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From the * Department of Physiology, Southern
Illinois University School of Medicine, Carbondale, Illinois; the
Instituto Multidisciplinario de Biologia
Celular, La Plata, Argentina; and the Edison
Biotechnology Institute and Biomedical Sciences Department, College of
Osteopathic Medicine, Konneker Research Laboratories, Ohio University, Athens,
Ohio.
| Correspondence to: Dr V. Chandrashekar, Department of Physiology, Life Science II Bldg, Southern Illinois University School of Medicine, Carbondale, IL 62901-6512 (e-mail: shekar{at}siu.edu). |
| Received for publication December 6, 2001; accepted for publication April 12, 2002. |
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Abstract |
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Key words: Sexual development, balanopreputial separation, seminal vesicles, insulin-like growth factor-I, testosterone
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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In experiment I, on days 25, 30, 35, 40, 45, 50, 55, and 60 of age, GHR-KO and normal mice were sacrificed by exposure to CO2; testes, seminal vesicles (SV), and epididymides were dissected from GHR-KO, and their normal siblings (n = 5-9 mice/age group) were weighed. Testes were kept frozen at -20°C for the measurement of intratesticular testosterone levels by radioimmunoassay (RIA). Additional animals were monitored for balanopreputial separation starting at weaning (on day 22 of birth) as described previously (Korenbrot et al, 1977). In experiment II, immature (age = 30 days) GHR-KO mice were treated with either recombinant human IGF-I (1 µg/g BW, subcutaneously, twice a day) or the vehicle. IGF-I (lot U0980102, Intergen Company, Purchase, NY) was dissolved in saline. This IGF-I solution was then mixed with equal amounts of 50% polyvinyl-pyrrolidone in saline and injected subcutaneously, morning and evening, for 5 days. Normal siblings received the vehicle. On day 6, mice (n = 8-10 animals/group) were injected (intraperitoneally) with either saline or ovine luteinizing hormone (NIH-26; 0.3 µg/g BW) and bled 1 hour later under isoflurane anesthesia (AErrane, Baxter, Deerfield, Ill). Our previous studies have shown that this dose of LH induced an increased testosterone secretion in normal mice (Chandrashekar et al, 1991; Chandrashekar and Bartke, 1992). Plasma samples were kept frozen at -20°C until assayed for testosterone by RIA.
Testosterone Assay
Testes obtained from both GHR-KO mice and their normal siblings were
homogenized in ice-cold distilled water, and the homogenates were used to
determine the intratesticular testosterone levels by RIA utilizing the
reagents supplied in an RIA kit (ICN Biomedicals, Costa Mesa, Calif). The
sensitivity of this assay was 5 pg/tube. The intraassay coefficient of
variation was 3.9%.
Plasma testosterone levels were measured by RIA after a standard ether extraction procedure as described previously (Chandrashekar et al, 1988, 1991; Chandrashekar and Bartke, 1992). The testosterone antiserum (GDN-S250) used in the testosterone RIA was kindly donated by Dr G. D. Niswender, and it cross-reacted 1.5% with androstenedione. The sensitivity of this assay was 5 pg/tube. All plasma samples were assayed on the same day using the same-day diluted specific antiserum and the radio-labeled steroid. The mean intraassay coefficient of variation was 4.1%.
Statistical Analyses
Statistical analysis was performed by analysis of variance, followed by
either the Fisher test or the Student Newman-Keuls test. The Student's
t test was used when values of 2 groups were compared. A P
value less than .05 was considered significant.
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Results |
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In all age groups examined, the average testicular weights were also reduced in mice with GHR gene disruption (Figure 2; 25 days, P < .05; 30 days, P < .05; 35 days, P < .001; 40 days, P < .001; 45 days, P < .001; 50 days, P < .001; 55 days, P < .001; and 60 days, P < .001). A significant increase in testicular weight occurred between ages of 35 and 40 days in both normal and GHR-KO males.
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Between 25 and 30 days of age, there were no differences in the absolute weights of SV emptied of their secretions in GHR-KO and normal mice. However, the empty SV weights were significantly (P < .001) lower in GHR gene-disrupted mice than in normal siblings at all other ages examined (Figure 3). In normal males, the SV weights increased between 30 and 35 days of age (P < .05) and again between 35 and 40 days (P < .05) and between 55 and 60 days of age (P < .05). In contrast, in GHR-KO males, the empty SV weight increased only after 35 days of age (P < .05). The age-related pattern of changes in the weight of SV, weighed together with their secretions, was identical to that described for empty SV (data not shown).
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The mean epididymal weights were also significantly lower in GHR-KO mice than in normal siblings (Figure 4; 25 days, P < .05; 30 days, P < .05; 35 days, P < .05; 40 days, P < .05; 45 days, P < .001; 50 days, P < .001; 55 days, P < .001; and 60 days, P < .001). In normal mice, the average epididymal weight increased between 35 and 60 days of age (P < .05). In contrast, in GHR-KO males, epididymal weights increased between 40 and 60 days of age (P < .05).
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Histology of the Testis
Histological cross sections of the testes were examined for the presence of
most advanced germ cells. In normal male mice, elongated spermatids were
detected in 1 of 5 25-day-old animals, in 2 of 6 30-day-old animals, and in
all of 5 animals examined at the age of 35 days. In GHR-KO male mice,
elongated spermatids were absent at the age of 25 days and were detected in 1
of 4 30-day-old and in 2 of 7 35-day-old animals. Starting at 40 days of age,
elongated spermatids were present in the testes of all of the examined normal
and GHR-KO males. Representative cross sections of the testes are shown in
Figure 5. Furthermore, between
ages 40 and 60 days, both normal and GHR-KO siblings had spermatozoa in the
epididymis.
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Balanopreputial Separation
The prepuce could be retracted in the normal siblings at an average of 27.7
plus or minus 0.28 days of age (n = 43). In GHR-KO mice, the balanopreputial
separation was delayed and occurred at 31.9 plus or minus 0.36 days of age,
P less than .05 (n = 24).
Intratesticular Testosterone Levels
The average intratesticular concentrations of testosterone levels (ng/mg
testes) are shown in Figure 6.
The intratesticular testosterone levels were similar in both GHR-KO and normal
mice on days 25 to 55. However, at 60 days of age, the intratesticular
testosterone concentrations were significantly (P < .001) lower in
GHR-KO mice than in normal siblings (Figure
6).
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The total content of testosterone in the testes (ng/2 testes) was similar in GHR-KO and normal siblings between 25 and 45 days, as well as on day 55 of age. However, relative to normal animals, the total testosterone content of testes of GHR-KO mice was significantly reduced at 50 days of age (P < .05) and at 60 days of age (P < .001; Figure 7). A significant increase in total testicular testosterone content was detected in normal mice between the ages of 35 and 40 days (P < .05). In contrast, GHR-KO males failed to exhibit significant age-related changes in the content of testosterone in the testes. The apparent increase between the ages of 40 and 45 days did not reach statistical significance (Figure 7).
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Plasma Testosterone Levels
Basal plasma testosterone levels were similar in both groups of mice. LH
treatment significantly (P < .001) increased plasma testosterone
levels in normal and GHR-KO mice (Figure
8). However, this testosterone response to LH treatment was
attenuated (P < .001) in GHR-KO mice. The plasma testosterone
levels after LH treatment were similar in GHR-KO mice injected with either
IGF-I or the vehicle (data not shown). However, the numerical increase
following LH administration in plasma testosterone levels was greater in
GHR-KO mice previously treated with IGF-I than in GHR-KO mice injected with
the vehicle (a threefold increase in IGF-I-treated mice vs a twofold increase
in vehicle-treated animals).
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Discussion |
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As expected, there was a decrease in BW in GHR-KO mice relative to their normal siblings at the different age groups examined. Although GHR-KO mice secrete large amounts of GH (Zhou et al, 1997) due to the absence of the GHR gene, IGF-I is not secreted; consequently, the somatic growth is reduced. The average testicular weights of GHR-KO mice were also reduced, suggesting that for normal growth of the testes, physiological amounts of GH, GHRs, and IGF-I are required. This finding is consistent with the previous study demonstrating a delay in testicular growth in rats lacking GH secretion (Bartlett, 1990) and in rats immunized against GHRH (Arsenijevic et al, 1989).
It is known that androgens are required for the normal growth of SV and epididymis. The decrease in the weights of these accessory sex organs in GHR-KO mice may be due to a decrease in testosterone production. This decrease is possibly due to the absence of testicular GHRs, which results in a lack of GH action on Leydig cells. It has also been suggested that prolactin (PRL) and GH may exert a direct action on the growth of the SV (Bartke, 1974; Keenan and Thomas, 1975). Our previous studies have shown that GHR-KO mice are hyperprolactinemic (Chandrashekar et al, 1999, 2001a). Despite increased PRL secretion, SV weights were smaller in these mice than in their normal siblings. Therefore, it is reasonable to assume that PRL is unable to exert its anabolic effect on SV in the absence of IGF-I in GHR-KO mice, suggesting that peripheral IGF-I is needed for the normal growth of SV.
The intratesticular testosterone levels were lower in 50- and 60-day-old GHR-KO mice than in normal siblings. The circulating testosterone response to LH treatment was attenuated in 36-day-old GHR gene-disrupted mice, suggesting an impairment of Leydig cell function in these mice. It has been shown that IGF-I augments the effect of gonadotropin treatment on testosterone release by the isolated Leydig cells (Lin et al, 1986; Kasson and Hsueh, 1987). It is also known that providing GH treatment to hypophysectomized rats (Zipf et al, 1978) and gonadally regressed hamsters (Bex et al, 1978) can enhance the LH receptor contents of the testes. In GH-, PRL-, and thyrotropin-deficient Snell dwarf mice, IGF-I treatment increased testicular LH receptors and steroidogenic response (Chatelain et al, 1991). Male mice carrying a null mutation of the IGF-I gene are infertile, and the weights of reproductive organs are reduced (Baker et al, 1996). The volume and number of Leydig cells are significantly reduced in these mice. These previous investigations and results of the present study suggest that IGF-I plays an important role in the regulation of testicular function.
Although the numerical increase following LH administration in plasma testosterone levels was greater in GHR-KO mice previously treated with IGF-I than in GHR-KO mice injected with the vehicle, this testosterone response was not statistically significant. This might have been due to the increase in IGF-binding proteins (IGFBPs), which are known to affect pituitary and testicular functions (Lin et al, 1993; Wang et al, 1994). A large amount of various IGFBP messenger RNA (mRNA) is expressed by the purified rat Leydig cells, and it was shown that IGFBP-3 inhibits Leydig cell steroidogenesis (Lin et al, 1993). In GHR-KO mice, peripheral levels of IGFBP-3 are drastically reduced (Coschigano et al, 2000). Therefore, in the present study, it is possible that IGF-I treatment would have increased IGFBP-3 synthesis within the testis, thus preventing the effect of IGF-I on androgen secretion. Also, it is possible that these animals require higher doses of IGF-I or longer durations of treatment to exert an effect on the testicular endocrine function. Moreover, the alteration in the testicular endocrine function in GHR-KO mice might have been due to the lack of GHRs on the Leydig cells and the consequent absence of GH action.
GHRs were identified in the testes of adult rats
(Lobie et al, 1990; Matsubara et al, 1995) and in
purified cultured rat progenitor (PLC), immature, and adult Leydig cells
(Kanzaki and Morris, 1999). It
has been previously reported that GHRs are absent in the testes of immature
hypophysectomized rats but that the administration of bovine GH increases
testicular IGF-I mRNA levels (Closset et
al, 1989) as well as IGF-I receptors
(Lin et al, 1988), which
suggests an indirect effect of GH on testicular function. However, there are a
number of studies suggesting that GH might have a direct effect on testicular
function. It has been shown that GH alone stimulates testosterone secretion by
the isolated adult rat Leydig cells
(Kanzaki and Morris, 1999), indicating a direct effect of GH on testicular steroidogenesis. The treatment
of rat PLCs with ovine GH, but not PRL, stimulated the steroidogenic acute
regulatory protein and 
5-3ß-hydroxysteroid dehydrogenase
mRNA activity (Kanzaki and Morris,
1999). Since GHR-KO mice lack GH receptor genes, it can be assumed
that the GH receptors are either absent or drastically reduced within the
testis of these animals. In the present study, the delay in balanopreputial
separation, the delayed growth of the accessory sex organs, and the attenuated
testosterone response to LH treatment in GHR-KO mice might also have been due
to the alterations in the number and function of the testicular GHRs in these
mice.
Balanopreputial separation is used as an index for the onset of puberty in the male rat and is androgen sensitive. In the rat, it has been demonstrated that prior to balanopreputial separation, motile sperms appear in caput epididymides, and there were increases in circulating androgen levels (Korenbrot et al, 1977), suggesting that preputial separation is an external sign of puberty. In the present study, there was a significant delay in balanopreputial separation in GHR gene-disrupted mice, indicating that puberty is delayed in these mice. Since we did not detect significant differences in plasma testosterone concentrations between normal and GHR-KO mice, we suspect that IGF-I deficiency might have caused or contributed to the delay of preputial separation.
Although our study of spermatogenesis was limited to identifying the most advanced stages of germ cell development, the absence of elongated spermatids in majority of GHR-KO mice before day 40 indicates that the normal spermatogenesis is delayed in GHR gene-disrupted mice. There is considerable evidence for the importance of FSH and testosterone in the regulation of spermatogenesis (Zirkin et al, 1994; McLachlan, 2000; Krishnamurthy et al, 2001). It has been demonstrated that FSH supports spermatogonial number, prevents the premature death of spermatogonial cells and spermatocytes, and plays an important role in the meiotic division of pachytene spermatocytes to produce round spermatids (Kerr et al, 1992; Russell et al, 1993; McLachlan et al, 1995). Testosterone supports spermatogenesis, particularly the conversion of round spermatids into elongated form (Sun et al, 1990; Cameron and Muffly, 1991; O'Donnell et al, 1994). There are also suggestions that FSH and testosterone act synergistically on spermatogenesis (O'Donnell et al, 1994; McLachlan, 2000). The intratesticular testosterone concentrations were reduced in GHR gene-disrupted mice. Our most recent study has shown that plasma FSH levels were significantly reduced in adult male GHR-KO mice relative to normal siblings (Chandrashekar et al, 2001a). Therefore, it is tempting to speculate that the delayed appearance of advanced germ cells within the testes of GHR-KO mice might have been due to the subnormal synthesis of FSH by the pituitary gland and lower testosterone levels within the testis. The delayed appearance of advanced testicular germ cells in GHR-KO mice observed in the present study was also most likely related to the absence of GH action that results from the lack of GHRs on the Leydig cells. Although the germ cell development is delayed and the fertility is reduced in male GHR-KO mice (Chandrashekar et al, 1999), they are not sterile. This suggests that the low levels of FSH and testosterone secretions, as well as the absence of plasma IGF-I, can delay but not prevent the attainment of sexual maturity in these mice. The reported presence of GH antigens in pituitary cells containing FSH mRNA and GnRH receptors suggests that GH may influence FSH synthesis and secretion (Childs, 2000). Therefore, the absence of GHRs in GHR-KO mice might have contributed to the subnormal FSH secretion in these animals.
In male rats, the suppression of GH secretion resulted in a delay in the normal prepubertal testicular and SV weight increase (Ramaley and Phares, 1983). Also, it has been shown in immature rats that the intracerebroventicular treatment with a specific IGF-I antiserum prior to the initiation of puberty resulted in reductions in testicular weight and circulating LH, FSH, and testosterone levels (Pazos et al, 1999), suggesting that IGF-I might induce changes in pituitary and gonadal functions that lead to the initiation of puberty. Furthermore, the onset of vaginal opening, a sign of sexual maturation, was delayed in female GHR-KO mice and could be advanced by treatment with IGF-I (Danilovich et al, 1999). In the present study, alterations in testicular function, SV weight, germ cell formation, and timing of balanopreputial separation in GHR-KO mice indicate that IGF-I plays an important role in the initiation of male puberty.
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Acknowledgments |
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Footnotes |
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G.-M. Wang, P. J. O'Shaughnessy, C. Chubb, B. Robaire, and M. P. Hardy Effects of Insulin-Like Growth Factor I on Steroidogenic Enzyme Expression Levels in Mouse Leydig Cells Endocrinology, November 1, 2003; 144(11): 5058 - 5064. [Abstract] [Full Text] [PDF]
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