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Article: K Mai, T Bobbert, V Kullmann, J Andres, H Rochlitz, M Osterhoff, M O Weickert, V Bähr, M Möhlig, A F H Pfeiffer, S Diederich, and J Spranger Free fatty acids increase androgen precursors in vivo J Clin Endocrinol Metab 2006; 0: jc.2005-2069v1 [Abstract]

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Letter re: Free Fatty Acids and Androgen Precursors in Vivo

Thomas Remer   (23 May 2006)

Letter re: Free Fatty Acids and Androgen Precursors in Vivo 23 May 2006
Thomas Remer, Research Scientist Research Institute of Child Nutrition Send letter to journal: Re: Letter re: Free Fatty Acids and Androgen Precursors in Vivo remer{at}fke-do.de Thomas Remer	In a recent issue of JCEM, Mai et al. (1) reported elevated circulating dehydroepiandrosterone (DHEA), DHEA-sulfate, and androstenedione values in healthy young men after infusion of free fatty acids (FFAs), a response that occurred before a FFA-induced elevation in insulin resistance was discernible. While their results demonstrate that blood levels of adrenal androgens change with metabolic alterations regardless of changes in insulin status, their conclusion that FFAs increase production of androgen precursors in vivo (and that hyperandrogenemia in polycystic ovary syndrome might be induced by elevated FFAs) is highly speculative because they did not measure androgen production rates. Circulating DHEA levels can change without altered hormone production or even change in the opposite direction. For example, during fasting blood DHEA-sulfate can increase up to 2-fold while DHEA- sulfate production rate and the urinary androgen metabolite excretion rate actually drop (for references, see (2)). In plasma, adrenal androgens--DHEA, DHEA-sulfate, and androstenedione--bind weakly to sex hormone binding globulins and are largely (>80%) bound to albumin, with more than 99% of available steroid binding sites unoccupied even in physiological states with high circulating steroid levels. During fasting, not only the concentration of DHEA-sulfate, but also of albumin and--during short-term fasting--of FFAs increase. FFAs are known to interfere with the binding of circulating molecules (including hormones, nutrients, and drugs) to albumin and other specific binding proteins (3-5). Several studies have shown enhanced binding affinities of steroid hormones (e.g., androsterone, progesterone, and corticosterone) to albumin by binding of FFAs to albumin (3-5). Conformational protein changes as well as electrostatic attractions and hydrophobic interactions between albumin and FFAs are assumed to play a causal role. In principle, an increase in steroid hormone binding to the albumin molecule alone, as is induced by FFAs, would result in a decrease in metabolic clearance rate and not an increase in hormone production. If blood production or glandular secretion of androgen precursors were really increased in the experiments described by Mai et al. then, one would predict that urinary androgen metabolite excretion would increase and the respective circulating metabolites’ half-lives would not have increased . Without such additional data, the findings of Mai et al. do not present clear evidence that elevation of FFAs increase production of androgen precursors in vivo. The problem of discrepant findings of serum androgen concentrations, on the one hand, and hormone production markers, on the other, has been recently discussed in some detail with respect to the potentially stimulating effects of insulin on both glandular secretion and metabolic clearance of the adrenarche marker DHEA-sulfate (2). References 1. Mai K, Bobbert T, Kullmann V, Andres J, Rochlitz H, Osterhoff M, Weickert MO, Bahr V, Mohlig M, Pfeiffer AF, Diederich S, Spranger J. 2006 Free fatty acids increase androgen precursors in vivo. J Clin Endocrinol Metab 91:1501-1507 2. Remer T, Maser-Gluth C, Boye KR, Hartmann MF, Heinze E, Wudy SA. 2006 Exaggerated adrenarche and altered cortisol metabolism in Type 1 diabetic children. Steroids 2006 Apr 5 [Epub ahead of print] 3. Ryan MT, Chopra RK. 1976 The paradoxical effect of fatty acid on steroid-albumin interaction. Biochim Biophys Acta 18;427:337-349 4. Watanabe S, Tani T, Watanabe S, Seno M. 1990 Effects of free fatty acids on the binding of steroid hormones to bovine serum albumin. Lipids 25:633-638 5. Boonstra R, Tinnikov AA. 1998 Increased corticosteroid binding capacity of plasma albumin but not of corticosteroid-binding globulin caused by ACTH-induced changes in free fatty acid concentrations in snowshoe hares and rabbits. J Endocrinol 156:205-212