title: Aging attenuates both the regularity and joint synchrony of LH and testosterone secretion in normal men: analyses via a model of graded GnRH receptor blockade.
abstract: Testosterone (T) secretion declines in the aging male, albeit for unknown reasons. From an ensemble perspective, repeated incremental signaling among gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and T is required to maintain physiological androgen availability. Pattern-regularity statistics, such as univariate approximate entropy (ApEn) and bivariate cross-ApEn, provide specific and sensitive model-free measurement of altered multi-pathway control. The present study exploits partial muting of one pathway (GnRH drive) to appraise adaptive regulation of LH and T secretion in young and aging individuals. Analyses comprised 100 paired 18-h LH and T concentration time series obtained in 25 healthy men ages 20-72 yr each administered placebo and three graded doses of a specific GnRH-receptor antagonist. Graded blockade of GnRH drive increased the individual regularity of LH and T secretion and the synchrony of LH-T feedforward and T-LH feedback in the cohort as a whole (P<0.001 for each). However, age markedly attenuated ganirelix-induced enhancement of univariate T orderliness and bivariate LH-T feedback and T-LH feedback synchrony (P <or= 0.0025). In summary, the present analyses support the thesis that aging disrupts coordinate control of T secretion, LH-T feedforward, and T-LH feedback in healthy men. Thus the experimental strategy of stepwise silencing of an agonistic pathway may have utility in dissecting the bases of altered neurohormonal linkages in other systems.
authors.affiliation: Endocrine Research Unit, Dept. of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Liu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pincus
authors.forename: Paul Y
authors.initials: PY
authors.lastname: Takahashi
authors.forename: Pamela D
authors.initials: PD
authors.lastname: Roebuck
authors.forename: Ali
authors.initials: A
authors.lastname: Iranmanesh
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Keenan
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging; D000704:Analysis of Variance; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007279:Injections, Subcutaneous; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D012044:Regression Analysis; D013739:Testosterone / Q000097:blood* / Q000378:metabolism
chemical_list: C484844:GNRHR protein, human; D006727:Hormone Antagonists; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone; C061018:ganirelix