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Biology of Reproduction 63, 1637-1641 (2000)
© 2000 Society for the Study of Reproduction, Inc.

Regular Article

Characteristics of Infertility and the Improvement of Fertility by Thyroxine Treatment in Adult Male Hypothyroid rdw Rats1

Jin-Yi Jiang2,a, Motoaki Umezua, and Eimei Satoa

a Laboratory of Animal Reproduction, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan

ABSTRACT

We previously reported that rdw rats were infertile in both sexes. The present study was conducted to determine whether hypothyroidism in adult male rdw rats induced infertility by impairing sexual behavior or testicular function, whether the infertility could be reversed by thyroxine (T4) treatment, and whether the mutant could be produced by infertile rdw rats via in vitro fertilization. The sexual behavior was analyzed by pairing with normal female rats. The fertility of epididymal sperm was determined by in vitro fertilization. The results indicated that the infertility resulted from both defective sexual behavior and testicular function. No untreated rdw rats mated. The weights of epididymides were significantly low, whereas those of testes were not different from those of untreated normal rats. Epididymal sperm with cytoplasmic droplets were observed at a significantly high frequency. No fertilization was detected either in vivo or in vitro. Thyroxine treatment markedly increased serum T4 levels and the weights of both epididymides and testes. Partial reversion of the impaired sexual behavior was observed, and the percentage of epididymal sperm with cytoplasmic droplets was markedly decreased after T4 treatment. Fertility of epididymal sperm was completely reversed when determined both in vivo and in vitro, and homozygous embryos developed to term after transfer without loss of viability.

epididymis, growth factors, IVF/ART, male sexual function, reproductive behavior, sperm, sperm maturation, spermatogenesis, testes

INTRODUCTION

Several investigators have reported studies on the role of thyroid hormones in reproductive tract growth and function. However, the effects of thyroid hormone deficiency on the developing or adult testis, especially as to whether testicular development affects reproductive behavior, are unclear, and contradictory results have been reported not only in different species but also in the same animal model. For example, results of very early studies showed that growth of the testis and epididymis was only slightly reduced in young rats [1], but later results suggested that thyroidectomy in immature male rats caused severe inhibition of gametogenesis and Leydig cell development [2, 3]. In the adult male rat, hypothyroidism induced by thyroidectomy or goitrogen treatment was found not to affect testicular size or seminiferous tubule morphology [4, 5], whereas other reports noted degenerative changes [6]. Hypothyroid (hyt) male mice were infertile in one study [7] but fertile in others [8, 9]. Hypothyroidism had a depressive effect on libido and general animation in stallions [10], but no such effect was observed in hypothyroid male rats [11].

Beamer et al. [7] reported that the infertility of hypothyroid male mice could be reversed by food supplemented with desiccated thyroid powder. Results of recent studies indicated that transient neonatal hypothyroidism results in marked increases of both testicular size and sperm production in the adult rat without loss of sexual behavior [11–13].

Males of a new hypothyroid mutant rat line, rdw, were originally reported to be fertile [14]. However, male rdw rats were later reported to be infertile by other investigators [15–21]. Whether infertility in male rdw rats is the result of impaired testicular function or sexual behavior, whether the infertility can be reversed by thyroxine (T4) treatment, and whether the mutant can be produced from infertile male and female rdw rats by in vitro fertilization are not clear. The purpose of the present study, therefore, was to address these points.

MATERIALS AND METHODS

Animal Preparation

The rdw rats and normal littermates (Wistar-Imamichi) were produced by mating adult F1 male and female rats as reported elsewhere [20]. The mutants were distinguished according to low body weight and retarded development of ears at approximately 2 wk of age. At 40 days of age, the mutant and normal animals were weaned and separated into groups of five animals in each cage. Rats were then subjected to experiments.

Thyroxine Treatment

Male rdw rats were divided into four groups: 1) 5-mo untreated rdw rats (i.e., 5-mo-old rdw rats without T4 treatment), 2) 11-mo untreated rdw rats (i.e., 11-mo-old rdw rats without T4 treatment), 3) 3-mo treated rdw rats (i.e., rdw rats with T4 treatment for 3 mo from 5 mo of age), and 4) 6-mo treated rdw rats (i.e., rdw rats with T4 treatment for 6 mo from 5 mo of age). Normal rats without T4 treatment at 11 mo of age (11-mo untreated normal) or with T4 treatment for 3 mo from 5 mo of age (3-mo treated normal) were used as controls. The T4 (Sigma Chemical Co., St. Louis, MO) was prepared by dissolving in 2 N NaOH and diluted in saline solution (final pH 7.0) to 20 µg/ml. Animals were weighed and T4 administered daily ad libitum in the drinking water and supplemented with T4 solution at a dose of 20 µg per 100 g body weight.

Sexual Behavior Tests

Male rats from each group were tested for sexual behavior based on earlier reports [9, 22, 23]. Female rats at 4 mo of age with normal cycles were used as mating partners. At 1600, each male rat was paired with a female in proestrus and observed in the plastic cage from a lateral viewing position. Mounting, intromission, and ejaculation were defined according to the method described by McGill [24] and recorded within 30 min after introduction of the female. Regardless of sexual behavior, all pairs were maintained until the next day, when smears were checked and eggs collected.

Fertility Examined by In Vivo Fertilization

Female rats were checked for sperm in vaginal smears at 1000 the next morning. All paired female rats were killed by cervical dislocation at 1300–1500. Ovaries and oviducts were transferred into glass dishes (60 x 60 mm in diameter) with medium mR1ECM [25]. Under a microscope, the adjunct fat was removed and the ovary and oviduct separated. Oocytes in mated female rats and oocyte-cumulus cell complexes in unmated female rats were flushed out of oviducts with the medium. The complexes were treated with 0.1% (w/v) hyaluronidase (Sigma). Oocytes were then examined for fertilization under a phase-contrast microscope according to criteria reported elsewhere [26, 27].

Blood Sample, Organ Specimen Collection, and Hormone Analysis

At the end of treatment, animals were anesthetized after measuring their body weight. Blood samples were taken, and serum was collected after centrifugation at 900 x g for 15 min at 4°C and stored at -20°C until examination. The weights of epididymides and testes were measured after removing the surrounding tissues. Total T4 was measured by a solid-phase radioimmunoassay method using a commercially available kit (T-4RIABEAD; Dainabot Co., Ltd., Tokyo, Japan). The intra- and interassay coefficients of variation were 2.5% and 4.0%, respectively. The sensitivity was 0.22 µg per 100 ml. Cross-reactivity with L-triiodothyronine and diiodothyronine were 0.6% and 0.1%, respectively.

Fertility Examined by In Vitro Fertilization

Induction of superovulation in immature rdw and normal rats was performed as described elsewhere [28]. Briefly, rdw rats were administered 10 µg of T4 per 100 g body weight intraperitoneally once daily beginning at postnatal Day 21 and ending at Day 40. Twenty IU of eCG (Sankyo Kabushiki Company, Tokyo, Japan) were subcutaneously administered at Day 38, and 20 IU of hCG (Sankyo Kabushiki Company) were i.p. administered at Day 40 (52 h after the eCG treatment in both rdw and normal rats).

In vitro fertilization was conducted as reported elsewhere [28]. The fertilization medium was mR1ECM containing raised NaCl (100 mmol) and BSA (4 mg/ml; no. A-7638, Fraction V; Sigma) without polyvinyl alcohol [29]. Fertilization and culture media (400 µl each drop) were previously prepared in polystyrene culture dishes (35 x 14 mm; Sumitomo Bakelite Co., Ltd., Tokyo, Japan), covered with paraffin oil (no. 261-17; Nacalai Tesque, Inc., Kyoto, Japan) and equilibrated in a CO2 incubator (5% CO2 in air at 37°C) overnight.

Spermatozoa were obtained from male rats according to the protocol described by Toyoda and Chang [26]. Briefly, one drop of a dense mass of spermatozoa was introduced into pre-equilibrated insemination medium (400 µl). After approximately 5 min of warming in the incubator, 10 to 60 µl of the sperm suspension was transferred into drops of insemination medium in other dishes to give final sperm concentrations of 1 x 106 cells/ml. The number of spermatozoa both having and not having a cytoplasmic droplet were counted under 100x magnification. The diluted sperm suspensions were preincubated for 5 to 7 h in a CO2 incubator.

Thirteen to fourteen hours after hCG injection, animals were killed by cervical dislocation. The oviducts were isolated, placed on a piece of sterilized filter paper to remove the liquid and blood outside, and put into dishes containing diluted sperm suspensions. The cumulus-oocyte complexes in the oviducts were carefully released into the sperm suspensions. The dishes were kept in the CO2 incubator for 16 h.

Embryo culture in vitro Culture and examination of embryo development were conducted according to the method described by Miyoshi et al. [25, 27]. Briefly, 16 h after insemination, eggs were freed from cumulus cells, washed three to six times with culture medium, and observed under a phase-contrast microscope for evidence of fertilization. Ten to twenty eggs with female and male pronuclei with corresponding tails were transferred into 400 µl of culture medium and cultured in the CO2 incubator for 24 h to develop into two-cell embryos.

Embryo transfer The procedures for inducing pseudopregnancy and transfer were basically the same as those described by Jiang et al. [28, 30]. Briefly, 3-mo-old rats (150–200 g) that had shown estrus for at least three consecutive, regular 4-day periods were stimulated by inserting a plastic rod connected to two electrodes (20 V) into the vagina and switching it on and off each for 3 sec, three times on the morning of Day 1. Seven to ten embryos were transferred to the right oviduct of each recipient at Day 1. The number of young born was counted on the day of parturition.

Statistical Analysis

All data were examined by one-way ANOVA. When ANOVA revealed a significant treatment effect, treatments were compared by the Duncan new multiple-range test.

RESULTS

No untreated rdw rats showed mating behavior when paired with proestrous female rats, in which no sperm in vaginal smears and no fertilized eggs were observed. However, all treated rdw male rats mated with female rats, in which 26% to 43% had sperm in vaginal smears. Of the eggs collected from female rats mated with treated rdw and normal male rats, 82% to 86% and 100% were fertilized, respectively (Table 1).


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  		TABLE 1. In vivo fertility of mature male untreated rdw, treated rdw, untreated normal, and treated normal rats

Both body weight and epidididymal weight in 11-mo untreated rdw rats were half or less (48% and 65%, respectively) of those in 11-mo untreated normal rats (P < 0.001), but testicular weight was almost the same between the two groups. The T4 treatment for both 3 and 6 mo markedly increased both epididymal and testicular weight in rdw rats (Table 2).


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  		TABLE 2. Weights (g) of bodies, epididymides, and testes in mature male untreated rdw, treated rdw, untreated normal, and treated normal rats.a

Administration of T4 markedly increased blood T4 levels in 6-mo treated rdw (66.6 ± 5.2 ng/ml) compared with 11-mo untreated normal (32.2 ± 2.6 ng/ml) and 11-mo untreated rdw male rats (8.0 ± 1.0 ng/ml, P < 0.001).

Cytoplasmic droplets were found in 4.4% ± 1.3%, 12.2% ± 4.2%, and 73.0% ± 6.4% of spermatozoa collected from the caudal epididymides from 11-mo untreated normal, 6-mo treated rdw, and 11-mo untreated rdw male rats, respectively (P < 0.01).

After in vitro insemination, no fertilization occurred when spermatozoa from 11-mo untreated rdw male rats were used. However, fertilization rates of 94% and cleavage rates of 97% were obtained with spermatozoa from 6-mo treated rdw male rats, compared with values of 98% and 98%, respectively, for 11-mo untreated normal rats. After transfer, 34% and 44% of embryos derived from 6-mo treated rdw and 11-mo untreated normal male rats developed to term. In addition, the proportion of mutant embryos (52%) derived from mutant male and female rats after T4 treatment that developed to term after transfer was similar to those of other groups (34%–44%) (Table 3).


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  		TABLE 3. In vitro fertilization with epididymal spermatozoa from untreated rdw, treated rdw, and untreated normal rats followed by embryo development in vitro and embryo transfer

DISCUSSION

The results of the present study indicate that the infertility of male rdw rats resulted from impaired sexual behavior and testicular and epididymal functions. Together with previous results, these findings showed that male rdw rats are different from both spontaneous hypothyroid (hyt) mice and chemically induced hypothyroid male rats but are similar to hypothyroid human male children [31]. Male hyt mice showed normal sexual behavior, testicular function, and fertility [8, 9]. Transient neonatal hypothyroidism induced by 6-propyl-2-thiouracil treatment from birth to Day 25 in rats did not impair fertility or alter sperm characteristics when these animals became adults [12]. In contrast, results from several studies indicate that hypothyroidism is associated with diminished libido and impotence in men [32–34]. In the male calf, thyroidectomy results in the complete absence of sexual drive in adulthood, which can be restored by thyroid therapy [35]. Induced hypothyroidism in young stallions has a depressing effect on libido and general animation but can be corrected by thyroprotein supplementation [10]. In the present study, hypothyroidism in male rdw rats might have been at least partially responsible for impaired sexual behavior, which could be partially reversed by T4 treatment. Incomplete reversal of impaired sexual behavior in the mutants may also be attributable to other endocrinological, neurological, anatomical, and genetic factors, as suggested by Chubb and Henry [23] for impotence in the stubby mouse. This evidence suggests that the mutant may also be an animal model for the study of impotence and sexual behavior.

Compared with normal control rats, reduced body weight and unchanged testicular weight of adult male rdw rats could be attributed to the reduced T4 hormone level. Because thyroid hormone is essential for normal postnatal growth and development [12, 36, 37], hypothyroidism is usually associated with impaired growth [38]. Recent in vivo and in vitro observations suggest that thyroid hormones play an important role in testicular development. Transient induction of hypothyroidism during early postnatal life by goitrogen in rats leads to large testicular size with increased sperm production in adult life, indicating that neonatal hypothyroidism affects testicular function [39, 40]. Results of a previous report indicated that severe hypothyroidism in men is associated with testicular atrophy [33]. Hypothyroidism has also been suggested as a cause of male infertility [41, 42]. Juvenile hypothyroidism in boys is frequently associated with a marked increase in testicular size, with impaired spermatogenesis [43], which was also observed in adult male rdw rats during this study.

Beamer et al. [7] reported that the infertility of hypothyroid male mice could be reversed by food supplemented with desiccated thyroid powder. Recent results indicate that transient neonatal hypothyroidism results in marked increases in both testicular size and sperm production in adult rats [11–13]. Results of studies of transient neonatal hypothyroidism in rats suggest that thyroid hormones might normally directly inhibit Sertoli cell proliferation while promoting maturation. Hypothyroidism causes prolonged Sertoli cell proliferation, delayed Sertoli cell maturation, and increased numbers of adult Sertoli cells [44]. The increased Sertoli cell population could also stimulate increased Leydig cell proliferation, and both types of cells could contribute to the increased adult testicular weight and sperm production [45]. For chronic hypothyroidism, methimazole given from birth to adulthood delays the cessation of Sertoli cell proliferative activity. Absence of the differential effect of T3 delays the appearance of the tubular lumen, leading to a reduced final testicular size [31]. In the present study, we found that adult male rdw rats have unchanged testicular weight compared with normal control rats. This finding cannot be explained by the mechanisms of transient or chronic hypothyroidism that is induced chemically, and the precise mechanisms triggering this phenomenon should be investigated in future studies.

Recent studies have demonstrated the presence of high affinity-low capacity thyroid-hormone receptor sites in fetal, neonatal, and, at a lower level, in prepubertal but not in adult testis of the rat. The testes are responsive to thyroid hormone only during a limited period of time coinciding with perinatal and prepubertal stages. The adult male gonad is unresponsive to thyroid hormone [31]. However, in the present study, T4 treatment in adult hypothyroid rdw rats markedly increased testicular weight and epididymal weight. Further investigations are needed to determine whether this increase is a direct effect of thyroid hormone on the maturation of Sertoli cells or is mediated via some other endocrinological factor(s).

The epididymis is the site for storage of spermatozoa, plays an active role in the process of spermatic maturation, and is controlled by the endocrine system [46–49]. The functions of the epididymal epithelium, including absorption, secretion, synthesis, and metabolism, produce an appropriate luminal environment for the acquisition of fertilizing ability and motility of spermatozoa [50, 51]. Results of several studies have shown that hypothyroidism induces epididymal hypofunction associated with decreased sperm motility [52–54]. In the present study, a significantly high percentage of epididymal sperm from male rdw rats contained cytoplasmic droplets and showed complete loss of fertility. After T4 treatment, the maturation and fertility of epididymal sperm were completely restored. The defects of maturation and fertility of epididymal sperm may result from histological and endocrinological hypofunction of the epididymis induced by hypothyroidism, which could eventually impair the fertility of sperm, because clear cells in the epididymal epithelium participate in disposal of the contents of cytoplasmic droplets detached from spermatozoa [55]. Hypothyroidism causes various changes in the lipid composition of the caput and cauda epididymis, and it lowers the quality and quantity of spermatozoa in the cauda epididymis [48, 53, 56]. Results of studies in hypothyroid rams have shown that hypothyroidism results in reduced testosterone secretion by Leydig cells, which alters the androgen-dependent maturation of spermatozoa and decreases spermatozoa motility in the epididymis [52, 57]. Thus, reduced energy production may cause the lack of penetration of the cumulus mass and fertilization.

In conclusion, the results of the present study indicate that the infertility in adult hypothyroid rdw rats was due to defects in both sexual behavior and testicular function. After T4 treatment for 6 mo, partial or complete reversion was observed in impaired sexual behavior and fertility of epididymal sperm. Homozygous embryos developed to term after transfer without loss of viability.

FOOTNOTES

First decision: 10 September 1999.

1 Supported by grants from the Program for Promotion of Basic Research Activities for Innovative Biosciences and the "Research for the Future" Program, the Japan Society for the Promotion of Science (JSPS-RFTF97L00904). Back

2 Correspondence: Jin-Yi Jiang, Laboratory of Animal Reproduction, Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-amamiyamachi, Aoba-ku, Sendai 981-8555, Japan. FAX: 81 22 717 8687; jiang{at}bios.tohoku.ac.jp Back

Accepted: July 13, 2000.

Received: July 30, 1999.

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J.-Y. Jiang and B. K. Tsang
Optimal Conditions for Successful In Vitro Fertilization and Subsequent Embryonic Development in Sprague-Dawley Rats
Biol Reprod, December 1, 2004; 71(6): 1974 - 1979.
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