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Endocrine Care: Matthew R. Smith, Hang Lee, and David M. Nathan Insulin Sensitivity during Combined Androgen Blockade for Prostate Cancer J Clin Endocrinol Metab 2006; 91: 1305-1308 [Abstract] [Full text] [PDF]

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Low estrogen state is not a factor in insulin resistance induced by androgen deprivation

Erik J. Giltay, Louis J.G. Gooren, Department of Endocrinology, Vrije Universiteit medical center, Amsterdam, The Netherlands   (7 June 2006)

Low estrogen state is not a factor in insulin resistance induced by androgen deprivation 7 June 2006
Erik J. Giltay, MD, PhD Psychiatric Center GGZ Delfland, Delft, The Netherlands, Louis J.G. Gooren, Department of Endocrinology, Vrije Universiteit medical center, Amsterdam, The Netherlands Send letter to journal: Re: Low estrogen state is not a factor in insulin resistance induced by androgen deprivation giltay{at}dds.nl Erik J. Giltay, et al.	Smith et al. (1) and another recent publication (2) indicate that men with prostate cancer, treated with GnRH agonist to induce androgen deprivation, develop an increase of fat mass, insulin resistance (measured by the HOMA IR technique), hyperinsulinemia and hyperglycemia (1,2) and an impaired lipid profile (1). This is consistent with recent studies finding a positive correlation between serum testosterone levels and insulin sensitivity in men across the full spectrum of glucose tolerance. Treatment with GnRH agonists not only reduces circulating levels of testosterone but also of 17β-estradiol. In men the main source of estrogens is androgens, mainly of testicular origin. A profound estrogen deficiency state, as encountered in men with aromatase deficiency, appears to be associated with signs and symptoms of insulin resistance and other features of the metabolic syndrome. This metabolic state improves or normalizes upon estrogen administration (3). So, we wondered whether the state of low estrogens in men with GnRH-induced androgen deprivation contributes to their insulin resistance and deterioration of the lipid profile. Therefore, we analyzed our studies in male-to-female transsexuals who receive treatment with the aim to deprive them of testosterone but at the same time receive estrogens to induce feminization, thus creating a state of androgen deprivation but not of low estrogens. In two studies with 36 male-to-female transsexuals receiving 100 μg ethinylestradiol per day (with or without 100 mg cyproterone acetate), plasma testosterone fell from eugonadal male levels to almost nill (4). The effects on insulin resistance and related parameters were largely in the same direction as in men with prostate cancer (1, 2). Insulin sensitivity (assessed by hyperinsulinemic euglycemic clamp) decreased by 6-30%, accompanied by a compensatory increase in fasting insulin levels by 20-50% without hyperglycemia (4). Furthermore, high-density lipoprotein (HDL) cholesterol and triglyceride levels increased, also similar to men treated for prostate cancer (1). However, total cholesterol was unaffected and low-density lipoprotein (LDL) cholesterol levels decreased by 12% in transsexuals (4), whereas total and LDL cholesterol levels rose by 9% and 9% in men treated for prostate cancer (1). Another study in male-to-female transsexuals administering GnRH agonists plus oral 17β-estradiol valerate found, similar to our findings in transsexuals, neither an impairment of lipid profiles. The use of cyproterone acetate instead of an GnRH agonist in our studies in transsexuals, might explain the difference with findings in men with prostate cancer, but a study using cyproterone acetate in prostate cancer patients found, similar to the men treated with GnRH, also a serious deterioration of the lipid profile (5). We believe that the deleterious effects of androgen deprivation on insulin sensitivity described by Smith et al. (1) are likely the effects of androgen deprivation and that the associated low estrogen state is probably not a significant factor. The latter was hypothesized from observations in men with a state of severe estrogen deficiency. Yet, the low estrogen state seems responsible for increases in total and LDL cholesterol, the latter not found in transsexuals. References 1. Smith MR, Lee H, Nathan DM 2006 Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 91:1305-1308 2. Basaria S, Muller DC, Carducci MA, Egan J, Dobs AS 2006 Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 106:581-588 3. Herrmann BL, Janssen OE, Hahn S, Broecker-Preuss M, Mann K 2005 Effects of estrogen replacement therapy on bone and glucose metabolism in a male with congenital aromatase deficiency. Horm Metab Res 37:178-183 4. Elbers JM, Giltay EJ, Teerlink T, Scheffer PG, Asscheman H, Seidell JC, Gooren LJ 2003 Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects. Clin Endocrinol 58:562-571 5. Chen KC, Peng CC, Hsieh HM, Peng CH, Hsieh CL, Huang CN, Chyau CC, Wang HE, Peng RY 2005 Antiandrogenic therapy can cause coronary arterial disease. Int J Urol 12:886-891