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Institute of Reproduction and Development, Monash University, Monash Medical Center, Clayton, Victoria 3168, Australia
Address all correspondence and requests for reprints to: Dr. M. P. Hedger, Institute of Reproduction and Development Monash University, Monash Medical Center, Clayton, Victoria 3168, Australia. E-mail: mark.hedger{at}med.monash.edu.au
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Infection and inflammation can be reproduced in vivo
by administration of bacterial lipopolysaccharides (LPS), and several
studies have observed inhibition of testicular steroidogenesis and
disruption of spermatogenesis in animals treated with LPS (4, 5) or
with septic agents that generate LPS (6). Studies in mice using
relatively high doses of LPS in vivo have demonstrated that
Leydig cell steroidogenesis is inhibited via reduced synthesis of the
cholesterol transport protein, steroidogenic acute regulatory protein
(StAR), and of the steroidogenic enzymes, cholesterol side-chain
cleavage enzyme, 17
-hydroxylase/C17,20-lyase,
and 3ß-hydroxysteroid dehydrogenase within several hours after
injection (7, 8, 9). There is considerable evidence that local production
of interleukin-1ß (IL-1ß) and tumor necrosis factor- may be
responsible for this inhibition (7, 8, 10, 11), although other
inflammatory mediators, including nitric oxide (NO), oxygen free
radicals, and PGs, also have inhibitory effects on Leydig cell
steroidogenesis in vitro (12, 13, 14). Moreover, several of
these mediators, most notably IL-1ß, NO, and serotonin, influence the
blood supply of the testis (15, 16, 17, 18), and both the Leydig cell and the
seminiferous epithelium are particularly sensitive to changes in either
blood flow or testicular interstitial fluid (IF) formation (19). In
addition to actions at the testicular level, administration of LPS
inhibits hypothalamic GnRH and pituitary LH release through the action
of IL-1ß (20, 21). Recent data indicate that IL-1ß also inhibits
Leydig cell testosterone secretion when administered via the cerebral
ventricles, an action that appears to be mediated not by inhibition of
LH secretion, but via neural pathways direct to the testis (22, 23).
Consequently, inflammation potentially exerts inhibitory effects on
steroidogenesis at several different levels.
Compared with a number of studies on the effects of inflammatory mediators on the brain-pituitary-Leydig cell axis, the effects of inflammation on spermatogenesis have received relatively little attention. Moreover, there has been no direct investigation of the relationship between inhibition of Leydig cell function and spermatogenic damage caused by inflammation. More importantly, most studies have employed very high doses of LPS, which also causes endotoxic shock (24), and relatively little is known about the effects of mild inflammation on pituitary-testicular function. In the following study we examined the in vivo response of the Leydig cells and spermatogenesis to both low and high dose LPS treatments to identify the primary sites of inhibition of testicular function during inflammation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LPS (from Escherichia coli, serotype 0127:B8), Mayer’s hematoxylin, and 3,3'-diaminobenzidine tetrahydrochloride were obtained from Sigma (St. Louis, MO). hCG (Pregnyl) was obtained from Organon (Cambridge, UK). Reagents for the LH RIA were supplied by the NIDDK (Bethesda, MD). Biotin-conjugated antisheep immunoglobulin and streptavidin-conjugated horseradish peroxidase were obtained from Amrad (Melbourne, Australia).
Exp 1: low dose and high dose LPS time-course study
Rats were injected ip with pyrogen-free saline (1.0 ml/kg BW)
alone or with saline containing 0.1 mg LPS/kg BW (low dose group), or
5.0 mg LPS/kg BW (high dose group). The doses of LPS employed were
determined in a pilot dose-response study that used body temperature
and physical activity levels to determine the severity of the response.
The animals were maintained under continuous observation, and their
condition was noted. At various time points up to 72 h after
injection, body temperature was measured by rectal digital thermometer,
and the animals were killed for collection of tissues as described
below.
At appropriate time intervals after injection, rats were anesthetized with ether, and the thorax and abdomen were exposed via a midline incision. One testis was removed for collection and measurement of testicular IF volume, as previously described (25). Although not used in the present study, the ipsilateral kidney and a lobe of liver also were removed. The renal and spermatic arteries supplying the removed organs were clamped. A sample of blood (between 1–5 ml) was collected via cardiac puncture. Tissues were fixed for histology by lower body perfusion (26). Briefly, the remaining testis was exposed by a longitudinal scrotal incision, and the abdominal organs were perfused via the descending aorta with warm saline for several minutes to clear the vasculature of blood. Heparin was not added to the saline solution. The abdominal organs subsequently were infused with a 5% solution of colloidal carbon in saline under a constant pressure. The times between the commencement of the carbon infusion, the appearance of the carbon solution within the capsular testicular artery of the exposed testis (perfusion time to artery), and the appearance of carbon solution in the testicular vein (testicular perfusion time) were recorded. Once the testicular vasculature was completely perfused with the carbon solution, a further saline-only infusion was used to clear the vasculature once more, and the abdominal organs were perfused with Bouin’s fixative for approximately 10 min. The perfusion-fixed tissues (testis and epididymis) were removed into fresh Bouin’s fixative for a further 5 h, then transferred to 70% ethanol. In the case of animals that were not used for histology, blood and tissues were collected before death under ether anesthesia.
To allow for the large variation in sex hormone levels in the serum and testis, which are due to the pulsatile pattern of LH release, and the circadian pattern of testosterone secretion by the testis (27), injection of each LPS-treated rat was alternated with that of a saline-treated control rat over a 2-h period. Animals were killed in the same sequence at the appropriate time intervals within 1 of the following 2-h periods: 0600–0800, 0900–1100, 1200–1400, 1500–1700, and 2100–2300. This procedure was repeated over several weeks under strictly identical conditions until sufficient animals were obtained. Rats that died before collection of samples were not included as part of the study. For assessment of body temperature, body and testis weights, and histology, final group numbers consisted of a minimum of 6 rats/group (low dose LPS treatment) or 5 rats/group (high dose LPS treatment) at each time point, and 5 control rats were collected at each time point for each LPS dose. Additional samples were collected at 3, 6, 12, 18, and 24 h from rats that were not processed for histology, so that the total numbers of serum and IF samples collected at each time point were as follows: low dose LPS treatment: 1 h (5 controls, 6 LPS-treated), 3 h (10 controls, 11 LPS-treated), 6 h (13 controls, 14 LPS-treated), 12 h (8 controls, 9 LPS-treated), 18 h (8 controls, 9 LPS-treated), 24 h (10 controls, 11 LPS-treated), 48 h (5 controls, 6 LPS-treated), and 72 h (5 controls, 6 LPS-treated); and high dose LPS treatment: 3 h (8 controls, 8 LPS-treated), 6 h (8 controls, 8 LPS-treated), 12 h (8 controls, 8 LPS-treated), 18 h (8 controls, 8 LPS-treated), 24 h (8 controls, 9 LPS-treated), and 72 h (5 controls, 6 LPS-treated).
Exp 2: hCG challenge study
Rats (n = 5/group) were injected ip with pyrogen-free
saline (1.0 ml/kg BW) alone or with LPS (0.1 or 5.0 mg/kg BW) in saline
and killed at 6 h (low and high dose groups), 18 h (low dose
group only), or 24 h (saline control and high dose group only)
after injection for collection of tissues. Rats in each treatment group
received an injection (100 µl, sc) of either pyrogen-free saline or
50 IU hCG in saline to stimulate Leydig cell testosterone production,
90 min before collection (28). Animals were anesthetized with ether, a
sample of blood was collected via cardiac puncture, and both testes
were removed for collection and measurement of testicular IF.
Histological studies
Tissues were processed for embedding in paraffin, sectioned (5
µm), and stained for histology with Mayer’s hematoxylin
(Sigma).
In situ end labeling of free DNA ends
The 3'-end of fragmented DNA in cells undergoing apoptosis were
labeled using a modification of the in situ cell death
detection method developed by Roche Molecular Biochemicals
(Mannheim, Germany). Briefly, endogenous peroxidase activity in dewaxed
and rehydrated testis sections was blocked by a 30-min incubation in
3% hydrogen peroxide. Sections were subsequently washed in 0.1
M PBS, pH 7.4, followed by 3'-end labeling of DNA
breaks with 5 U terminal deoxynucleotidyl transferase in 0.2
M potassium cacodylate, 25
mM Tris-HCl with 0.25 mg/ml BSA, 20
µM deoxy (d)-ATP, 20 µM
dCTP, 20 µM dGTP, 13 µM
dTTP, and 7 µM digoxigenin (DIG)-conjugated
dUTP for 30 min at 37 C. Incorporated DIG was detected using a DIG
antiserum, and the signal was amplified using antisheep Ig conjugated
to biotin and streptavidin-conjugated horseradish peroxidase.
Preincubating sections with 10% sheep serum minimized nonspecific
antibody binding. Apoptotic cells were visualized using
diaminobenzidine tetrahydrochloride and counterstained with
hematoxylin.
Hormone assays
Serum LH was measured by specific double antibody RIA (29).
Serum testosterone levels were measured by
[3H]testosterone RIA after ether extraction
(30). Testicular IF was assayed without extraction for testosterone
content by [125I]testosterone RIA (31).
Stereological analyses
A point-counting approach was used to determine changes in the
volume ratio of the seminiferous epithelium, the tubular lumen, and the
interstitial compartment (32). Slides were coded to perform the
analysis with a blinded approach. A grid of four points per field was
fitted into the ocular of the microscope. The analysis was performed at
low objective magnification (x10). The locations of all 4 points per
field were determined in 25 fields, which were randomly selected to
sample the full area of 2 testicular cross-sections. As 100 points were
counted for each animal, the number of points falling onto each
structure presents the relative volume ratio (percentage) of each
component.
Statistics
Data were analyzed by one- or two-way ANOVA after appropriate
transformation to normalize data and equalize variance where necessary,
in conjunction with Student-Newman-Keuls multiple range test (Exp 1).
Student’s t test was used to compare data between two
groups (Exp 2). All data presented are the mean ±
SEM. All statistical analyses were performed
using SigmaStat version 1.0 software (Jandel Corp., San Rafael,
CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Low dose LPS had no effect on testicular perfusion, as indicated by the time for the carbon solution to perfuse the testis. However, after high dose LPS treatment, perfusion time through the testis was significantly increased (P < 0.05) compared with the control value (21.6 ± 1.9 sec) and those at 3 h (46.2 ± 6.4 sec) and at 12 h (50.2 ± 7.6 sec).
Fluid volume and hormonal responses
After treatment with low dose LPS, IF volume decreased to a
minimum of 60% of control levels by 6 h, then returned to normal
levels (Fig. 1A
). In the high dose
LPS-treated rats, IF volume was reduced throughout 3–18 h after
treatment, reaching a minimum of 6% of control levels at 12 h
(Fig. 2A).
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). These changes were
matched by changes in serum testosterone, except that the decline in
serum testosterone concentrations was more marked, falling to less than
10% of the control value at 18 h (Fig. 1C). A similar pattern of
biphasic testosterone response was observed in the high dose
LPS-treated animals (Fig. 2, B and C). Interstitial fluid testosterone
concentrations fell to 50% of the control level at 6 h, were
similar to the control level at 12–18 h, and fell to about 30% of the
control level at 24 h (Fig. 2B). The changes in serum testosterone
concentrations also matched the changes in IF testosterone, except that
the decline in serum concentrations was detectable somewhat earlier (at
3 h), and the effect of high dose LPS treatment on serum
testosterone was generally more pronounced than that observed in the IF
(Fig. 2C). The IF and serum testosterone concentrations had returned to
normal by 72 h. Compared with the response to the low dose of LPS, the high dose of LPS caused a more rapid and pronounced fall in serum testosterone, and the second inhibitory phase appeared to be delayed by about 6 h. It is interesting to note, however, that the reductions in IF and serum testosterone concentrations induced by high dose LPS treatment were of a similar magnitude to those observed after treatment with the low dose of LPS. Interstitial fluid testosterone concentrations remained at or above 30% of control values at all time points.
There was no consistent effect of LPS treatment on serum LH in the low
dose LPS-treated rats (Fig. 1D). A marked inhibition of serum LH was
observed, however, in the high dose group, with a more than 50%
reduction in LH levels at 6 and 12 h, followed by a recovery at
18 h (Fig. 2D).
Pooling the data for saline-injected control rats collected during
different time periods established that there was a marked (2-fold)
circadian variation in serum and testicular (IF) testosterone levels,
which peaked during the morning and reached a nadir in samples
collected during the evening, although there was no detectable
circadian variation in either serum LH levels or IF volume (Figs. 1 and 2).
hCG challenge response
The observation that both low and high dose LPS treatments caused
a reduction in testosterone production, independent of changes in serum
LH, indicated that LPS inhibits the ability of the Leydig cell to
respond to stimulation. To confirm this, the testosterone response was
determined 90 min after administration of hCG (50 IU) during the first
and second inhibitory response phases after LPS treatment. Injection of
hCG caused a 5-fold increase in testicular testosterone and a 3-fold
increase in serum testosterone in control rats (Fig. 3). However, this response to hCG was
severely attenuated in rats that had been treated with LPS (low dose or
high dose) 6 h previously. At 18 h (low dose group) and
24 h (high dose group) after LPS treatment, the Leydig cells had
recovered their responsiveness to the exogenous hCG challenge, although
basal and hCG-stimulated serum testosterone concentrations continued to
be lower than those in controls that had not received LPS.
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Histological observations
In high dose LPS-treated rats, the organization of the
seminiferous tubules at 3 and 6 h after treatment was not
different from that in saline-injected control rats (Fig. 4 C).
Thereafter, at 12, 18, 24, and 72 h after treatment, there was
increasing evidence of degeneration of the seminiferous epithelium.
This evidence included cytoplasmic and nuclear vacuoles in round
spermatids during stages I–IV of the seminiferous cycle (Fig. 4B) and
focal areas of disordered epithelium that were suggestive of disruption
of cell-cell contacts and loss of germ cells at stages II–III (Fig. 4D). This type of disorganization of the seminiferous epithelium was
most marked at the 18 h point. By 72 h after treatment,
numerous round germ cells, indicative of sloughing from the
seminiferous epithelium, were present in the caput epididymis (Fig. 4, E–G). Although there was no detectable increase in apoptosis at
earlier time points, there was a dramatic increase in apoptosis of
spermatocytes and possibly some spermatogonia at stages II–V in the
seminiferous epithelium observed at 72 h after treatment (Fig. 5). In low dose LPS-treated testes, there was
relatively little change in the appearance of the seminiferous
epithelium throughout the study period, no increase in round cells in
the epididymis, and no increase in apoptotic germ cells.
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, H
and I). In contrast, carbon leakage into the interstitial tissue was
observed in only one animal from the low dose group, at 24 h after
LPS treatment. In both the low dose and high dose LPS treatment groups,
there was an increase in leukocytes (monocytes and neutrophils)
attached to the vascular endothelium during vascular damage and
infiltration of circulating leukocytes into the interstitial tissue in
association with regions of vascular damage. A detailed quantitative
analysis of the changes in testicular inflammatory cells within these
testes is being undertaken and will be presented in a subsequent
manuscript. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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At a high dose that caused significant mortality due to endotoxic shock, a single injection of LPS reduced LH secretion in adult male rats for at least 12 h, which may be attributed to inhibition of hypothalamic GnRH release by inflammatory cytokine action (20, 21). However, both low and high doses of LPS inhibited the ability of the Leydig cell to respond to LH/hCG regardless of whether there was a corresponding reduction in serum LH levels. These data indicate that direct inhibition of Leydig cell function is the primary reason for the decline in androgen levels during systemic inflammation, rather than inhibition of the hypothalamo-anterior pituitary axis. This inhibition is most likely due to the effects of inflammatory cytokines and other mediators on the Leydig cell (7, 8, 9, 10, 11, 12, 13, 14), although adrenal corticosteroids, which are released as a protective response during inflammation and exert direct inhibitory effects mediated by specific glucocorticoid receptors on the Leydig cell itself (33), or inhibition of direct neural pathways to the testis (22, 23) also may be involved.
Unexpectedly, after the inhibition of steroidogenesis at 6 h after LPS treatment, we observed a transient recovery of testicular and serum testosterone levels by 12 h, which was followed by a secondary decline around 18 h in the low dose group and at 24 h in the high dose group. This was followed by full recovery of steroidogenesis within 24 h in the low dose group and by 72 h in the high dose group. The secondary decline occurred in the presence of serum LH levels in the normal range even though the Leydig cells had recovered the ability to respond to LH/hCG by this time. Although inhibition of steroidogenesis, StAR protein, and steroidogenic enzyme expression has been observed over the short term (between 2–8 h) and at longer time intervals (24 h and longer) after injection of LPS or septic agents (7, 8, 9), this biphasic phenomenon has not been reported previously. The mechanisms underlying this apparent recovery and secondary failure are unknown, but the fact that a larger amount of LPS appeared to both delay and prolong the response suggests that it may be related to a secondary response to the inflammation, such as adrenal steroid production and the release of antiinflammatory cytokines (34). Alternatively, as the recovery phase overlapped the period of lowest diurnal testosterone secretion, the possibility that there is some photoperiodic influence involved cannot be discounted.
It was of particular interest to observe that IF testosterone concentrations, which are a direct index of intratesticular testosterone levels (35, 36), remained at or above 30% of the control value even in high dose LPS-treated rats. This indicates that the Leydig cells continue to produce testosterone under these conditions in vivo, albeit at lower levels. Testicular IF volume and testosterone concentrations are related through local androgen-dependent regulatory mechanisms, which modulate testicular blood flow characteristics to control IF formation and the transport of products from the testis (37, 38, 39). Consequently, intratesticular testosterone concentrations, but not serum testosterone, may have been maintained despite reduced local synthesis through the reductions in IF volume and testicular blood flow that were observed in the LPS-treated testes. Regardless of the mechanism, however, the maintenance of intratesticular testosterone at around 30% of the control level is an important observation, as it is known that qualitatively normal adult rat spermatogenesis can be maintained with intratesticular testosterone concentrations as low as 15–20% of normal (30, 35, 40). Moreover, androgen withdrawal selectively affects spermatocytes, round spermatids, and elongating spermatids around stages VII–VIII (41, 42). The damage seen in the present study after high dose LPS treatment was largely confined to stages I–V, which are not acutely affected by androgen withdrawal. It appears that damage to the seminiferous epithelium after severe inflammation in the LPS-treated rat is due not to the loss of Leydig cell steroidogenesis but to other causes.
Several alternative causes of the seminiferous damage exist: 1) hyperthermia (43); 2) restricted testicular blood flow due to the action of local inflammatory vasoconstrictors, such as serotonin (44), or reduced arterial pressure through the vasodilatory action of NO (17, 18); and 3) direct effects of LPS and its products on the seminiferous epithelium (45). The damage observed in the high dose LPS-treated group, which actually experienced a reduction in body temperature, was not consistent with increased temperature. Moreover, the germ cells that are affected by hyperthermia are the early and late spermatocytes as well as early round spermatids (43), and we saw no effect on the early spermatocytes in this study, nor were the data consistent with damage due to restricted blood supply or reperfusion injury, which preferentially causes apoptosis of germ cells entering mitosis, and first occurs within hours in spermatogonia and in early primary spermatocytes (46, 47). In fact, apoptosis after ischemia precedes disruption of the seminiferous epithelium (47), whereas in the present model, apoptosis of spermatocytes was not observed until several days after treatment and the loss of epithelial organization. Moreover, a recent study of the response of testicular blood flow to sepsis induced by ip fecal matter actually demonstrated an increase in testicular blood flow 24 h later (48), providing further argument against a restriction of blood flow as the cause of damage in the present model. Nonetheless, minor vascular changes such as those seen in varicocele are associated with spermatogenic disruption (19), and it cannot be ruled out that more subtle vascular effects are involved.
The possibility that the spermatogenic damage after high dose LPS
treatment was due to a direct effect of inflammatory mediators on the
seminiferous epithelium itself is supported by the fact that the same
stages of the spermatogenic cycle that are affected by LPS treatment
also are damaged during inflammation induced by hyperstimulation with
hCG (49). Several inflammatory cytokines, most notably IL-1 and
IL-6, appear to be involved in the regulation of spermatogenesis (45).
Although the testicular resident macrophages themselves are deficient
in the production of inflammatory cytokines (50), numerous in
vitro studies have established that the Sertoli cells and Leydig
cells secrete inflammatory cytokines and NO in response to LPS and
other inflammatory stimuli (45, 51). Moreover, there is evidence of
increased circulating leukocytes (monocytes and neutrophils) within the
testis that may contribute to the production of inflammatory mediators.
The up-regulation of these regulatory cytokines and factors during
inflammation is certain to interfere with normal regulation of the
spermatogenic process.
Finally, although caution needs to be exercised when extrapolating the results of this acute inflammation model to human illness and infection or chronic inflammatory diseases, the present study has exposed several novel elements of the testicular response to inflammation, most notably that there is a clear dissociation between the effects of inflammation on steroidogenesis and those on spermatogenesis. With respect to the implications for human fertility, these data indicate that blocking the inflammatory mediators themselves may be more important in protecting spermatogenesis during severe inflammation or illness than trying to minimize the secondary effects of these agents on androgen production, blood flow, or testicular temperature during inflammation. Moreover, infertility due to inflammatory disease may arise and will persist despite normal circulating testosterone levels in the patient.
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Acknowledgments |
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Footnotes |
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2 Current address: Institut für Reproductionsmedizin der
Universität Münster, Domagkstrasse 11, 48149 Munster,
Germany.
Received May 14, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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release in adult rat testis: role in Leydig
cell desensitization to hCG. Life Sci 24:2151–2158[CrossRef][Medline]
, induces acute inflammation-like changes in the
testicular microcirculation of adult rats. J Reprod Immunol 17:155–165[CrossRef][Medline]
and -1ß regulate interleukin-6 expression in Leydig
and Sertoli cells. Recent Prog Horm Res 50:367–372
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M. K. O'Bryan, S. Schlatt, O. Gerdprasert, D. J. Phillips, D. M. de Kretser, and M. P. Hedger Inducible Nitric Oxide Synthase in the Rat Testis: Evidence for Potential Roles in Both Normal Function and Inflammation-Mediated Infertility Biol Reprod, November 1, 2000; 63(5): 1285 - 1293. [Abstract] [Full Text]
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)
and matched saline-injected control rats (
). Significant differences
between control and LPS-treated responses at each time point are
indicated (*, P < 0.05).
