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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 4 1477-1486
Copyright © 2000 by The Endocrine Society

Original Studies

Older Men Manifest Multifold Synchrony Disruption of Reproductive Neurohormone Outflow1

J. D. Veldhuis, A. Iranmanesh, M. Godschalk and T. Mulligan

Division of Endocrinology, Department of Internal Medicine, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908; Endocrine Section, Salem Veterans Affairs Medical Center (A.I.), Salem, Virginia 24153; and Hunter Holmes McGuire Veterans Affairs Hospital (M.G., T.M.), Richmond, Virginia 23249

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


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Under a working clinical hypothesis that aging putatively disrupts neuroendocrine control mechanisms, here we test a specific corollary notion that transitions in sleep stage, oscillations in nocturnal penile tumescence (NPT; a neurogenically organized signal), and the rates of instantaneous secretion of LH and/or testosterone are jointly synchronous in healthy young, but not older, men. To this end, we evaluated 10 young (aged 21–31 yr) and 8 older (aged 65–74 yr) men by intensive overnight multisite monitoring, viz. simultaneous electroencephalogram and NPT recordings (every 30 s) and remote blood sampling (every 2.5 min) to quantitate LH and testosterone release. Waveform-independent deconvolution and cross-correlation analyses of these neurohormone outflow measures revealed that healthy young men sustain four salient physiological linkages overnight: 1) a strong inverse (confirmatory) relationship between sleep stage and NPT activity, such that deeper sleep is accompanied by suppression of NPT; 2) consistent coupling between NPT and testosterone secretion, wherein heightened NPT activity respectively precedes and follows increased testosterone secretion by 12.5–32.5 and 50–60 min; 3) evident synchrony between sleep stage and testosterone secretion, in which testosterone secretion increases over a 30-min window (-2.5 to 25 min) while sleep deepens; and 4) a close temporal linkage between instantaneous LH release and NPT oscillations, whereby LH secretion increases 55–62.5 min before and again 5–30 min after NPT declines. In contrast, older men manifested global loss of expected young adult synchrony; namely, 1) abolition of the inverse relationship between sleep stage and NPT, 2) decorrelation of NPT oscillations and testosterone secretion, 3) decoupling of testosterone release and deep sleep, and 4) abrogation of the linkage between LH secretion and penile detumescence.

In summary, high intensity overnight monitoring of multiple reproductive neuroendocrine outflow measures simultaneously in young men delineates prominent neurophysiological coupling among sleep transitions and NPT activity, LH and testosterone secretion or NPT oscillations, and testosterone secretion and deepening sleep stage. In contrast, healthy older men exhibit near-universal disruption of physiological young adult synchronicity. Thus, we conclude that male reproductive aging is marked by erosion of coordinate regulation among sleep transitions, central nervous system-directed NPT activity, and hypothalamically driven episodic GnRH/LH (and thereby Leydig cell testosterone) secretion. Whether analogous multifold uncoupling of neurohormone signals emerges in the course of reproductive aging in women or in nonhuman species is not yet known.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE CENTRAL NERVOUS system (CNS) supervises sleep transitions and in men also coordinates sleep-associated neurogenic reflexes, such as nocturnal penile tumescence (NPT) (1, 2, 3, 4). Previous clinical studies in healthy young adults have documented an inverse relationship between sleep stage and NPT and, conversely, a positive correlation between rapid eye movement (REM; lighter stage) sleep and spontaneous NPT activity (3).

A so-called hypothalamic pulse generator is believed to govern the intermittency of arcuate nucleus GnRH release, which drives episodic bursts of pituitary LH secretion (5). Accordingly, monitoring of pulsatile LH release offers a surrogate marker of outflow from the hypothalamic GnRH neuronal ensemble. Blood LH elevations, in turn, activate Leydig cell testosterone secretion after a brief time lag (6, 7, 8). Thus, more broadly the adult male reproductive axis can be visualized as an interactive homeostatic network. Homeostasis is maintained by coordinate time-delayed signaling among key regulatory sites, viz. CNS sleep-wake centers, neurally directed NPT oscillations, the hypothalamic GnRH pulse generator, anterior pituitary gonadotropes, and LH-responsive steroidogenic cells in the testes. To our knowledge, this implicit hypothesis of multilocus interactive coupling within the human male reproductive axis has never been tested more directly, e.g. by high intensity simultaneous monitoring of brain sleep-wake activity, NPT oscillations, and LH and testosterone secretion in the same subject.

To examine the foregoing thesis of network-like control, we here quantitate the pairwise synchrony among four major neurally supervised reproductive signals in healthy young men. In view of earlier evidence of altered sleep, disrupted NPT patterns (3, 4, 9, 10) and diminished LH-testosterone synchrony (6, 11, 12) in older men, we also explore the corollary hypothesis that specific within-axis synchrony is disrupted in healthy aging.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Clinical protocol

This study was approved by the University of Virginia human investigations committee. We studied healthy young (aged 21–31 yr; n = 10) and older (aged 65–74 yr; n = 8) men, who had no acute or chronic illnesses, ingested no drugs or medications, were nonsmokers, were within 20% of ideal body weight, and had not undergone any transmeridian travel in the past 10 days.

Volunteers spent 2 consecutive nights in the sleep laboratory of the General Clinical Research Center. The first night allowed adaptation to polysomnography and NPT monitoring. The second night was used for blood sampling as well. Subjects were sampled remotely via tubing connected to a forearm catheter. Access was maintained by slow infusion of heparinized saline. Blood (2.0 mL) was withdrawn every 2.5 min, and the first 0.5 mL was discarded. Blood samples were allowed to clot at room temperature, and the serum was frozen at -20 C for later assays. Electroencephalogram (EEG) and NPT records were made concurrently. Sleep stages were defined by to the criteria of Rechtschaffen and Kales (2). For cross-correlation purposes, REM sleep was assigned a numerical value of 0, and other (deeper) stages were assigned respective values of 1–4, corresponding to EEG stages I–IV. Thirty-second sleep stage and NPT data over a mean of 7 h of sleep time were averaged over successive 2.5-min bins to correspond to simultaneous blood samples. The LH and testosterone concentration data (but not EEG or secretory data) in some of these volunteers were reported previously in cross-approximate entropy analyses (11).

Assays

Serum LH concentrations were assayed in duplicate via an automated two-site monoclonal immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA), with a sensitivity of (First International Reference Preparation) 0.20 IU/L and inter- and intraassay coefficients of variation less than 6.5%. Serum testosterone was measured by solid phase RIA (Diagnostic Products, Los Angeles, CA), with a sensitivity of 20 ng/dL, a within-assay precision of 4.5%, and an interassay coefficient of variation less than 6.5%. Sample SDs in each overnight hormone series were used in a power-function fit of the relationship hormone concentration (dose) vs. within-sample variance (13).

Analysis of instantaneous secretion rates

The disparate clearance rates of LH and testosterone introduce not only hormone-specific time delays, but also strong autocorrelations in both time series (8, 14). The latter can yield spurious cross-correlations in the analysis (15). To address these technical problems, we applied waveform-independent deconvolution analysis (PULSE) to each serum LH and testosterone concentration time series (13, 14, 15). This technique calculates sample secretion rates using known (directly measured) two-component disappearance kinetics, as reported previously for both of these hormones (16, 17), while allowing for the observed population variances in these estimates (13). We thereby detrend the overnight hormone profile and obviate expected autocorrelations within the original concentration time series.

Analysis of time-lagged cross-correlations

Cross-correlation analysis was used to correlate paired serial measures at various time lags (14). A time lag of zero denotes that simultaneously collected samples are evaluated for their linear correlation across the paired series. Both forward and reverse lags were evaluated, wherein the first named time series led (positive lag) or lagged (negative lag) the second by a give time interval, here ±2.5 to ±150 min. The r values determined in each subject at each lag time were normalized to standard deviate (z) scores based on their corresponding SD determined analytically at each lag, using the pooled (bivariate) dose-dependent within-sample variances. Group significance of r values in each cohort at any given lag was evaluated using the nonparametric Kolmogorov-Smirnov statistic to test the null hypothesis that z scores (above) at any given lag are randomly distributed with unit SD about a zero mean (14). Analogous correlations were performed (pairwise) between sample LH or testosterone secretion rates and/or serial NPT values.

Statistics

Statistical significance was assumed for protected P <= 0.01 embodying at least 2 consecutive time lags to restrict false positive correlations to 1 or less per 100 evaluations and demonstrate consistency across 2 sampling observations.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Young men displayed strong inverse cross-correlations between sleep stage and NPT activity; i.e. deeper sleep was associated with reduced NPT activity. Conversely, REM (lighter) sleep was accompanied by heightened NPT activity within 2.5–7.5 min. There was also delayed, albeit brief (47.5–50 min time-lagged), concordance of deep sleep with penile tumescence. In contrast, the group of older individuals exhibited no significant NPT/sleep correlations (Fig. 1Go).



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  		Figure 1. Cross-correlation coefficient r ({rho}) values plotted at various time lags in young (top; n = 10) and older (bottom; n = 8) men. Cross-correlation quantitates the bivariate linear (Pearson’s) relationship between two variables, such as (here) sleep stage (determined in 30-s EEG epochs) and NPT measurements (recorded continuously) overnight. Data are the median and absolute range of r values at each lag time (plotted at 2.5-min intervals). Zero lag denotes simultaneous sleep stage and NPT values. On the right side of each panel, the first named measure precedes the second by the indicated lag time (and conversely for the left side). *, P < 0.01 defines the probability that the observed group distribution of r values at that lag is purely random (see Materials and Methods).

 
Young men also exhibited a significantly positive cross-correlation between NPT and sample testosterone secretion rates, in which an increase in NPT activity respectively preceded and followed increased testosterone secretion by 12.5–32.5 and 50–60 min. In older men, neither of these correlations existed (Fig. 2Go).



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  		Figure 2. Cross-correlation plots for the time-lagged relationship between NPT activity and calculated sample testosterone secretion rates in young (top) and older (bottom) men monitored at 2.5-min intervals overnight. Data are presented as described in Fig. 1Go. *, P < 0.01.

 
Sleep stage and sample LH secretion tended to correlate positively (at P = 0.03), but only at a nearly 2-h time lag and only in young men, i.e. in the latter group, LH secretion rose 115–133.5 min before sleep stage deepened. There was no such correlation at any time lag in older men (Fig. 3Go).



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  		Figure 3. Cross-correlation plots for the time-lagged relationship between EEG sleep stages and instantaneous LH secretion rates in young (top) and older (bottom) men evaluated at 2.5-min intervals overnight. Data are presented as described in Fig. 1Go. There was a trend (P = 0.03) for LH secretion rates to rise 115–133.5 min before sleep stage deepened, but only in young men.

 
In young men, sleep stage and instantaneous testosterone secretion rates were strongly related, such that elevations in testosterone secretion occurred -2.5 to 25 min after sleep deepened, i.e. during a 30-min time window starting 2.5 min before and extending until 25 min after sleep deepened. In older men, testosterone secretion evinced no significant correlation with sleep stage (Fig. 4Go).



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  		Figure 4. Cross-correlation plots for the time-lagged relationship between EEG sleep stages and sample testosterone secretion rates in young (top) and older (bottom) men assessed at 2.5-min intervals overnight. Data are presented as described in Fig. 1Go.

 
In young men, LH secretion rates and NPT activity correlated inversely, e.g. LH secretion rose 55–62.5 min before and again 5–30 min after NPT activity fell (i.e. during detumescence). Neither correlation was detectable in older men (Fig. 5Go).



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  		Figure 5. Cross-correlation plots for the time-lagged relationship between 2.5-min LH secretory rates and NPT activity in young (top) and older (bottom) men monitored overnight. Data are presented as described in Fig. 1Go.

 
Figure 6Go depicts illustrative profiles of all four neurohormone outflow measures in one young and one older man.



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  		Figure 6. Illustrative profiles of sleep stage, NPT, and serum testosterone and LH concentrations in one young (left column of subpanels) and one older (right column) man. To convert testosterone values in nanograms per dL to nanomoles per L, multiply by 0.03467. Data were obtained at 0.5-min (sleep stage and NPT) and 2.5-min (testosterone and LH) intervals overnight.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present clinical investigation tests the primary hypothesis that network-like coordination operates within the healthy young male reproductive axis; i.e. there is multifold synchrony among overnight NPT oscillations, sleep transitions, and moment to moment LH and/or testosterone secretion. Concurrently, we explore the secondary postulate that synchrony within this specific feedback control system is disrupted in older individuals. To these ends, we have quantitated the degree and time latency of coordination among key neuroendocrine outflow signals by simultaneous electrical recordings and concomitant high frequency (2.5-min interval) blood sampling in the same healthy individuals. To relate neurogenic signaling (e.g. NPT and EEG changes) more explicitly to neuroglandular secretion (rather than to time-delayed serum hormone concentrations), we first reformulated each overnight serum LH and testosterone concentration profile as its matching (half-life corrected) series of instantaneous sample secretion rates (13, 15). This enhanced analytical strategy was implemented to limit temporal confounding of correlations by the 3- to 4-fold disparity in blood LH and testosterone half-lives (17). Thereby, we could corroborate the earlier reported relationship between NPT and sleep stages and demonstrate for the first time that healthy young men also sustain lag-specific coupling between 1) rhythmic NPT activity and episodic LH and testosterone secretion, and 2) sleep transitions and testosterone release. All four of these readily demonstrable time-dependent linkages were abolished in the group of healthy older men. Thus, the present clinical studies in older volunteers unveil global disruption of the anticipated multifold synchrony among sleep stage, NPT, and LH and testosterone secretion.

Earlier clinical studies have reported aging-associated loss of neurohormone synchrony for the paired release of LH and FSH and for certain other feedback control axes, such as GH-insulin-like growth factor I and ACTH-cortisol (18, 19). In addition to erosion of coordinate hypothalamo-pituitary neuroregulation in the older human, orderly insulin release patterns are disrupted both basally and during exogenous glucose drive in aging men and women (20, 21). Thus, the present evidence of multifold synchrony loss within the gonadotropic axis in older men points to a broader hypothesis that aging is marked by a more general attenuation of CNS-neuroendocrine signal integration. The proximate basis for such inferential network level regulatory disarray in the older human is not yet known.

Even correlation values associated with P < 10-3 in clinical studies (as observed here) may not reflect the full strength of the actual relationship that operates physiologically in vivo. Imperfect correlation could arise in part from the ethical constraint that neurohormone measures in the human cannot usually be made at the secretory source. For example, when direct spermatic vein blood sampling is performed in middle-aged men (7), median LH-testosterone cross-correlation coefficients are higher than those observed here in peripheral blood and approach 0.65–0.93. In addition, other systemic changes with aging, such as reduced testosterone metabolic clearance, blunted NPT activity, and greater sleep fragmentation, could influence the apparent correlation structure in aging.

Synaptological studies of the hypothalamic GnRH neuronal population in the male rodent have revealed a 3- to 10-fold increase in perikaryal synaptic inputs to medial preoptic GnRH neurons in older animals (22). Aging male rats also exhibited more pleomorphic vesicles within synaptic boutons on GnRH perikarya and dendrites, but the size, distribution, and total number of GnRH neurons did not vary with age. The precise functional relationship, if any, between such morphological alterations and the (relative) hypogonadotropism inferred in either the aging male rat (23, 24, 25) or human (26, 27, 28, 29, 30, 31, 32, 33, 34) remains undefined. Indeed, to our knowledge neither monitoring of mediobasal hypothalamic multiunit electrical activity (taken as an electrophysiological correlate of GnRH release) nor direct measurements of hypophyseal portal blood GnRH are available in older animals to establish the precise nature of putative alterations in pulsatile hypothalamic GnRH secretion associated with aging.

Peripheral blood as well as spermatic vein blood-sampling studies have documented a consistent (~35 ± 5 min) time-lagged positive correlation between LH and testosterone release in young and middle-aged men (6, 7, 35). Comparable direct testicular sampling data are not available to our knowledge in older individuals. However, peripheral blood sampling in older men has demonstrated significant blunting of both LH-testosterone (feedforward) and testosterone-LH (feedback) (7). The latter inferences would be congruent with the present thesis of multifold synchrony loss within the aging male reproductive axis. In addition, other biomathematical analyses of the so-called conditional pattern irregularity of LH and testosterone corelease in the older male further suggest impaired within-axis feedback integration, as quantitated via the novel lag-independent, nonlinear cross-approximate entropy statistic (11).

Older men are known to have a damped 24-h (circadian-like) rhythmicity of serum testosterone concentrations (36). This defect could, in principle, also reflect reduced reproductive network control in the aging male (36, 37), assuming that CNS regulatory centers that govern circadian and sleep-associated rhythms are coupled to LH-testosterone secretion (38). Aging men also exhibit evident disturbances in estrogen (26, 39)-, androgen (40, 41, 42, 43)-, and opioid receptor (34, 44)-dependent restraint of pulsatile LH release. These several alterations in feedback control are also consistent with CNS-hypothalamic dysregulation of the gonadotropic axis.

Previous clinical studies in older men have disclosed a presumptive defect in Leydig cell steroidogenesis as well (45, 46, 47). Coexistent Leydig cell failure might contribute plausibly to some, but not all, of the present observations, i.e. the loss of sleep/testosterone and NPT/testosterone coupling. However, the abolition of joint NPT/LHsecretory synchrony in older men cannot be attributed readily to impaired androgen biosynthesis. One would need to invoke the hypothesis that testosterone itself controls CNS-hypothalamic integration among sleep transitions, NPT oscillations, and LH secretion. Against this speculation is the lack of correlation between normal serum testosterone concentrations and age-associated changes in either EEG or NPT (3, 48). In contrast to such data in healthy men, clinically hypogonadal patients may have diminished REM and NPT activity (4, 49, 50, 51, 52, 53), which can be reversed by testosterone repletion in most (3, 50, 51, 52), but not all (53), studies. Notably, none of the men studied here was hypogonadal.

One previous overnight evaluation in young men reported that peak serum testosterone concentrations tend to occur in proximity to REM sleep episodes (38). In contrast, another study failed to detect any relationship between variations in testosterone and sleep stage (54). However, most earlier assessments of overnight EEG, NPT, and serum LH, FSH, and/or testosterone concentrations implemented a blood sampling frequency of 15 or 20 min, used paired (but not multiple) neurohormone monitoring, and/or included relatively few subjects. In addition, prior analyses did not adjust for the 3- to 4-fold differences in the plasma half-lives of LH and testosterone. To address these considerations, we applied intensive 2.5-min blood sampling; performed simultaneous LH, testosterone, EEG, and NPT monitoring; and adjusted analytically for unequal hormone half-lives. These strategies in combination were able to delineate consistent and specific relationships between not only testosterone secretion and sleep stages, but also between testosterone release and NPT activity in young men.

Previous overnight monitoring studies in older men have revealed declines in NPT activity (3), total and deep sleep (55), and REM sleep (9). In one analysis, reduced REM and NPT episodes in aging men correlated with lower serum testosterone concentrations (9). However, another investigation of a larger cohort of 67 healthy individuals observed that the correlation between serum bioavailable testosterone concentrations and measures of NPT vanished after statistical adjustment for age as a covariate (4). Thus, advancing age, rather than hypoandrogenemia, was the primary apparent determinant of declining NPT activity.

In summary, young men manifest multifold synchrony among NPT activity, sleep transitions, and instantaneous LH and testosterone secretion. This robust coordination among EEG, NPT, and GnRH/LH/testosterone secretory outputs probably reflects CNS-dependent integration of corresponding neuroregulatory pathways. In contrast, each of the foregoing prominent neurohormone linkages is abolished in healthy older men. Such global attrition of synchrony control in older individuals suggests a broader idea of the pathophysiology of the earlier phases of reproductive axis aging in the male, i.e. disruption of otherwise coupled neuroendocrine outflow. Whether analogous loss of multivalent regulatory coordination within the reproductive axis occurs in the course of healthy aging in women or in nonhuman species is not known.


   Acknowledgments
 
We thank Patsy Craig for her skillful preparation of the manuscript; Paula P. Azimi for the deconvolution analysis, data management, and graphics; Brenda Grisso for performance of the immunoassays; and Sandra Jackson and the expert nursing staff at the University of Virginia General Clinical Research Center for conduct of the research protocols.


   Footnotes
 
1 This work was supported in part by NIH Grant MO1-RR-00847 (to the General Clinical Research Center of the University of Virginia Health Sciences Center), the NSF Center for Biological Timing (Grant DIR89-20162), the NIH U-54 Specialized Cooperative Centers Program in Reproductive Research (Grant HD-28934), Veterans Affairs Merit Review Research Funds (to T.M.), and NIA Grant RO1-AG-14799 (to J.D.V.). Back

Received October 13, 1999.

Revised December 29, 1999.

Accepted January 5, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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