SPECIFIC LINKAGES AMONG LUTEINIZING-HORMONE, FOLLICLE-STIMULATING-HORMONE, AND TESTOSTERONE RELEASE IN THE PERIPHERAL-BLOOD AND HUMAN SPERMATIC VEIN - EVIDENCE FOR BOTH POSITIVE (FEEDFORWARD) AND NEGATIVE (FEEDBACK) WITHIN-AXIS REGULATION

We have investigated possible (negative) feedback and (positive) feed- forward activity within the human male gonadotropic axis by measuring serum concentrations of LH, FSH, and testosterone in blood sampled fre quently and for a prolonged interval (every 20 min for 19 h) simultane ously from the peripheral circulation and the left spermatic vein. Cro ss-correlation analysis with time lag was used to evaluate relationshi ps among serial serum LH, FSH, and/or testosterone concentrations over time (i.e. consistency or dissociation of trends in concentrations). Separately, Cluster analysis was applied to identify discrete LH, FSH, and testosterone pulses, which were cataloged for possible peak coinc idence. The hypergeometric probability distribution was then used to t est the null hypothesis that LH, FSH, and testosterone pulses are rand omly associated. Cross-correlation analysis revealed: 1) peripheral bl ood LH and testosterone concentrations correlate positively at lags of 40-120 min with LK increases preceding testosterone increases, viz. , feed forward (P < 0.001); 2) LH and FSH concentrations in peripheral b lood are positively correlated in simultaneous blood samples, as well as when FSH lags LH by 20 min (P < 0.01); 3) unexpectedly, LH and FSH concentrations in peripheral blood are inversely related at a lag of 8 0-100 min (P = 0.002 and 0.004, respectively) where LH lags FSH; 4) LH and testosterone concentrations in the spermatic vein show strongly p ositive correlations at lags of 80, 100, and 120 min (P = 0.002, 0.004 , and 0.021, respectively); 5) spermatic vein testosterone concentrati ons correlate negatively with peripheral blood LH concentrations 20 or 40 min later (P = 0.012 and 0.05, respectively), which indicates auto negative feedback; and 6) in contrast, testosterone levels in the sper matic vein correlate negatively with FSH values in the periphery 100 a nd 120 min later (P < 0.01), indicating more delayed negative feedback of testosterone on serum FSH concentrations. Discrete pulse coinciden ce analysis disclosed: 1) a total of 30 testosterone pulses in the spe rmatic vein and 25 testosterone pulses in peripheral blood, with 28 LH and 29 FSH pulses in the periphery; 2) individual LH and FSH peak con cordance was significantly nonrandom for FSH pulse maxima lagging LH p ulse maxima by 20 min (P < 0.05 us. randomness), with 6 observed coinc idences vs. 2.9 +/- 1.5 (SD) expected; 3) peripheral LH pulses and spe rmatic vein testosterone pulses were strongly nonrandomly coupled at a n 80-min lag, with 8 events observed us. 3.0 +/- 1.5 events expected ( P = 0.004); and 4) LH peaks in peripheral blood followed testosterone peaks in the spermatic vein by 40 min in a nonrandom manner, specifica lly, n = 11 observed vs. 3.0 +/- 1.5 expected (P < 0.001), indicating possible LH escape from testosterone's negative feedback. In summary, physiological regulation of the human male LH, FSH, and testosterone a xis comprises multidirectional interactions, consisting of both (posit ive) feed-forward and (negative) feedback coupling. Based on a concept of network integration, we propose that age and other pathophysiologi cal factors might modulate and/or disrupt these dynamic within-axis mu ltihormonal linkages.