title: Analytical construct of reversible desensitization of pituitary-testicular signaling: illustrative application in aging.
abstract: Luteinizing hormone (LH) administered in pharmacological amounts downregulates Leydig cell steroidogenesis. Whether reversible downregulation of physiological gonadotropin drive operates in vivo is unknown. Most of the analytical models of dose-response functions that have been constructed are biased by the assumption that no downregulation exists. The present study employs a new analytical platform to quantify potential (but not required) pulsatile cycles of LH-testosterone (T) dose-response stimulation, desensitization, and recovery (pulse-by-pulse hysteresis) in 26 healthy men sampled every 10 min for 24 h. A sensitivity-downregulation hysteresis construct predicted marked hysteresis with a median time delay to LH dose-response inflection within individual T pulses of 23 min and with median T pulse onset and recovery LH sensitivities of 1.1 and 0.10 slope unit, respectively (P < 0.001). A potency-downregulation model yielded median estimates of one-half maximally stimulatory LH concentrations (EC(50) values) of 0.66 and 7.5 IU/l for onset and recovery, respectively (P < 0.001). An efficacy-downregulation formulation of hysteresis forecasts median LH efficacies of 20 and 8.3 ng·dl(-1)·min(-1) for onset and offset of T secretory burst, respectively (P = 0.002). Segmentation of the LH-T data by age suggested greater sensitivity, higher EC(50) (increased LH potency), and markedly (2.7-fold) attenuated LH efficacy in older individuals. Each of the three hysteresis models yielded a marked (P < 0.005) reduction in estimated model residual error compared with no hysteresis. In summary, model-based analyses allowing for (but not requiring) reversible pituitary-gonadal effector-response downregulation are consistent with a hypothesis of recurrent, brief cycles of LH-dependent stimulation, desensitization, and recovery of pulsatile T secretion in vivo and an age-associated reduction of LH efficacy. Prospective studies would be required to prove this aging effect.
authors.affiliation: Department of Statistics, University of Virginia, Charlottesville, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Keenan
authors.forename: Ali
authors.initials: A
authors.lastname: Iranmanesh
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism*; D002940:Circadian Rhythm / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010902:Pituitary Gland / Q000378:metabolism*; D013737:Testis / Q000378:metabolism*; D013739:Testosterone / Q000097:blood* / Q000378:metabolism; D055815:Young Adult
chemical_list: D013739:Testosterone; D007986:Luteinizing Hormone