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.
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.
Liu
Peter Y
PY
Endocrine Research Unit, Dept. of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, MN 55905, USA.
Pincus
Steven M
SM
Takahashi
Paul Y
PY
Roebuck
Pamela D
PD
Iranmanesh
Ali
A
Keenan
Daniel M
DM
Veldhuis
Johannes D
JD
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
C484844:GNRHR protein, human; D006727:Hormone Antagonists; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone; C061018:ganirelix