIVE: Oral but not transdermal oestrogen administration reduces IGF-I, and increases GH binding protein (GHBP) reflecting effects on hepatic endocrine function in postmenopausal women. As progestogens attenuate the effects of oestrogen on circulating lipid levels according to their androgenic properties, we have investigated the impact of progestogen types on the hepatic endocrine effects of oestrogen. DESIGN: Four progestogens differing in androgenicity were co-administered in a monthly cyclical regimen in random order to postmenopausal women receiving either oral (n = 9, premarin 1.25 mg) or transdermal (n = 10, Estraderm 100 microg patches twice weekly). The four progestogens were cyproterone acetate (CA 5 mg, antiandrogenic), dydrogesterone (20 mg, neutral), medroxyprogesterone acetate (MPA 10 mg, mildly androgenic), norethisterone (2.5 mg, androgenic). PATIENTS: Nineteen postmenopausal women (age 57 +/- 3 years, mean +/- SE) were studied. MEASUREMENTS: The effects of oestrogen alone and the combined effects with each progestogen type on IGF-I, GHBP, SHBG, cholesterol, triglycerides and lipoprotein(a) were investigated. RESULTS: Mean IGF-I fell while GHBP and SHBG levels increased with oral (P < 0.01) but not transdermal oestrogen administration. When the combined effects were examined, progestogens did not affect IGF-I, GHBP and SHBG during oral oestrogen treatment, while they significantly increased (P < 0.01) mean IGF-I levels during transdermal therapy. Among the progestogen types, only norethisterone prevented the fall in IGF-I induced by oral oestrogen. During transdermal therapy, MPA and norethisterone but not CA or dydrogesterone significantly increased (P < 0.005) IGF-I. The rise in GHBP induced by oral oestrogens tended to be lower during co-administration of MPA and norethisterone. The increase in SHBG induced by oral oestrogen was attenuated (P < 0.05) by norethisterone which was the only progestogen that lowered SHBG (P < 0.05) during transdermal oestrogen treatment. Mean IGF-I was higher (P < 0.001), GHBP and SHBG lower during co-administration of androgenic progestogens (MPA and norethisterone). CONCLUSIONS: Oestrogen effects on IGF-I, GHBP and SHBG are dependent on the route of administration with progestogens having variable effects. Among the progestogen types, norethisterone, the most androgenic, had the greatest effect, particularly on IGF-I. Progestogens modulate the effects of oestrogen on hepatic endocrine function in relation to their intrinsic androgenic properties. The modulatory effects of progestogens on IGF-I during oestrogen therapy may have long-term implications for lean body mass.