This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Foresta, C. Articles by Veldhuis, J. D. Search for Related Content PubMed PubMed Citation Articles by Foresta, C. Articles by Veldhuis, J. D.

Specific Linkages Among Luteinizing Hormone, Follicle-Stimulating Hormone, and Testosterone Release in the Peripheral Blood and Human Spermatic Vein: Evidence for Both Positive (Feed-Forward) and Negative (Feedback) Within-Axis Regulation¹

Instuto di Semeiotica Medica, Universita Degli Studi Di Padova (C.F., P.B., M.R., R.M.), Patologia Medica III, Via Nazareth 2, 35128 Padua, Italy; and Division of Endocrinology, Department of Internal Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: J.D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, Box 202, University of Virginia Health Sciences Center, Charlottesville, VA 22908. E-mail:JDV{at}Virginia.Edu

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 frequently and for a prolonged interval (every 20 min for 19 h) simultaneously from the peripheral circulation and the left spermatic vein. Cross-correlation analysis with time lag was used to evaluate relationships 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 coincidence. The hypergeometric probability distribution was then used to test the null hypothesis that LH, FSH, and testosterone pulses are randomly associated. Cross-correlation analysis revealed: 1) peripheral blood LH and testosterone concentrations correlate positively at lags of 40–120 min with LH increases preceding testosterone increases, viz., feed-forward (P < 0.001); 2) LH and FSH concentrations in peripheral blood 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 80–100 min (P = 0.002 and 0.004, respectively) where LH lags FSH; 4) LH and testosterone concentrations in the spermatic vein show strongly positive correlations at lags of 80, 100, and 120 min (P = 0.002, 0.004, and 0.021, respectively); 5) spermatic vein testosterone concentrations correlate negatively with peripheral blood LH concentrations 20 or 40 min later (P = 0.012 and 0.05, respectively), which indicates autonegative feedback; and 6) in contrast, testosterone levels in the spermatic vein correlate negatively with FSH values in the periphery 100 and 120 min later (P < 0.01), indicating more delayed negative feedback of testosterone on serum FSH concentrations. Discrete pulse coincidence analysis disclosed: 1) a total of 30 testosterone pulses in the spermatic vein and 25 testosterone pulses in peripheral blood, with 28 LH and 29 FSH pulses in the periphery; 2) individual LH and FSH peak concordance was significantly nonrandom for FSH pulse maxima lagging LH pulse maxima by 20 min (P < 0.05 vs. randomness), with 6 observed coincidences vs. 2.9 ± 1.5 (SD) expected; 3) peripheral LH pulses and spermatic vein testosterone pulses were strongly nonrandomly coupled at an 80-min lag, with 8 events observed vs. 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, specifically, 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 axis comprises multidirectional interactions, consisting of both (positive) feed-forward and (negative) feedback coupling. Based on a concept of network integration, we propose that age and other pathophysiological factors might modulate and/or disrupt these dynamic within-axis multihormonal linkages.

This article has been cited by other articles:

				P. Y. Takahashi, P. Votruba, M. Abu-Rub, K. Mielke, and J. D. Veldhuis Age Attenuates Testosterone Secretion Driven by Amplitude-Varying Pulses of Recombinant Human Luteinizing Hormone during Acute Gonadotrope Inhibition in Healthy Men J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3626 - 3632. [Abstract] [Full Text] [PDF]

				D. M. Keenan, P. Y. Takahashi, P. Y. Liu, P. D. Roebuck, A. X. Nehra, A. Iranmanesh, and J. D. Veldhuis An Ensemble Model of the Male Gonadal Axis: Illustrative Application in Aging Men Endocrinology, June 1, 2006; 147(6): 2817 - 2828. [Abstract] [Full Text] [PDF]

				P. Y. Liu, S. M. Pincus, P. Y. Takahashi, P. D. Roebuck, A. Iranmanesh, D. M. Keenan, and J. D. Veldhuis 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 Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E34 - E41. [Abstract] [Full Text] [PDF]

				P. Y. Liu, P. Y. Takahashi, P. D. Roebuck, A. Iranmanesh, and J. D. Veldhuis Aging in Healthy Men Impairs Recombinant Human Luteinizing Hormone (LH)-Stimulated Testosterone Secretion Monitored under a Two-Day Intravenous Pulsatile LH Clamp J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5544 - 5550. [Abstract] [Full Text] [PDF]

				P. Y. Liu, P. Y. Takahashi, P. D. Roebuck, A. Iranmanesh, and J. D. Veldhuis Age-specific changes in the regulation of LH-dependent testosterone secretion: assessing responsiveness to varying endogenous gonadotropin output in normal men Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R721 - R728. [Abstract] [Full Text] [PDF]

				A. Iranmanesh and J. D. Veldhuis Combined Inhibition of Types I and II 5 {alpha}-Reductase Selectively Augments the Basal (Nonpulsatile) Mode of Testosterone Secretion in Young Men J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4232 - 4237. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis and A. Iranmanesh Pulsatile Intravenous Infusion of Recombinant Human Luteinizing Hormone under Acute Gonadotropin-Releasing Hormone Receptor Blockade Reconstitutes Testosterone Secretion in Young Men J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4474 - 4479. [Abstract] [Full Text] [PDF]

				D. M. Keenan and J. D. Veldhuis Divergent gonadotropin-gonadal dose-responsive coupling in healthy young and aging men Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2004; 286(2): R381 - R389. [Abstract] [Full Text] [PDF]

				R. Luboshitzky, Z. Shen-Orr, and P. Herer Middle-Aged Men Secrete Less Testosterone at Night Than Young Healthy Men J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3160 - 3166. [Abstract] [Full Text] [PDF]

				T. Mulligan, A. Iranmanesh, and J. D. Veldhuis Pulsatile iv Infusion of Recombinant Human LH in Leuprolide-Suppressed Men Unmasks Impoverished Leydig-Cell Secretory Responsiveness to Midphysiological LH Drive in the Aging Male J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5547 - 5553. [Abstract] [Full Text] [PDF]

				R. Luboshitzky, Z. Zabari, Z. Shen-Orr, P. Herer, and P. Lavie Disruption of the Nocturnal Testosterone Rhythm by Sleep Fragmentation in Normal Men J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1134 - 1139. [Abstract] [Full Text]

				J. D. Veldhuis, S. M. Pincus, R. Mitamura, K. Yano, N. Suzuki, Y. Ito, Y. Makita, and A. Okuno Developmentally Delimited Emergence of More Orderly Luteinizing Hormone and Testosterone Secretion during Late Prepuberty in Boys J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 80 - 89. [Abstract] [Full Text]

				C. V. Obiezu, E. J. Giltay, A. Magklara, A. Scorilas, L. J.G. Gooren, H. Yu, D. J.C. Howarth, and E. P. Diamandis Serum and Urinary Prostate-specific Antigen and Urinary Human Glandular Kallikrein Concentrations Are Significantly Increased after Testosterone Administration in Female-to-Male Transsexuals Clin. Chem., June 1, 2000; 46(6): 859 - 862. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, A. Iranmanesh, M. Godschalk, and T. Mulligan Older Men Manifest Multifold Synchrony Disruption of Reproductive Neurohormone Outflow J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1477 - 1486. [Abstract] [Full Text]

				J. D. Veldhuis, Ali Iranmanesh, Thomas Mulligan, and Steven M. Pincus Disruption of the Young-Adult Synchrony between Luteinizing Hormone Release and Oscillations in Follicle-Stimulating Hormone, Prolactin, and Nocturnal Penile Tumescence (NPT) in Healthy Older Men J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3498 - 3505. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, A. Iranmanesh, L. M. Demers, and T. Mulligan Joint Basal and Pulsatile Hypersecretory Mechanisms Drive the Monotropic Follicle-Stimulating Hormone (FSH) Elevation in Healthy Older Men: Concurrent Preservation of the Orderliness of the FSH Release Process: A General Clinical Research Center Study J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3506 - 3514. [Abstract] [Full Text] [PDF]

				S. J. Winters, J. Takahashi, and P. Troen Secretion of Testosterone and Its {Delta}4 Precursor Steroids into Spermatic Vein Blood in Men with Varicocele-Associated Infertility J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 997 - 1001. [Abstract] [Full Text]

				J. Yang, D. W. Long, N. Inpanbutr, and W. L. Bacon Effects of Photoperiod and Age on Secretory Patterns of Luteinizing Hormone and Testosterone and Semen Production in Male Domestic Turkeys Biol Reprod, November 1, 1998; 59(5): 1171 - 1179. [Abstract] [Full Text]

				K. Hakola, D. D. Pierroz, A. Aebi, B. A.M. Vuagnat, M. L. Aubert, and I. Huhtaniemi Dose and Time Relationships of Intravenously Injected Rat Recombinant Luteinizing Hormone and Testicular Testosterone Secretion in the Male Rat Biol Reprod, August 1, 1998; 59(2): 338 - 343. [Abstract] [Full Text]