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Article: Eric Orwoll, Lori C. Lambert, Lynn M. Marshall, Kathy Phipps, Janet Blank, Elizabeth Barrett-Connor, Jane Cauley, Kris Ensrud, Steve Cummings for the Osteoporotic Fractures in Men (MrOS) Study Group Testosterone and Estradiol Among Older Men J Clin Endocrinol Metab 2005; 0: jc.2005-1830v1 [Abstract]

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Pitfalls when interpreting a threshold level for bioavailable estradiol and testosterone.

Willem de Ronde   (21 April 2006)

Pitfalls when interpreting a threshold level for bioavailable estradiol and testosterone. 21 April 2006
Willem de Ronde, M.D. dept of endocrinology, VU University Center Amsterdam Send letter to journal: Re: Pitfalls when interpreting a threshold level for bioavailable estradiol and testosterone. p.deronde{at}vumc.nl Willem de Ronde	In the large cohort study by Orwoll et al (1), levels of total and bioavailable testosterone and estradiol have been assessed in older men. In both the discussion of the paper and the editorial by Bilezikian (2) a comparison is made with bioavailable estradiol levels in elderly men presented by others, such as Khosla et al. (3), who suggested a bioavailable estradiol threshold of 40 pmol/l, below which men show higher rates of bone loss. Orwoll et al. put much emphasis on their accurate measurement of total and bioavailable sex steroid levels. In their study, bioavailable hormone levels had been calculated using the algorithm described and validated by Vermeulen et al. (4). In the study by Vermeulen et al. and other studies, the calculated results were shown to correlate well with the measured levels using the ammonium sulphate precipitation technique, which is still the gold standard for measuring levels of bioavailable testosterone and estradiol. In the study by Khosla et al. (3), bioavailable testosterone and estradiol levels had been measured using this ammonium sulphate precipitation technique. However, the results obtained were very different from the calculated results described by Orwell et al (1). Although mean levels of total testosterone and SHBG in elderly men were roughly similar in both studies, the bioavailable testosterone fraction was only 18% in the Khosla study (3) as compared to 51% in the Orwoll study (1). Although the mean levels of bioavailable estradiol in both studies was similar (40 versus 44 pmol/l, respectively), total estradiol levels were highly different (110 versus 65 pmol/l), resulting in very different bioavailable estradiol fractions (36 versus 68%). This simple comparison shows that calculating and measuring levels of bioavailable testosterone and estradiol will not always lead to similar results. This is not entirely surprising knowing that accurate measurement of bioavailable testosterone levels using ammonium sulphate precipitation is a demanding procedure. It relies on selectively and reproducibly precipitating all SHBG without precipitating albumin which, among others, requires a critical concentration of ammonium sulfate (5). A proposed threshold for bioavailable estradiol or testosterone levels appears very much dependent on the measuring techniques and should be interpreted with great caution. If Khosla et al. (3) would have calculated bioavailable estradiol using the same algorithm as Orwoll et al. (1), their proposed threshold may have been as high as 75 pmol/l. In light of the obvious differences in estimated bioavailable hormone fractions, comparison of results obtained by Orwoll et al. (1) and Khosla et al. (3) seems inappropriate. References 1. Orwoll E, Lambert LC, Marshall LM, Phipps K, Blank J, Barrett-Connor E, Cauley J, Ensrud K, Cummings S, for the Osteoporotic Fractures in Men Study Group. 2006. Testosterone and Estradiol among Older Men. J Clin Endocrinol Metab 91:1336-1344 2. Bilezikian JP. What's Good for the Goose's Skeleton is Good for the Gander's Skeleton. 2006. J Clin Endocrinol Metab 91:1223-1225 3. Khosla S, Melton LJ, III, Atkinson EJ, O'Fallon WM. 2001. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab 86:3555-3561 4. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. 1999. J Clin Endocrinol Metab 84:3666-3672 5. Davies R, Collier C, Raymond M, Heaton J, Clark A. 2002. Indirect measurement of bioavailable testosterone with the Bayer Immuno 1 system. Clin Chem 48:388-390