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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 2 529-535
Copyright © 2001 by The Endocrine Society

From the Clinical Research Centers

Muting of Androgen Negative Feedback Unveils Impoverished Gonadotropin-Releasing Hormone/Luteinizing Hormone Secretory Reactivity in Healthy Older Men1

J. D. Veldhuis, A. Zwart, T. Mulligan and A. Iranmanesh

Division of Endocrinology (J.D.V., A.Z.), Department of Internal Medicine, General Clinical Research Center, Center for Biomathematical Technology, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202; Department of Geriatric Medicine (T.M.), McGuire Veterans Affairs Medical Center, Richmond, Virginia 23249; and Endocrine Section (A.I.), Medical Services, Veterans Affairs Medical Center, Salem, Virginia 24153

Address all correspondence and requests for reprints to: J. D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, P.O. Box 800202, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202. E-mail: jdv{at}virginia.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Plasma bioavailable testosterone concentrations decline in healthy older men without a uniformly commensurate rise in serum LH concentrations, which disparity is consistent with a hypothesis of relative hypogonadotropism. Likewise, preserved gonadotrope responsiveness to exogenous GnRH stimulation, despite an attenuated amplitude of endogenous LH pulses, points to reduced hypothalamic GnRH feedforward signaling in aging males. To appraise GnRH/LH secretory reserve more directly in older men, we have compared daily LH secretion, driven by profound short-term blockade of androgen biosynthesis by oral ketoconazole administration, in nine young (ages, 18–32 yr) and seven older (ages, 60–73 yr) volunteers. The ability to unleash endogenous GnRH-driven LH secretion in response to acute testosterone withdrawal was quantitated by sampling blood every 10 min, for 24 h, followed by high-precision immunoradiometric assay. The resultant serum LH concentration profiles were analyzed by: 1) model-free discrete peak detection (Cluster) analysis; 2) the approximate entropy statistic to quantitate pattern regularity; and 3) 24-h rhythmic (cosinor) analysis. At baseline, mean and integrated (24-h) serum LH concentrations were similar in both age cohorts. However, Cluster analysis established an elevated LH peak frequency [18 ± 0.86 (older) vs. 13 ± 1.3 pulses/24 h (young), P = 0.0028] and a reduced incremental LH pulse area [37 ± 6.9 (older) vs. 106 ± 20 (young) IU/L x min, P = 0.016] in older men. Approximate entropy calculations also revealed more irregular LH release patterns in older men before intervention (P = 0.00089). Feedback stress, achieved by ketoconazole-induced androgen deprivation, unmasked further neuroregulatory defects in older volunteers, who failed to equivalently increase the: 1) mean (24-h) serum LH concentration [i.e. to 5.0 ± 0.99 (older men) vs. 9.0 ± 1.1 (young) IU/L, P = 0.000071]; 2) maximal LH peak height (to 6.1 ± 1.1 vs. 10.4 ± 1.2 IU/L, P = 0.00043); 3) incremental LH pulse area (to 41 ± 8.8 vs. 87 ± 20 IU/L x min, P = 0.016); 4) interpeak nadir serum LH concentration (to 4.0 ± 0.77 vs. 7.9 ± 1.0 IU/L, P < 10-6); 5) the quantitable irregularity of LH release (P = 0.00089); and 6) the mesor of 24-h rhythmic LH secretion (P = 0.000062).

In summary, experimental imposition of a novel hypoandrogenemic open-loop feedback stressor, for 48 h, to heighten hypothalamic GnRH feedforward drive, unveils impoverished augmentation of LH pulse mass, impaired orderliness of LH release, and diminished 24-h rhythmic LH secretion in older men. The foregoing trilogy of neuroregulatory defects identifies unequivocally attenuated hypothalamo-pituitary reactivity to muting of androgen negative feedback in the aging male.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TESTOSTERONE BIOAVAILABILITY DECLINES progressively with increasing age in healthy, community-living, ambulatory, and unmedicated men (1, 2, 3). However, serum LH concentrations often do not increase reciprocally in the older male (2, 4, 5, 6, 7). This discrepancy could indicate that hypothalamo-pituitary failure accompanies the Leydig-cell insufficiency inferred earlier in aging (4, 6, 7, 8, 9, 10, 11, 12, 13, 14). However, secondary hypogonadotropism has been difficult to establish directly in healthy older humans (3, 8, 15).

To probe a postulated defect in endogenous GnRH’s feedforward drive of LH secretion in older men, we have applied a novel clinical investigative paradigm of short-term marked ketoconazole (KTCZ)-induced hypoandrogenemia. This intervention unleashes pulsatile, entropic (pattern-dependent), and 24-h rhythmic LH release more powerfully than partial androgen-receptor antagonism by flutamide, at least in young men (14, 16, 17, 18). To appraise GnRH/LH secretory responsiveness to such reversible Leydig-cell steroidogenic blockade, we have quantitated reactivity of the thematically complementary, but statistically independent, pulsatile (19), entropic (feedback-sensitive) (20) and 24-h rhythmic (9) modes of LH secretion in young and older healthy men subjected to acute testosterone depletion.


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

A total of 16 healthy volunteers [9 young men with a mean age of 21 (range, 18–32) yr and 7 older men of mean age 67 (range, 60–73) yr] participated, after providing written informed consent approved by the Human Investigation Committee of the University of Virginia Health Sciences System. Medical history, physical examination, and screening tests of hepatic, renal, metabolic, endocrine, and hematological function were normal.

KTCZ was administered orally with a dairy-free snack as 400 mg, every 6 h for 48 h, beginning at 0800 h, after a single midnight loading dose of 1000 mg (16). Blood was sampled every 10 min, beginning at 0800 h, during the second 24 h of KTCZ exposure (17). Dexamethasone was given concurrently at a dose of 0.75 mg orally, twice daily, to avert adrenal glucocorticoid insufficiency (21) and to allow for possible KTCZ-enhanced hepatic drug metabolism.

Assays

Serum LH concentrations were assayed in duplicate in each subject, in a single run (289 samples), via a validated two-site monoclonal immunoradiometric assay (IRMA; Nichols Institute Diagnostics Laboratory, San Juan Capistrano, CA) with automated (robotics) pipetting, bead-washing, and data reduction (9, 14, 22, 23). Sensitivity of the modified LH IRMA is 0.2 IU/L (First International Reference Preparation). Cross-reactivity is less than 1% with FSH, and free {alpha} or LH ß-subunits. Median coefficients of variation were 5.1% (intraassay) and 8.3% (interassay). This IRMA correlates well with in vitro rat Leydig-cell bioassay. Serum concentrations of total testosterone, dehydroepiandrosterone (DHEA)-sulfate, and androstenedione were assayed by RIA; and FSH, PRL, insulin-like growth factor-I, and TSH were determined by chemiluminescence assay or IRMA (9, 13, 16, 17).

Cluster analysis

Cluster analysis was used as a model-free computer-assisted method for objective peak detection, as validated earlier (24, 25). Conservative (<5.0% false-positive rate) test cluster sizes of 2 points for the putative peak and 1 for each flanking test nadir were used with pooled t-statistics of 2.0 to detect significant upstrokes (peak onset) and downstrokes (peak offset) in LH time series. Comparable inferences were obtained using a 2 x 2 test cluster configuration. The highest concentration in a pulse was designated the peak maximum; the lowest interpeak hormone concentration, the nadir; the time (min) separating consecutive peak maxima, the interpulse interval; the number of peaks per 24 h, the frequency; and the integrated peak concentration (above the mean of the pre- and postpeak nadirs), the incremental peak area (8, 24).

Approximate entropy (ApEn) analysis

ApEn was used as a model-free metric of the orderliness of LH release patterns (26). ApEn serves as a sensitive barometer of within-axis feedback changes (20). ApEn is computed as the sum of the negative logarithms of the conditional probabilities that subpatterns of length m in a time series recur upon next (m + 1) incremental comparison within a given tolerance range r. Here, we used m = 1 and r = 20% of the intraseries SD, which provides a normalized (scale-independent) ApEn statistic (20, 27).

Cosine regression

The 24-h rhythmicity of serum LH concentrations was quantitated by unweighted regression of a cosine function of 1440-min periodicity (28, 29). Ninety-five percent statistical confidence intervals were determined for the fitted amplitude (50% of the nadir-zenith difference), mesor (cosine mean), and acrophase (clocktime of rhythm maximum).

Statistical analysis

ANOVA was applied, in a repeated-measures design, to the log-transformed derived parameters. Duncan’s new multiple-range test was used post hoc to contrast means. Data are presented as the mean ± SEM (median). P < 0.05 was construed as statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go gives pooled (24-h) serum concentrations of sex steroids and ancillary hormones. There were anticipated age-related contrasts in several baseline measures. KTCZ suppressed androgen concentrations markedly in both age groups, with greater inhibition of testosterone levels in older volunteers.


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  		Table 1. Selected hormonal measurements in young and older men studied after placebo (control) or KTCZ administration

 
Figure 1Go summarizes mean and 24-h integrated serum LH concentrations. Values were comparable in young and older men at baseline. However, LH rose by 2.9-fold in young, but only by 1.8-fold in older, men in response to KTCZ administration (P = 0.000071).



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  		Figure 1. Mean (top) and integrated (bottom) 24-h serum LH concentrations in nine young and seven older healthy men, each administered placebo (control) or the steroidogenic enzyme inhibitor, KTCZ, for 48 h, in randomized order, several weeks apart. Blood was sampled at 10-min intervals during the second 24 h of placebo and KTCZ ingestion. LH was quantitated by high-specificity and high-precision two-site monoclonal IRMA (Subjects and Methods). Numerical values are the cohort means ± SEM. P values were calculated via repeated-measures ANOVA. Unshared alphabetic superscripts denote significantly different means.

 
Figure 2Go illustrates 24-h serum LH concentration profiles in four older and four young men.



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  		Figure 2. Illustrative 24-h serum LH concentration profiles, obtained at baseline (A, placebo) and during short-term (48-h) androgen depletion induced by oral KTCZ administration, (B) in four young and four older men. Vertical bars associated with the sample values denote dose-dependent within-subject intraassay SDs estimated from all 145 replicated measurements in each LH time series. Arrows mark Cluster-identified LH peaks (Subjects and Methods).

 
Cluster analysis disclosed a higher LH pulse frequency in older volunteers at baseline (18 ± 0.86 vs. 13 ± 1.3 peaks/24 h, P = 0.0028). KTCZ administration increased LH peak number comparably, to 20 ± 0.88 in older and 16 ± 1.6 pulses/day in young men (Fig. 3AGo). Corresponding LH interpeak interval (min) means were 72 ± 5.1 (older, baseline), 99 ± 8.5 (young, baseline), 67 ± 2.4 (older, KTCZ), and 89 ± 9.2 (young, KTCZ) (P = 0.016; Fig. 3BGo). LH peak maxima (IU/L) were similar at baseline, 3.0 ± 3.3 (older) and 4.4 ± 0.56 (young), but failed to rise equally in older men in response to KTCZ administration, i.e. to 6.1 ± 1.1 (older) vs. 10.4 ± 1.2 (young) IU/L (P = 0.00017; Fig. 4AGo). Nadir serum LH concentrations averaged 1.6 ± 0.18 (older) and 2.1 ± 0.29 (young) IU/L at baseline (placebo), and they increased to 4.1 ± 0.77 in older, but 7.8 ± 1.0 IU/L in young, men during KTCZ ingestion (P < 10-6; Fig. 4BGo). LH peak areas (IU/L x min) were reduced at 37 ± 69 in older vs. 106 ± 20 in youngvolunteers, before KTCZ intervention (P = 0.016). Peak areas did not rise during KTCZ administration in older men; viz. 41 ± 8.8 (older) vs. 87 ± 20 (young) IU/L x min.



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  		Figure 3. Serum LH concentration peak frequency (upper panel) and interpulse interval (lower panel) values, as assessed by model-free discrete peak-detection analysis (Cluster) of 24-h serum LH concentration profiles (see Fig. 1Go legend). Numerical values are the mean ± SEM (n = 9 young, n = 7 older men). P values were determined by repeated-measures ANOVA. Unshared alphabetic superscripts denote significantly different means.

 


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  		Figure 4. Serum LH concentration peak maxima (upper panel), interpeak nadirs (middle panel), and pulse areas (lower panel) in nine young and seven older men studied as described in the legend of Fig. 1Go. Data are presented as defined in Fig. 3Go.

 
Elderly men exhibited higher LH ApEn at baseline (P = 0.00089), which values did not increase further during stimulation (Fig. 5Go, upper panel). This age-related contrast in ApEn persisted after algebraic first-differencing of the original serum LH concentration time series (P < 0.00015), and after waveform-independent deconvolution-based detrending of sample LH secretion rates (30) (P < 10-10). Young and older men’s observed LH ApEn values averaged, respectively, 16 ± 2.0 vs. 8.3 ± 1.5 SDs (P = 0.00017), removed from maximally random, based on surrogate series created by shuffling each data set 1000 times. KTCZ reduced the foregoing SD values significantly only in young men; i.e. to 7.1 ± 0.86 (young) vs. 7.4 ± 1.0 (older) (Fig. 5Go, lower panel).



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  		Figure 5. Upper, ApEn (1.20%) of 24-h serum LH concentration profiles in nine young and seven older men sampled during randomly ordered placebo (control) and KTCZ administration. Higher ApEn denotes greater disorderliness or irregularity of hormone release. Lower, Estimated distance in standard deviations (SD or Z-score) of each observed LH ApEn from maximally random. The latter was determined empirically by shuffling each LH time series 1000 times, to generate a null distribution of random ApEns. Data presentation is given in the legend of Fig. 3Go.

 
Cosine regression analysis revealed that KTCZ elevated the mesor less (P = 0.000062) and the amplitude more (P < 0.001) in older men, while significantly delaying the acrophase (P = 0.033) of 24-h rhythmic LH release.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present studies use a novel clinical experimental paradigm of profound reversible short-term KTCZ-induced combined blockade of adrenal and testicular androgen biosynthesis to unleash hypothalamic GnRH feedforward drive in young and older men. Thereby, we test the postulate that endogenous GnRH/LH secretory reserve is impaired in the healthy aging male. The latter hypothesis of neuroendocrine aging arises from a constellation of indirect observations in older men (3, 8, 15). Assuming that aging men retain gonadotrope secretory responsiveness to GnRH stimulation (3, 9, 31, 32, 33) and that detectable LH pulse frequency is a surrogate marker of GnRH pulse-generator activity (8, 25, 34, 35, 36, 37), then our findings establish that elderly men fail to augment the amplitude, but not the frequency, of pulsatile and 24-h rhythmic GnRH/LH secretion in response to acute depletion of testosterone negative feedback.

The experimental steroidogenic inhibitor, KTCZ, achieved marked inhibition of daily testosterone output in both age cohorts, thus creating an experimentally effectual hypoandrogenemic open-loop, to enhance GnRH/LH secretion. In this model, KTCZ-induced secondary hypergonadotropism is specific to testosterone withdrawal per se, because continuous iv or transdermal testosterone addback restores 24-h pulsatile, entropic, and rhythmic LH secretion to baseline in young men (17, 21). To prevent adrenal glucocorticoid insufficiency, KTCZ is given with a low-dose of dexamethasone, which does not affect LH secretion but maintains a clinically euadrenal state despite KTCZ’s concomitant blockade of cortisol biosynthesis and its propensity to accelerate hepatic drug metabolism (16, 17, 21, 38).

Model-free discrete peak-detection (Cluster) analysis was used to delimit assumptions about the resultant LH waveform, baseline-release properties, or half-life evoked by the KTCZ castration-like stimulus in the two different age cohorts (16, 17, 19, 39, 40, 41). This analysis disclosed that older men fail to respond to 48 h of testosterone deprivation with equivalent gonadotropin amplitude enhancement, as defined by all three of absolute and incremental LH pulse amplitude and LH peak area. Based on pulse modeling considerations (35), the lack of any KTCZ-stimulated increase in LH pulse area above nadir in older men identifies an impoverishment of LH secretory pulse mass. A recent random-effects stochastic differential-equation based biomathematical reconstruction of admixed pulsatile and basal LH secretion in older men also predicted 2-fold attenuation of LH secretory burst mass with normal young-adult basal (nonpulsatile) LH secretion and biexponential LH half-lives (42, 43). Thus, available analyses point to reduced LH secretion per burst in the aging male. Mechanistically, this deficit could reflect attenuated hypothalamic GnRH feedforward drive in older men, given their preserved short-term (14-day) and accentuated acute (bolus) gonadotrope secretory response to exogenous GnRH stimulation, and increased LH stores evident post mortem (3, 9, 15, 33, 44).

To quantitate the orderliness of LH release patterns in young and older men, we used the nonpulse-dependent regularity statistic, ApEn (20, 45). This metric provides a scale-invariant and model-free index of feedback changes within a neuroregulatory axis (9, 16, 20, 26, 46). Baseline LH ApEn was elevated in older men, which (from a biostatistical perspective) denotes a more irregular LH release process (P = 0.00089). This inference was confirmed by first-differencing and deconvolution detrending of 24-h serum LH concentration time series (P < 10-10 and P = 0.00015) (30). Interestingly, KTCZ-induced testosterone withdrawal prompted a significant rise in LH ApEn in young men, to a value no different from that observed at baseline in older men. This observation could indicate that disruption of orderly LH secretion (higher LH ApEn) in older men, at baseline, reflects their lower serum bioavailable testosterone concentration, which results in partial withdrawal of androgen negative feedback. In addition, older men manifested apparent feedback-adaptive failure, because they evinced no further elevation of LH ApEn in response to the 8- to 10-fold reduction in systemic testosterone levels. Monte Carlo simulations (Results) showed that LH release patterns had not attained maximal numerical randomness in either age cohort. The neuroadaptive basis for impaired GnRH/LH pattern reactivity to interruption of androgen-dependent negative feedback in aging men is not yet evident, but may well signal hypothalamic dysregulation.

Relief of androgen negative feedback unveiled a blunted mesor of the 24-h rhythm in serum LH concentrations in older men, which was not evident at baseline. This analytically independent finding also would be consistent with reduced GnRH/LH secretory reserve in the aging male. Administration of KTCZ further elicited an anomalous advance in the LH acrophase and, paradoxically, augmented the LH cosine amplitude in older men. The former observation is reminiscent of the baseline and fasting-accentuated ACTH/cortisol phase advance recognized in aging individuals (47, 48). The basis for paradoxical enhancement of the amplitude of 24-h rhythmic LH release in older men subjected to acute hypoandrogenemic drive is less evident, but it could reflect disinhibition of otherwise accentuated testosterone-dependent feedback repression of nyctohemeral GnRH/LH secretion in aging. This notion is adumbrated by the heightened suppressive effect on LH secretion of exogenously administered testosterone or 5 {alpha} DHT in older men (12, 49).

Impaired GnRH feedforward drive in the older male, as inferred here, would not exclude concurrent defects at other regulatory loci, including accentuated (above) or reduced feedback actions of androgens and impaired LH-stimulated Leydig-cell steroidogenesis (3, 14, 15, 50, 51, 52). Attenuation of endogenous LH-dependent testosterone secretion in the aging male has been reaffirmed recently, based on evident erosion in vivo LH-testosterone (feedforward) stimulus-secretion coupling (53), decreased testosterone production after 14 days of pulsatile iv GnRH stimulation (9), and blunted short-term testosterone secretion driven by consecutive iv pulses of recombinant human LH in leuprolide-down-regulated older men (52). Thus, available clinical data favor at least a bipartite hypothesis of reproductive-axis aging in men; viz. diminished hypothalamic GnRH signaling and impaired LH-dependent Leydig-cell steroidogenesis (3). The relative importance of these (and other) deficits to the progressive fall in testosterone bioavailability in the aging male is not yet known.

In summary, at baseline, healthy clinically eugonadal older men exhibit tripartite neuroregulatory disturbances comprising an elevated daily LH pulse frequency, diminutive LH pulse amplitude, and more disorderly patterns of LH release. Muting of testosterone negative feedback highlights these and unmasks additional neurosecretory defects in the elderly male. Primary defects include impaired up-regulation of LH pulse amplitude, absent modulation of the regularity of LH release patterns, and blunted 24-h rhythmic LH secretion in response to acute hypoandrogenemic stress. Accordingly, aging men exhibit multiple adaptive defects in GnRH neurointegrative control.


   Acknowledgments
 
We thank Patsy Craig for skillful preparation of the manuscript, 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. This focused report necessarily omits many primary references because of editorial constraints. We, therefore, acknowledge numerous colleagues who have made earlier foundational observations.


   Footnotes
 
1 Supported in part by NIH Grant MO1-RR-00847 (to the General Clinical Research Center of the University of Virginia Health Sciences Center), by the Center for Biomathematical Technology, by NIH Grant RO1-AG-14799 (to J.D.V.), and by a Veterans Affairs Merit Review grant (to T.M.). Back

Received June 13, 2000.

Revised October 5, 2000.

Accepted October 18, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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