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From the Clinical Research Centers |
Division of Endocrinology (J.D.V.), Department of Internal Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; Endocrine Section, Medicine Service (A.I.), Salem Veterans Affairs Medical Center, Salem, Virginia 24153; Geriatrics Medicine (T.M.), Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia 23249; Moose Hill Road (S.M.P.), Guilford, Connecticut 06437
Address correspondence and requests for reprints to: Division of Endocrinology, Department of Internal Medicine, Box 202, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; E-mail: JDV{at}Virginia.Edu
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Abstract |
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In ensemble, the present clinical experiments indicate that, within the aging male reproductive axis, bihormonal network disruption is more pronounced than individual signal disruption. We suggest that abrogation of joint synchrony among hypothalamically directed pituitary hormones and a neurogenically organized sexual response (nocturnal penile tumescence) can be unified thematically under an hypothesis of disrupted central nervous system hypothalamo-pituitary network coordination in human aging. Such implicit disarray of multinodal communication is of consequence both scientifically and clinically, especially in proposing aging theories and intervention strategies.
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Introduction |
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A notion of altered feedback/feedforward neuroendocrine interactions in mediating bihormonal asynchrony is supported by a number of clinical pathophysiological paradigms of control-signal withdrawal, as considered further in the Discussion section of this paper. Accordingly, pertinent statistical assessment of both one-variable irregularity and of two-variable asynchrony can potentially offer pivotal insights into altered network-level behavior within biological feedback systems (9).
Clinical investigations of the aging (human) male reproductive axis have disclosed alterations in both the pulsatile mode and the serial orderliness of LH secretion considered univariately (1, 10, 11, 12, 13). Pulsatile LH release in healthy older men tends to be marked by lower-amplitude and more frequent secretory events (10, 11, 12, 13). Concomitantly, LH secretion, as assessed by approximate entropy (ApEn), becomes significantly and consistently more irregular with advancing age in both men and women (1, 3, 12). Disruption of hypothalamic GnRH release may subserve both of these (pulsatile and nonpulatile) alterations in LH control, as pulsatile iv GnRH infusion for two weeks in older men restores LH pulsatility and entropy estimates to values equivalent to those achieved in similarly treated young adults (12). However, serum testosterone concentrations fail to rise significantly during GnRH infusion in older subjects (unlike in young men), which can be explicated by earlier studies in aging individuals showing diminished Leydig-cell steroidogenic reserve under short-term drive by human chorionic gonadotropin. Thus, clinical observations in older men point to at least two distinct functionally defective loci within the aging male hypothalamo-pituitary-gonadal axis: viz., diminished steroidogenic activity of testicular Leydig cells and impaired output of the GnRH-LH (hypothalamo-pituitary) unit.
Assuming that hypothalamo-pituitary and gonadal alterations coexist in aging men, then any interpretations of the basis for the previously reported loss of coupled LH-testosterone secretion in older subjects should include both attenuated Leydig-cell responsiveness to circulating LH and dysregulation of (hypothalamic) GnRH-directed LH secretion (1). Accordingly, here to evaluate more directly an hypothesis of loss of coordinated central neuroendocrine control of release of the hypothalamo-pituitary unit in older men, we assess pairwise synchrony of the pituitary hormones LH-FSH and LH-prolactin as well as joint LH-NPT oscillatory patterns in healthy older individuals compared with young counterparts. NPT was used as an integrated neurophysiological surrogate for central nervous system (CNS) sleep-wake regulation, as it is a strong correlate of REM sleep (14). Furthermore, and critically, we evaluate whether changes with this multihormonal axis with increasing age mechanistically reflect primarily disruption of the underlying network (e.g. pathway-dependent or central control aspects), or mirror alterations in specific nodal (individual hormone release) characteristics. As suitable analytic strategies to quantify the notions under investigation, we assess changes in joint variable asynchrony (conditional irregularity) via cross-approximate entropy (cross-ApEn) (1, 15), and we evaluate single-variable sequential irregularity by approximate entropy (ApEn) (15, 16), both described in Materials and Methods.
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Methods |
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Healthy young men (n = 10, ages 21–34 yr) and older men (n = 8, ages 62–72 yr) were recruited from the Charlottesville, Richmond, and Salem Virginia communities for study in the General Clinical Research Center (GCRC) at the University of Virginia Health Sciences Center. After provision of written informed consent, each volunteer underwent one night of prior adaptation in the GCRC. This was followed on a second night by blood sampling at 2.5-min intervals while sleeping (from 2300 clocktime, average sampling interval 7 h). A long nonthrombogenic catheter was used, from an adjacent room, to withdraw blood samples, to avoid disturbing the subject (1). Nocturnal penile tumescence (NPT) was monitored concurrently by recording penile circumference continuously (see below). No volunteer was receiving any systemic medications, had any acute or chronic illness, had undertaken recent transmeridian travel (across more than 3 time zones within 2 weeks), had experienced recent weight loss or gain (more than 2 kg in 10 days), or had any evidence by screening biochemical assessments, physical examination, or medical history of hepatic, renal, hematologic, metabolic, or endocrine disease. Baseline morning fasting serum concentrations of prolactin, LH, FSH, GH, TSH, IGF-I, thyroxine, resin T3 uptake, total testosterone, and estradiol were normal for age (2).
Assays
Serum LH, FSH, testosterone, and prolactin concentrations were
assayed in each serum sample in an automated random-access
chemiluminescence-based assay (ACS: 180, Chiron Corp.
Diagnostic, Corp., Walpole, MA) in singlet. Independent studies
demonstrated a strongly positive linear correlation between LH, FSH,
testosterone, and prolactin concentrations measured by
chemiluminescence and corresponding values obtained by RIA or
immunoradiometric assays (all r 
+ 0.873; P <
10-5, n = 18 samples) (2, 17). Reference
standards were Second World Health Organization International Standards
80/552 and 94/6532 for LH and FSH, respectively. The within-assay
coefficients of variation were less than 6.5%, and the between-assay
coefficients of variation were less than 9.5%. All samples from an
individual were analyzed together to eliminate interassay
variability.
Calculation of sample LH secretion rates
For paired comparisons between LH and NPT time series, both untransformed serum LH concentrations and waveform-independent deconvolved LH secretion time series were used. The latter technique computes sample LH secretion rates without any assumptions regarding the form or amount of underlying basal or pulsatile LH release, by using a priori determined biexponential hormone kinetics (18). Here, we assumed an LH mean rapid-phase half-life of 18 min, a slower phase of 90 min, and a fractional amplitude (ratio of the slow component to the total amplitude) of 0.37, as determined directly earlier (19). The sample LH secretory rates or serum LH concentrations were then paired with 2.5-minutely (binned) NPT values (below).
Nocturnal penile tumescence (NPT)
NPT was monitored as a neurophysiological correlate of CNS sleep-wake regulation by continuous recordings of penile circumference via a strain gauge applied overnight, as described in other sleep studies (14). The subject was adapted to the monitoring device during an earlier night in the GCRC. Penile circumference was recorded in 30-second epochs, the values of which were averaged to yield 2.5-minutely bins for further analysis.
Approximate Entropy (ApEn) and Cross-ApEn
ApEn comprises a class of translation-, model- and scale-independent statistics designed to assess the pattern randomness or ad seriatim irregularity within a time series (16). ApEn quantifies the subpattern replicability or orderliness of successive measurements, which is not necessarily identified by pulse-detection algorithms (9). ApEn is a non-negative number calculated as an ensemble value for a data series (e.g. any given profile of serial hormone concentrations or sample secretion rates). Larger ApEn values denote greater randomness or less pattern reproducibility in the time series. Technically, ApEn quantifies the logarithmic likelihood that runs of patterns in the data that are similar remain similar on next incremental comparison. The formal definition of calculated ApEn is given in recent publications (8, 15). Briefly, for any given data series containing N observations two input parameters, namely m and r, are fixed to compute ApEn from vector sequences constructed from the serially observed data. Here, m represents the vector or window length of consecutive hormone measurements, and, r, the tolerance for testing subpattern regularity. To maintain scale invariance, r is typically defined as a percentage of the between-sample SD of each time series, e.g. 20%, and m as a value of 1 or 2 denoting consecutive vectors of length 1 or 2 data points. In the time series analyzed here, we calculated ApEn values with r = 20% and m = 1, and hence the designation, ApEn (1, 20%). This parameter set, standard in virtually all clinical applications, provides an appropriate ApEn statistic for assessing irregularity in data series of this length.
To quantify joint asynchrony (conditional irregularity), we used
cross-ApEn, introduced in reference (15), definition 5. As noted there,
cross-ApEn can be employed to compare sequences from two distinct yet
intertwined variables in a network, herein applied to relevant pairs of
hormonal time-series. The precise definition is thematically similar to
that for ApEn (15). For this study, we applied cross-ApEn with
m = 1 and r = 0.2 to standardized u-v
time-series data; i.e., for each subject, we applied
cross-ApEn(1,0.2) to the [u1(i), v1(i)] series, where u1(i) =
(u(i)—mean u)/SD u and v1(i) = (v(i)—mean
v)/SD v. To develop visual intuition, Figure 1
of
reference 9, taken from a recent study of paired ACTH-cortisol dynamics
in Cushing’s disease, illustrates the cross-ApEn quantification
and changes in the measure under pathophysiology.
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To establish statistical replicability of ApEn and cross-ApEn with the specified parameter choices m = 1, r = 20% SD, standard deviation calculations have previously been performed for these measures, via extensive Monte Carlo calculations. It was established that 1 SD of ApEn and cross-ApEn with these parameter choices, for data lengths N > 100 points, is less than 0.06 for wide classes of diverse mathematical models, encompassing both orderly (regular) and highly disorderly time-series settings (15, 16, 20). It is this small standard deviation of ApEn and cross-ApEn, that provides its usefulness, via good reproducibility, to time-series data analysis as performed herein.
Further technical discussion of mathematical and statistical properties of ApEn and cross-ApEn, including robustness to noise and artifacts, mesh interplay, relative consistency of (m, r) pair choices, asymptotic normality under general assumptions, statistical bias, and error estimation for general processes can be found elsewhere (16).
For ApEn and cross-ApEn calculations involving NPT, the original 30-sec NPT data were averaged across 2.5-minutely epochs. To maintain equal values of N (series lengths), all comparisons were carried out for overnight sampling data beginning at sleep onset recorded by EEG (n = 178 sample observations).
Statistics
Statistical comparisons were made by two-tailed unpaired Student’s t tests.
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Results |
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illustrates in one young
and one older man 2.5-min sampled overnight serum LH, FSH, and
prolactin concentrations and concomitant NPT profiles. Corresponding
calculated (predicted) secretory or smoothed NPT profiles are denoted
by continuous lines to represent the deconvolution fits (21).
Overnight mean serum LH concentrations (IU/L) were similar in older and
young men, as were serum (total) testosterone concentrations: Table 1. The overnight mean serum FSH
concentration was higher in older men, whereas that of prolactin was
reduced (Table 1).
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, the mean
(unvariate) ApEn values for overnight serum LH concentration time
series were significantly elevated in older (n = 8) compared with
young (n = 10) individuals, thereby affirming greater
disorderliness of LH release in older men (P = 0.0019).
Mean univariate ApEn values for overnight testosterone, FSH, prolactin,
and NPT time series in older men were not different from corresponding
values in young individuals.
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, 3, and 4 and Table 3 for bivariate (paired) LH-FSH,
LH-prolactin, an FSH-prolactin serum concentration time series, and for
paired LH concentration or LH secretory rate and NPT measurements.
Figures 2–4 display, respectively, the dispersion of individual
subject cross-ApEn values for several of the foregoing sets of
significant paired comparisons. In these joint comparisons, cross-ApEn
was greater in the older cohort, marking greater asynchrony in the
paired signals under consideration. We also confirm the earlier
reported age-related increase in LH-testosterone irregularity (1), and
note for the first time elevated testosterone-NPT cross-ApEn values in
older men (Table 3).
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Discussion |
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The presently quantified disruption of synchronous LH and prolactin, as
well as LH and FSH release in older men could point to reduced
hypothalamically directed coordination of moment-to-moment pituitary
release of these glycoprotein-hormone pairs. We demonstrated similar
asynchrony, albeit to a less vivid extent, for paired pituitary FSH and
prolactin secretion, and confirmed the LH-testosterone asynchrony
reported earlier in an older male cohort (1). Several important
plausible mechanisms may underpin this erosion of pituitary
(bihormonal) secretory-pattern synchrony. First, we speculate that
aging impairs hypothalamic signaling of pituitary gonadotrope (LH- and
FSH-secreting) and lactotroph (prolactin-secreting) cells. This could
arise from altered neurotransmitter regulation of the arcuate-nucleus
GnRH-neuronal ensemble, impaired median-eminence release of GnRH, or
disrupted stimulation by other putative neuromodulators of LH, FSH, and
prolactin secretion (32). A possible structural basis for such
postulated dysregulation of GnRH secretion, as intimated by studies in
the aged male virgin rat, is an age-related change in the density of
multisynaptic inputs to hypothalamic GnRH neurons (33). Second,
age-associated disturbances in intrapituitary autocrine and/or
paracrine regulatory mechanisms could impose LH-prolactin asynchrony,
e.g. as mediated via local intrahypophyseal effector
release, e.g. 
-subunit, which inter alia is
postulated to link lactotroph and gonadotrope cellular activities (34, 35). Third, altered sex-steroid feedback sensitivity of the
GnRH-gonadotrope unit may operate in older men and women (13, 36).
Fourth, since NPT is a neurophysiological correlate of the CNS
sleep-wake cycle (viz., NPT is associated preferentially
with REM sleep) (14), the significant pattern linkage of NPT
oscillations to LH secretion, as documented here in young men, likely
reflects the physiological coupling of relevant CNS pathways that
govern sleep-wake cycle activity with those that direct intermittent
output of the GnRH neuronal ensemble. Accordingly, the loss of
young-adult synchrony between LH (concentrations or secretory rates)
and NPT oscillations evident in aging men points to declension of
CNS-hypothalamic network control in older individuals, as schematically
envisioned in Fig. 5. This hypothesis of
disrupted CNS network communication is reinforced by the similar
univariate NPT ApEn values in young and older men; i.e.
there is preserved pattern orderliness of NPT oscillations in older
individuals, despite potential age-associated changes in sleep
architecture (14, 37). Consequently, impoverished joint LH-NPT
synchrony, rather than disrupted orderliness of NPT patterns per se,
may mark an early stage in the healthy aging process in men.
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Overnight mean serum LH and total testosterone concentrations in the young and older male cohorts were statistically similar. However, so-called bioavailable testosterone concentrations are often reduced in aging individuals (24). The impact, if any, of this relative androgen deficiency that accompanies healthy aging in men on the CNS-neuroendocrine processes that coordinate synchronous LH-FSH, LH-prolactin, FSH-prolactin, and LH-NPT oscillatory patterns is not known. Evaluating healthy older men before and after testosterone administration in a physiological pattern and (young-adult) amount would be required to clarify this query. Moreover, because the activities of multiple specific neurotransmitter pathways (e.g. noradrenergic, cholinergic, dopaminergic, glutaminergic, etc.) change in aging (43, 44), future studies with clinically suitable receptor specific neuromodulators should help to define (putative) neurochemical mechanisms that underlie inferred age-associated loss of central synchronous control of the (male) reproductive axis.
For both scientific and clinical reasons, we would highlight that the network aspects (paired-signal disruption) of age-related changes observed here in older men are more pronounced than univariate (single-process) changes. Our corresponding proposition of multi-nodal disruption in aging has evident implications to clinical theory and intervention strategies. For example, in relation to male (or female) sexual dysfunction and loss of libido in aging, attempts to restore capabilities toward those anticipated in younger life may require primarily restoration of axis synchronicity, rather than sex-hormone supplementation or local therapy alone. That is, if a clinical disorder is determined by an overall system decoupling, then reestablishment of full network coordination (rather than replacing a single target-hormone deficiency) may be optimal for recovery of full physiological function. In this regard, the exploration of selective neuromodulators to restore (synchronous) CNS-hypothalamus-pituitary regulatory control, while simultaneously reconstituting CNS sleep/activity coupling to relevant neuroendocrine output of one or more axes (e.g. LH, GH, prolactin), could therefore have clinical merit in therapies of aging.
Complementary to our postulated notion of hypothalamic neural-network aging in the healthy human male are the decrements in LH-FSH irregularity differences recognized recently in older men as well as in women (3) and the proposed CNS regulatory disturbances in the reproductively aging rodent (33, 44, 45). Thus, aging-associated alterations in interacting hypothalamic networks may constitute a more unifying aging mechanism subserving (progressive) reproductive failure in both the human and experimental animal. The possible extension of this postulate to other (e.g. nonreproductive) neuroendocrine axes and/or other (non-neuroendocrine) biological feedback-control systems in aging will be pertinent to evaluate further.
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Acknowledgments |
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Footnotes |
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Received December 30, 1998.
Revised June 9, 1999.
Accepted July 26, 1999.
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