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Departments of Cell Biology and Physiology (S.R., T.M.P.) and Pediatrics (G.R.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; and the Medical Research Council Reproductive Biology Unit, University of Edinburgh (A.S.M), Edinburgh, United Kingdom EH3 9EW
Address all correspondence and requests for reprints to: Dr. T. M. Plant, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
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Abstract |
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-C were monitored
in 12-h series of sequential blood samples collected before, on the day
of UO (day 0), and on days 1, 2, 4, 8, 16, 32, and 42 or 43 after UO.
In the UO monkeys, the remaining testis was taken on day 44. Sertoli
and germ cells in the removed and remaining testes were counted and
expressed either as number per testis or, in the case of the
differentiated spermatogonia (B1, B2,
B3, and B4), as number per cross-section of the
seminiferous tubule. UO was associated with a marked increase in the number of all germ cells more mature than undifferentiated spermatogonia (Ap) in the remaining testis. Sertoli cell number, on the other hand, did not change, and it is therefore reasonable to propose that the primary locus of the spermatogenic compensation was the differentiated spermatogonia. The additional finding that the relationship between the number of Sertoli cells and total germ cells in the remaining testis became robust (r = 0.92; P < 0.01 vs. r = 0.44; P > 0.05 for the removed testis) indicated that in the monkey, spermatogenesis does not normally operate at its ceiling. The increased drive to the seminiferous tubule of the remaining testis is hypothesized to be mediated by the sustained increase in FSH secretion that was observed after UO, although a role for increased testicular T production cannot be excluded. The stimulus for increased FSH secretion was presumably provided by the abrupt, 50% decline in circulating inhibin B levels. Interestingly, inhibin B secretion by the remaining testis was not dramatically affected by UO, and therefore, the deficit in circulating levels of this hormone and thus the error signal to FSH secretion were maintained for the duration of the experiment. In contrast, the changes in circulating LH and T concentrations were only transient, and within 48 h of UO, these hormonal parameters had returned to control values. The mechanisms by which the remaining testis rapidly acquires the capacity to double T production in the face of an unchanging LH drive remains to be determined.
The foregoing body of evidence suggests that sperm output by the monkey testis is regulated by the circulating concentration of FSH and that in physiological situations, FSH secretion is insufficient to stimulate spermatogenesis to its ceiling. The results also indicate that FSH secretion is controlled by a feedback system in which the feedforward arm (FSH-inhibin B) is less robust than the feedback loop (inhibin B-FSH). Thus, a decrease in the inhibin B feedback signal results in a sustained increase in FSH secretion that drives the testes toward their spermatogenic ceiling, which is presumably set by Sertoli cell number.
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Introduction |
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The foregoing response of the adult testis to UO is presumably effected by perturbations in the feedback loops that govern gonadal function. In the adult monkey, the secretion of FSH and LH is regulated by the negative feedback actions of testicular inhibin B and testosterone (T), respectively (4, 5, 6, 7). In the bonnet macaque, UO elicited a sustained increase in circulating FSH, but, surprisingly, circulating levels of inhibin, as measured with the Monash RIA (8), returned to precastration control levels (1). On the other hand, LH secretion monitored in daily samples appeared to be maintained at control levels, and this was associated with a recovery in circulating T concentrations to pre-UO levels (1). Thus, the present study was also designed to reevaluate the dynamic changes in the FSH-inhibin loop, using an enzyme-linked immunosorbent assay (ELISA) specific for inhibin B, and to examine the moment to moment changes in the LH-T loop that are effected by UO. For this purpose, adult male rhesus monkeys fitted with indwelling venous catheters to facilitate unrestrained and remote access to the venous circulation were used.
The results generated by the present study also provided insight into the value of circulating inhibin B as an index of Sertoli cell function, an issue that we had not set out to address at the time the experiment was designed. For this reason and because of the contemporary interest in clinical markers of Sertoli cell function, the relationship between Sertoli cell number and circulating inhibin B levels before and after UO in the monkey was presented separately in an earlier publication (9).
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Materials and Methods |
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Morphometry
From each of at least 3 paraffin blocks of individually embedded
testicular tissue, 20 4-µm thick sections were prepared and stained
with periodic acid-Schiff-hematoxylin. The volume fractions of the
interstitium and seminiferous tubule were determined by the
point-counting method (10, 11), as described previously (12). A total
of 4000 test points were examined on 2 randomly selected histological
sections.
The diameters of 25 cross-sections of seminiferous tubule per testis were measured with a calibrated ocular micrometer, and the total length of the tubules was derived from volume fraction, as described previously (12). The number of Sertoli cell nucleoli and all germ cell nuclei was counted in 250 randomly chosen cross-sections of seminiferous tubule defined by circular profiles and centrally located circular lumen and was corrected by the method of Abercrombie (13). The corrected numbers of Sertoli cells, Ad stem cells, Ap spermatogonia, differentiated spermatogonia (B spermatogonia), pachytene spermatocytes, and round spermatids per cross-section and total seminiferous length were used to derive the total number of these cells per testis, also as previously described (12). It should be noted that differentiated spermatogonia and round spermatids occur in stages of the spermatogenic cycle that contribute to only 75% and 80%, respectively, of the total duration (14); therefore, the total number of these particular cells per testis may have been systematically overestimated. Individual types of differentiated spermatogonia (B1, B2, B3, and B4) in stages containing these cells were expressed as the mean number of cells per cross-section.
Assays
Gonadotropins. Plasma FSH was measured using a homologous
RIA system, as described recently (7). In brief, recombinant cynomolgus
FSH (NICHHD Rec-MoFSH-RP-1, AFP 6940A) was employed for the reference
preparation and the radioiodinated tracer, and a polyclonal rabbit
antiserum (AFP782594) raised against recombinant cynomolgus FSH was
used as the first antibody. The average sensitivity of the assay was
0.04 ng/ml. The intra- and interassay coefficients of variation were
less than 5.4% and less than 10.3%, respectively. Plasma LH was
estimated using the RIA kit supplied by the National Hormone and
Pituitary Program. It consists of a cynomolgus LH:antihuman CG (rabbit
13, pool D) RIA system that uses a rhesus pituitary LH preparation
(NICHHD rhLH RP-1) as standard (15). The average sensitivity of the
assay was 7.8 ng NICHHD rhLH RP-1/ml, and the intra- and interassay
coefficients of variation were less than 3.5% and less than 9.1%,
respectively.
Inhibins. Inhibin B concentrations in plasma, measured by
the two-site ELISA described by Groome et al. (16), have
been previously reported (9). Plasma pro--C was measured using a
two-site ELISA, as described previously for the monkey (7). The
sensitivity of the assay was 20 pg/ml. The coefficient of variation was
9.7%.
Testosterone. Plasma T was assayed in duplicate by a previously described RIA (17) that employs antiserum T3–125 (Endocrine Sciences, Inc., Tarzana, CA). This assay was also used for measurement of testicular T content. For the latter purpose, testicular tissue (40–100 mg) was homogenized in a known volume of PBS gel buffer, and the homogenate, containing a known amount of tritiated T (4000 cpm) to determine recovery, was extracted twice in 10 ml diethyl ether. After evaporation of the ether, the extract was reconstituted in a known volume of the PBS gel buffer before assay. The mean sensitivity of the assay was approximately 0.08 ng/ml, the intra- and interassay coefficients of variation were 6.5% and 10.7%, respectively, and the recovery from testicular tissue was 49 ± 4%.
Statistical analyses
The significance of differences in the initial testicular volume
of the monkeys used in the summer and the winter months (n = 5
each) was determined by comparing the mean values for each season,
obtained by averaging the volume of two testes from each monkey.
Similarly, the significance of differences in the mean weight and the
percent increase in the volume of the remaining testis after UO were
also compared between the seasons (n = 3
each).3 These comparisons
were made using unpaired Student’s t test
The changes in testicular volume in the UO and sham groups were determined by two-way ANOVA with repeated measures. The effect of time within a treatment was tested by one-factor ANOVA with repeated measures, followed by Duncan’s new multiple range test.
The significance of differences in the mean values of morphometric parameters of the removed and the remaining testis were compared using paired Student’s t test. Correlations between Sertoli cell and total germ cell numbers were tested by calculating the Pearson product-moment correlation coefficient (r).
The significance of differences in the mean values of hormone concentrations, pulse frequency, and pulse amplitude before and after UO or sham UO was determined by two-way ANOVA with repeated measures, as described above for testicular volume. A mean concentration for each hormone during each 12-h window of frequent blood sampling was obtained for each monkey by averaging the individual values obtained for the respective hormones. Hormone levels below the sensitivity of the assays were assigned a concentration equivalent to the minimum detectable concentration in the respective assay. Overall group means for each hormone were then calculated at each time point.
Episodes of LH and T secretion (pulses) during each of the 12-h (0800–2000 h) windows of sequential sampling were identified by a pulse detection algorithm (18) that determines the number and amplitude of the hormone pulses. The G values used, which produce a 1% false positive rate, were: G (1) = 4.4, G (2) = 2.6, G (3) = 1.96, G (4) = 1.46, and G (5) = 1.13. For purposes of calculation, the respective assay limit of detection was substituted for undetectable levels. On two occasions (days 0 and 32) in one sham UO monkey, circulating concentrations of LH were generally undetectable, although distinct pulses of T were observed. On these occasions, the T pulses were therefore used to determine the number of LH pulses, a procedure consistent with the high fidelity relationship between LH and T secretion (19).
Differences were considered significant at P < 0.05, and SDs are shown.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Moreover, the
mean weight of this testis (37.3 ± 3.3 g) was significantly
greater than that of the testis (27.4 ± 2.9 g) removed at
UO.
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Morphometry of seminiferous tubules
Representative histological profiles of seminiferous tubules from
the testis removed at UO and those from the remaining testis on day 44
are shown for one monkey in Fig. 2.
Although the mean diameter of the seminiferous tubules in the remaining
testis (212 ± 13 µm) was significantly greater than that of the
removed testis (183 ± 16 µm), the mean tubule length did not
differ between the two testes (913 ± 115 and 911 ± 165
m). Differences were not observed in the volume fractions of either the
seminiferous tubular or the interstitial compartments of the removed
and remaining testis.
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). The number of round
spermatids per Sertoli cell was significantly higher in the remaining
testis (1:8.4 vs. 1:5.8, Sertoli cell to round spermatid).
Interestingly, as shown in Fig. 4, although total germ cell number was not correlated
(r2 = 0.19; P > 0.05) to Sertoli
cell number in the removed testis, this relationship in the remaining
testis became significant (r2=0.85;
P < 0.01). The mean number of Ad spermatogonia was
significantly less in the remaining testis, compared with that in the
removed testis (166 ± 55 vs. 145 ± 42 x
106, respectively).
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24%) of circulating inhibin B
concentrations was observed during the initial 4 days after UO, levels
of this hormone were stable thereafter. Also, inhibin B concentrations
after UO remained significantly lower than those before UO.
In contrast to inhibin B, circulating concentrations of FSH were not
immediately affected by UO (Fig. 5).
However, the abrupt reduction in circulating inhibin B levels on day 0
was followed during the next few days by a robust increase in
circulating FSH levels that reached on day 4 a peak value over
2-fold greater than that observed previously UO (Fig. 5). Circulating
FSH concentrations then declined progressively over the next 12 days to
plateau at a value intermediate between those of the pre-UO control and
the post-UO peak on day 4. The plateau concentration of FSH was
significantly greater than the control value and significantly less
than the peak value on day 4. Differences within the sham group (Table 1) and between the groups were not
significant.
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-C. The mean concentration of circulating pro--C
before UO was 703 ± 571 pg/ml, and this declined by 24% to
535 ± 511 pg/ml on day 1 before returning to precastration values
by day 8. Although the UO-induced changes in mean pro--C levels in
the six monkeys were not significant, they were considered of interest.
Examination of data from individual monkeys revealed that the post-UO
decline in circulating pro--C levels was particularly robust in four
of the six animals, and in these animals the return to pre-UO control
levels of this peptide appeared to be related to the increase in FSH at
this time (Fig. 6). Again, however, the
changes were not significant. Differences within the sham group (Table 1
) and between the groups were also not significant.
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). Within the next 24 h,
however, mean circulating T concentrations showed a rapid recovery, and
on day 2, the levels of this steroid had rebounded to values (4.6
± 1.4 ng/ml) indistinguishable from those before UO. Thereafter,
although a small, but significant, fall in the circulating T level was
observed between days 4 and 8, mean circulating T concentrations
remained relatively stable for the remaining duration of the experiment
(Fig. 7).
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). During the next 24 h, mean circulating LH
rebounded rapidly to reach a peak level of 18.9 ± 3.7 ng/ml,
which was significantly higher than the pre-UO concentration (Fig. 7).
Subsequently, mean circulating LH declined gradually and significantly
to reach a concentration of 12.9 ± 2.9 ng/ml by day 8.
Thereafter, concentrations of this gonadotropin were maintained within
the pre-UO range for the duration of the experiment (Fig. 7).
Differences in mean LH and T concentrations within the sham group
(Table 1) and between the groups were not significant.
Figure 8 shows the moment to moment
changes in circulating LH and T concentrations in two representative
monkeys before UO, on day 2 after UO, when the mean T concentration had
returned to the precastration range, and at the end of the experiment.
Data obtained from Pulsar analyses of the moment to moment changes in
LH and T are shown for the experimental and control groups in Tables 2 and 3,
respectively. In general, on the day of surgery (day 0), the mean pulse
frequency and amplitude of LH and T were markedly reduced in both
groups. Subsequently, in the UO group, an immediate increase in LH
pulse frequency and amplitude was observed, and within 24 h (day
1) these parameters had returned to values indistinguishable from those
before UO. Although the immediate post-UO changes in T pulse frequency
and amplitude were similar to those in LH, full restoration of episodic
T secretion was not observed until day 2. In the sham group, the
changes in the intermittent patterns of LH and T secretion were
unremarkable (Table 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Growth of the remaining testis after UO was primarily the result of an expansion in the population of germ cells,4 because, as was to be expected (2, 3), Sertoli cell number in the removed and remaining testes, as empirically determined and as reflected by seminiferous tubular length (28), was identical. In the present study there was no evidence for an increase in the number of Ap spermatogonia in the remaining testis, and therefore, it is unlikely that this undifferentiated germ cell represented a major locus contributing to the spermatogenic compensation induced by UO. On the other hand, the increase in the number of all four generations of type B spermatogonia strongly suggests that an important component of the spermatogenic compensation is achieved by amplification of the population of differentiated spermatogonia. The cycle of the seminiferous epithelium in the rhesus monkey is 10.5 days, and progression from B1 spermatogonia to step 9 round spermatids requires three cycles or 32 days (14, 29). Therefore, it is reasonable to propose that the amplification of germ cells up to step 9 round spermatids observed on day 44 may be accounted for exclusively by an action on differentiated spermatogonia.
The most likely stimulus for the increase in number of B spermatogonia in the remaining testis was the sustained elevation of FSH secretion. FSH administration to either normal or T-treated hypophysectomized adult male monkeys resulted in stimulation of the seminiferous epithelium (30, 31), and in the latter paradigm FSH produced a selective amplification of differentiated spermatogonia in the absence of a change in the number of Ap spermatogonia (31). This putative effect of FSH on B spermatogonia in the remaining testis was presumably the result of increased survival of these cell types (32), an idea that does not contradict the conclusion that the efficiency of spermatogenesis in the macaque is high (33), because the latter was based on the behavior of cell types more mature than B spermatogonia.
It has been generally accepted that the postpubertal testis is operating at its maximal spermatogenic capacity and that this ceiling is set by the final complement of Sertoli cells (2), which, in primates, is established during puberty (12, 34). Under ceiling conditions, therefore, it is to be predicted that the correlation between germ cell and Sertoli cell number would be tight. As shown in the present study, however, the correlation between these parameters in the gonadally intact situation was not very impressive, but became robust after UO. The poor correlation between germ cell and Sertoli cell number has been previously documented for the intact macaque (33). This finding together with the observation of a compensatory increase in spermatogenesis in the remaining testis in the face of an unchanging number of Sertoli cells indicate that the monkey testis is not normally operating at its maximal potential, but may be driven toward ceiling in association with a sustained increase in FSH secretion. In this regard it is interesting to note that, as shown in this and another study (35), the Sertoli cell/spermatid ratio in the monkey is about 50% less than that in most nonprimate species (2).
Although the T content of the remaining testis was not significantly greater than that in the removed gonad, an increase in T production may be inferred because circulating levels of this steroid were rapidly restored to values indistinguishable from those in the intact control state. Whether this increased testicular T production contributed to the compensation observed in the seminiferous tubule cannot be excluded.
The sustained increase in T secretion by the remaining testis, which was also inferred previously in the bonnet monkey (1), must have resulted from an increase in the number of Leydig cells and/or an increase in the sensitivity of this cell to an unchanging LH stimulus. The former possibility is supported by the finding that in the bonnet monkey there was an increase in the number of 3ß-hydroxysteroid dehydrogenase-positive cells (36). In this regard, it is interesting to note that Leydig cell number is increased in adult rat testis within 1 week of initiating hCG stimulation (37). Thus, the acute hypersecretion of LH that was detected in the present study 24 h after UO may have been the signal responsible for the increase in T production by the remaining testis.
The idea that the sustained elevation of FSH secretion may also be involved in maintaining the increased T production by the remaining testis is more difficult to support. Recombinant human FSH administration for 48 h to juvenile male rhesus monkeys, in which the pituitary-testicular axis was driven with a pulsatile infusion of GnRH (38), and treatment of adult monkeys with this gonadotropin for 16 days (30) were not associated with an increase in plasma T concentrations. On the other hand, in men undergoing inguinal canal surgery, an iv bolus of recombinant human FSH resulted in an acute increase in the T concentration in spermatic vein blood (39). Additionally, in the immature hypophysectomized rat, FSH treatment for 7 days increased T production (40), and there is an extensive literature describing in vitro studies that implicate FSH in the control of steroidogenesis by the Leydig cell (41).
The possibility that testicular nerves play a role in mediating the increased T production by the remaining testis also needs to be considered. That the testis is innervated is well established (42), and morphological and biochemical evidence for a direct innervation of Leydig cells has been obtained in a variety of species, including primates (43, 44, 45). Interestingly, the established compensatory T production after UO in the adult rat is associated with morphological changes in the Leydig cell nucleus, and denervation of the inferior spermatic nerve to the remaining testis inhibits both the endocrine and morphological responses (46). Clearly, the relative roles of endocrine and neural factors in the response of the Leydig cell after UO need to be established.
The dynamics of the endocrine changes in the FSH-inhibin B feedback loop after UO of the adult monkey were of considerable interest. As expected, removal of one testis resulted in a rapid and approximately 50% decline in circulating inhibin B levels, which was followed by a robust increase in FSH secretion in accord with the established feedback role of testicular inhibin in the monkey (5, 6, 7). On the other hand, the modest 24% restoration in circulating inhibin B levels that was observed in association with the elevation in FSH secretion was less than that anticipated. This is because an earlier study found that sc injection of recombinant human FSH in normal men resulted in a significant 1-fold increase in circulating inhibin B levels (47). Whether this quantitative difference in inhibin B responsiveness to FSH stimulation simply reflects the fact that the increase in the circulating FSH signal achieved in men by injection of recombinant hormone was markedly greater than that elicited in the monkey by UO remains to be determined. In any event, it may be concluded that the inhibin B response of the monkey testis to a physiological increase in circulating FSH levels is not particularly robust.
The modest restoration of inhibin B production by the remaining testis
during the first 4 days after UO, however, was associated with a
blunting in the rise in FSH secretion, presumably reflecting the
negative feedback action of the testicular hormone at the level of the
pituitary. Thus, the response of the FSH-secreting gonadotroph to
either an increase or a decrease in circulating inhibin tone is robust
and contrasts with the less sensitive relationship between testicular
inhibin B production and FSH stimulation. Although the rise in plasma
FSH concentrations in response to UO appeared to be limited by the
restoration of inhibin B secretion, it is important to note that an
increased secretion of FSH was sustained for the duration of the
experiment. Taking the foregoing considerations together, it seems
reasonable to conclude that the sustained deficit in inhibin B
secretion after UO and, therefore, the persistent error signal for the
release of FSH are achieved by a differential gain in the feedforward
(FSH-inhibin B) and feedback (inhibin B-FSH) components of this loop.
That the post-UO equilibrium in the FSH-inhibin B loop observed in the
present study may be permanent is suggested by the finding that
circulating FSH concentrations in three chronically UO monkeys (2–5
yr) were significantly greater than those in intact animals (Ramaswamy,
S., and T. M. Plant, unpublished observations).
The dramatic decrease in LH pulse frequency and mean LH concentrations observed immediately after UO was probably a reflection of an effect of anesthesia and surgery to inhibit pulsatile GnRH release (48) and no doubt contributed to the fall in plasma T to below 50% of pre-UO control concentrations. This decrease in the plasma T level was followed within 12 h by a rebound in LH secretion that produced circulating levels of the gonadotropin in excess of those before UO. A similar acute response in LH secretion to UO has also been noted in some, but not all, studies of the adult rat (49, 50, 51, 52). Interestingly, by day 2, LH concentrations returned to levels that were not significantly different from the control value. This presumably reflected the restoration of the negative feedback signal provided by circulating T and reinforces the view that this testicular steroid is the principal regulator of LH secretion in the male monkey (see introduction). The sustained doubling of T production by the remaining testis in the face of an unchanging LH drive is very interesting and, as discussed above, must be due to an increase in Leydig cell number and/or responsivity.
The finding in the present study that circulating concentrations of
pro--C, unlike those of inhibin B, were restored to values
indistinguishable from those seen before UO was not surprising, because
a similar restoration of immunoactive inhibin levels had been
previously reported for the bonnet macaque (1). The association between
the restoration of circulating pro--C and the increase in FSH
secretion after UO suggests that the secretion of pro--C by the
primate testis is closely regulated by circulating FSH concentrations.
This view is consistent with an increase in circulating levels of this
inhibin precursor form in normal men after recombinant human FSH
treatment, although, as discussed above, this treatment also resulted
in a similar inhibin B response (47). The differential responses of
inhibin B and pro--C after UO in the adult monkey are consistent
with our understanding of the regulation of the inhibin subunit genes.
Expression of the rat gene encoding for inhibin is up-regulated
through a cAMP mechanism (53, 54), whereas the rat inhibin ßB gene
does not have a classical cAMP response element (55) and is not
markedly influenced by hypophysectomy or FSH stimulation (56).
We conclude that 1) the rate of sperm production by the monkey testis is regulated by the circulating concentration of FSH that, under physiological situations, is insufficient to stimulate spermatogenesis to its ceiling; and 2) FSH secretion is controlled by a feedback system in which the feedback loop (inhibin B-FSH) is more robust than the feedforward arm (FSH-inhibin B). Thus, a decrease in the inhibin B feedback signal results in a sustained increase in FSH secretion, which drives the testes toward their spermatogenic ceiling that is set by Sertoli cell number.
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Acknowledgments |
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Footnotes |
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2 One monkey was used in both groups, with an
interval of 12 weeks between sham castration and UO.
3 In one of the UO monkeys, GnRH pulse generator
activity, as reflected by LH discharges, was unaccountably arrested
from day 8 until the end of the experiment. Hence, the results from
this animal were not included in the numerical analysis.
4 It should be noted, however, that the
significant decrease in the number of Ad spermatogonia in the remaining
testis was unexpected, and we have no explanation for this
result.
Received August 9, 1999.
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References |
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- and ßB-subunit genes suggests
two different regulatory mechanisms. Mol Endocrinol 3:1914–1925[Abstract]
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