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Plasma Melatonin Concentration before and during Testosterone Replacement in Klinefelter’s Syndrome: Relation to Hepatic Indolamine Metabolism and Sympathoadrenal Activity

Departments of Endocrinology and Metabolism (S.C., M.O., G.O., E.B., I.C.O.), Hydroclimatology (M.T.), Internal Medicine (C.O.), Nuclear Medicine (N.A.), Clinical Biochemistry (K.E.), and Medical Genetics (D.G.), Gulhane School of Medicine, Etlik-Ankara 06018, Turkey

Address all correspondence and requests for reprints to: Metin Ozata, M.D., Department of Endocrinology and Metabolism, Gulhane School of Medicine, Etlik-Ankara 06018, Turkey. E-mail: mozata{at}obs.gata.edu.tr

The mechanisms leading to alterations in plasma melatonin (MT) levels with testosterone replacement in Klinefelter’s syndrome (KS) remain elusive. We investigated early morning plasma MT levels, urinary 6-sulfatoxymelatonin (6-SM) levels, and urinary catecholamine levels before and 6 months after testosterone treatment in 31 patients with KS and 20 healthy males to demonstrate whether alterations in plasma MT levels in such patients are due to subtle changes in sympathoadrenal activity and/or alterations in the hepatic indolamine metabolism influenced by testosterone replacement.

The plasma MT level was measured by RIA. The sensitivity of the test was 10.7 pmol/L. The 6-SM level was measured by enzyme-linked immunosorbent assay. Urinary catecholamines were determined by high performance liquid chromatography. The pretreatment mean plasma MT level was insignificantly higher in the patient group than in the control group (72.57 ± 74.82 vs. 42.37 ± 29.02 pmol/L; z = -1.218; P = 0.223). The pretreatment urinary 6-SM and norepinephrine (NE) levels were significantly lower and, the epinephrine (E) and dopamine levels were insignificantly lower in the patient group than those in the control group [6-SM, 76.54 ± 31.92 vs. 125.49 ± 50.16 nmol/L (z = -3.727; P < 0.001); NE, 120.79 ± 58.33 vs. 178.84 ± 81.61 nmol/day (z = -2.585; P = 0.01); E, 31.27 ± 27.42 vs. 34.65 ± 28.33 nmol/day (z = -0.39; P = 0.692); dopamine, 1577.02 ± 863.02 vs. 1812.32 ± 677.59 nmol/day (z = -1.03, P = 0.308)]. After testosterone replacement, plasma MT levels were significantly decreased (72.57 ± 74.82 vs. 24.73 ± 23.61 pmol/L; z = -4.29; P < 0.001), and urinary 6-SM, NE, E, and dopamine levels were significantly increased [6-SM, 25.04 ± 10.44 vs. 40.05 ± 17.65 ng/mL (z = -4.78; P < 0.001); NE, 120.78 ± 58.33 vs. 154.08 ± 61.35 nmol/day (z = -4.27; P < 0.001); E, 31.27 ± 27.42 vs. 40.74 ± 30.04 nmol/day (z = -4.22; P < 0.001); dopamine, 1577.02 ± 863.02 vs. 2162.67 ± 823.15 (z = -6.127; P < 0.001)].

There was no relation between plasma MT levels, urinary 6-SM, and catecholamine levels and levels of gonadotropins or gonadal steroids either before or after treatment.

We demonstrate that in untreated KS, plasma MT levels tend to be higher than those in normal controls, whereas those of the melatonin metabolite 6-SM and those of NE in urine tend to be lower. After testosterone treatment, however, plasma MT levels fall significantly, whereas urinary levels of 6-SM and NE rise. Our data show that the effect of testosterone is mediated by enhanced metabolism of melatonin, not by any effect on net sympathetic outflow, and that the increase in plasma melatonin in untreated KS patients also results from an alteration in the rate of melatonin metabolism and not from increased net sympathetic activity.