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Minireview |
a Department of Physiology, Monash University, Victoria 3800, Australia
b Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONNEGATIVE FEEDBACK REGULATION BY...NEGATIVE FEEDBACK BY INHIBINSUMMARYREFERENCES |
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follicle-stimulating hormone, gonadotropin-releasing hormone, inhibin, luteinizing hormone, neuroendocrinology, testosterone
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONNEGATIVE FEEDBACK REGULATION BY...NEGATIVE FEEDBACK BY INHIBINSUMMARYREFERENCES |
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In this minireview, we consider the feedback regulation of the secretion and actions of GnRH in males by testicular steroids and inhibin, and we consider the interactions between the two. Although considerable research has been performed on the interactions of hormones in the hypothalamo-pituitary-testicular axis of male rodents, much of this literature has been inconsistent and has provided conflicting findings [4]. An obvious major limitation of research in human males is the inability to apply invasive experimental approaches. The most definitive studies to establish the interrelationships between hormones within the hypothalamo-pituitary-testicular axis have been conducted with male sheep and rhesus monkeys. Accordingly, we focus on information from these species, and we assess the current state of knowledge regarding feedback regulation of the secretion and actions of GnRH.
Male sheep, unlike male rhesus monkeys, may undergo seasonal changes in the secretion of LH and FSH, primarily because of alterations in photoperiod [10]. These changes are most marked in rams from breeds of sheep that are adapted to life in temperate climates. It has mostly been found that concentrations of LH [11, 12], frequency of LH pulses [11–14], and concentrations of FSH [11, 12] are greater during the breeding season than during the nonbreeding season. These seasonal variations in secretion of the gonadotropins have been observed in castrated rams [10, 15–18], indicating that photoperiod may act directly to affect the activity of the hypothalamo-pituitary unit. Furthermore, indirect affects of photoperiod can alter the feedback actions of testicular hormones [19]. Thus, this species may show differences in the actions of testicular hormones to regulate the secretion and actions of GnRH between the stages of the seasonal breeding cycle. Where appropriate, we have highlighted these differences in this review.
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NEGATIVE FEEDBACK REGULATION BY TESTICULAR STEROIDS |
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TOPABSTRACTINTRODUCTIONNEGATIVE FEEDBACK REGULATION BY...NEGATIVE FEEDBACK BY INHIBINSUMMARYREFERENCES |
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The relationship between GnRH and LH secretion has often been used to draw conclusions about the extent to which testicular steroids act at the level of the hypothalamus or pituitary. Changes in the frequency of LH pulses following treatment with testicular steroids are usually considered to reflect changes in the frequency of GnRH pulses, indicating a hypothalamic site of action. Determining sites of action from changes in the amplitude of LH pulses, however, is not possible, because this could occur from a change in the responsiveness of the pituitary to GnRH and/or to changes in the amplitude of GnRH pulses. Furthermore, assessing pituitary actions on the basis of LH release following an injection of GnRH is not ideal, because the pituitary is still under the influence of endogenous GnRH and because a single dose of GnRH does not reflect the pulsatile nature of GnRH secretion that occurs under physiological conditions. To firmly delineate the extent to which testicular steroids act at the hypothalamus or pituitary, GnRH must be measured in hypophysial portal blood in response to castration and treatment with testicular steroids, and these data must be considered in conjunction with studies that can assess the actions of GnRH directly on the pituitary.
Experimental paradigms that apply a hypophysiotropic clamp have been used in rams and male rhesus monkeys to allow assessment of the direct pituitary action of testicular hormones. In these in vivo models, stimulation of the pituitary gland by endogenous GnRH is removed or absent, and the pattern of secretion of the gonadotropins is controlled by infusion of a fixed dose of GnRH at regular intervals. In rams, the hypothalamo-pituitary disconnection (HPD) model developed by Clarke et al. [20] has been used to examine pituitary actions of testicular hormones [3, 19, 21, 22]. In male rhesus monkeys, two approaches have been used. In one, endogenous GnRH release is abolished by a lesion in the arcuate nucleus of the hypothalamus (i.e., the site of most GnRH neurons in this species), after which pulses of GnRH are infused [23]. Another model is that of the juvenile, in which the secretion of GnRH is interrupted during sexual development [24]. In these models, the direct pituitary actions of various treatments are assessed on the basis of changes in the pattern of secretion of the gonadotropins in response to treatment with GnRH.
In rams, testosterone is capable of decreasing the secretion of GnRH. Following castration of rams, a clear and progressive increase was observed in the frequency of GnRH pulses [1], and treatment of castrated rams with testosterone decreased the frequency of GnRH pulses [2, 3, 25]. This may not involve regulation of GnRH gene expression, because, following treatment of castrated rams with testosterone, the secretion of GnRH [25] and LH [25, 26] was reduced but no effect was observed on the levels of mRNA for GnRH [25, 26]. In contrast to these clear hypothalamic effects, it appears that testosterone does not suppress LH secretion through direct actions on the pituitary in rams. In castrated HPD rams treated with GnRH pulses, treatment with testosterone has repeatedly been shown not to affect the amplitude of LH pulses or the plasma concentrations of LH [3, 19, 22], and these effects are not influenced by the stage of the seasonal breeding cycle [19]. Similar findings have been obtained in castrated rams that were passively immunized against GnRH, treated with testosterone, and then challenged with a GnRH agonist that was not recognized by the injected antibodies [27]. Injection of the agonist when the rams were treated with testosterone always resulted in a clear LH pulse [27]. Despite this, it has been suggested that testosterone can act at the level of the pituitary gland in rams to regulate gonadotropin secretion, and that the extent to which this occurs varies with the stage of the breeding season [28]. These conclusions, however, were based on differences in the amplitude of LH pulses and the ratio of LH to GnRH amplitude during various stages of the breeding season. Because of the various factors that may be involved in such a dynamic, intact system, these data probably are not as definitive as those obtained with the rigid experimental models mentioned above. Because testicular steroids inhibit GnRH secretion but have negligible effects at the level of the pituitary to affect LH secretion, the balance of evidence is that, in rams, the predominant site of action of testicular steroids is within the central nervous system.
Research with male rhesus monkeys also supports the notion that the predominant site of action by testosterone to suppress the secretion of LH is within the central nervous system, although direct measurements of GnRH have not been made. Castration of adult male rhesus monkeys resulted in an increased frequency of LH pulses, and subsequent testosterone treatment corrected this [7]. Furthermore, because castration of adult male rhesus monkeys resulted in increased secretion of LH and GnRH mRNA levels in the mediobasal hypothalamus, the testes may exert an action at the hypothalamus to inhibit GnRH gene expression [29]; this result differs from that obtained in the ram. Use of the hypophysiotropic clamp models has confirmed that testicular steroids do not act at the pituitary gland to suppress secretion of the gonadotropins in male rhesus monkeys. For instance, in hypophysiotropically clamped adult rhesus monkeys, castration resulted in only a small increase in LH pulse amplitude and LH concentrations [23], and passive immunization against estradiol [30] or administration of testosterone at the time of castration did not affect LH secretion [30, 31]. The findings in hypophysiotropically clamped juvenile male rhesus monkeys have been similar, with castration plus treatment with testosterone not affecting LH secretion [24, 32, 33] or steady-state levels of mRNA for the LH-ß and -
subunits [33]. Moreover, when adult male rhesus monkeys were castrated, treated with testosterone, and infused intermittently with GnRH, the circulating concentrations of LH were similar to those normally seen in the hypophysiotropic clamp model following castration [34]. Finally, in cultures of pituitary cells from male rhesus and cynomolgus monkeys, testosterone did not affect basal or GnRH-stimulated secretion of LH or FSH [35]. Thus, it seems that, in monkeys as in rams, the predominant site at which testicular steroids act to regulate the secretion of LH is within the central nervous system, not at the level of the pituitary gland.
Contribution of Testosterone Metabolites to Negative Feedback
Considerable evidence indicates that either androgens or estrogens could mediate the feedback actions of testicular steroids on gonadotropin secretion. Aromatization of testosterone to estradiol-17ß and reduction to 5-dihydrotestosterone occurs in peripheral [36] and central tissues [37, 38]. Furthermore, androgen receptors and estrogen receptors are found in the hypothalamus of males [39], providing the means by which both androgens and estrogens could act. Interestingly, we recently found mRNA for progesterone receptors in the hypothalamus of rams [40], although the physiological relevance of this is unknown. Despite considerable research, the relative importance of the conversion of testosterone to estradiol and dihydrotestosterone to regulate GnRH secretion is unknown.
Estradiol is suggested to mediate the feedback effects of testosterone in rams, because the secretion of LH increases in intact and castrated rams that are passively or actively immunized against estradiol [6] and following administration of an aromatase inhibitor to intact rams [41] and to castrated rams treated with testosterone [6]. Moreover, administration of aromatase inhibitor into the third cerebral ventricle of intact rams increases the frequency of LH pulses but does not affect plasma concentrations of estradiol, which suggests that aromatization of testosterone to estradiol within the brain is important in the feedback regulation of LH secretion [41]. Indeed, in castrated rams, implants of estradiol into the arcuate nucleus/ventromedial region of the hypothalamus decreased the secretion of LH [42, 43], highlighting this region as an important site at which estradiol acts to inhibit the secretion of GnRH. In castrated rams infused with estradiol, however, the mean concentrations of LH and the amplitude of LH pulses were reduced within 4–8 h, but no effect was observed on GnRH levels in hypophysial portal blood [44]. This implicates a pituitary site of action for estradiol, at least in the short term. Nevertheless, when GnRH-pulsed, castrated HPD rams were treated with estradiol or dihydrotestosterone, neither steroid affected the secretion of LH or FSH, suggesting that these steroids have negligible feedback effects at the level of the pituitary gland [3].
Conversion of testosterone to dihydrotestosterone may also be an important step in the negative feedback regulation of gonadotropin secretion in rams. This was exemplified by the increase in plasma LH concentrations following the infusion of a 5-reductase inhibitor into castrated rams that were treated with testosterone; levels were higher than those in animals given testosterone alone but were not higher than those in animals given 5-reductase inhibitor alone [36]. In contrast, neither injection of a 5-reductase inhibitor [45] nor intracerebroventricular infusion of a 5-reductase inhibitor [46] affected plasma LH levels in intact rams, which questions the importance of this pathway. Implants of testosterone [42, 43] or dihydrotestosterone [43] into the preoptic area or arcuate nucleus/ventromedial region of the brain of castrated rams did not suppress the secretion of LH, but these androgens may act at different loci. Notably, to our knowledge, no published reports have described both reductase and aromatase inhibitors being infused into castrated rams treated with testosterone.
Less extensive research has been conducted in male monkeys to establish the extent to which the negative feedback effects of testicular steroids result from androgens or estrogens, although the serum concentrations of LH and the GnRH content of the basal hypothalamus were reduced following administration of either testosterone or estradiol to castrated male rhesus monkeys [47]. Following injection of 3H-testosterone into male monkeys, 3H-estradiol was the predominant steroid that accumulated in hypothalamic nuclei [48]. Also, treatment of castrated male rhesus monkeys with testosterone suppressed LH secretion and increased aromatase activity in specific nuclei of the hypothalamus, whereas 5-reductase activity was not affected in any area [49]. This implies a role for aromatization in the feedback regulation of GnRH secretion. In support of this notion, treatment of adult male rhesus monkeys with aromatase inhibitor stimulated both LH and testosterone secretion [50], whereas, in male cynomolgus monkeys, treatment with aromatase inhibitor resulted in variable increases in LH secretion [51]. On the other hand, different results were obtained in castrated cynomolgus monkeys treated with testosterone; treatment with aromatase inhibitor did not prevent the negative feedback actions of testosterone on LH secretion [51].
Mechanisms of Action by Testosterone at the Hypothalamus
How testosterone and/or its primary metabolites act within the brain to suppress the synthesis and/or secretion of GnRH remains essentially unknown. A small number of GnRH neurons contain estrogen receptor in female rats [52] and progesterone receptors in female guinea pigs [53], but most studies, involving a range of species and both sexes, have demonstrated that GnRH neurons do not contain estrogen receptor [54–57] or estrogen receptor ß [57]. Neither does any substantial evidence exist that the GnRH cells contain androgen receptors [58, 59] or progesterone receptors [60, 61]. It follows, therefore, that the actions of testicular steroids on GnRH neurons must be mediated via neuronal systems that are responsive to steroids and influence the activity of GnRH neurons. These actions could manifest directly on the cell bodies or terminals of GnRH neurons or via interneurons that project or relay to GnRH neurons. Many neuronal systems contain the relevant receptors and, therefore, are potential mediators of steroid action (Fig. 1). Work in both sexes and a variety of species has identified numerous afferent inputs to GnRH neurons, and many of these have the potential to receive and transmit steroidal feedback signals [5, 39, 62, 63]. Nevertheless, the neuronal systems relevant to the negative feedback actions of testicular steroids have not been identified in any species. A common approach to investigating this issue has involved administration, both peripherally and centrally, of agonists and antagonists of various neurotransmitters. The systems that have been investigated in greatest detail include the endogenous opioid peptides, dopamine, and the inhibitory neurotransmitter gamma-amino butyric acid (GABA).
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Evidence indicates that the endogenous opioid peptides may play a role in mediating the negative feedback effects of testosterone in rams. For example, secretion of LH in castrated rams increased following treatment with the opioid antagonist naloxone and decreased following treatment with the opioid agonist morphine [64, 65], and these effects increased in the presence of testosterone [65, 66] or estradiol [67]. Naloxone also increased GnRH secretion to a greater extent in intact than in castrated rams [68]. Some studies have suggested that the role of endogenous opioid peptides in mediating the effects of negative feedback by testosterone in rams is confined to the breeding season [64, 69], whereas others have shown that testosterone reduced LH secretion and the amount of pro-opiomelanocortin (POMC) mRNA in castrated rams during inhibitory [26, 70] but not stimulatory photoperiods [26]. Recently, an increase in GnRH secretion was reported in castrated rams following administration of naloxone in both the presence and absence of testosterone, suggesting that endogenous opioid peptides regulate GnRH secretion but are not the primary mediators of the negative feedback effect of testosterone in the ram [71].
Whether dopaminergic systems are involved in mediating the negative feedback effects of testicular steroids on GnRH secretion in rams is unclear. Lateral ventricular infusion of the dopaminergic D2-receptor antagonist pimozide in the presence and absence of testosterone did not affect the ability of testosterone to suppress LH secretion in castrated rams, suggesting that dopamine does not mediate the negative feedback actions of testicular steroids [72]. Other studies, in which the dopaminergic antagonist sulpiride and the agonist bromocriptine have been administered to rams under stimulatory and inhibitory photoperiods, have suggested that dopaminergic pathways are involved in the inhibitory regulation of gonadotropin secretion in rams during the nonbreeding season [73–75], and recently, it was proposed that the activity of GnRH neurons is influenced by interactions between dopaminergic and opioidergic systems that are modulated by photoperiod [75]. Nonetheless, these studies were not designed to investigate the involvement of dopaminergic systems in the negative feedback actions of testosterone. Indeed, the direct actions of androgens to regulate GnRH secretion are unlikely to be mediated via dopaminergic neurons, because the majority of this cell type in the ram hypothalamus do not contain androgen receptors [58]. This does not exclude the possible involvement of dopamine as an interneuron, however, and whether dopaminergic neurons in the hypothalamus of rams contain estrogen receptors has not been determined.
Although GABA can inhibit GnRH secretion in rams, whether GABA mediates the negative feedback effects of testosterone is, once again, not clear. The secretion of LH was reduced in castrated rams following administration of a GABAA-receptor agonist into the preoptic area and arcuate nucleus/ventromedial region of the hypothalamus, suggesting that GABA may act through the GABAA receptor to suppress GnRH secretion [76]. This finding was supported in a subsequent study, in which, following administration of a GABAA-receptor antagonist into the arcuate nucleus/ventromedial region, LH secretion was increased in castrated rams with and without treatment with testosterone [77].
In male monkeys, the opioidergic and GABA systems may be involved in the negative feedback actions of testicular steroids. The levels of POMC mRNA in the arcuate nucleus of male monkeys were reduced following castration, and treatment with testosterone prevented this [78]. Moreover, the increased secretion of LH and levels of GnRH mRNA in the mediobasal hypothalamus following castration of adult male rhesus monkeys is associated with a decrease in mRNA levels for POMC and GAD65 (i.e., a GABA synthesizing enzyme), whereas no changes in mRNA levels for neuropeptide Y, galanin, and transforming growth factor- were observed [29]. This strongly implicates a role for POMC-derived peptides and GABA, at least in this species. It has not been determined if GABA neurones can directly mediate the effects of testicular steroids on GnRH neurons, because whether GABAergic neurons, in males of any species, contain androgen or estrogen receptors is not known.
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NEGATIVE FEEDBACK BY INHIBIN |
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subunit linked by disulfide bonds to different ß subunits, which are termed ßA and ßB. Thus, inhibin A is a dimeric protein consisting of ßA, whereas inhibin B consists of ßB. The sequences for five distinct ß subunits have been described [79], but only the ßA and ßB subunits have been investigated in the context of feedback regulation of the gonadotropins. The testes are the principal source of circulating inhibin [80, 81], and within the testes, the Sertoli cells are generally agreed to be the predominant site of inhibin production [80, 81]. In male monkeys [82–85] and men [86–88], the principal form of circulating inhibin is inhibin B, and the inverse relationship between circulating inhibin B and FSH suggests that this is the physiologically relevant form involved in the testicular regulation of FSH secretion in these species. Nonetheless, the lack of availability of inhibin B makes it difficult to test this hypothesis. The predominant form of dimeric inhibin in the circulation has not been determined in rams, nor has it been established which form of inhibin is responsible for the negative feedback regulation of FSH secretion in this species. Regulation of FSH Secretion by Inhibin
That testicular steroids do not fully account for the negative feedback regulation of FSH secretion in rams was clearly demonstrated when treatment of castrated rams with a dose of testosterone that resulted in physiological plasma concentrations and normalization of LH secretion only decreased the plasma concentrations of FSH by approximately 15%, well above the concentrations seen in the intact ram [3]. The most compelling evidence that inhibin is an important feedback regulator of FSH secretion in male ungulates has come from experiments in which castrated rams have been administered human recombinant inhibin (hr-inhibin) A. In particular, when castrated rams were infused for 12 h with a dose of hr-inhibin A that resulted in the plasma inhibin concentrations found in intact rams, the plasma concentrations of FSH were reduced to values similar to those found in intact rams [89]. This result was achieved without any effect on LH secretion [89]. Furthermore, administration of hr-inhibin A to castrated HPD rams treated with GnRH pulses suppressed the plasma concentrations of FSH, illustrating that the negative feedback actions of FSH occur at the level of the pituitary gland [19, 21, 22]. A functional inhibin feedback system exists from an early age in rams, because hr-inhibin A can suppress FSH secretion from 1 mo of age, although the pituitary gland was maximally responsive to the actions of inhibin by the time of puberty [90].
In hypophysiotropically clamped adult [23, 30] and juvenile male rhesus monkeys [24], castration resulted in increased plasma concentrations of FSH, and this increase was not overcome by treatment with testosterone [24, 30] or passive immunization against estrogen [30]. Also, when adult male rhesus monkeys with an intact central nervous system were castrated, treated with testosterone, and administered GnRH intermittently, the FSH concentrations increased substantially [34]. Collectively, these studies indicate that testicular steroids are not involved in the feedback regulation of FSH secretion in male monkeys. Subsequently, a series of studies demonstrated without doubt that the principal testicular hormone responsible for feedback regulation of FSH secretion in this species is inhibin. Administration of testosterone and charcoal-extracted porcine follicular fluid as a source of inhibin to hypophysiotropically clamped adult male rhesus monkeys maintained circulating FSH concentrations at the intact level following castration. On the other hand, FSH secretion increased when testosterone was given to animals on this paradigm [31]. Passive immunization against the subunit of human inhibin resulted in increased FSH secretion, with no effect on LH or testosterone, in hypophysiotropically clamped juvenile rhesus monkeys infused intermittently with GnRH [32] and in normal intact male rhesus monkeys [91]. In hypophysiotropically clamped juvenile rhesus monkeys, treatment with hr-inhibin A alone (and in combination with testosterone) held circulating FSH and FSHß mRNA at control levels following castration, whereas testosterone alone did not restrain the postcastration rise in FSH synthesis and secretion [33]. In cultures of pituitary cells from male rhesus and cynomolgus monkeys, purified bovine inhibin suppressed FSH but not LH secretion [35]. Finally, FSH secretion was suppressed in adult male rhesus monkeys that were infused for 4 days with hr-inhibin A [92]. Clearly, in the male rhesus monkey, the feedback regulation of FSH secretion is accounted for exclusively by the direct pituitary actions of inhibin. It is tempting to suggest that this is also the case in human males, but definitive experiments have not been conducted.
Interactions of Inhibin with Testosterone in the Regulation of FSH Secretion in Rams
In rams, unlike monkeys, both inhibin and testosterone can act at the level of the pituitary gland to regulate FSH secretion [19, 21, 22], and these responses are affected by the stage of the breeding season. Plasma concentrations of FSH were reduced in castrated rams by treatment with testosterone during the breeding season [3, 19, 22] but not during the nonbreeding season [19]. These direct actions of testosterone to suppress FSH secretion during the breeding season occurred in castrated rams with an intact hypothalamo-pituitary unit and in those that had undergone HPD, indicating that this effect of season on the direct actions of testosterone occurred, at least in part, at the level of the pituitary gland [19]. During the nonbreeding season, however, the effects of inhibin to suppress FSH were enhanced during treatment with testosterone, suggesting that inhibin and testosterone synergized to negatively regulate the secretion of FSH [19, 21]. The mechanism by which the pituitary could change its responsiveness to the actions of testicular hormones is unknown, but the degree of stimulation of the pituitary by GnRH does not influence the actions of inhibin or testosterone on FSH secretion in rams [22]. Despite the capability of testosterone to suppress the secretion of FSH in rams, the individual actions of inhibin are greater than those of testosterone [13, 21, 22]. Together with the finding that a physiological treatment with inhibin in the absence of testosterone can reduce plasma FSH concentrations to intact levels [89], this firmly suggests that inhibin is the most significant feedback regulator of FSH secretion in rams.
Mechanisms of Action by Inhibin in Males
Inhibin also reduces FSHß mRNA in male rhesus monkeys [33], ewes [93, 94], heifers [95], rats [96], and male hamsters [97]. Nevertheless, the mechanism by which inhibin acts at the pituitary to achieve this and to suppress the secretion of FSH in males is totally unknown. Neither receptors for inhibin nor inhibin-activated signal transduction mechanisms have been identified in any species, although it was recently suggested that specific and high-affinity inhibin receptors exist [98]. It has also been proposed that inhibin antagonizes the actions of activin, a protein with FSH-stimulating effects that is formed from disulfide linking of the various ß subunits contributing to the inhibin molecule [98]. We suggested that inhibin may act to reduce FSHß mRNA through mechanisms separate from those involving transcription of the gene, possibly by influencing factors that interact with the 3'-untranslated region of the FSHß gene to destabilize the FSHß mRNA [80, 93], but this hypothesis has not been fully tested. The relevant form of inhibin in rams may be inhibin B, but we have obtained physiological effects with infusion of inhibin A. This implies that any receptor for inhibin might recognize equally both forms of inhibin. In rams and male rhesus monkeys, it seems to be unlikely that the mechanisms of action of inhibin depend on events that are mediated via GnRH receptors. This notion is supported by the lack of effect of inhibin on LH secretion in most studies in males, and recently, we found that the degree of stimulation of the pituitary by GnRH in rams did not affect the actions of inhibin to suppress FSH secretion [22].
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SUMMARY |
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The feedback regulation of FSH is controlled by inhibin acting exclusively at the pituitary gland, but again, species differences are apparent. In male rhesus monkeys, the physiologically relevant form of inhibin likely is inhibin B, and the feedback regulation of FSH likely is accounted for completely by the actions of inhibin. In rams, the physiologically relevant form of inhibin has not been identified, and the feedback regulation of FSH is more complex, involving interactions between inhibin and testosterone and, in some circumstances, direct actions of testosterone. Despite the participation of testosterone in the feedback regulation of FSH secretion in rams, inhibin is more potent than testosterone in suppressing FSH secretion. Finally, the mechanisms by which inhibin acts at the level of the pituitary gland to regulate FSH secretion are unknown.
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FOOTNOTES |
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1 Correspondence: Alan J. Tilbrook, Department of Physiology, P.O. Box 13F, Monash University, Victoria 3800, Australia. FAX: 61 3 9905 2547; alan.tilbrook{at}med.monash.edu.au 
Accepted: October 6, 2000.
Received: July 20, 2000.
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