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Pulsatile Intravenous Infusion of Recombinant Human Luteinizing Hormone under Acute Gonadotropin-Releasing Hormone Receptor Blockade Reconstitutes Testosterone Secretion in Young Men

Division of Endocrinology and Metabolism (J.D.V.), Department of Internal Medicine, Mayo Medical and Graduate School of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; and Endocrine Section (A.I.), Medical Services, Veterans Affairs Medical Center, Salem, Virginia 24153

Address all correspondence and requests for reprints to: Dr. Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate School of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

The present study tests the hypothesis that iv infusion of discrete pulses of recombinant human (rh)LH after overnight GnRH-receptor blockade can restore midphysiological concentrations of testosterone (Te) in normal young men. In a pilot time-course analysis, injection of the GnRH antagonist ganirelix (2.0 mg sc) at 2200 h lowered LH concentrations (mean ± SEM) from 3.4 ± 0.7 to 0.8 ± 0.1 IU/liter (P < 0.01) and Te concentrations from 416 ± 48 to 107 ± 16 ng/dl (P < 0.01) (to convert to nmol/liter, multiply by 0.0347) at 0800 h the next morning. LH and Te concentrations remained suppressed thereafter for an additional 15 h (interval, 10–25 h after ganirelix administration) at mean values of 1.2 ± 0.1 IU/liter and 67 ± 10 ng/dl, respectively (P < 0.005 vs. baseline). Based on these data and earlier dose-finding studies, eight men received a single ganirelix injection followed by seven consecutive iv pulses of rhLH (15.3 IU Second International Reference Preparation) each delivered over 6 min every 2 h beginning at 0800 h. Recurrent rhLH stimuli restored mean LH concentrations (IU/liter of homologous standard) to 4.8 ± 0.3, LH peak maxima to 7.1 ± 0.6, incremental LH peak amplitudes to 3.7 ± 0.4, and interpeak nadir LH concentrations to 3.3 ± 0.3 (each P < 0.01 vs. saline infusion after ganirelix). These values were indistinguishable from the normal 95% range established in 23 young adults of comparable age. Injected LH pulses increased total Te concentrations (ng/dl) to 440 ± 52, Te peak maxima to 552 ± 64, incremental Te amplitudes to 188 ± 23, and interpeak nadir Te concentrations to 366 ± 43 (each P < 0.01 vs. saline addback; P value not significant vs. untreated men). Under combined ganirelix inhibition and pulsatile rhLH drive, Te concentrations rose from a nadir of less than 120 ng/dl to an asymptotic plateau of 611 ng/dl with an estimated half-time of 97 ± 9.1 min. Cross-correlation analysis of paired serial LH and Te concentrations verified that infused LH pulses stimulate Te elevations within 40–70 (median 50) min (P < 0.001). Kinetic estimates of the half-life of exogenous rhLH averaged 107 ± 3.8 min, which value exceeded that of secreted LH monitored after pharmacological GnRH stimulation (83 ± 12 min; P = 0.012).

We conclude that intermittent iv pulses of rhLH delivered over 12 h under selective GnRH-receptor blockade can restore young adult-like pulsatile LH and Te concentrations with an appropriate time delay coupling the lutropic stimulus to the steroidogenic response. Whether a comparable near-physiological paradigm can maintain human Leydig-cell testosterone production for a more extended interval is not known.

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