| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Minireview |
Department of Physiology,3 Southern Illinois University School of Medicine, Carbondale, Illinois 62901
Internal Medicine,4 Southern Illinois University School of Medicine, Springfield, Illinois 62794
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONCONSEQUENCES OF GH RESISTANCE...CONSEQUENCES OF ALTERED IGF-I...FUTURE DIRECTIONSREFERENCES |
|---|
growth hormone, neuroendocrinology, ovary, pituitary hormones, testis
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONCONSEQUENCES OF GH RESISTANCE...CONSEQUENCES OF ALTERED IGF-I...FUTURE DIRECTIONSREFERENCES |
|---|
There is considerable evidence that GH as well as systemic and locally produced IGF-I can exert stimulatory, synergistic, or permissive effects at each level of the hypothalamic-pituitary-gonadal axis (HPG), in the reproductive tract, external genitalia, and mammary gland. However, data obtained in transgenic animals overexpressing GH indicate that chronic elevation of GH and IGF-I levels above the normal range can interfere with many aspects of reproduction. Studies in children with congenital GH deficiency or GH resistance and in adults [11, 12] with GH-secreting pituitary tumors [13, 14] indicate that relationships of the somatotropic axis (particularly GH and IGF-I) to reproduction identified in laboratory rodents and domesticated ungulates apply more broadly, including to our own species.
In this article, we will provide a brief overview of the actions of GH/IGF-I on reproduction followed by a more detailed discussion of findings obtained in GH-resistant GHR-KO mice. Data derived from these animals provide some insights into the physiological roles of GH and both GH-dependent and GH-independent IGF-I signaling.
For more detailed presentation of the role of the somatotropic axis and intragonadal IGF-I signaling in reproduction, the reader is referred to several recent reviews [15– 18] and the information is summarized in Figure 1 and in Table 1. Reproductive deficits in transgenic mice overexpressing various GH were discussed in our previous publications [19–22].
|
|
Sites of Action of GH and IGF-I on Reproduction
Analysis of the effects of GH deficiency, GH resistance, suppression of GH release, and GH or IGF-I administration indicates that GH can influence the HPG axis, including gonadotropin release [23–27] and both gametogenic and steroidogenic functions of the gonads [28–32], and that it can influence the selection of the dominant follicle(s) and ovulation [33–35], oocyte maturation [32], sperm motility [36, 37], erectile function [38, 39], fertility [1, 16–18, 40], and lactation [41, 42].
Some of the actions of GH on reproductive processes form the basis for its practical applications. Recombinant bovine GH is very effective in increasing milk yield and is used widely in the U.S. dairy industry [41]. Treatment with recombinant human GH was used with some success to augment the effects of exogenous gonadotropins in female and male patients treated for infertility [43, 44]. Growth hormone treatment of children with GH deficiency promotes sexual development [45, 46].
Distribution of IGF-I receptors in the brain, pituitary, gonads, and reproductive tract [47, 48] reinforces the conclusion that virtually every component of the HPG axis and the reproductive system is a potential target for signals emanating from the somatotropic axis. However, it is important to emphasize that actions of IGF-I at many of these sites represent not only the actions of endocrine GH-dependent IGF-I, which is produced primarily in the liver and reaches its targets via the circulatory system, but also those of locally derived paracrine IGF-I, which may be regulated independently of GH. It is well documented that local production of IGF-I plays an important role in the intricate paracrine control of function of different types of somatic cells in the ovary and in the testis. Studies related to the action of ovarian IGF-I on follicle growth and selection of the dominant follicle [34] clarified many aspects of the role of IGF-I and the IGF binding proteins (IGFBPs) in the control of ovulation. Additional information pertaining to the influence of the IGF-I system in female reproduction will be discussed later in this review.
In the testis, IGF-I is produced by the Sertoli and Leydig cells [49, 50] and plays a role in spermatogenesis and in the control of the endocrine function of the testis. More detailed information related to the role of IGF-I on testicular endocrine function is presented later in this review.
Growth Hormone, Reproductive Development, and Reproductive Aging
The somatotropic axis interacts with the HPG axis in the control of sexual maturation. Data obtained in different species indicate that these actions include stimulatory, synergistic, or permissive effects of GH and IGF-I on the release of GnRH from the hypothalamus [25–27] and gonadotropins from the pituitary [9, 10]; on the level of gonadotropin receptors in the ovarian granulosa cells [35] and testicular Leydig cells [31, 51], on development of the mammary glands [41, 42], and on penile growth [52]. In turn, gonadal steroids promote GH release [53], and GH acts synergistically with sex steroids to promote somatic growth and physical maturation that precede and accompany pubertal development [45, 46]. Influence of the somatotropic axis on the HPG axis almost certainly represents one of the mechanisms linking sexual maturation to nutrition and physical growth. Production of both GH and IGF-I is positively related to energy intake, and sexual maturation appears to be linked more closely with growth than with chronological age. It is known that sexual maturation is delayed in men with Laron syndrome [11, 12]. This clinical syndrome is due to mutated GH receptor genes with subsequent resistance to GH and IGF-I-deficiency. In the female rat, hypothalamic actions of peripherally produced IGF-I have been identified as a signal for puberty [26, 27]. In the immature male rat, GH acts directly (via GH receptors) on Leydig cell progenitors to stimulate activity of enzymes involved in androgen production [54].
Relationships between the somatotropic axis and reproductive aging are very complex and the amount of information pertinent to this issue is limited. Circulating levels of GH and IGF-I decline progressively starting during early adulthood [55], but it is unclear whether the resulting somatopause contributes to the age-related decline in reproductive function. The use of GH replacement therapy in the elderly is a subject of intense current interest. Although most endocrinologists consider the available data to be incomplete and somewhat inconclusive, recombinant human GH, as well as a host of GH-releasing and GH-related products, are aggressively promoted as antiaging agents [55, 56]. Improvements in libido and sexual functioning are frequently listed among the benefits of these therapies. Most of these claims appear to be based on the well-documented beneficial effects of GH therapy in younger adults with severe GH deficiency resulting from development of pituitary tumors or from their treatment. It is presently unclear to what extent data derived from this group of patients can be extrapolated to endocrinologically normal elderly individuals.
In contrast with the role of declining GH in the process of aging, there is evidence that, in GH-deficient and GH-resistant mice, the aging is delayed and life span prolonged [40, 57]. Moreover, transgenic mice overexpressing GH are short-lived and exhibit some symptoms of accelerated aging [1, 58], including early loss of reproductive competence [1, 58]. There is little information on the reproductive aging and reproductive life span in long-lived GH-resistant and GH/IGF-I-deficient mice, and the reported findings are not consistent in aging mutant mice. In IGF-I receptor gene knockout female mice, the life span is extended without an effect on either fertility or reproduction [59]. However, it has been shown that the reproductive senescence is advanced in long-lived IGF-I-deficient female GHR-KO mice [57]. These investigations have also suggested that an effect of aging on reproduction is less severe in male mice than in aging female mice.
|
CONSEQUENCES OF GH RESISTANCE ON FEMALE REPRODUCTIVE FUNCTION: EMPHASIS IN FEMALE GHR-KO MICE |
|---|
|
TOPABSTRACTINTRODUCTIONCONSEQUENCES OF GH RESISTANCE...CONSEQUENCES OF ALTERED IGF-I...FUTURE DIRECTIONSREFERENCES |
|---|
In addition to the indirect effects of GH via IGFs, GH might exert a direct effect on the ovary. GH receptor mRNA expression and GH binding protein (GHBP) have been detected in the ovary of human [67] and in several animal species, including mice [68–74]. A number of in vitro studies have shown that GH can affect oocyte maturation, increase receptors to gonadotropin aiding folliculogenesis [75]. In GH receptor-deficient mice, the reduced ovulation rate, decreased number of antral follicles, and increased number of atretic follicles could not be reversed by IGF-I treatment, suggesting that GH may have a direct effect on the ovary [76]. However, our studies in GHR-KO mice reveal a more indirect action of GH via IGF-I than its direct action on ovarian function [77]. This aspect is detailed in the following section. The possible role of IGF-I in the control of the ovarian function is summarized in Figure 2.
|
Puberty and Sexual Maturation in Female GHR-KO Mice
GHR-KO mice were initially reported to have delayed sexual maturation as evidenced by greater maternal age at first conception in matings between homozygous GHR-KO males and females (–/– x –/–) versus those between homozygous or heterozygous normal animals (+/+ x +/+ or +/– x +/–, respectively) [2]. Vaginal opening, which serves as an external indicator of puberty onset in mice, is delayed by approximately 1 wk in GHR-KO mice as compared with +/+ or +/– females, which do not differ from one another [33]. Administration of human recombinant IGF-I to GHR-KO mice advanced, but did not fully normalize, vaginal opening and increased uterine weight [33]. Treatment with leptin also influenced vaginal opening in GHR-KO mice, either advancing or preventing it, depending on the female's age when treatment was initiated, and coadministration of human recombinant IGF-I blocked leptin's inhibitory effect (Mattison et al., unpublished observation).
In females housed continually in the presence of a normal adult male during the juvenile-to-adult transition period, latency to first mating and the age of the female at first mating were greater in GHR-KO mice than in normal animals, suggesting that later events in sexual maturation (i.e., first ovulation/estrus and/or female receptivity toward the male) were also delayed in GH-insensitive mice [77]. The age of the female at pairing was negatively correlated with latency to first mating only in GHR-KO females, further supporting the existence of developmental delays in these animals. However, under these social/pheromonal conditions, for those females that did conceive, maternal age at first conception did not differ between GHR-KO and normal mice. Not unexpectedly, the tempo of sexual maturation was retarded in both normal and GHR-KO females when reared in the absence of males or male pheromonal influences during the juvenile-to-adult transition period. Interestingly, however, in the absence of male-derived stimuli, GH insensitivity did alter the tempo of female sexual maturation. Maternal age at first conception was significantly greater for GHR-KO mice than for normal females, possibly related to nutritional stress in GH-insensitive mice, as this parameter could be normalized by supplemental feeding ([77], Zaczek et al., unpublished observation). We have preliminary evidence that hypoinsulinemia, secondary to GH resistance, may also contribute to the retardation of sexual maturation in GHR-KO mice [77].
Reproductive Function in Adult Female GHR-KO Mice
In contrast with IGF-I KO mice, which are infertile due to persistent juvenility of the reproductive tract and absence of spontaneous or gonadotropin-induced ovulation [3], the majority of female GHR-KO mice exhibit some level of reproductive competence. In our colony, GHR-KO females generally exhibit one of three patterns of reproductive performance. A small subset of females exhibits near-normal reproductive function except for a reduction in litter size compared with normal females. The majority of females exhibit more compromised reproductive function characterized by multiple reproductive deficits that can include delayed puberty onset/sexual maturation and/or reduced fecundity (due to increased intervals between matings and/or increased incidence of nonfertile matings), and/or reduced litter size. Last, a small subset appears infertile, failing to conceive when housed continuously with and bred repeatedly by males of proven fertility. We suspect that these differences may be related to genetic differences between individual animals in this noninbred population.
Growth hormone receptor gene ablation was shown to affect estrous cyclicity, but the effect was dependent on social/pheromonal conditions. When female mice were housed individually, estrous cycle duration did not differ between normal and GHR-KO mice, with cycles lasting roughly 5 days in both populations [77]. When females were housed in groups, estrous cycle duration increased in both normal and GHR-KO mice, but the effect was significantly more pronounced in GHR-KO animals, possibly due to altered pheromonal sensitivity in these mice [77].
Stress is known to negatively impact ovarian function and reproductive cyclicity in many species [78–80]. Measurements of plasma corticosterone levels in unstressed and stressed GHR-KO and normal female mice at different ages suggest an alternative or additional explanation for the differential effects of housing condition on estrous cycle duration in GHR-KO and normal mice. The GHR gene ablation produces subtle differences in stress response and/or age-related differences in the function of the hypothalamic-pituitary-adrenal axis that could influence estrous cyclicity [81].
Growth hormone insensitivity also impairs the ability of young adult female mice to form functional corpora lutea (CL) of pregnancy [77]. When mated to normal, vasectomized, adult males, pseudopregnancy (defined as intervals of 11 ± 3 days between consecutive vaginal plugs) occurred in all normal female mice observed, in response to every mating [77]. In contrast, pseudopregnancy was consistently established in only 22% of the GHR-KO females, with only 54% of all matings of GHR-KO females resulting in pseudopregnancy. In the GHR-KO population, intervals that failed to meet the definition of pseudopregnancy were shorter than 8 days in duration and generally resembled estrous cycle duration of 4–7 days. Interestingly, however, with time and/or repeated mating, pseudopregnancy was established in GHR-KO females at a frequency comparable with that seen in normal animals [77]. Thus, this particular aspect of the GHR-KO reproductive phenotype is either age-dependent or responds to priming effects of repeated matings that could be mediated by alterations in prolactin (PRL) and/or progesterone release. Our findings in female GHR-KO mice indicated a delay in the onset and in progression of sexual maturation and are consistent with findings in human Laron syndrome patients [82]. This delay might have been due to alterations in the secretions of gonadotropins and PRL [83]. It is possible that, after puberty is established, the majority of female GHR-KO mice do acquire some level of reproductive competence. Thus, the GH resistance in mice has more profound deleterious effects on the pubertal process than on fertility. Similarly, it has been shown that pubertal mechanisms were more profoundly disturbed than was adult reproductive function in human Laron-type dwarfs [82].
Disruption of the GHR gene alters neuroendocrine function related to reproduction in female mice, as it does in males [1, 83]. Although the basal plasma LH levels were similar in estrogen-primed ovariectomized normal and GHR-KO mice, the LH response to GnRH treatment was attenuated in GHR gene-disrupted mice [83]. GHR-KO females exhibited reduced 10-day postovariectomy plasma LH levels and significantly elevated plasma PRL levels [83]. Because male GHR-KO mice are also hyperprolactinemic and exhibit an attenuated LH response to GnRH administration and have reduced levels of testicular LH and PRL receptors [10], it is interesting to speculate that GH receptor gene disruption may similarly alter gonadotropin and PRL receptor levels in female GHR-KO mice. Coitus-induced changes in the pattern of PRL secretion, which lead to morning and afternoon surges of PRL release, are required for formation of functional CL of pregnancy in mice. While the mechanism by which GHR gene ablation impairs formation of a functional CL of pregnancy remains unclear, it is likely related to aberrant hypothalamic secretion of, or gonadal sensitivity to, PRL in GHR-KO mice. Neuronal plasticity, known to be modulated by both GH [84] and IGF-I [85], may also be altered by GHR gene disruption and influence this aspect of reproductive function in GHR-KO mice.
The reduced litter size, which was initially reported by Zhou et al. [2] and has been subsequently confirmed in other studies [33, 86], appears to be the prevailing aberration in reproductive function in adult GHR-KO mice and is influenced by both male and female factors [33, 86]. The number of antral and preovulatory follicles and CL are significantly reduced in ovaries of GHR-KO adult mice [76, 77]. Moreover, the number of uterine blastocyst implantation sites in early pregnancy is also dramatically reduced in GHR gene-disrupted mice [76, 77] and correlates with the number of active CL [77]. Collectively, these findings suggest that reduced ovulation rate, defined as the number of eggs released per cycle, is the main maternal variable related to reduced litter size in GHR-KO mice. The ovulatory response to exogenous gonadotropin treatment is markedly reduced in GHR gene-disrupted mice, although autoradiographic studies failed to detect any clear differences in ovarian LH and FSH binding [76]. Thus, the reduced ovulation rate in GHR-KO mice likely reflects an ovarian defect related to decreases in the number of recruitable follicles and/or impairment of terminal follicular growth and development rather than to a central defect in gonadotropin secretion or differences in ovarian gonadotropin sensitivity. To date, however, differences in ovarian gonadotropin sensitivity due to defects in postreceptor binding events cannot be ruled out.
Gene expression in ovaries collected at estrus was investigated using semiquantitative reverse transcription-polymerase chain reaction analysis. Levels of ovarian mRNA expression for several key steroidogenic enzymes, such as cytochrome P450 side chain cleavage, aromatase, and 
5-3ß-hydroxysteroid dehydrogenase (3ßHSD), were similar in normal and GHR-KO mice, suggesting that the developing follicles in the GHR-KO ovary possess adequate steroidogenic potential [77]. However, plasma estradiol levels at estrus were significantly reduced in GHR-KO mice, most likely a reflection of the reduced number of terminally differentiated follicles within their ovaries [77]. Reports of ovarian IGF-I mRNA expression in GHR-KO mice are equivocal. We reported a 37% reduction in ovarian IGF-I mRNA expression in GHR-KO mice compared with normal females [77], while another investigator found similar levels of ovarian IGF-I mRNA expression in normal and GHR-KO mice [76]. Furthermore, the pattern of IGF-I receptor gene expression in GHR-KO mutants was indistinguishable from normal, wild-type mice [77]. These discrepant findings may be due to differences in the genetic backgrounds of the mice employed in each study or to differences in the stage of the estrous cycle in which the ovaries were collected. Taken together, they suggest that some level of ovarian IGF-I expression occurs independent of GH action, but may be GH responsive and cycle-stage dependent. In rats and pigs, the ovarian IGF-I expression has been reported to be GH responsive [87, 88]. In vitro studies suggest that gonadotropins and estradiol [88] as well as growth factors [89] influence porcine ovarian IGF-I activity and may also be important regulators of GH-independent ovarian IGF-I expression in rodents.
Absence of GH signaling had no overt effects on implantation [76, 77] or fetal wastage during gestation, as the number of resorbing fetuses was similar in GHR-KO and normal females [33]. However, disruption of the GHR gene did affect embryonic and placental development. Reductions in fetal size and weight with concomitant increases in placental size were evident in GHR-KO litters in late pregnancy [days 16–18] and were influenced exclusively by maternal genotype [33, 86]. Accordingly, when females were allowed to go to term, average body weight of live pups at birth was significantly reduced in litters of GHR-KO dams versus those of normal females [33, 86].
Similar to the findings of Zhou et al. [2], we have also noted numerically higher levels of perinatal pup mortality in litters born to GHR-KO versus normal dams, but these differences did not reach statistical significance [77]. Perinatal pup mortality in litters of GHR-KO dams appears to be related, at times, to obstetrical difficulties arising from maternal-fetal size mismatch ([77], Zaczek et al., unpublished observation). In addition, insufficient lactation may contribute to pup mortality due to decreased milk consumption in offspring from some GHR-KO dams [2] and impairment of ductal mammary gland development in virgin GHR-KO mice [90].
|
CONSEQUENCES OF ALTERED IGF-I SECRETION ON MALE REPRODUCTION: EMPHASIS IN MALE GHR-KO MICE |
|---|
|
TOPABSTRACTINTRODUCTIONCONSEQUENCES OF GH RESISTANCE...CONSEQUENCES OF ALTERED IGF-I...FUTURE DIRECTIONSREFERENCES |
|---|
A number of experimental and clinical studies have shown that isolated GH deficiency and GH resistance resulted in delayed puberty and attenuated response to gonadotropin treatment [11, 12, 100]. The important role of IGF-I on Leydig cell steroidogenesis was demonstrated in GH-deficient Snell dwarf mice in which IGF-I treatment increased the number of Leydig cell hCG receptors and the steroidogenic responsiveness to gonadotropin treatment [101]. Similarly, GH treatment to adult GH/IGF-I-deficient Ames dwarf mice increased plasma IGF-I secretion and increased androstenedione and testosterone release from the isolated testis [102]. Recently, it has been shown that the absence of IGF-I in IGF-I null mutant mice resulted in failure of adult Leydig cells to mature, and the reduced steroidogenic capacity of these cells was due to disproportionate mRNA expressions associated with the testosterone biosynthetic enzymes [103]. The treatment with IGF-I antiserum decreased the steroidogenic capacity of rat Leydig cells cultured either alone or with rat Sertoli cells [104].
The in vivo effects of IGF-I on androgen secretion by the testis might be due to its direct action or through its influence on hypothalamic-pituitary function. A number of investigations have suggested a role of GH in pituitary and gonadal functions [9, 10, 17–19, 105–108]. In hypophysectomized rats [31] and in gonadally regressed golden hamsters [109], GH administration resulted in an increase in the LH receptor content of the testes and GH has been shown to enhance the testicular responsiveness to gonadotropin treatment [30]. Furthermore, it has been shown that there is a relationship between somatotrophs and gonadotrophs within the pituitary gland. It has been demonstrated that GH antigens are present in pituitary cells containing FSH or LH mRNAs and in cells containing GnRH receptors, indicating that either GH cells are transitory gonadotrophs or GH is present in these pituitary cells possibly helping to control their function [110, 111]. In addition, GH-binding protein antigens were identified in pituitary cells that contained LH and FSH, indicating a possible paracrine effect of GH on the function of the gonadotrophs [112]. Thus, GH may function as a cogonadotropin [110, 111] and play a role in the control of the neuroendocrine function. Perhaps the somatotrophs under some circumstances may be converted to gonadotrophs. The LH and FSH antigen contents of the GHRH target cells indicate that LHß and FSHß are translated in this population of adenohypophyseal cells [113]. In addition, the pituitary cells with FSH and LH antigens expressed GH mRNA, suggesting that there are multihormonal cells that could produce all three hormones [96]. Furthermore, GHRH target cells contained PRL [114], suggesting that there is a possible functional interrelationship among somatotrophs, gonadotrophs, and lactotrophs.
In mammals, GH-dependent hepatic production of IGF-I might target testis to induce spermatogenesis. It is also possible that IGF-I is formed independently of GH action by the Sertoli and Leydig cells [99] and IGF-I can initiate the process of spermatogenesis. It has been shown that IGF-I treatment increases the motility of spermatozoa [36, 115]. Furthermore, IGF-I gene-deleted male mice are infertile [3]. Similarly, the reproductive function in patients with Laron syndrome is subnormal and it has been demonstrated that administration of IGF-I initiates puberty in these subjects [116], clearly suggesting that IGF-I exerts a profound influence on sexual maturation in the male. The Sertoli, Leydig, and peritubular cells within the testis produce IGFBPs [99]. In the rat testes, IGFBP-2,-3, and -4 mRNAs are identified. The peritubular cells produce IGFBP-2, while the prepubertal Sertoli cells synthesize IGFBP-3 [117, 118]. Purified rat Leydig cells express IGFBP-2, -3, and -4 genes [119]. Also, it was shown that seminiferous tubules expressed low amounts of IGFBP-3. IGFBP-1 is not found in the rat testis [120]. Similarly, human testis is devoid of IGFBP-1 gene expression while mRNA for IGFBP-2 was detected in both Sertoli and Leydig cells [120]. IGFBP-3 was present only in the endothelium of the testicular blood vessels, whereas IGFBP-4 and IGFBP-5 were present in the Leydig cells and the IGFBP-6 gene was expressed in some peritubular cells of the human testis [120]. Although there is a suggestion that IGFBP-3 and IGFBP-4 might inhibit IGF-I-induced testosterone production by the purified Leydig cells [119], the precise role of these binding proteins in testicular growth and in male puberty is unknown. However, it has been shown that neither gene knockout nor overexpression of IGFBP-2, -3, -4, -5, and -6 genes had a substantial effect on male reproduction [121–123]. A recent study in male transgenic mice expressing the IGFBP-1 gene showed reduced spermatogenesis and a reduction in testosterone secretion, suggesting that this IGFBP may have an effect on male fertility [124]. The role of IGF-I in the control of testicular function is summarized in Figure 3.
|
Although it is believed that the action of GH on Leydig cells is via IGF-I, there is evidence to show that GH may act directly on Leydig cells to produce androgens. The GH receptor gene is expressed in progenitor, immature, and adult rat Leydig cells [54], and GH treatment to cultured Leydig cells obtained from adult rats increased testosterone secretion [125]. Additionally, GH treatment increased the steroidogenic acute regulatory protein (StAR) and 3ßHSD gene expressions in rat Leydig cells [54], suggesting direct effects of GH on testicular steroidogenesis.
Although it is known that IGF-II plays an important role in the control of ovarian function in domestic animals [34] and in humans [62], there is very little information available related to its effect on reproduction in rodents. IGF-II was identified in the Leydig cells of rat testes only from Day 1 to Day 11 of birth [126]. This suggests that this peptide may participate in the regression of fetal-type Leydig cells and/or in the proliferation of adult-type Leydig cells. In immature mice, Sertoli cells secrete IGF-II and it may act as a regulator of gene expression in spermatogonia, indicating a role of IGF-II in spermatogenesis [127]. However, IGF-II mRNA was undetectable in ovaries and testes of adult rats [128]. Furthermore, it has been shown that the sexual maturation and fertility are not affected in IGF-II gene-disrupted male mice [129]. These studies suggest that IGF-II may have little or no effect on female and male reproduction in adult mice and rats.
GH-receptor gene knockout mice are IGF-I deficient [9, 10]. Therefore, these GHR-KO mice are good experimental animals to test the role of IGF-I in neuroendocrine and gonadal functions. We have evaluated the status of onset of puberty, pituitary, gonadal functions, and reproduction in male GHR-KO mice.
Puberty and Sexual Maturation in Male GHR-KO Mice
Preputial separation is an external sign of pubertal development in the male rodents [130]. We have shown that the balano-preputial separation was delayed 5 days, and significant increases in the weights of the seminal vesicles occurred later in GHR-KO mice than in normal siblings [8]. The elongated spermatids appeared later in the testes of GHR-KO mice relative to testes of normal siblings. In addition, the weights of testes and epididymii were significantly reduced in GHR-KO mice. The intratesticular testosterone levels and the testosterone response to LH treatment were attenuated in these IGF-I-deficient mice [8]. These results suggest that the absence of IGF-I secretion delays the normal course of sexual maturation in male GHR-KO mice, indicating that IGF-I plays an important role in the initiation of puberty in male mice.
Pituitary-Gonadal Function and Reproduction in Adult Male GHR-KO Mice
In adult male GHR-KO mice, the size of the testes is reduced approximately in proportion to the difference in their body weights between normal and GHR gene-ablated animals [9, 10]. It has been shown by morphometric studies that the length and diameter of seminiferous tubules and the percent of volume density of Leydig cells are reduced in young adult GHR-KO mice [10]. Although the basal plasma LH levels were similar in GHR-KO mice relative to those in their normal siblings, the plasma LH response to GnRH treatment was significantly reduced [9]. In young adult male GHR-KO mice, plasma FSH levels were significantly reduced while plasma PRL levels were elevated [9, 10]. We have also shown that the plasma testosterone response to LH treatment was attenuated in GHR-KO mice, while circulating androstenedione levels were not different than in their normal siblings [9, 10]. This suggests that, within the testes of GHR-KO mice, 17ß-hydroxysteroid dehydrogenase, the key enzyme that converts androstenedione to testosterone, is defective/or less responsive to the exogenous LH. In contrast with GHR-KO mice, in IGF-I gene-disrupted mice, the male sex accessory structures were reduced, these animals were infertile, and the in vitro testosterone response to LH treatment was reduced [3]. However, in GHR-KO mice, fertility is reduced but not totally suppressed [9]. The mechanism responsible for the maintenance of fertility in GHR-KO mice is unknown but it is likely to be related to GH-independent production of IGF-I within the testis. In GH-deficient dwarf rats, GH treatment elevated IGF-I secretion and increased the total number of viable spermatozoa [131], and the neuroendocrine and testicular functions in GHR-KO mice are altered [9, 10]. These studies imply that, whether produced independently or under the influence of GH, IGF-I plays an important role in male reproduction.
Emerging evidence suggest that not all effects of GH are stimulatory and the duration of exposure of the hypothalamo-hypophyseal-gonadal system to GH might have a strong impact on the secretions of gonadotropins and gonadal steroids. It is important to realize that the IGF binding proteins might influence the IGF-I action. Therefore, the ratio of IGF binding proteins and IGF-I within the body might play an important role in action of IGF-I on the neuroendocrine-gonadal system. Recently, we have evaluated the effects of exogenous IGF-I on gonadal function in IGF-I-deficient GHR-KO mice. Acute treatment with IGF-I to GHR-KO mice, unexpectedly, suppressed the LH-induced testosterone secretion in GHR gene-disrupted mice ([132], Chandrashekar et al., unpublished observation). The total testosterone response of the isolated testes of normal siblings to LH treatment was higher than the response of the testes of GHR-KO mice. Incubation of testes of normal mice with IGF-I enhanced the total testosterone release, while the testes of GHR-KO mice were unresponsive to IGF-I treatment. IGF-I did not enhance the LH effect on the total testosterone release. The inhibitory in vivo effect of IGF-I on LH action on testosterone secretion in GHR-KO mice and the increased total testosterone response of isolated testes of normal mice to IGF-I treatment suggest an interference of exogenous IGF-I action in vivo. The differences between the in vivo and in vitro effects of exogenous IGF-I suggest that a proper ratio of IGF-I and IGFBPs might be required for the normal testosterone secretion in GHR-KO mice. It has been shown that the circulating IGFBP-1, 2, and 3 are reduced in GHR-KO mice [133]. It is known that IGF-I increases the synthesis and secretion of IGFBPs and transgenic mice expressing IGFBP-1 gene are infertile [124, 134] and IGFBP-3 inhibits steroidogenesis in the cultured Leydig cells [119]. These observations suggest that IGFBPs may have a role in the action of IGF-I and male reproduction.
In this review, we have attempted to elucidate the importance of the somatotropic system on reproduction. It is obvious that GH, acting directly or indirectly via IGF-I or IGF-II, can influence both female and male reproduction.
|
FUTURE DIRECTIONS |
|---|
|
TOPABSTRACTINTRODUCTIONCONSEQUENCES OF GH RESISTANCE...CONSEQUENCES OF ALTERED IGF-I...FUTURE DIRECTIONSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
2 Correspondence: V. Chandrashekar, Department of Physiology, Life Science II Building, Southern Illinois University School of Medicine, Carbondale, IL 62901-6512. FAX: 618 453 1517; shekar{at}siu.edu
Received: 26 December 2003.
First decision: 16 January 2004.
Accepted: 9 March 2004.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONCONSEQUENCES OF GH RESISTANCE...CONSEQUENCES OF ALTERED IGF-I...FUTURE DIRECTIONSREFERENCES |
|---|
