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Geriatrics and Extended Care Service Line (T.M.), McGuire Veterans Affairs Medical Center, Richmond, Virginia 23249; Endocrine Section (A.I.), Medical Service, Salem Veterans Affairs Medical Center, Salem, Virginia 24153; and Division of Endocrinology (J.D.V.), Department of Internal Medicine, General Clinical Research Center, Center for Biomathematical Technology, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202
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
The present investigation tests the clinical hypothesis that Leydig-cell responsiveness to pulsatile and midphysiological LH drive is impaired in older men. To this end, we implemented a novel clinical investigative paradigm consisting of preadministration of an LH-down-regulating dose (3.75 mg) of leuprolide acetate followed, 3–4 wk later, by controlled challenge of the testis, with pulsatile iv infusions of saline vs. recombinant human (rh) LH. Based on a preliminary dose-finding experiment, we evaluated LH action in 8 young (ages, 18–25 yr) and 7 older (ages, 60–85 yr) volunteers by infusing eight consecutive 6-min squarewave pulses of saline or 50 IU rhLH iv every 2 h. Analyses were carried out 48 or 72 h apart in a prospective, randomly assigned, double-blind, within-subject cross-over design. Serum concentrations of T (RIA) and LH (immunoradiometric assay) were measured in blood sampled every 10 min concurrently. Leuprolide injection suppressed pre-LH-infusion (0800 h baseline) serum T concentrations (pooled mean ± SEM) markedly in both age groups (P < 10-3); namely, to 40 ± 20 ng/dl (young) and 12 ± 3.1 ng/dl (older; P < 0.05 vs. young) (to convert to nM, multiply by 0.0347). Successive iv pulses of rhLH stimulated T output, over time, to an asymptotic maximum of 166 ± 42 ng/dl in young men (P = 0.0008 vs. saline) and 57 ± 9.8 ng/dl in older subjects (P = NS vs. saline, and P < 0.05 vs. young). Further regression analyses identified significant reductions of both the initial rate and maximum of the time-dependent incremental rise in LH-driven serum T concentrations in older men. In contrast, infused serum LH concentrations, distribution volumes, and calculated LH half-lives were comparable in the two age cohorts.
We conclude that older men manifest both a delayed initial and reduced maximal serum T concentration rise compared with young men exposed to identical controlled midphysiological pulsatile LH drive.
OLDER MEN EXHIBIT variably blunted peak serum T concentrations in response to acute injection of human (h) CG (1, 2, 3). However, reduced steroidogenic responsiveness to a supramaximal hCG stimulus, though relevant pharmacologically, is difficult to interpret physiologically for several reasons (4, 5, 6). First, the half-life of intact hCG in the human is nonphysiologically prolonged by 10- to 20-fold, compared with that of infused pituitary LH extracts or secreted native LH (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14). Second, unlike LH, hCG binds nearly irreversibly to gonadal LH/hCG receptors (4, 15, 16). Thus, the actions of exogenous hCG cannot mimic fully the expected "on-off" kinetics of endogenous pulsatile LH stimulation of Leydig cells (6, 17, 18). Third, hCG readily down-regulates gonadal steroidogenesis in the human and experimental animal, at both receptor and postreceptor levels (4, 16, 19, 20). Fourth, the high lutropic potency of the doses of hCG used to date would test only (supra)maximal testis responsiveness, because equivalent LH drive is probably never achieved physiologically in healthy men. Last, from an experimental perspective, earlier hCG stimulation studies were confounded by the effects of variable endogenous LH secretion during the stimulation paradigm (1, 2, 4, 21, 22, 23, 24, 25, 26, 27, 28, 29). Accordingly, impaired maximal T output after pharmacological hCG exposure may hold little, if any, mechanistic relevance to the hypoandrogenemia in older men, who maintain near-physiological pulsatile LH release (4, 5, 6).
To our knowledge, only two studies have documented impaired Leydig-cell responsiveness to endogenous LH pulses (e.g. as stimulated by clomiphene or an exogenous pulsatile GnRH pump) (see Ref. 38), and none have explored this relationship during controlled pulsatile infusions of midphysiological amounts of LH (Discussion). Thus, the present experiment examines the hypothesis that Leydig-cell steroidogenic responsiveness in aging men is reduced in the face of midphysiological pulsatile LH stimulation. To test this postulate, we implemented a clinical investigative paradigm comprising pulsatile iv infusions of recombinant human (rh) LH vs. saline, after GnRH agonist-induced down-regulation of endogenous gonadotropin secretion in young and older men.
Subjects and Methods
Subjects
Fifteen healthy men (ages, 18–25, n = 8; and ages 60–85, n = 7) volunteered for and completed the infusion studies. Another 5 men (age range, 21–49 yr) undertook a pilot LH dose-finding study (below). Subjects provided written informed consent approved by Institutional Review Boards of the University of Virginia, the Medical College of Virginia, and the McGuire Veterans Affairs Medical Center. A complete history; physical examination; and screening biochemical tests of hepatic, renal, hematological, metabolic, and endocrine function were normal. Exclusion criteria included recent weight gain or loss (>2 kg, over 10 d), transmeridian travel (>3 time zones crossed in the preceding week), alcohol or drug abuse, psychiatric illness, systemic medications, history of mumps orchitis, infertility or testicular atrophy, elevated baseline (0800 h) serum gonadotropin concentrations (>10 IU/liter for LH or >20 IU/liter for FSH), a reduced serum total T concentration (<300 ng/dl), untreated thyroid disease, increased serum PRL (>25 µg/liter) or E2 (>60 pg/ml) concentrations, failure to provide voluntary written informed consent, acute or chronic systemic disease, and/or lack of ambulatory community-living status. Volunteers received a 3.75-mg leuprolide acetate injection followed, 3–4 wk later, by the inpatient infusion studies (below).
Infusion studies
Volunteers were admitted to the inpatient General Clinical Research Center after leuprolide pretreatment (above). Then, rhLH (see doses below) or saline pulses (2 ml) were infused iv on separate randomly ordered occasions, 48–72 h apart. Infusions consisted of 6-min squarewave injections, administered iv every 2 h via a Harvard infusion pump, beginning immediately after withdrawal of the first 0800-h blood sample. Blood was sampled concurrently from a contralateral forearm vein, every 10 min for 16 h, from 0800 until 2400 h, for later assay of serum LH and T concentrations. Meals were provided at 0800, 1200, and 1700 h. Volunteers remained supine, except for occasional lavatory use. Smoking was disallowed.
Hormone assays
Serum LH concentrations were measured in duplicate by two-site monoclonal immunoradiometric assay (IRMA; Nichols Institute Diagnostics, San Juan Capistrano, CA), exactly as described earlier (22, 30, 31, 32). Infusate samples were measured analogously. Intra- and interassay coefficients of variation averaged 8.5 and 9.8%, respectively, for LH measurements made during the saline infusions and 6.3 and 8.8% during the rhLH infusions. Sensitivity was 0.05 IU/liter (First International Reference Preparation). Normal young male values in our population average 4.1 ± 0.8 IU/liter. Serum total T concentrations were assayed by solid-phase RIA (Diagnostic Products, Los Angeles, CA), wherein the sensitivity was 5 ng/dl, and mean intra- and interassay coefficients of variation were 7.3 and 10.7% during saline and 5.2 and 8.6% during rhLH injections, respectively (13, 33, 34).
Statistical analysis
The elimination kinetics of infused rhLH were calculated via biexponential deconvolution analysis using the preinjection (0800 h) serum LH concentration as a baseline value (14). The rise serum total T concentrations across the 16-h observation interval was fit as a simple cosine function. The profile of incremental (LH minus saline-infused) serum total T concentrations was fit as an ascending (inverse) monoexponential function (9). The initial incremental rise (time interval, 10–130 min) in serum total T concentrations was approximated by linear regression. Data in the two age cohorts were compared via 95% joint statistical confidence intervals (C.I.) for the foregoing fitted group parameters (35, 36). Values are presented as the mean ± asymptotic SEM or mean with 95% C.I.
Results
Aliquots of infusate were assayed for LH content, which disclosed recoveries of 103 ± 4%. The equivalency of 50 IU Serono LH standard averaged 20 IU in the IRMA (First International Reference Preparation) and corresponded to 2.3 µg protein.
A pilot dose-finding experiment in five leuprolide-suppressed men was performed first, wherein we administered consecutive iv pulses of 7.5, 15, 30, 50, or 75 IU rhLH every 2 h, while concomitantly monitoring serum LH concentrations every 10 min for 6 or 16 h. Serum LH concentrations attained the midnormal young-adult range (2–10 IU/liter) during recurrent infusions of 30, 50, and 75 IU rhLH. Thus, pulsatile infusions subsequently used an intermediate dose of 50 IU rhLH.
Figure 1
illustrates serum LH
concentration profiles obtained in two young and two older male
volunteers sampled every 10 min for 16 h during pulsatile iv
infusions of rhLH (50 IU), and saline (2 ml) every 2 h.
|
presents group mean serum LH and T concentration profiles for all 8
young and 7 older subjects given randomly ordered saline (A) and rhLH
(B) infusions on separate occasions. In young men, baseline (post
leuprolide but preinfusion) 0800 h serum total T concentrations
were similar before the saline (37 ± 18 ng/dl) and rhLH (43
± 21 ng/dl) infusions (P = NS). Corresponding values
were significantly lower in older than young men (P <
0.05) but comparable in the two study sessions at 11 ± 5.3
ng/liter (saline) and 12 ± 3.1 ng/dl (LH infusion). Study days
post leuprolide were 2.5 ± 2 (young) and 24 ± 2 (older)
(P = NS). In both age groups, there was a small, but
consistent, rise in the serum T concentration, over time, during saline
infusion, for which the cosine-approximated amplitude was 39 ± 20
ng/dl (young) and 43 ± 20 ng/dl (older men) (P =
NS). During LH infusion, the corresponding value rose significantly
only in young men; namely, to 166 ± 42 ng/dl (P =
0.0008 vs. saline infusion) vs. to 57 ± 9.8
ng/dl in older men (P = NS vs. saline;
P < 0.05 vs. young). The zenith of the
latter rhythm occurred at 1550 h (±19 min) (young) and 1504
h (±71 min) (older men) (P = NS). In absolute terms,
peak (mean of the three successive highest) serum total T
concentrations during rhLH infusions were 136 ± 47 (young)
vs. 64 ± 11 ng/dl (older men) (P <
0.05).
|
). Incremental T
concentrations rose according to a simple inverse monoexponential
function, with an estimated half-time (min) to the global maximum of 90
(95% C.I., 61–185) min (young) and 156 (125–169) min (older)
(P = NS). The asymptotically predicted maximal
increment was significantly higher [54 (95% C.I., 53–57 ng/dl] in
young volunteers than in older men [37 (36–38) ng/dl]
(P < 10-3).
|
).
|
, mean (16-h) serum LH concentrations
measured during saline or rhLH injections, the deconvolution-calculated
volumes of distribution of injected LH, and estimated LH biexponential
elimination kinetics did not differ by age.
|
The present clinical investigation uses a paradigm of leuprolide-induced down-regulation of endogenous gonadotropin secretion to reduce and equalize baseline serum LH concentrations in young and older men. In this experimentally controlled milieu, we administered pulsatile iv infusions of midphysiological amounts of rhLH vs. saline, to monitor Leydig-cell T secretory responsiveness over 16 h of exogenous LH drive. Pretreatment with the GnRH agonist suppressed baseline serum LH concentrations markedly and equivalently in the two age cohorts. Intermittent iv delivery of rhLH restored normal serum LH concentration profiles in an age-independent manner. Pulsatile LH infusions evoked time-dependent increase in T secretion, beginning with the first stimulus. Statistical comparisons by age unveiled a significant 3-fold impairment in exogenous LH-stimulated T production in older men; namely, a reduction in the maximal (absolute peak) response, initial rate, and delayed incremental rise in T secretion.
Absolute peak serum total T concentrations under exogenous LH drive
were approximately 2-fold lower in older men despite comparable mean
and integrated (16-h) serum LH concentrations in the two age groups
(Table 1
). Whereas leuprolide pretreatment suppressed 0800-h baseline
(pre-LH-infusion) serum LH concentrations equally (above), the GnRH
agonist lowered serum total T concentrations more in older than young
men. Unexpectedly, leuprolide blockade did not abolish a gradual
daytime rise in T concentrations in either age cohort (median increase,
41 ng/dl) during saline (control) infusions. The basis for this
residual T rhythmicity is not clear, in the face of profound LH
withdrawal. However, to adjust analytically for this systemic baseline
variation, we also analyzed exogenous LH-stimulated incremental
(baseline-corrected) T production in the two age groups (Subjects
and Methods). This corollary analysis corroborated a 50%
attenuation of pulsatile LH-driven T secretion in older men and
disclosed a trend toward prolongation of the total doubling time of the
incremental T rise. The latter trend was explained by a 2.5-fold
blunted initial increase in T secretion after the first pulse of rhLH.
Therefore, healthy older men exhibit deficient initial and delayed
incremental T secretory responses to pulsatile and midphysiological LH
exposure.
Impaired Leydig-cell responsiveness to controlled pulsatile LH stimulation and lower (leuprolide-suppressed) baseline serum T concentrations in older men could point to an intrinsic age-related defect in gonadal steroidogenesis. This concept would extend earlier clinical inferences based on maximal pharmacological hCG stimulation (26, 29, 37). Whether the inferred deficit in testicular androgen biosynthesis is remediable to prolonged physiologically pulsatile LH stimulation is not known. However, respectively, earlier and more recent clinical studies showed that elevated serum LH concentrations, induced by clomiphene administration or via pulsatile iv GnRH infusions for 14 d, fail to rescue hypoandrogenemia in older men (32, 38). Thus, a Leydig-cell steroidogenic defect is inferable during enhanced endogenous pulsatile LH drive also.
We found that iv infusion of rhLH, in a physiologically pulsatile manner for 16 h, did not fully restore young-adult serum total T concentrations in the leuprolide-down-regulated state. In principle, this could reflect direct testicular suppression by the GnRH agonist. However, GnRH agonists do not inhibit human (unlike rodent) Leydig-cell steroidogenesis consistently in vitro (4, 6, 39). Thus, an alternative and more probable explanation is that the (leuprolide-induced) suppression of endogenous gonadotropins for several weeks withdrew necessary trophic stimulation of Leydig-cell steroidogenic gene expression; which, in turn, resulted in impaired responsiveness to acute LH stimuli (4, 5, 6, 15).
Estimates of the elimination kinetics of exogenously infused rhLH were comparable in young and older men, as recognized recently also for endogenously secreted LH (14). However, a relatively prolonged half-life of secreted LH has been inferred in postmenopausal women and gonadectomized sheep, rats, and monkeys (14, 40, 41, 42, 43, 44, 45). The foregoing distinction could mirror more profound sex-steroid deprivation in the gonadoprival state than in the aging male. This consideration arises because sex steroids can regulate LH isoform composition and thereby influence in vivo gonadotropin kinetics (45, 46). Indeed, in heterologous assays, the elimination rate of hLH isotypes can vary by up to 10-fold, because of differences in posttranslational sialylation and sulfation of oligosaccharide moieties. Here, we document young-adult kinetics of rhLH in older men, thus establishing that irreversible metabolic clearance of this LH preparation is unimpaired in the aging male. If LH removal mechanisms are analogously preserved in postmenopausal women, then a prolonged apparent half-life of endogenous LH in the latter setting could reflect a spurious inference attributable to incomplete initial suppression of LH secretion by the antagonist (43) or indicate the pituitary production of altered (more acidic) LH isoforms in the estrogen-withdrawn female.
In summary, pulsatile iv infusion of midphysiological amounts of rhLH in leuprolide-down-regulated healthy young and older men unmasks 3-fold attenuation of maximal, initial, and delayed incremental rates of LH-driven T secretion in aging individuals. Controlled injections of rhLH achieved statistically indistinguishable serum LH concentration profiles and comparable biexponential kinetics of LH elimination and distribution volumes in the two age cohorts. The lack of complete restoration of serum total T concentrations in leuprolide-suppressed young men exposed to 16 h of pulsatile LH stimulation could indicate direct inhibition of the testis by the GnRH agonist or underscore the requirement for trophic LH support to maintain full Leydig-cell steroidogenic responsiveness in the human.
Acknowledgments
We thank Arthur Chapin, Patsy Craig, and Olivia Veldhuis for skillful preparation of the manuscript; Paula P. Azimi for the statistical analysis, data management, and graphics; Brenda Grisso for performance of the immunoassays; and the expert nursing staffs in the General Clinical Research Center for execution of the research protocol. This focused report necessarily omits many primary references because of editorial constraints. We, therefore, acknowledge numerous colleagues who have made earlier foundational observations.
Footnotes
This work was supported in part by the Specialized Cooperative Centers Program in Reproduction Research, by NIH Grant RO1-AG-14799 (to J.D.V.), and by a Veterans Affairs Merit Review grant (to T.M.).
Abbreviations: C.I., Confidence intervals; hCG, human CG; IRMA, immunoradiometric assay; rh, recombinant human.
Received January 26, 2001.
Accepted July 17, 2001.
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