title: Pulsatile intravenous infusion of recombinant human luteinizing hormone under acute gonadotropin-releasing hormone receptor blockade reconstitutes testosterone secretion in young men.
abstract: 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.
authors.affiliation: 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, USA. veldhuis.johannes@mayo.edu
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
authors.forename: Ali
authors.initials: A
authors.lastname: Iranmanesh
mesh_terms: D000293:Adolescent; D000328:Adult; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D006801:Humans; D007262:Infusions, Intravenous; D007986:Luteinizing Hormone / Q000008:administration & dosage*; D008297:Male; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000008:administration & dosage; D013739:Testosterone / Q000378:metabolism*
chemical_list: D011966:Receptors, LHRH; D011994:Recombinant Proteins; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone; C061018:ganirelix