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Andrology Laboratory, Department of Medicine (D02), University of Sydney, Sydney, New South Wales 2006, Australia; and Andrology Unit (D.J.H.), Royal Prince Alfred Hospital
Address all correspondence and requests for reprints to: Professor D. J. Handelsman, Department of Medicine (D02), University of Sydney, Sydney, New South Wales 2006, Australia. E-mail: djh{at}med.usyd.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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Exploiting this naturally occurring genetic inactivation of the GnRH
gene, we previously showed that androgens alone, acting through the
androgen receptor and without need for aromatization, can initiate
qualitatively complete spermatogenesis in the presence of low
intratesticular testosterone and undetectable circulating FSH (12). In
this model of complete functional FSH deficiency, the spermatozoa
produced have quantitatively normal fertilizing ability in
vitro (12) and in vivo (Allan, C. M., and D.
J. Handelsman, unpublished data). The appearance of round and elongated
spermatids in hpg mouse testis induced by androgen
treatment—when these cells are completely lacking before
treatment—demonstrates that T, without FSH, is required
physiologically for the completion of meiosis (round spermatids) and
spermiogenesis (elongated spermatids). The rate-limiting step appears
to be the completion of meiosis that is remarkably sensitive to T.
Although androgens (T or DHT) produced a striking growth response in
hpg testes, maximal testis size was 30–50% of
non-hpg control. This was attributable to the number of
Sertoli cells being also 30–50% of non-hpg controls,
whereas the number of germ cells per Sertoli cell was quantitatively
normal (12). These findings were confirmed in mice with inactivated
genes for the FSH ß-subunit (13) or the FSH receptor (14), but where
endogenous LH and testosterone secretion were unimpaired. In both
models, the same reproductive phenotype as observed in T-treated
hpg mice—small testis (
30–50% normal) of normal
morphology and producing fertile spermatozoa—was observed. These
findings are consistent with the concept that mature testis size is
largely determined by extent of Sertoli cell proliferation during late
prenatal and early postnatal life before germ cell replication occurs.
The stock of Sertoli cells thereby determines final testis size because
each Sertoli cell has a fixed, finite capacity for numbers of germinal
cells that it can support. This mechanism is supported by the fact that
neonatal FSH treatment increases Sertoli cell number (and thereby final
germ cell capacity and mature testis size) (15), whereas even intensive
FSH treatment after the age when Sertoli cell replication usually
ceases is ineffective (16). Similar modifications of mature testis size
by manipulation of the postnatal stock of Sertoli cells have been
achieved by neonatal hemicastration (17), hypothyroidism (18), or FSH
treatment (19).
Given that we had clearly established the T dosage threshold and locus of action involved in induction of spermatogenesis, the question arose whether the hormonal-dependent mechanism that maintains spermatogenesis is the same as that required to initiate it. To characterize these mechanisms, the present study aimed to determine whether the androgenic threshold required to maintain spermatogenesis was the same as the well characterized threshold required to induce it.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Genotyping
Mice were genotyped by a duplex PCR on proteinase-K digests of
tail snips as described previously (12) and modified from the original
method (20). The PCR products were separated on agarose gel to
distinguish three genotypes (N/N, N/hpg and
hpg/hpg) deduced from the presence and size of one or two
expected bands.
SILASTIC implants
SILASTIC brand implants filled with crystalline T (Sigma Chemical Co.) were prepared from SILASTIC brand tubing (id 1.47
mm,od 1.95 mm; Dow Corning Corp., Midland, MI, catalog no.
602–235) and sealed at both ends with SILASTIC brand adhesive
(Dow Corning Corp. 734RTV). Given the fixed thickness of
the tubing and the diffusion rate of testosterone through SILASTIC, the
length of SILASTIC brand tubing determines testosterone release rate.
The implant length refers to the length of SILASTIC brand tubing filled
with crystalline steroid exposed to the extracellular fluid and
therefore available for steroidal release. The shortest tubing length
that could be manufactured satisfactorily was 0.06 cm. Subdermal
SILASTIC brand T implants provide accurate and predictable blood and
intratesticular concentrations as described previously (12).
Experimental design
Regression of spermatogenesis (Exp 1). To estimate the
testosterone requirement for maintenance of spermatogenesis, it was
necessary first to establish the time-course of spermatogenic
regression after removal of T-filled implants. The duration of the
experiment was based on the duration of the spermatogenic cycle (35
days) in the mouse (21). Weanling (day 21) hpg mice had
spermatogenesis induced by subdermal implantation of a 1 cm T-filled
SILASTIC brand tubing under anesthesia (n = 6–8 per group) for 6
weeks as described previously (12). Following this induction of
spermatogenesis, the 1 cm T implant was removed from all mice. The rate
and extent of spermatogenic regression was determined by estimating
testis weight and elongated spermatid counts at 0, 1, 2, 3, 4, and 6
weeks after implant removal. The experiments ended with the mice being
killed by anesthetic overdose and testes rapidly excised. The right
testis was weighed and used for quantitation of elongated spermatids by
the homogenization method (22).
Maintenance of spermatogenesis (Exp 2)
To determine the androgenic threshold for maintenance of
spermatogenesis, full spermatogenesis was first induced in weanling
hpg mice by subdermal implantation of a 1 cm T-filled
SILASTIC brand tubing for 6 weeks. At 9 weeks of age, mice (n =
8–19 per group) were then randomly allocated to subsequent treatments
consisting of replacement of the original 1 cm implant with T-filled
SILASTIC brand implants of various lengths (0, 0.06, 0.20, 0.25, 0.5, 1
cm) for a further 4 weeks. At the end of this experiment, all mice were
killed to harvest testes for measurement of testis weight, for
enumeration of elongated spermatids by homogenization (n = 8–19
per group) and for stereological measurements (n = 2–4 per
group).
Long-term maintenance of spermatogenesis by low-dose T (Exp 3)
To determine if low T doses could maintain spermatogenesis over
a longer period, the design of Exp 2 was repeated with induction of
full spermatogenesis by subdermal implantation of a 1 cm T-filled
SILASTIC brand tubing into weanling hpg mice for 6 weeks. At
9 weeks of age, mice (n = 4–8 per group) had the original 1 cm
implant removed and were then switched to a maintenance implant of
either 0.0625 or 0.125 cm for a further 6 or 11 weeks. For the 11 week
group, the implant was changed after 6 weeks to maintain steady T
delivery. At the end of Exp 3, mice were killed to harvest testes for
measurement of testis weight, for enumeration of elongated spermatids
by homogenization (n = 4–8 per group) and for stereological
measurements (n = 2–5 per group).
Testicular histology
In each experimental group, 2–5 mice underwent vascular
perfusion fixation by whole body perfusion while anesthetized. Briefly,
30 ml warm physiological saline containing 10 IU/ml heparin (Monoparin,
Australia) was perfused through the left ventricle, while the vena cava
was incised to allow efflux of perfusate. This was followed by 30 ml of
fixative consisting of 2% glutaraldehyde, 2% paraformaldehyde and
0.1% picric acid buffered in 0.2 M sodium phosphate (pH
7.4). After fixation, well-perfused testes were cut into blocks that
were immersed overnight in fixative and then dehydrated in graded
concentrations of ethanol and embedded in Spurr’s resin oriented to
ensure maximal perpendicular orientation of seminiferous tubules to the
cut edge. Semithin (1 micron) sections were cut by an ultramicrotome
(Reichert-Jung, Austria) and stained with 1% toluidine blue.
Stereological estimation
Germ cells were classified into spermatogonia, primary
spermatocytes and round spermatids according to Russell (23).
Corrections were made for shrinkage of tissue during processing as
described previously (12). The numerical density (Nv) of germ cells
(spermatogonia, primary spermatocytes and round spermatids) and Sertoli
cells within the testis was determined from areal density of nuclei
using a Carl Zeiss image analysis system
(Kontron KS400). Nuclear profiles in cross sectional view
from random tubules were traced using a 40x objective to provide mean
area and mean intercept length/chord length for each nucleus. The
number of each germ cell type was quantitated as described previously
(12) according to the de Hoff and Rhines equation (24), with the
assumption that each cell has a single nucleus. The numerical density
was then multiplied by the volume of the testis (determined from
testicular weight and specific gravity, V = Testis weight/specific
gravity) to give absolute number of each germ cell type per testis. The
number of Sertoli cell nuclei per testis was determined as described
previously (12) according to the equation of Zhengwi (25) and
established methods (26). The volume density of tubules in the testis
was derived from tubular area obtained by tracing tubular perimeter
from cross-sectional views using 10x objective. Tubular and luminal
diameters were also determined from perimeter measurements.
Testicular homogenization
Individual testes were weighed, decapsulated and the parenchyma
homogenized (Potter S, Braun, Germany) at maximum speed (1500
rpm) for 1 min in 1–2 ml of homogenizing fluid containing 150
mM sodium chloride, 0.1% (vol/vol) Triton X-100 (22).
Elongated spermatid nuclei resistant to homogenization (steps 14–16)
were counted in hemocytometer chambers. Counts for five chambers were
averaged and the numbers of spermatids expressed per whole testis and
per gram of testis.
Data analysis
Analysis of stereological data were carried out using JMP
statistical software (SAS Institute, Inc., Cary, NC). Data
were expressed as mean and SEM. The presence of
statistically significant differences among the various treatment
groups was determined using one way ANOVA with suitable posthoc
contrasts using SAS software. A P value of <0.05 was taken
to indicate statistical significance and all references to no
quantitative differences being evident imply a P value
>0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, upper panel).
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, lower
panel). This T dose was as effective as a single 1 cm T implant in
maintaining testis weight at 4 weeks (24.2 ± 1.8 vs.
27.2 ± 1.8 mg, P > 0.05). Testis weight was also
not significantly different (P > 0.05) at 6 (29.5
± 2.5 mg) and 11 (24.2 ± 5.4 mg) weeks indicating sustained
maintenance by a T dose of 0.06 cm for up to 11 weeks. For comparison,
testis weight in mature non-hpg mice of the same strain is
96.1 ± 2.4 mg (12).
Testicular histology
Four weeks after removal of the T implant that induced full
spermatogenesis, the histological appearance of the testis of the
androgen withdrawn hpg testis was essentially similar to the
untreated hpg (not shown). Germ cells up to the pachytene
spermatocyte stage were observed but there were no elongated or round
spermatids present in the germinal epithelium. The tubules showed a
marked reduction in diameter and the tubular lumen was absent in all
tubules observed. The stratification of the epithelium appeared
distorted in some tubules with Sertoli cell nuclei positioned randomly
within the epithelium (Fig. 2a).
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, c and d). Replacement with a 1
cm implant (Fig. 2b) produced similar germ cell development with fully
differentiated sperm present.
Stereology
Tubular and luminal diameters. In the maintenance experiment,
tubular diameter (Fig. 3, lower panel) in
the untreated (91 ± 2 microns) was increased to 139 ± 17
microns with 4 weeks of 1 cm T treatment. This increase reflected
mainly the enlargement in lumen diameter (Fig. 3, upper
panel) from 0 in untreated to 49 ± 3 microns in the 1 cm
group. At 4 weeks, even the lowest T dose (0.06 cm) maintained the
tubular (160 ± 0 microns) and luminal (42 ± 6 microns)
diameters at levels comparable with a single 1 cm T implant. The same
low (0.06 cm) T dose maintained tubular and luminal diameters at 6
(159 ± 13, 47 ± 2 microns) and 11 (148 ± 9, 54
± 6 microns) weeks, respectively (all P > 0.05). The
tubular and luminal diameters were similarly maintained by the 0.125 cm
T dose at 6 and 11 weeks (data not shown, P > 0.05).
For comparison, the tubular and luminal diameters of non-hpg
control mice of the same strain was 215 ± 7 microns and 84
± 2 microns, respectively (12).
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). This
was not significantly different from the numbers of round spermatids
produced by the 1 cm implant (8.29 ± 0.33 million/testis).
Primary spermatocyte numbers were moderately increased by T (untreated
1.23 ± 0.31 million/testis, lowest T dose 2.58 ± 0.13
million/testis, highest T dose 3.47 ± 0.33 million/testis).
Spermatogonial numbers were not significantly increased by T (untreated
1.23 ± 0.22 million/testis, lowest T dose 1.05 ± 0.05
million/testis, highest T dose 1.43 ± 0.15 million/testis). The
numbers of Sertoli cells (Fig. 4, inset) was unchanged by T
treatment (untreated 0.69 ± 0.06 million/testis, lowest dose
0.77 ± 0.12 million/testis, highest dose 0.86 ± 0.04
million/testis). The germ cell populations were fully maintained by the
lowest T dose (0.06 cm) at 6 and 11 weeks (Fig. 5) as well as a higher T dose (0.125 cm)
of T (data not shown). For comparison with non-hpg mice of
the same strain, the numbers of spermatogonia, spermatocytes, round
spermatids and Sertoli cells were 1.57 ± 0.05, 6.34 ± 0.3,
17.24 ± 0.9 and 2.66 ± 0.16 million per testis,
respectively (12).
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, upper panel). The ratio of
round spermatids to Sertoli cells is maintained by the lowest T dose
(8.73 ± 1.91) at levels similar to the highest T dose (10.33
± 1.01). No T dose had any significant effect on the ratio of
spermatogonia to Sertoli cells whereas the lowest T dose produced an
increase in the ratio of spermatocytes to Sertoli cells (3.1 ±
0.49 vs. 1.74 + 0.28 in untreated) but this was no different
from the effects of the highest T dose (4.01 ± 0.26). Similar
findings were observed for both lower T doses (0.06, 0.125 cm) at 6 and
11 weeks (data not shown, P > 0.05). For comparison
with non-hpg mice of the same strain, the numbers of
spermatogonia, spermatocytes, round spermatids and Sertoli cells were
0.59 ± 0.15, 2.38 ± 0.25, 6.48 ± 0.70, and 2.66
± 0.16 million per testis, respectively (12).
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, lower panel). T dramatically increased the
ratio of round spermatids to primary spermatocytes reflecting
T-stimulated induction of round spermatid production (0 in untreated
vs. 2.82 ± 0.07 at lowest T dose) and this ratio was
no further increased at the highest T dose (2.62 ± 0.48). Similar
effects were also observed in the ratio of spermatocytes to
spermatogonia, whereby the lowest T dose produced maximal increase in
the ratio. Both lower T doses (0.06, 0.125 cm) maintained the same
ratios at 6 and 11 weeks (data not shown, P >
0.05).
Testicular elongated spermatid counts
The number of homogenization-resistant elongated spermatids at the
end of 6 weeks induction of spermatogenesis by a 1 cm T implant was
0.90 +0.04 million/testis. This declined sharply to 0.14 ± 0.03
million/testis at 2 weeks after T implant removal and at 3 weeks
spermatids were totally absent (Fig. 1a).
The lowest T dose (0.06 cm) produced a significant increase in
homogenization-resistant elongated spermatid numbers (0.47 ± 0.09
million/testis) but a 0.25 cm T implant was required for a maximal
induction of homogenization-resistant elongated spermatids number
(1.73 ± 0.31 million/testis) (Fig. 1b). The number of
homogenization-resistant elongated spermatids maintained by the 0.06 cm
dose at 6 (0.39 ± 0.08 million/testis) and 11 (0.36 ± 0.07
million/testis) weeks as well as the numbers maintained by the 0.125 cm
dose at 6 (0.38 ± 0.08 million/testis) and 11 (0.34 ± 0.05
million/testis) weeks were all closely comparable but had a
nonsignificant trend (P > 0.05) to be maintained at
lower numbers compared with 4 weeks (0.47 ± 0.09 million/testis).
For comparison with non-hpg mice of the same strain, the
numbers of homogenization-resistant elongated spermatids was 13.3
± 0.7 million/testis (12). When the numbers of
homogenization-resistant spermatids were alternatively expressed as
million per mg testis, a similar dose-response to T was observed (data
not shown) and values were not significantly different from
non-hpg mice of the same strain (0.11 ± 0.1 million/mg
testis weight) (12).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, the elongated spermatid population required a somewhat higher T dose (0.25 cm) for full maintenance at 4 weeks, and there was a tendency for lower T doses to be unable to fully sustain the elongated spermatid numbers at longer durations. This high T threshold was still 4-fold lower than required for induction of spermatogenesis. This is consistent with our previous quantitative studies in that the lowest T dose produced 79% of maximal round spermatids but only 17% of maximal elongated spermatids (12). In addition, this is consistent with other evidence that spermiogenic differentiation (round to elongated spermatids) in the rat may have a higher T threshold (32, 33). It is also possible, however, that this apparently higher threshold may be artificially elevated if at lower T doses the elongated spermatid nuclei are less well condensed and being more fragile are less resistant to homogenization. If so, this would result in artefactually lowered estimates of elongated spermatid numbers but direct evidence for this interpretation is lacking. It also cannot be excluded that FSH may influence the quantitative requirement for maintenance of late stage elongated spermatids (34). In this context, it is conceivable that the evidence suggesting that FSH may be an important regulator of meiosis (33) and of testicular seasonality in the hamster (35), may reflect a mechanism whereby FSH increases Sertoli cell sensitivity to testosterone.
This study supports numerous previous observations that T is necessary to maintain mammalian spermatogenesis (2), although the precise dose requirement and mechanism of action remain unclear. Beyond the absolute need for T, this study demonstrates for the first time that, in the absence of FSH, the threshold dose of T required to maintain complete spermatogenesis is much lower than that required to induce it. While many studies have investigated the effect of T on the initiation or reinitiation of spermatogenesis after regression, fewer studies have examined the quantitative requirement for testosterone in maintenance of mammalian spermatogenesis. There appear to be no previous studies examining the hormonal requirements for maintenance of spermatogenesis in the mouse. Previous studies of the maintenance of rat spermatogenesis from a variety of models of gonadotropin deficiency have suggested the androgenic threshold to maintain quantitatively normal spermatogenesis is relatively high. The reason for these discrepancies between studies mainly conducted in the rat and our present findings in the mouse may be more than simply species variation. For such a evolutionarily vital mechanism such as reproduction, major variations in regulation seem inherently unlikely. Other possible reasons for these discrepancies may be differences between the models. For example, none of the other models apart from hypophysectomy eliminate FSH consistently, whereas hypophysectomy removes all other pituitary hormones and many pituitary-dependent growth factors. In particular, administration of T leads to increases in circulating FSH where a state of transient gonadotrophin deficiency has been created in rats with previously normal FSH secretion by GnRH immunization (36) or GnRH analogs (37, 38). Similarly the use of T plus estradiol in SILASTIC brand implants to create gonadotropin deficiency effectively eliminates LH but not FSH secretion (28, 29, 30, 31).
Following the induction of spermatogenesis in the hpg mouse, the removal of T leads to complete loss in the haploid germ cell populations but the premeiotic cells are either little (spermatocytes) or not (spermatogonia) affected. Consistent findings are observed in tfm mice which, despite a complete lack of functioning androgen receptors, maintain early spermatogenesis arrested at the first meiotic division (3) indicating that the early premeiotic stages of spermatogenesis are androgen independent. Because T alone is necessary and sufficient to induce and maintain the haploid germ cell population, we infer there must be an important effect on pachytene spermatocytes that switches on progression to complete meiosis.
The present study confirms that testosterone is not only absolutely required for meiosis and for efficient spermiogenesis, but that once spermatogenesis has been initiated, the T requirement to sustain meiosis is reduced substantially. These differing thresholds for T effects suggests that the mechanism of action of T may be different for induction and maintenance of spermatogenesis. Sertoli cell plays a central role in the structural support and compartmentalization of the germinal epithelium to provide a unique nutritional environment for developing germinal cells (39). Androgen receptors are located on the Sertoli cell (40) where their expression is critical for spermatogenesis, whereas germ cell expression is not (3). Hence the effect of T on completion of meiosis and spermiogenesis are most likely mediated via Sertoli cells despite demonstration of androgen receptors on step XI elongated spermatids (41). A single 0.06 cm T implant can fully maintain differentiated Sertoli cell histology, whereas in our previous initiation study a 1 cm T implant was required for these maturational changes to occur. In contrast, the maintenance of spermatogonia and spermatocytes appears to be independent of T. This suggests that T-dependent Sertoli cell activity must be closely linked to meiotic and post meiotic events in the germinal epithelium. The spermiogenic effects of T could involve enhanced binding by spermatids to Sertoli cells, which prevents their premature detachment from the epithelium (42, 43). Androgen binding protein (ABP) secretion may also be important for the maintenance of step 18–19 spermatids, indicating an indirect mechanism of T on germ cells via Sertoli cell transport of the hormone across the tight junction barrier while bound to ABP (34). The reduced requirement for T during maintenance of spermatogenesis may reflect the requirement of a fully differentiated and functional Sertoli cell in contrast to that of a immature Sertoli cell, which matures during initiation. It is well established that the Sertoli cell undergoes many morphological and functional changes during the initiation of spermatogenesis. For example, cell shape changes to tall columnar with the nucleus becoming irregular and migrating to a basal position in the epithelium (44). Fluid secretion by the Sertoli cell (45) also commences into the tubular lumen and is regulated primarily by androgens (46, 47, 48), whereas FSH has negligible effects (49). In the present study, in the absence of T, tubular lumen diameter decreased and haploid cells are lost but both were maintained with T treatment. This indicates a close functional linkage between T-dependent Sertoli cell secretory activity and the requirements of spermatid maturation and release (50). The molecular basis for this heightened androgen sensitivity is unknown but would be consistent with a increased expression of androgen receptors or their coactivators.
We conclude that the androgenic threshold requirement for maintenance of spermatogenesis in the mouse is much lower than the threshold for full induction of spermatogenesis. This androgenic effect is manifest most directly in the completion of meiosis with secondary and less sensitive effects on the completion of spermiogenesis. The very low androgenic requirement to maintain spermatogenesis has important implications for understanding the hormonal regulation of spermatogenesis.
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Acknowledgments |
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Footnotes |
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Received December 1, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T. R. Pak, G. R. Lynch, D. M. Ziegler, J. B. Lunden, and P.-S. Tsai Disruption of pubertal onset by exogenous testosterone and estrogen in two species of rodents Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E206 - E212. [Abstract] [Full Text] [PDF]
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M. Haywood, N. Tymchenko, J. Spaliviero, A. Koch, M. Jimenez, J. Gromoll, M. Simoni, V. Nordhoff, D. J. Handelsman, and C. M. Allan An Activated Human Follicle-Stimulating Hormone (FSH) Receptor Stimulates FSH-Like Activity in Gonadotropin-Deficient Transgenic Mice Mol. Endocrinol., November 1, 2002; 16(11): 2582 - 2591. [Abstract] [Full Text] [PDF]
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 M. C. Meriggiola, A. Costantino, W. J. Bremner, and A. M. Morselli-Labate Higher Testosterone Dose Impairs Sperm Suppression Induced by a Combined Androgen-Progestin Regimen J Androl, September 1, 2002; 23(5): 684 - 690. [Abstract] [Full Text] [PDF]
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C. M. Allan, M. Haywood, S. Swaraj, J. Spaliviero, A. Koch, M. Jimenez, M. Poutanen, J. Levallet, I. Huhtaniemi, P. Illingworth, et al. A Novel Transgenic Model to Characterize the Specific Effects of Follicle-Stimulating Hormone on Gonadal Physiology in the Absence of Luteinizing Hormone Actions Endocrinology, June 1, 2001; 142(6): 2213 - 2220. [Abstract] [Full Text] [PDF]
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0.25 cm). There was no significant
dose-dependent change in spermatogonial or Sertoli cell numbers.
