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Testosterone Suppresses Spermatogenesis in Juvenile Spermatogonial Depletion (jsd ) Mice

^b Department of Urology, Osaka University Medical School, Suita, Osaka 565-0871, Japan ^c Department of Science for Laboratory Animal Experimentation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan ^d Department of Food Science and Nutrition, Mukogawa Women's University, Nishinomiya 663-8558, Japan

ABSTRACT

Male juvenile spermatogonial depletion (jsd/jsd) mice are sterile because of a failure of spermatogonial differentiation. We have previously reported the recovery of spermatogonial differentiation by suppressing the levels of gonadotropins and testosterone with Nal-Glu, a GnRH antagonist. To determine whether suppression of testosterone or the gonadotropins was responsible for spermatogenic recovery, we examined the effect of supplementation of LH or FSH along with Nal-Glu treatment. Systemic administration of flutamide, an androgen receptor antagonist, was also examined. LH supplementation elevated both serum and intratesticular testosterone levels and suppressed the recovery of spermatogonial differentiation in a dose-dependent manner. Supplementation with FSH did not affect either testosterone levels or spermatogonial differentiation. Furthermore, the mice treated with flutamide showed some recovery of spermatogonial differentiation. The overall findings revealed that testosterone action mediated by androgen receptors suppressed the spermatogonial differentiation in jsd/jsd mice and suggested that spermatogonial differentiation in the jsd mutant is highly sensitive to testosterone suppression.

luteinizing hormone, male reproductive tract, spermatogenesis, testosterone

INTRODUCTION

Spermatogenesis in adult male mammals depends on a precise orchestration of spermatogonial cell differentiation, meiosis, and spermiogenesis. These processes are regulated by many growth factors, hormones, and cell-cell interactions of germ cells with Sertoli cells that in turn are regulated by gonadotropins and androgens. Failure of any of these processes leads to male infertility.

Among the animal models for such spermatogenic failure, male mice homozygous for juvenile spermatogonial depletion (jsd) gene experience the first wave of spermatogenesis but fail to maintain spermatogonial differentiation into spermatocytes [1, 2]. Only Sertoli cells and undifferentiated type A spermatogonia are observed in the seminiferous tubules by 8–10 wk of age [2]. The mechanism of spermatogonial arrest in jsd/jsd mice is not well understood, but is thought to involve a defect of spermatogonia, not their supporting cell environment [3, 4]. Many reports have shown that treatment with GnRH analogues protects spermatogenesis against drug or radiation-induced damage in rats [5–7]. Recently, we have reported that treatment with GnRH antagonist has the same effect on genetically infertile mutant jsd/jsd mice [8].

Gonadotropin-releasing hormone antagonist or agonist treatment reduces the serum levels of all the gonadotropins and testosterone, and also the level of intratesticular testosterone (ITT) [9]. However, impairment of spermatogenesis induced by toxic drugs, radiation, or even a mutation such as jsd/jsd is reversed by treatment with GnRH antagonist or agonist. These animal models of damaged spermatogenesis also showed elevated LH, FSH, and ITT levels and normal serum testosterone levels [1, 6–10]. Although the cause of the recovery was ascribed to the suppression of ITT levels [8, 10], this still remains to be proven. To date, only one report has attempted to determine whether suppression of testosterone or gonadotropins is responsible for the recovery of spermatogenesis in the irradiated rat, and the results indicated that ITT levels were mostly correlated with recovery but could not rule out a role for FSH [11]. The present study examined the specific role of gonadotropins, testosterone, and androgen receptor in the suppression of GnRH antagonist-induced spermatogenic recovery in jsd mutant mice.

MATERIALS AND METHODS

Animals

C57BL/6(B6)-jsd/jsd mice, derived from original stocks obtained from Jackson Laboratory (Bar Harbor, ME), were maintained at the laboratory animal facilities of The Research Institute for Microbial Diseases, Osaka University, under standard conditions. B6-jsd/jsd males were identified by scrotal palpation in which their testes were smaller than those of the wild type at 5–7 wk of age. This experiment was approved by the Animal Care Committee of The Research Institute for Microbial Diseases, Osaka University.

Hormone Treatment

The GnRH antagonist Nal-Glu ([AC-D²-Nal¹, D⁴Cl-Phe², D³-Pal³, Arg⁵, D-Glu⁶ (AA), D-Ala¹⁰] GnRH) was supplied by Dr. H.K. Kim of the Contraception and Reproductive Health Branch of NICHD, Rockville, MD. It was dissolved in distilled water and given to mice through miniosmotic pumps (Alzet model 2004; Alza Corporation, Palo Alto, CA) placed under the back skin. The pumps delivered a dose of 2500 µg kg^-1 day^-1 that had previously been reported to stimulate spermatogenesis in jsd/jsd mice [4].

Highly purified human LH (NIDDK-hLH-B-SIAFP2) and recombinant FSH were supplied by Dr. A.F. Parlow of The National Hormone and Pituitary Program (NHPP), Torrance, CA. They were dissolved in saline and given to mice s.c. every 2 days.

Flutamide was given by s.c. implantation of a pellet delivering 1.2 mg/day (Innovative Research of America, Sarasota, FL).

Experimental Design

In a previous report [2], we showed that at 8 wk of age in jsd mutant mice, spermatogenesis was already impaired, so that very few differentiated germ cells remained except for some undifferentiated type A spermatogonia.

The experimental design is summarized in Figure 1.

View larger version (24K): [in this window] [in a new window]   FIG. 1. Experimental design. More than four homozygous male mutant mice (jsd/jsd) were used in each group at the age of 8 wk. Arrows indicate the injection of saline, LH, or FSH as described in Materials and Methods

Controls The control group consisted of five untreated male jsd/jsd mice maintained from 8 to 12 wk of age. At 12 wk, these males were killed by cervical dislocation, and the whole body, bilateral testes, and seminal vesicles were weighed. The left testis was frozen immediately for measurement of ITT. The right testis was used for histological examination.

GnRH antagonist treatment Male jsd/jsd mice (8 wk of age; n = 6) were injected with 0.1 ml of saline (vehicle) every 2 days, and were given Nal-Glu via osmotic pumps delivering 2500 µg kg^-1 day^-1.

LH supplementation Three groups of 8-wk-old jsd/jsd male mice (n = 5/group) receiving Nal-Glu 2500 µg kg^-1 day^-1 were each injected with 1, 5, or 10 IU of LH every 2 days.

FSH supplementation One, 5, or 10 IU of FSH was injected into Nal-Glu-administered jsd/jsd mice every 2 days (four mice per group) as described above for LH supplementation. In the LH-, FSH-, and Nal-Glu-treated groups, the animals were killed 24 h after the last injection of LH, FSH, or saline.

Flutamide treatment To investigate the mechanism of testosterone action on spermatogonial differentiation in jsd/jsd mutant mice, the effect of flutamide, an androgen-receptor antagonist, on spermatogonial differentiation was studied. Five male jsd/jsd mice at 8 wk of age were administered pellets that released flutamide at 1.2 mg/day for 4 wk.

The differences in body weight among experimental groups were not significant at the beginning of the experiment.

Histological Analysis

The right testis was fixed in Bouin solution and embedded in glycol methacrylate (Technovit 8100; Heraeus Kulzer GmbH, Germany). Histological sections were stained with Mayer hematoxylin, and the percentage of differentiated tubules (%dt) was analyzed as described previously [8]. Briefly, all cross sections of the seminiferous tubules were categorized as either differentiated (containing more than two spermatocytes) or not differentiated, and the percentage of differentiated tubules per total number of tubules was calculated. Each value was an average obtained from more than two cross sections of a testis, and more than 100 seminiferous tubules were counted in each section.

Hormone Assays

The left testis was homogenized in 0.5 ml of water using a Teflon homogenizer that was fitted into a microfuge tube chilled in ice. Each sample was centrifuged at 10 000 rpm for 10 min. The supernatant was removed, frozen, and stored until the hormone assay. Blood was collected soon after the mice were killed, and serum prepared from it was frozen and stored until the assay. Serum testosterone and ITT levels were measured by a RIA using a DPC total testosterone kit (Diagnostic Products Co., Los Angeles, CA). The limit of detection of the assay for testosterone was 0.04 ng/ml. Therefore, the limit of detection for ITT was 0.02 ng/whole testis and 2 ng/g-testis when the testicular weight was 10 mg. The accuracy of the assay was confirmed by adding a known amount of testosterone to the samples. Serum LH and FSH levels were measured by RIA using the Biotrak Rat LH (rLH) ¹²⁵I assay system RPA552 and the Biotrak Rat FSH (rFSH) ¹²⁵I assay system RPA550 (Amersham Life Science Ltd., Buckinghamshire, England), respectively. Rat LH and rat FSH were used as the standards for the assays, and the accuracy was confirmed by diluting the samples and adding a known amount of rat LH or rat FSH to the samples, respectively. The limits of detection of the assays for LH and FSH were 0.8 ng/ml and 0.9 ng/ml, respectively.

Statistical Analysis

Data are presented as arithmetic means ± SEM. Statistical analysis was done by Welch t-test to examine the significance of the differences between the groups treated with Nal-Glu alone and the group treated with Nal-Glu in combination with gonadotropin or between the control and the Nal-Glu- or flutamide-treated groups. The Kruskal-Wallis test was also performed to examine the significance of differences between the Nal-Glu- and LH-treated groups or Nal-Glu- and FSH-treated groups, with P < 0.01 considered significant. The correlation between the doses of LH or FSH and %dt was examined by Spearman rank correlation with P < 0.01 considered significant.

RESULTS

Changes in Serum Testosterone and ITT Levels in jsd/jsd Mutant Mice Caused by Treatment with Nal-Glu in Combination with FSH or LH

Both serum testosterone and ITT levels were markedly decreased by the administration of Nal-Glu to the mutant mice (Fig. 2, A and B). The serum testosterone level was decreased to one-third and the ITT level to 1.3% of the control level. The weight of a target organ, the seminal vesicle, was also decreased to 12% of the control level (Fig. 2C).

View larger version (21K): [in this window] [in a new window]   FIG. 2. Hormonal changes caused by the administration of Nal-Glu and gonadotropins. Serum (A) and intratesticular (B) testosterone (ITT) levels and the weight of the seminal vesicle (B) in Nal-Glu- and gonadotropin-treated mice were determined. **P < 0.01, ***P < 0.001 compared to untreated control group. P < 0.05, P < 0.01, P < 0.001 compared to Nal-Glu treated group. •P < 0.05, ••P < 0.01, •••P < 0.001 compared to the different doses of LH

To elucidate further the changes induced by the administration of GnRH antagonist, the effects of gonadotropin supplementation were separately observed with LH or FSH. In the LH-supplemented groups, both serum testosterone and ITT levels increased in a dose-dependent manner (Fig. 2, A and B) (P < 0.01 by Kruskal-Wallis test). The increases in testosterone level were accompanied by the dose-dependent weight gain of the seminal vesicle (Fig. 2C) (P < 0.01 by Kruskal-Wallis test). In contrast, FSH supplementation did not affect serum testosterone, the weight of the seminal vesicle, or the ITT level (Fig. 2, A–C) (not significant by Kruskal-Wallis test).

Effects of Gonadotropin Treatment on the Differentiation of Testicular Germ Cells Induced by GnRH Antagonist Nal-Glu

Only a few differentiating tubules if any were observed in jsd/jsd mutant testes by 12 wk of age (Fig. 3A). The only remaining germ cells in the testis were undifferentiated type A spermatogonia, which accounts for the male infertility of this mutant. Nal-Glu administration to these mutant mice induced spermatogonial differentiation to the spermatocyte stage [8] (Fig. 3B). To determine the mechanism of germ cell differentiation induced by GnRH antagonist treatment, the effect of LH supplementation was analyzed. LH significantly suppressed germ cell differentiation (Fig. 3C) in a dose-dependent manner (Fig. 4) (P < 0.01 by Spearman rank correlation). In contrast, FSH did not affect the Nal-Glu-induced spermatogonial differentiation (Figs. 3D and 4).

View larger version (143K): [in this window] [in a new window]   FIG. 3. Light micrographs of testicular cross sections of jsd/jsd mutant mice (bar = 100 µm). A) At the age of 12 wk, only Sertoli cells and undifferentiated type A spermatogonia were observed in the seminiferous tubules (untreated control). B) Nal-Glu treatment for 4 wk caused restoration of spermatogonial differentiation. C) LH supplementation suppressed the spermatogenic recovery induced by Nal-Glu treatment. D) FSH supplementation had no effect on the spermatogonial differentiation induced by Nal-Glu treatment. Testicular samples were taken from the animals treated with 10 IU of LH (C) or FSH (D)

View larger version (33K): [in this window] [in a new window]   FIG. 4. Histological analyses of testicular germ cell differentiation induced by hormonal treatments. The numbers of differentiated tubules were scored in testicular cross sections and the % of differentiated tubules per total number of tubules was calculated. The average of more than four testes was determined in each experimental group. ***P < 0.001 compared to control group. P < 0.05, P < 0.01 compared to Nal-Glu-treated group. •P < 0.05, ••P < 0.01 compared to different doses of LH

Effect of Antiandrogen Administration on the Differentiation of Testicular Germ Cells in jsd/jsd Mice

Flutamide given by continuous administration also induced spermatogonial differentiation to the spermatocyte stage in 6.0% of the seminiferous tubules (Fig. 5 and Table 1), although the rate of differentiation induction was not as high as in the Nal-Glu-treated group. With flutamide treatment, all of the LH, FSH, serum testosterone, and ITT levels increased (Table 1) as a result of the blockade of the androgen receptor-containing neurons in the hypothalamus [12]. Taken together, these results indicate that the deleterious effect of the jsd mutation on spermatogenesis is caused by a harmful effect of testosterone mediated by the androgen receptor.

View larger version (134K): [in this window] [in a new window]   FIG. 5. Light micrograph of testicular cross section of jsd/jsd mutant treated with flutamide for 4 wk. Spermatogonial differentiation to spermatocytes was observed (bar = 100 µm)

DISCUSSION

We previously reported that GnRH antagonist treatment could induce spermatogenic recovery in jsd/jsd mice [8] just as it can in instances of toxic drug- or radiation-induced testicular damage. However, it was still unclear whether the mechanism of spermatogenic recovery is due to the suppression of testosterone or gonadotropins in these animal models. In this study, we answered this question by observing the effects of administering LH or FSH along with the GnRH antagonist Nal-Glu on spermatogenic recovery in jsd/jsd mice. Treatment with Nal-Glu induced spermatogonial differentiation in 26% of seminiferous tubules (Figs. 3B and 5) as reported previously [8]. Administration of LH along with GnRH antagonist suppressed the spermatogenic recovery in a dose-dependent manner (Fig. 4) by dramatically increasing the serum and testicular testosterone levels (Fig. 2). Supplementation with FSH did not cause any change in either the testosterone level or spermatogonial differentiation in jsd/jsd mice treated with GnRH antagonist (Figs. 2 and 4). Taken together, these data indicate that suppression of LH or testosterone is responsible for the Nal-Glu-mediated spermatogonial differentiation, but suppression of FSH is not. Although it is controversial whether FSH has an effect on spermatogenesis [13–15], Nal-Glu-mediated germ cell differentiation can be demonstrated in animals with low levels of FSH [8]. High levels of FSH did not suppress spermatogonial differentiation in jsd/jsd mice (Fig. 4).

Treatment with flutamide induced spermatogonial differentiation in 6.0% of seminiferous tubules (Table 1), indicating that the inhibition of testosterone action mediated by the androgen receptor induced the spermatogenic recovery in jsd/jsd mice even in a high gonadotropin environment. Thus, intratesticular androgen action mediated by the androgen receptor is one of the major mechanisms of the defect of germ cell differentiation in this mutant.

The cause of deficient spermatogenesis in jsd/jsd mice has been reported to lie in the seminiferous tubules rather than in the extratubular microenvironment [16]. Recently, using the germ cell transplantation technique, the defect was demonstrated to be in the spermatogonia themselves, not in the supporting cell function [3, 4]. Androgen receptor within seminiferous tubules has been detected in nuclei of Sertoli cells but not in spermatogonia [17–19]. Thus, we hypothesize that spermatogonia of jsd/jsd mice show hypersensitivity to some inhibitory factors for differentiation secreted by Sertoli cells in response to androgens in their environment. The alternative explanation is a higher requirement of mutant spermatogonia for the differentiation-inducing factors of Sertoli cells whose production is negatively controlled by intratesticular androgen levels. These hypotheses also explain the observation that germ cells of jsd/jsd mice complete the first wave of spermatogenesis, because the testosterone level is not elevated at the time of the first wave in juvenile mice.

Spermatogonia in untreated jsd/jsd mutant mouse testes were shown to be proliferating actively, whereas some of the spermatogonial clones, especially larger ones, are known to be apoptotic [3, 20]. In irradiated rats, increased proliferation and apoptosis of spermatogonia were also observed. Administration of GnRH antagonist in this animal model caused a decrease in apoptosis and an increase in larger clones of type A_aligned spermatogonia [21]. In wild-type rats, administration of GnRH antagonist instead induced apoptosis in preleptotene, pachytene spermatocytes, and spermatids but had no effect on spermatogonial kinetics [22]. However, when wild-type germ cells were injured by radiation or toxic drugs, they give rise to spermatogonia with impaired ability to differentiate, and suppression of testosterone levels stimulated the recovery of spermatogenesis, just as it does in the jsd/jsd mutant [5–7]. We suggest that a common mechanism of testosterone action plays an important role in the regulation of spermatogonial differentiation, and that the differentiation of jsd mutant germ cells is more sensitive to a high testosterone environment than that of wild-type germ cells. Further investigation of the roles of testosterone in the regulation of spermatogenesis in jsd/jsd mice will contribute to a general understanding of the mechanisms of hormonal regulation of spermatogenesis.

ACKNOWLEDGMENTS

Nal-Glu was synthesized at the Salk Institute (under contract NO1-HD-0-2906 with the National Institutes of Health) and made available by the Contraception and Reproductive Health Branch, Center for Population Research, NICHD. Highly purified hLH (NIDDK-hLH-B-SIAFP2) and rhFSH were obtained through NHPP, NIDDK and Dr. A.F. Parlow.

FOOTNOTES

First decision: 13 February 2001.

¹ Correspondence: Kiyomi Matsumiya, Department of Urology, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. FAX: 81 6 6879 3539; kmatsu{at}uro.med.osaka-u.ac.jp

Accepted: April 3, 2001.

Received: January 22, 2001.

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