Effects of the route of oestrogen administration on IGF-1 and IGFBP-3 in healthy postmenopausal women: results from a randomized placebo-controlled study
Emmanuel Sonnet, Karine Lacut,
Nathalie Roudaut, Dominique Mottier,
Véronique Kerlan, Emmanuel Oger,
Karine Lacut
EA 3878 GETBO, CHU de Brest, Hôpital Cavale Blanche, Brest, France
Search for more papers by this authorDominique Mottier
EA 3878 GETBO, CHU de Brest, Hôpital Cavale Blanche, Brest, France
Search for more papers by this authorEmmanuel Oger
EA 3878 GETBO, CHU de Brest, Hôpital Cavale Blanche, Brest, France
Search for more papers by this authorEmmanuel Sonnet, Karine Lacut,
Nathalie Roudaut, Dominique Mottier,
Véronique Kerlan, Emmanuel Oger,
Karine Lacut
EA 3878 GETBO, CHU de Brest, Hôpital Cavale Blanche, Brest, France
Search for more papers by this authorDominique Mottier
EA 3878 GETBO, CHU de Brest, Hôpital Cavale Blanche, Brest, France
Search for more papers by this authorEmmanuel Oger
EA 3878 GETBO, CHU de Brest, Hôpital Cavale Blanche, Brest, France
Search for more papers by this author Dr Emmanuel Sonnet, service Endocrinologie, Hôpital de la Cavale Blanche, CHU de Brest, Boulevard Tanguy Prigent, 29609 Brest cedex, France. Fax: 33 2 98 34 78 00; E-mail: [email protected]
Summary
Objective Oestrogens can modulate the action or secretion of GH. Previous studies in postmenopausal women have shown a differential effect between transdermal 17β-oestradiol and oral ethynyl-oestradiol on GH and IGF-1 concentrations. This secondary analysis, based on a large randomized trial, aimed to estimate the effect of the route of administration of 17β-oestradiol in combined hormone replacement therapy with progesterone on IGF-1 and IGFBP-3 levels.
Design IGF-1 and IGFBP-3 were evaluated in a randomized study of 196 healthy postmenopausal women who were randomly allocated to receive on a continuous basis either 1 mg of 17β-oestradiol orally combined with a daily intake of 100 mg progesterone (group 1; n = 63), or 50 µg of 17β-oestradiol transdermally combined with a daily intake of 100 mg progesterone (group 2; n = 68), or triple dummy placebo (group 3; n = 65) over a 6-month period. IGF1 and IGFBP-3 levels were available for 133 women.
Results Oral oestrogen significantly decreased IGF-1 levels compared to placebo (P = 0·04) and transdermal oestrogen (P = 0·004), whereas transdermal oestrogen had no effect on IGF-1 levels compared to placebo (P = 0·56). As regards IGFBP-3, no significant difference was detected between the three groups.
Conclusions Our data indicate that the route of oestrogen administration can influence IGF-1 levels. IGF-1 concentrations decreased significantly with oral oestrogen, whereas no significant change was observed with transdermal oestrogen at 6 months. The clinical relevance of these differential effects remains to be determined, particularly with regard to the risk for cardiovascular diseases.
References
- 1 Hulley, S., Grady, D., Bush, T., Furberg, C., Herrington, D., Riggs, B. & Vittinghoff, E. (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Journal of the American Medical Association, 280, 605–613.
- 2 Rossouw, J.E., Anderson, G.L., Prentice, R.L., LaCroix, A.Z., Kooperberg, C., Stefanick, M.L., Jackson, R.D., Beresford, S.A., Howard, B.V., Johnson, K.C., Kotchen, J.M. & Ockene, J.; Writing Group for the Women's Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative randomized controlled trial. Journal of the American Medical Association, 288, 321–333.
- 3 Lacut, K., Oger, E., Le Gal, G., Blouch, M.T., Abgrall, J.F., Kerlan, V., Scarabin, P.Y. & Mottier, D.; SARAH Investigators (2003) Differential effects of oral and transdermal postmenopausal estrogen replacement therapies on C-reactive protein. Thrombosis and Haemostasis, 90, 124–131.
- 4 Conti, E., Carrozza, C., Capoluongo, E., Volpe, M., Crea, F., Zuppi. C. & Andreotti, F. (2004) Insulin-like growth factor-1 as a vascular protective factor. Circulation, 110, 2260–2265.
- 5 Juul, A., Scheike, T., Davidsen, M., Gyllenborg, J. & Jorgensen, T. (2002) Low serum insulin-like growth factor 1 is associated with increased risk of ischemic heart disease. A population-based control study. Circulation, 106, 939–944.
- 6 Laughlin, G.A., Barrett-Connor, E., Criqui, M.H. & Kritz-Silverstein, D. (2004) The prospective association of serum insulin-like growth factor 1 (IGF-1) and IGF-binding protein 1 levels with all cause and cardiovascular disease mortality in older adults: the Rancho Bernardo Study. Journal of Clinical Endocrinology and Metabolism, 89, 114–120.
- 7 Vasan, R.S., Sullivan, L.M., D’Agostino, R.B., Roubenoff, R., Harris, T., Sawyer, D.B., Levy, D. & Wilson, P.W.F. (2003) Serum insulin-like growth factor-1 and risk of heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Annals of Internal Medicine, 139, 642–648.
- 8 Johnsen, S.P., Hundborg, H.H., Sorensen, H.T., Orskov, H., Tjonneland, A., Overvad, K. & Jorgensen, J.O.L. (2005) Insulin-like growth factor (IGF) I-II, and IGF binding protein-3 and risk of ischemic stroke. Journal of Clinical Endocrinology and Metabolism, 90, 5937–5941.
- 9 Leung, K.C., Johannsson, G., Leong, G.M. & Ho, K.K. (2004) Estrogen regulation of growth hormone action. Endocrine Review, 25, 693–721.
- 10 Weissberger, A.J., Ho, K.K. & Lazarus, L. (1991) Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor 1, and GH-binding protein in postmenopausal women. Journal of Clinical Endocrinology and Metabolism, 72, 374–381.
- 11 Nugent, A.G., Leung, K.C., Sullivan, D., Reutens, A. & Ho, K.K.Y. (2003) Modulation by progestogens of the effects of estrogen on hepatic endocrine function in postmenopausal women. Clinical Endocrinology, 59, 690–698.
- 12 Campagnoli, C., Abbà, C., Ambroggio, S. & Peris, C. (2003) Differential effects of progestins on the circulating IGF-I system. Maturitas, 46 (Suppl. 1), S39–S44.
- 13 Oger, E., Alhene-Gelas, M., Lacut, K., Blouch, M.T., Roudaut, N., Kerlan, V., Collet, M., Abgrall, J.F., Aiach, M., Scarabin, P.Y. & Mottier, D.; SARAH Investigators (2003) Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arteriosclerosis, Thrombosis, and Vascular Biology, 23, 1671–1676.
- 14
Blum, W.F. &
Schweizer, R. (2003) Insulin-like growth factors and their binding proteins. In: M.B. Ranke ed.
Diagnostics of Endocrine Function in Children and Adolescents. Karger, Basel, 166–199.
10.1159/000073550 Google Scholar
- 15 Helle, S.I., Omsjo, I.H., Hughes, S.C., Botta, L., Hulls, G., Holly, J.M. & Lonning, P.E. (1996) Effects of transdermal oestrogen replacement therapy on plasma levels of insulin-like growth factors and IGF binding proteins 1 and 3: a cross-over study. Clinical Endocrinology, 45, 727–732.
- 16 Cano, A., Castelo-Branco, C. & Tarin, J.J. (1999) Effect of menopause and different combined estradiol-progestin regimens on basal and growth hormone-releasing hormone-stimulated serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-3 levels. Fertility and Sterility, 71, 261–267.
- 17 Karjaleinen, A., Paassilta, M., Heikkinen, J., Backstrom, A.C., Savolainen, M. & Kesaniemi, Y.A. (2001) Effects of peroral and transdermal estrogen replacement therapy on glucose and insulin metabolism. Clinical Endocrinology, 54, 165–173.
- 18 Paassilta, M., Karjalainen, A., Kervinen, K., Savolainen, M.J., Heikkinen, J., Backstrom, A.C. & Kesaniemi, Y.A. (2000) Insulin-like growth factor binding protein-1 (IGFBP-1) and IGF-1 during oral and transdermal estrogen replacement therapy: relation to lipoprotein(a) levels. Atherosclerosis, 149, 157–162.
- 19 Kam, G.Y.W., Leung, K.C., Baxter, R.C. & Ho, K.K.Y. (2000) Estrogens exert route and dose-dependent effects on insulin-like growth factor (IGF) binding protein-3 and the acid-labile subunit of the IGF ternary complex. Journal of Clinical Endocrinology and Metabolism, 85, 1918–1925.
- 20 Decensi, A., Bonanni, B., Baglietto, L., Guerrieri-Gonzaga, A., Ramazotto, F., Johansson, H., Robertson, C., Marinucci, I., Mariette, F., Sandri, M.T., Daldoss, C., Bianco, V., Buttarelli, M., Cazzniga, M., Franchi, D., Cassano, E. & Omodei, U. (2004) A two-by-two factorial trial comparing oral with transdermal estrogen therapy and fenretinide with placebo on breast cancer biomarkers. Clinical Cancer Research, 10, 4389–4397.
- 21 Vongpatanasin, W., Tuncel, M., Wang, Z., Arbique, D., Mehrad, B. & Jiala, I. (2003) Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women. Journal of the American College of Cardiology, 41, 1358–1363.
- 22 Ravn, P., Overgaard, K., Spencer, E.M. & Christiansen, C. (1995) Insulin-like growth factors 1 and 2 in healthy women with and without established osteoporosis. European Journal of Endocrinology, 132, 313–319.
- 23 Garnero, P., Tsouderos, Y., Marton, I., Pelissier, C., Varin, C. & Delmas, P. (1999) Effects of intranasal 17β-estradiol on bone turnover and serum insulin-like growth factor 1 in postmenopausal women. Journal of Clinical Endocrinology and Metabolism, 84, 2390–2397.
- 24 Herrington, J. & Carter-Su, C. (2001) Signaling pathways activated by the growth hormone receptor. Trends in Endocrinology and Metabolism, 12, 252–257.
- 25 Metcalf, D., Greenhalgh, C.J., Viney, E., Willson, T.A., Starr, R., Nicola, N.A., Hilton, D.J. & Alexander, W.S. (2000) Gigantism in mice lacking suppressor of cytokine signaling-2. Nature, 405, 1069–1073.
- 26 Leung, K.C., Doyle, N., Ballesteros, M., Sjogren, K., Watts, C.K.W., Low, T.H., Leong, G.M., Ross, R.J.M. & Ho, K.K.Y. (2003) Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. Proceedings of the National Academy of Sciences of the United States of America, 100, 1016–1021.
- 27 Friend, K.E., Hartman, M.L., Pezzoli, S.S., Clasey, J.L. & Thorner, M.O. (1996) Both oral and transdermal estrogen increase growth hormone release in postmenopausal women – a clinical research center study. Journal of Clinical Endocrinology and Metabolism, 81, 2250–2256.
- 28 Veldhuis, J.D., Anderson, S.M., Patrie, J.T. & Bowers, C.Y. (2004) Estradiol supplementation in postmenopausal women doubles rebound-like release of growth hormone (GH) triggered by sequential infusion and withdrawal of somatostatin: evidence that estrogen facilitates endogenous GH-releasing hormone drive. Journal of Clinical Endocrinology and Metabolism, 89, 121–127.
- 29 Mah, P.M., Webster. J., Jönsson, P., Feldt-Rasmussen, U., Koltowska-Häggstrom, M. & Ross, R.J.M. (2005) Estrogen replacement in women of fertile years with hypopituitarism. Journal of Clinical Endocrinology and Metabolism, 90, 5964–5969.
- 30 Rosen, T. & Bengtsson, B.A. (1990) Premature mortality due to cardiovascular disease in hypopituitarism. Lancet, 336, 285–288.
- 31 Janssen, J.A., Stolk, R.P., Pols, H.A., Grobbee, D.E. & Lamberts, S.W. (1998) Serum free and total IGF-1, free IGF-1 and IGFBP-1 levels in an elderly population: relation to cardiovascular risk factors and disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 18, 277–282.
- 32 Baxter, R.C. (2003) Circulating binding proteins for the insulin-Iike growth factors. Trends in Endocrinology and Metabolism, 4, 91–95.
- 33 Ho, K.K.Y., O'Sullivan, A.J., Wolthers, T. & Leung, K.C. (2003) Metabolic effects of oestrogens: impact of the route of administration. Annals of Endocrinology, 64, 170–177.
- 34 Heald, A., Selby, P.L., White, A. & Gibson, J.M. (2000) Progestins abrogate estrogen-induced changes in the insulin-like growth factor axis. American Journal of Obstetrics and Gynecology, 183, 593–600.
- 35 Bellantoni, M.F., Vittone, J., Campfield, A.T., Bass, K.M., Harman, S.M. & Blackman, M.R. (1996) Effects of oral versus transdermal estrogen on the growth hormone/insulin-like growth factor 1 axis in younger and older postmenopausal women: a clinical research center study. Journal of Clinical Endocrinology and Metabolism, 81, 2848–2853.
- 36 Vestergaard, P., Hermann, A.P., Orskov, H. & Mosekilde, L. (1999) Effect of sex hormone replacement therapy on the insulin-like growth factor system and bone mineral: a cross-sectional and longitudinal study in 595 perimenopausal women participating in the Danish Osteoporosis Prevention Study. Journal of Clinical Endocrinology and Metabolism, 84, 2286–2290.
- 37 Cardim, H.J.P., Lopes, C.M.C., Giannella-Neto, D., Maggio da Fonseca, A. & Pinotti, J.A. (2001) The insulin-like growth factor 1 system and hormone-replacement therapy. Fertility and Sterility, 75, 282–287.
- 38 Biglia, N., Ambroggio, S., Ponzone, R., Sgro, L., Ujcic, E., Actis Dato, F. & Sismondi, P. (2003) Modification of serum IGF-I, IGFBPs and SHBG levels by different HRT regimens. Maturitas, 45, 283–291.
Citing Literature
