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From the Clinical Research Centers |
Division of Endocrinology, Departments of Medicine (C.W., T.D., V.D., B.S., R.S.S.) and Pediatrics (N.G.B.), Harbor-UCLA Medical Center, Torrance, California 90509; and Division of Endocrinology and Metabolism (J.D.V.), Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Christina Wang, M.D., Clinical Study Center, Harbor-UCLA Medical Center, 1000 West Carson Street, California 90509. E-mail: wang{at}harbor6.humc.edu
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Abstract |
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Analyses of LH secretory pulses showed that LH pulse width, height, area, and total area under the curve (LH concentration vs. time) were significantly more suppressed in Asians than in whites during the lowest infusion dose of testosterone. With increasing testosterone dose, the suppression of pulsatile LH secretion was not different in the two ethnic groups. In contrast to pulsatile LH secretion, the responsiveness of pulsatile FSH secretion to exogenous testosterone infusion was not different between the two ethnic groups. At baseline, Asian men had a significantly higher mean number of FSH pulses and mean incremental pulse heights than did white men. Serum inhibin B levels were not distinguishable in the two ethnic groups, but the FSH profiles were quantifiably more irregular (higher approximate entropy) in the Asian volunteers.
Our data suggest that, compared with white men, Asian men respond earlier and with more marked suppression of pulsatile LH secretion to ramped testosterone infusions. The elevated basal serum FSH concentrations (and more irregular FSH release pattern) observed in Asian men may suggest a small relative decrease in spermatogenic reserve and/or gonadal negative feedback. Whether these differences contribute to the observed differences in suppression of spermatogenesis in Asians vs. non-Asians in male contraceptive studies is not yet known.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase activity in the nonsuppressors,
resulting in higher residual 5-dihydrotestosterone levels within the
testes (4). This low level of 5-dihydrotestosterone might be able to
maintain a low rate of spermatogenesis despite the apparent withdrawal
of gonadotropins. The ethnic differences between the degree of suppression of spermatogenesis in response to exogenous testosterone administration in Asian and white men could also be caused by differences in: 1) the responsiveness of the hypothalamus-pituitary unit to testosterone’s negative feedback actions; 2) the responsiveness of the testes to the suppressed gonadotropin levels; 3) the metabolism of testosterone in vivo; and 4) the spermatogenic potential. In this study, we report differences in pulsatile gonadotropin secretion in response to negative-feedback imposed by ramped increases in infused testosterone doses in normal Asian and white men living in the United States.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Nine Asian and eight white healthy volunteers were recruited into the study after screening by medical and social history; physical examination; normal blood counts; urinalysis and serum biochemistry; normal baseline serum LH, FSH, and testosterone levels; and normal semen analyses. To reduce the ethnic variability of the subjects, we selected subjects whose parents and grandparents were of the same ethnic group. Asians were recruited from subjects of Chinese, Korean, or Japanese descent; and the white men were recruited from families of European descent. Of the Asian subjects, three were born in their native country, whereas the remaining six were first-generation Asian Americans. All the white subjects were born in the United States. The mean age of the Asians was 27 ± 1.8 yr (mean ± SE), which was not much different from that of the whites (33 ± 2.5 yr). The Asians were shorter in height (171.7 ± 2.1 cm) than the whites (180.7 ± 2.4 cm, P < 0.05), but their weight was not significantly different (Asians 71.4 ± 3.7 kg, whites 80.3 ± 4.6 kg). The mean combined testes volume was significantly lower in Asians (39.8 ± 2.6 mL), compared with the whites (47.0 ± 1.9 mL, P < 0.05). The study was approved by the institutional Human Subjects Committee, and all subjects gave informed consent.
Preparation of testosterone infusion
Testosterone (2 g) crystalline base was dissolved in 20 mL ethanol and then diluted with 380 mL normal saline, prepared as a stock solution (5 mg/mL) using aseptic techniques, by the institutional research pharmacist. This stock solution was aliquoted into 30-mL sterile vials and then tested for sterility and pyrogenicity. The volume of testosterone, based on the dose required for infusion and body surface area of subjects, was determined for each subject for each 48-h period. The appropriate volume of testosterone was added to 1 L of normal saline after the same volume of saline was removed from the infusion bag. The solution was infused over 48 h by an infusion pump (Baxter Flo-Gard-200, Deerfield IL) at 20 mL/h. The rate of the infusion pump was checked by weighing of the infusion bag and the tubing before and immediately after the completion of each infusion.
Study design
Each subject was admitted to the General Clinical Research Center at Harbor-UCLA Medical Center on the evening before the start of the infusion study. At 0800 h on day 1, a saline infusion (0.9% normal saline) was started and continued for 8 h (until 1600 h). At 1600 h on days 1, 3, and 5, the continuous infusions were changed to deliver testosterone at 7 mg/1.7 m2 (body surface area)·24 h, 14 mg/1.7 m2·24 h, and 28 mg/1.7 m2·24 h, respectively, for 48 h at each dose. The doses were selected to approximate one, two, and four times the estimated production rate of testosterone in normal men (5).
During the 8 h of the saline infusion and the last 8 h of each dose of the testosterone infusion (i.e. 0800 to 1600 h on days 1, 3, 5, and 7), 2 mL blood were withdrawn every 10 min. Sera were separated, and 100-mL aliquots were pooled from samples collected every hour for measurement of serum testosterone and inhibin levels. The remaining individual samples were saved for serum LH and FSH determinations. Serum samples were stored at -20 C until assay. All samples from any one subject were analyzed in the same assay.
Assays
Serum LH and FSH were measured by sensitive fluroimmunometric assays (Delphia, Pharmacia, Gaithersberg, MD), as previously described. The sensitivities of the LH and FSH assays were 0.1 IU/L for both assays (6), according to the Second International Reference Preparation. The intraassay coefficients of variation for LH and FSH fluroimmunometric assays were less than 5% for both, and the interassay variations for LH and FSH were 8.3% and 11.1%, respectively. Serum testosterone levels were determined by previously described RIA (6), using reagents from ICN (Costa Mesa, CA), after extraction of serum by ethylacetate and hexane. The sensitivity of the T assay is 0.35 nmol/L, and the intraassay and interassay coefficients of variation are 8.0% and 13% for the normal adult male range, respectively. Serum inhibin B was measured by a sensitive and specific enzyme immunoabsorbent assay with reagents from Rian-Bioproducts (Indianapolis, IN), as previously described (7, 8). The intraassay and interassay coefficients of variation are 5 and 7%, respectively. Any duplicates showing more than 10% variance were repeated.
Analyses of gonadotropin secretion
Cluster analysis. Cluster analysis was used for the analyses of pulsatile serum LH and FSH release, as described (9). We used test cluster sizes of two and one (LH) and two and two (FSH) data points in the nadir and peaks, respectively, with threshold t statistics of 2.0 for both a significant upstroke and downstroke in the time series, as validated earlier (10).
Cross-correlation. Cross-correlation analysis was used to measure the strength of the tendency of paired serum LH and FSH concentrations to vary in the same or the opposite direction over time. The r values were converted to z scores, as described previously (11).
Deconvolution analysis of LH and FSH secretory pulses. Deconvolution analysis was used to express the serum concentration profiles of LH and FSH, in terms of secretory and half-life measures of interests (12, 13, 14, 15, 16, 17). Deconvolution was carried out blind to ethnicity and dose of testosterone infusion. For each data series, the following parameters were calculated: mean and integrated serum hormone concentration, half-duration of secretory bursts (duration of calculated secretory pulse at half-maximal amplitude), hormone half-life, interpulse interval, frequency, mass secreted/pulse, amplitude of secretory burst (maximal secretory rate attained within a burst), and 8-h production rate.
Approximate entropy (ApEn). To quantify irregularity of the LH or FSH release profiles, we used ApEn, a model-independent statistic (18, 19). ApEn measures the logarithmic likelihood that the runs of hormone measures that are close (within r) for m contiguous observations will remain close (within the same tolerance width) on next incremental comparisons. In this study, we set m = 1 and r = 20% of the SD of the individual subject time-series for all data sets.
Cross-ApEn. By way of a lag-independent quantitation of synchrony or conditional regularity between LH and FSH release profiles, we used cross-ApEn, as introduced in earlier studies of the gonadotropic axis (13). Cross-ApEn is calculated as ApEn above but using standardized (z-score transformed) LH and FSH time series to insure good statistical replicability properties (13).
Statistical analyses
The primary model for data analysis was a two-way ANOVA model with one repeated measure (day) and one between-groups factor, race, and interaction. A one-way repeated measures ANOVA was used to test for dose effects within groups. Group comparisons, at each day, were done using t tests for independent groups. The z score distributions from the cross-correlation analyses at each lag within each group of men were tested for nonzero central values, i.e. systematic correlation between the hormone pairs of interest, using the Wilcoxon one-sample signed rank test against the null hypothesis. The Wilcoxon 2-sample rank sum test was used to compare the ethnic groups by day and lag.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mean serum testosterone and inhibin levels at baseline and
during the last 8 h of 48-h infusions of testosterone at doses of
7 mg, 14, and 28 mg/1.7 m2·24 h are shown in Table 1
. The mean serum testosterone levels
increased significantly with the different doses of testosterone
infused (P < 0.0001) in both ethnic groups and showed
no significant differences between the Asians and whites. There were no
ethnic differences in the serum inhibin levels and no significant
changes with testosterone infusion.
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Using cluster analysis, we observed that the number of peaks, mean
peak width, mean peak height, mean peak area, increases above basal
levels, mean levels, area under the 8-h concentration vs.
time curve (AUC) and nadir (P < 0.0001 for all), and
percent increase in mean peak height (P = 0.004) of LH
pulses were all significantly and progressively reduced by increasing
doses of testosterone (Figs. 1 and 2). Significant suppression of these
parameters was seen in both ethnic groups, even with the lowest dose of
testosterone infused (7 mg/1.7 m2·24 h). At the infusion
dose of 14 mg/1.7 m2·24 h, many of the subjects showed
abolition of detectable pulsatile LH release. At the highest infusion
dose of 28 mg/1.7 m2·24 h, most of the subjects showed
complete absence of LH pulsatility. Deconvolution analyses showed that
the mass of LH secreted per burst decreased markedly in Asians
(P = 0.0001), which seemed to be less marked in whites
(P = 0.05). The apparent half-life of LH and secretory
pulse frequency and duration (data not shown) were not altered by
increasing doses of testosterone infusion. There was no interaction
between dose and ethnicity for any of the parameters tested.
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Suppression of pulsatile FSH release by graded doses of testosterone infusion
Similar to LH, pulsatile FSH release was suppressed progressively
by increasing doses of testosterone (Figs. 3 and 4).
The number of FSH pulses (P = 0.016), the mean peak
width (P = 0.037), the percent increase in peak height
(P = 0.007), the percent increase in mean peak height
(P = 0.010), the mean peak area (P =
0.004), the mean FSH level (P = 0.0001), and the AUC
(P = 0.0001) were all significantly decreased by graded
increases in the testosterone infusion doses. Deconvolution analyses
disclosed that the mass of FSH secreted per burst (P =
0.0013), the secretory pulse amplitude (P = 0.0014),
and the total (8-h) secretion rate (P = 0.0001) were
suppressed significantly with increasing doses of testosterone. At the
lowest dose of testosterone infused (7 mg/1.7 m2·day),
FSH secretory pulses were significantly suppressed vs.
saline in both ethnic groups.
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). As with measures of LH secretion, for FSH
there was no interaction between dose and ethnicity in the ANOVA.
During testosterone infusions, many of the FSH pulse characteristics
remained higher, although not statistically significant, in Asian,
compared with white, men. ApEn of LH and FSH pulsatile secretions
Before testosterone infusion, Asian men showed higher absolute
ApEn values for FSH than did their white male counterparts
(P 
0.0063). Higher ApEn values denote relatively
greater disorderliness or irregularity of FSH release. In contrast,
ethnicity did not affect the ApEn values for LH release basally, nor
the cross-ApEn values (the latter denoting the synchrony of LH and FSH
release patterns). There were no testosterone dose effects on ApEN or
cross-ApEn in either group.
Cross-correlation between LH and FSH concentrations in Asians and whites during testosterone infusion
In the Asian population, the test for significant LH-FSH cross-correlation for nonzero center was significant on day 1 at lag 0 (simultaneous LH and FSH concentrations) but nowhere on day 3. In the whites, on day 1, the test was significant at all points from lag -4 to lag +2 (i.e. LH preceding FSH by 20 min to LH lagging FSH by 40 min), and on day 3, from lag -3 to lag +2. In the total population, we found significant correlations on day 1 at lags from -3 to +2, and -4 to +1 on day 3. The only differences (FSH lagging LH by 20 and 30 min) found were on day 3, lags +2 and +3 (P = 0.018 and 0.034, respectively). The analysis was not run for days 5 and 7 because both LH and FSH pulsatile secretions were abolished in many subjects.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-dihydrotestosterone also decreases pulsatile LH secretion
(24, 25, 26). The dose of testosterone used in these previous studies
ranged from 14–28 mg/day (20, 21). With administration of testosterone
at 15 mg/day, Finkelstein et al. (21) showed that mean serum
LH and FSH concentrations were suppressed to 34.5 and 52.5%,
respectively. LH pulse amplitude and frequency decreased to one-third
of the baseline levels. These changes were associated with a doubling
of the mean total serum testosterone level during the testosterone
infusion (21). Based on these earlier observations, we designed our study to compare the responsiveness of the hypothalamus-pituitary unit to graded testosterone infusions. The lowest dose of 7 mg/1.7 m2·day was intended to mimic the physiological daily production rate of testosterone in normal men. Higher doses were used to test further the sensitivity of the hypothalamus-pituitary unit to the negative feedback actions of testosterone. The highest dose of 28 mg/1.7 m2·day, approximately four times the normal production of testosterone in men, was expected to induce nearly complete suppression of gonadotropin secretion. The intermediate infusion dose of testosterone (14 mg/1.7 m2·day) was anticipated to suppress gonadotropin secretion partially, and thus possibly reveal subtle ethnic differences of the hypothalamic-pituitary axis’s response to negative feedback by testosterone. We used a ramped format of infusion, increasing the testosterone dose after each 48-h period. This was based on previous observations that blood sampling towards the end of 48-h infusions would be adequate to assess responsiveness of the hypothalamus-pituitary unit. We recognized that the graded increase in infusion dose may be confounded, in part, in time and dose effects, because e.g. a suppression of gonadotropin secretions on day 5 could be caused by the previous 4 days of testosterone infusion or the increase in dose after day 3. However, such confounding would not be relevant to the first (lowest) dose of testosterone (day 3 sampling), when we observed the principal ethnic differences.
During increasing doses of testosterone infusion, serum testosterone levels were significantly increased but not in a direct dose-related manner. At the highest dose, delivering about four times the daily production of testosterone, serum testosterone concentrations were increased only by about 1.5-fold. During the graded testosterone infusions, there is a progressive suppression of endogenous testosterone secretion, and the resultant serum testosterone levels are achieved by the combination of suppressed endogenous production plus the exogenously administered testosterone. Exogenous testosterone administration increases the MCR of testosterone (4). Moreover, graded testosterone infusions may not dose-dependently increase serum testosterone levels, because of saturation of the binding proteins. This has been recognized when comparing continuous and pulsatile delivery of the same total daily dose of testosterone in healthy men whose steroidogenesis was suppressed by ketoconazole (27).
Our results indicated that using serum concentration measurements, LH pulse width, height, area, and total AUC were significantly more suppressed in Asians than in whites during the lowest infusion dose of testosterone, i.e. 7 mg/1.7 m2·day. Deconvolution analysis disclosed the mechanism underlying these differences, because the mass of LH secreted per burst also was reduced more in Asians than whites. Thus, hypothalamic-pituitary regulation of the amplitude of pulsatile LH secretion was more susceptible to negative feedback by testosterone in Asians vs. whites. Whether this increased sensitivity to negative feedback of androgen requires aromatization to estradiol was not tested in this study. When the dose of testosterone infused was increased to twice the anticipated normal daily production rate (14 mg/1.7 m2·day), equivalent suppression of serum LH pulse amplitude, height and area was detected in both ethnic groups. When the dose of testosterone was further increased to four times the physiological production rate, as anticipated, pulsatile LH secretion was abolished in most subjects, with no distinction between the ethnic groups.
In contrast to pulsatile LH secretion, the responsiveness of pulsatile FSH secretion to exogenous testosterone infusion was not significantly different between the two ethnic groups. Serum FSH pulse frequency, peak width, height, area and AUC were suppressed in both groups by increasing doses of testosterone, although these parameters remained greater (but not statistically significant) in Asian vs. white men. At baseline, consistent with the differences in testicular volume (whites significantly larger than Asians), the mean serum FSH concentration was lower in the white vs. the Asian men. The Asian men had more frequent, but larger, FSH pulses than whites at baseline.
Of qualitative interest, the regularity of FSH release in the Asian group seemed to be visually reduced, compared with that in the white men. Statistical testing of this possible unequal orderliness of the FSH release process, via an ApEn statistic, revealed that on day 1 (pre-androgen infusion) Asian men showed higher absolute ApEn values. This finding signifies significantly greater variability, irregularity, or disorderliness of serial FSH measurements in the Asian group and is consistent with their higher FSH pulse frequency. This difference was specific to FSH, because ApEn values for LH were similar in the two ethnic study groups. In addition, the relative orderliness of LH and FSH release (conditional regularity, or synchrony between LH and FSH measures) was statistically similar in the Asians and Caucasians, as reflected by the cross-ApEn values. Cross-correlation analysis of serum LH and FSH concentrations also revealed no ethnic differences at baseline, although Caucasians (but not Asians) showed significant LH-FSH cross-correlations on day 3, suggesting somewhat greater synchrony of LH and FSH release in white individuals at this time.
Serum inhibin B levels, a serum biomarker of Sertoli cell function, were not different between the two ethnic groups. It should be noted also that serum inhibin B levels did not change, despite suppression of both LH and FSH secretion with the highest dose of testosterone infusion. In GnRH-deficient men, serum inhibin B levels were low but progressively increased with pulsatile GnRH treatment for 8 weeks (28). When normal men were administered exogenous testosterone plus levonorgestrel for 6 months, serum inhibin levels decreased (8). When recombinant human FSH was administered to normal men, serum inhibin B levels were unchanged for 12 h and became significantly increased after 24 h (8). Low inhibin B levels were present when gonadotropin levels were suppressed for weeks or months. The duration and degree of gonadotropin suppression required to suppress serum inhibin B levels have not yet been determined. The short duration of near-complete suppression of pulsatile FSH secretion with the highest dose of testosterone (about 48 h) in our study might not have been adequate to reduce serum inhibin levels.
The elevated basal serum FSH concentrations in Asian men may suggest an inherent relative reduction in Sertoli cell function, reduced gonadal feedback of FSH release, and/or lower spermatogenic capacity in Asian vs. white men. It was not accounted for by differing baseline serum testosterone or inhibin B concentrations. A previous study in our group, on testis specimens obtained at autopsy, showed that the number of Sertoli cells per man and the daily production rate of spermatids per man were lower in Asians living in Asia vs. whites living in the United States (29). Studies from our laboratory also indicated that the apoptotic germ cell rates for spermatogonia and spermatids were higher in Asian vs. white men (30). The combination of smaller testes volumes, elevated blood FSH levels, small decreases in daily sperm production and Sertoli cell numbers, together with an increased apoptotic germ cell rate in Asians suggest that spermatogenic reserve might be relatively reduced in Asian men. This inferred reduction in spermatogenic reserve did not affect basal semen parameters, such as sperm count, motility, and morphology because these parameters were comparable in Asian and white men (31). However, when subjected to agents suppressing gonadotropin production and spermatogenesis, such as exogenous testosterone, the testes of Asian men showed greater inhibition of germ cell development and maturation, resulting in greater prevalence of azoospermia (usually over 90%) (1, 2). Only Asian men currently living in the United Studies were included in this study. It is well known that dietary or environmental factors may alter steroid metabolism. Asian men in Asia might show greater or lesser differences when compared with white men. However, complex ramped infusions and multiple blood sampling would be difficult in centers in Asia without the availability of the necessary infrastructure designed to support this type of clinical research.
We conclude from the data obtained in this study that Asian men respond earlier and with more marked suppression of pulsatile LH secretion to ramped testosterone infusions than white men. In addition, elevated basal serum FSH concentrations and reduced testes volume observed in the Asian men suggest a relative decrease in spermatogenic reserve in the Asian men, which may become more apparent when gonadotropin levels are inhibited by exogenous androgen. Whether and how the foregoing inherent differences in the feedback responsiveness of the hypothalamic-pituitary unit to testosterone actions in Asian and white men contribute to their unequal suppression of spermatogenesis in male contraceptive development studies is not yet known.
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Acknowledgments |
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Footnotes |
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Received September 17, 1997.
Revised November 25, 1997.
Accepted December 1, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase activity in
oligozoospermic men administered supraphysiological doses of
testosterone. J Clin Endocrinol Metab. 81:902–908.[Abstract]
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