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The Clayton Foundation Laboratories for Peptide Biology (S.L., C.R.), The Salk Institute, La Jolla, California 92037; and School of Veterinary Medicine (R.M.), University of Pennsylvania, Philadelphia, Pennsylvania
Address all correspondence and requests for reprints to: Catherine Rivier, Ph.D., The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: crivier{at}salk.edu.
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Introduction |
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We recently made the unexpected discovery that testicular responsiveness to human chorionic gonadotropin (hCG) was significantly blunted by the intracerebroventricular (icv) injection of catecholamines or treatments that release catecholamines, such as CRF and IL-1ß. This effect, which resulted from decreased testicular levels of the steroidogenic acute regulatory protein that regulates T biosynthesis (21), occurred within minutes and did not depend on circulating LH because it was comparable in rats in which the release of this hormone had been blocked with a potent LHRH antagonist, and in animals pretreated with the vehicle. It is also present in adrenalectomized rats, indicating that it is not mediated by glucocorticoids. In addition, we showed that prolactin or other peripheral signals were not involved in this phenomenon (7, 22). Finally, there is evidence that sympathetically mediated increases in vasoconstriction that would restrict gonadotropin access to and/or T release from the testes, do not play an important role in our model (7, 22). Briefly, histological evaluation of the testes of rats injected with IL-1ß or CRF icv failed to indicate signs of decreased vascularization (21). Second, reductions in blood flow induced by testicular nerve stimulation, for example, are under the control of 
-, not ß-, adrenergic pathways (6). In our model, however, only the ß-adrenergic antagonist propranolol, whether injected systemically or icv, reversed the effect of icv IL-1ß on the T response to hCG (7). This finding is not consistent with an important modulating influence of vascular events in testicular vascularization. Finally, as mentioned above, the icv injection of IL-1ß decreased testicular levels of the steroidogenic acute regulatory protein, but not of other steroidogenic enzymes (21). The presence of a specific enzymatic defect at the exclusion of others, and its persistence once Leydig cells had been removed from the animals, point to a mechanism that is distinct from a nonspecific influence of vasoconstriction. Collectively, our findings led us to propose the existence of a descending neural pathway between the brain and the testes, that controlled Leydig cell activity independently of the pituitary and/or of the direct gonadal influence of stress-induced factors. However, although our studies supported the concept of the existence of this circuit, they did not demonstrate it.
In the rat, sympathetic fibers are critical for maintaining testicular responsiveness to LH-like molecules, and surgical transection of the superior spermatic nerves or their anesthesia by the local application of lidocaine lowers Leydig cell LH receptors and interferes with hCG-induced T release (4, 21). Consequently, severing these fibers did not represent a viable approach for determining whether the known testicular innervation (i.e. pelvic) was important for the inhibitory effect of icv IL-1ß, CRF, or adrenergic agonists. We therefore decided to map the proposed neuronal circuit with a retrograde tracer injected into the testis and seek evidence that this pathway modulated the inhibitory influence of specific brain signals on Leydig cell activity. We used the transneuronal labeling technique based on pseudorabies virus (PRV), an extremely powerful neuroanatomical tool that allows the identification of hierarchical chains of central neurons innervating a central nervous system cell group or a specific end-organ. This technique, which has been used to delineate the brain areas involved in the somatic and/or motor control of the adrenals, bladder, pancreas, heart, and ovaries (23, 24, 25, 26, 27), among others, relies on the injection of PRV into the peripheral structure of interest. This is followed by replication of viruses that are transported retrogradely through ascending chains of synaptically connected neurons (28). Immunohistochemical procedures are then used to label brain neurons that have become infected and that represent the origin of a particular autonomic outflow to the periphery. The brain PRV labeling we observed in intact rats injected with PRV intratesticularly agreed with a recent report published while our experiments were in progress (29), but it also indicated that hypothalamic staining, in particular, was similar to that reported following PRV injection in a variety of visceral organs (see, for example, Refs. 23, 24, 25, 26, 27). This similarity has been attributed, at least in part, to the fact that the hypothalamus represents an important component of the vascular and/or sympathetic control of these organs. A compounding problem of our studies, also encountered by Gerendai et al. (29), was that possibly due to the sparse innervation of the rat testis, we had to inject large quantities of PRV. We knew that, regardless of the precautions we took for preventing virus leakage into the abdominal cavity, this leakage might still take place. We therefore also determined the functional importance of the proposed pathway by comparing the inhibitory effect of icv injected IL-1ß or CRF on the T response to hCG in intact rats and rats with spinal cord injury (SCI).
The results presented here, showing that testicular activity is controlled by a brain-testicular pathway, will now allow studies of the respective role of decreased LH release, of changes in circulating and/or intratesticular factors, and of stimulation of the proposed neural circuit, in modulating the influence of specific stressors on Leydig cell activity. We propose that the rapidity with which stimulation of this pathway inhibits androgen production (7) may provide a fine-tuned, minute-to-minute regulation of testicular responsiveness to LH that is not possible through slower pituitary-based or other mechanisms. Our results may also provide the basis for testing hypotheses related to the role, hitherto unsuspected, that the proposed brain-testicular circuit plays in a variety of experimental and clinical situations. Finally, our findings may be useful for developing therapies for a variety of pathologies, including those associated with abnormally elevated catecholamines levels in the brain, when a primary Leydig cell defect of unknown origin induces a catabolic state that contributes to a poor prognosis (19).
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Materials and Methods |
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Surgery
SCI. Spinal cord transections were performed under anesthesia using well-established procedures (see, for example, Ref. 30). Under an operating microscope, surgical exposure of T7-T8 vertebrae was done by laminectomy after opening and lateral reflection of the dura (see, for example, Ref. 31). These vertebrae were removed, and the spinal cord was completely transected. The space between the retracted ends of the spinal cord was packed with Gelfoam (Pharmacia, Kalamazoo, MN), and the incision was sutured. Sham-operated rats underwent the same procedures but did not have their cord severed. After surgery, all animals were given the antibiotic Sulfatrim Pediatrics (Alpharma, Baltimore, MD) in the drinking water. Food was placed on the bottom of the cages, and the rats had access to water bottles with long sippers. Bladders were emptied manually three to four times daily for 10 d, at which time the rats started to exhibit a micturition reflex at the spinal level that is characteristic of this species (32). The animals showed the expected paralysis of their hind limbs, but nevertheless quickly acquired a significant degree of locomotion.
Intracerebroventricular and iv surgeries. Intracerebroventricular cannulae were inserted in the left lateral ventricle of rats anesthetized by sc injections of a mixture of ketamine (100 mg/kg)/acepromazine (4 mg/kg)/xylazine (10 mg/kg). Intravenous cannulae were inserted in the jugular vein under isoflurane anesthesia 2–3 d before the assay (7, 22). Intracerebroventricular cannulae placement was verified at the end of each experiment by inspection of brain coronal sections following icv injection of dye and only rats with correct placement were included in the analysis of the data.
Protocol
On the day of the experiment, the animals were removed to a sound-proof room and singly housed in opaque buckets. Blood samples (0.3 ml) were taken through the iv cannula before hCG injection as well as at the times indicated on the figures. They were immediately replaced with an equivalent volume of apyrogenic isotonic saline. In our hands, this procedure does not alter neuroendocrine function, including T release, whereas heterologous replacement with donors’ red blood cells does (Rivier, C., unpublished data). Blood was drawn into tubes that contained EDTA (10 µl of a 60-mg/ml solution). Intracerebroventricular treatments (dissolved in apyrogenic water) were injected in 5-µl volumes at doses we previously showed to be active (7, 22). hCG was injected iv 15–30 min after icv treatments. Control rats were injected with the appropriate vehicle.
Plasma T measurement
T levels were measured in duplicate 50 µl unextracted plasma with a kit purchased from Diagnostic Products (Los Angeles, CA) (22).
Reagents
PRV (Bartha strain) was prepared as previously described (28, 33, 34), and fresh aliquots of the stock (made at 1 x 108 plaque-forming units/ml) were thawed immediately before injection. hCG was purchased from Sigma (St. Louis, MO). Rat/human (r/h) CRF was synthesized by solid phase methodology and generously provided by Dr. Jean Rivier (The Salk Institute). Recombinant human (rh) IL-1ß was generously provided by Otsuka Pharmaceutical Co. (Tokushima, Japan). The choice of the doses of icv injected CRF (3 µg) or IL-1ß (80 ng) was based on our previous studies (7, 22). Intracerebroventricular treatments were dissolved in apyrogenic water and slowly infused in 5-µl volumes.
PRV injections
PRV injections were performed in a Biosafety level 2 containment facility at The Salk Institute, and standard safety procedures were followed (see Ref. 33). The rats were anesthetized with ketamine (100 mg/kg)/acepromazine (4 mg/kg)/xylazine (10 mg/kg). A microsyringe containing PRV was slowly inserted approximately 2/3 into the gonad, where a first delivery of the virus was made (30–50 µl). The syringe was then slowly pulled back until it was located approximately in the center, then in the lower 1/3 portion of the gland, and a second and third injection were made at these sites. The syringe was maintained in placed for 2 min after the last injection and withdrawn under a dry cotton-tipped stick to absorb reflux and prevent spilling of the virus outside the gland. The scrotal membrane was sutured and the animals recovered from the procedure uneventfully. The animals were given a normal diet of rat chow and water ad libitum and kept on a 12-h light, 12-h dark schedule (lights on at 0600 h). The animals showed no sign of viremia until they were killed up to 12 d later and, when present, signs of illness were limited to a somewhat sluggish behavior.
Tissue collection
The rats were killed by an overdose of chloral hydrate followed by transcardial perfusion with saline followed by 4% paraformaldehyde/0.1 M borate buffer, pH 9.5. Spinal cords were divided into portions containing segments C1–C4, C5–C8, T1–T5, T6–T9, T10–T13, and L1–L5. Brains were cut in the coronal plane at 30-µm thickness. Every third brain stem, spinal cord, and brain section was incubated in rabbit polyclonal antiserum generated against acetone-inactivated PRV (for a detailed description of the methodology, see Refs. 28, 33 , and 34). For negative controls, we determined that sections in which the primary antibody was replaced by the buffer, were negative. The number of PRV-labeled neurons in the brain were counted bilaterally from three to five sections spaced at 50- to 200-µm intervals, depending on the tissue (35), with a Leitz (Wetzlar, Germany) optical system coupled to a Macintosh computer.
Immunocytochemistry
PRV-positive cells were detected with a polyvalent antiserum generated against the entire virion (Rb134) and a goat monospecific, polyvalent antiserum (g282) generated against gIII, the major envelope glycoprotein of PRV (28, 33, 34).
Statistical analysis
Results were first analyzed using ANOVA with repeated measures, followed by comparison of individual time points employing Student’s t test or Bonferroni/Dunn. In all cases, a difference was considered statistically significant if it reached the P < 0.01 level.
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, left panel). Administration of smaller volumes did not lead to any detectable staining except for a few scattered labeled cells in the spinal cord (data not shown).
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, right panel). SCI rats did not have any viral particles at the T5 levels (i.e. above cord transection), in the substantia nigra, in the NTS or in the cortex, whereas many labeled cells were observed in sham-operated animals (see Fig. 1, left panel). Following SCI, the only brain area where we found PRV-labeled cells was the PVN (Fig. 1, right panel). Even though the number of these cells was significantly (P < 0.01) lower compared with sham-operated animals, a small number of virus-positive neurons remained detectable. In view of this residual PVN staining, we considered the possibility that, despite the precautions we had taken, some viral particles might have leaked to the abdominal cavity and were taken-up by visceral organs associated with PVN staining (23, 24, 25). We therefore placed 3 or 15 µl PRV on the surface of the testis of spine-intact rats and processed the brains as described above. PVN PRV-positive cells were only observed in the PVN (as well as the rest of the brain) of rats injected with 15, but not 3 µl PRV (results not shown). In view of the stringent precautions we used to prevent leakage, it is highly unlikely that even 3 µl PRV might have escaped from the testis. These results therefore indicate that, even when the spine is intact, the injection of a volume of PRV significantly larger than the one that might be expected to leak out of the testis, did not result in PVN staining.
Consequence of severing the spinal cord on the inhibitory effect of icv-injected IL-1ß or CRF on the T response to hCG
In view of the possibility that SCI might interfere with the T response to hCG (4, 21), we first developed dose-response curves in intact and SCI animals to determine the hCG doses that would be used in subsequent studies. We conducted preliminary experiments in which we examined the ability of the icv injection of IL-1ß to block the T response of spine-intact rats to escalating doses of hCG (36). On the basis of these results, most subsequent studies were conducted with 1–5 U/kg hCG dose (7, 22, 37), which served as a guideline for the present studies. As we (7, 22) and others (38, 39) had previously reported, basal T levels were significantly (P < 0.01) lower in SCI rats, compared with controls (Fig. 2). Both groups of animals displayed dose-related increases in plasma T levels when injected with hCG, though the absence of the spinal cord significantly (P < 0.01) decreased this response. In the next set of experiments, we investigated the influence of the icv injection of r/hCRF (3 µg) or rhIL-1ß (80 ng) to decrease the T response to hCG when injected 30 min before the gonadotropin. Because of the low T response of SCI rats to 1 U hCG/kg (see Fig. 2), most of the comparisons between intact and SCI rats were done by injecting them with 1 or 5 U hCG/kg, respectively. As illustrated in Fig. 3, basal T levels of spine-intact slightly but significantly (P < 0.05) decreased in response to the icv injection of IL-1ß or CRF (ng testosterone/ml: icv vehicle = 1.45 ± 0.33; icv IL-1ß = 1.19 ± 0.11; icv CRF = 1.16 ± 0.17). Probably because basal T levels of SCI rats were already so low, no further reduction was seen. The icv injection of IL-1ß or CRF induced the expected (7, 22) inhibitory influence in rats with an intact spinal cord, but this phenomenon completely disappeared in SCI rats (Fig. 3). As the possibility remained that the lack of effectiveness of icv-injected IL-1ß or CRF in SCI rats might be due to the inability of these treatments to overcome the stimulatory influence of a large dose of hCG, we also conducted an experiment in which IL-1ß or its vehicle was injected icv to SCI subsequently treated with 1 U/kg hCG. As expected, the T response of these animals was low, but it was nevertheless statistically comparable following icv injection of the vehicle (6.24 ± 0.79 ng testosterone/ml) or 80 ng IL-1ß (5.95 ± 0.61 ng testosterone/ml; P > 0.05). Collectively, these results indicate that the lack of effect of icv IL-1ß or CRF in SCI rats is not related to the dose of hCG.
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One difficulty of using PRV is that if one administers large volumes of the virus, some particles may leak into the abdominal cavity and result in labeling of neural circuitries regulating blood flow to visceral tissues, rather than that specific to the organ of interest (26, 44). In our case, this might make it difficult to distinguish between areas involved in the autonomic/vascular control of the testes and those specifically involved in the regulation of Leydig cell activity, which is indeed a problem widely recognized even in experiments that only rely on small quantities of the virus (see, for example, Ref. 28). However, when we used a classical protocol (i.e. <5–10 µl PRV), we were unable to detect any central nervous system labeling. In contrast, the intratesticular injection of 100–150 µl PRV caused detectable viral staining in the cord, the brain stem, and the diencephalon. This observation agrees with another report showing that similarly large quantities of PRV had to be injected into the testis to cause consistent brain labeling (27, 29). Despite these large volumes, the brain PRV labeling we (present work) and others (27, 29) observed following testicular injection of the virus was significantly less intense than that reported after injection of smaller quantities into other organs (see, for example, Refs. 23, 24, 25, 26, 27). This probably results from the low number of nerve terminals present in the rat testicular capsule (5). This sparse innervation also led to the significantly longer amount of time (minimum 4 d), compared with labeling originating from structures such as the adrenals, the ovaries, the heart, and the bladder, that was necessary until the first observation of labeled neurons could be made (present work and Ref. 27). In PRV studies, the time-course of brain labeling is considered to provide important clues regarding the areas most likely to represent the origin of the proposed pathway between a peripheral organ and the brain, and indeed Card and colleagues (45) reported a significant correlation between the magnitude of the infection of transynaptically connected neurons and the density of nerve terminals in the infected area . In our studies as well as those of Gerendai et al. (29), the hypothalamus showed labeled neurons before other structures such as the frontal cortex, the amygdala, or the bed nucleus of the stria terminalis. We therefore assume that the virus traveled from the diencephalon to the cortex.
Informative as these results are, it was apparent that the areas that were found to be viral positive were also those that become labeled after PRV injection into most visceral organs (see, for example, Refs. 23, 24, 25). As mentioned above, this problem may be due to the commonality of brain regions involved in sympathetic and parasympathetic outflow to many peripheral organs, as well as to the possible leakage into the abdominal cavity, of a few viral particles originally injected into the testis. Consequently, it was important to differentiate between brain staining potentially due to the autonomic control of visceral organs and/or PRV uptake by abdominal terminals unrelated to the testes, and that specifically due to the proposed pathway. As it seemed reasonable to assume that the proposed neural circuit traveled through the spinal cord, we investigated the consequences of severing this structure, on the propagation of PRV from the testis to the brain. We show here that, in SCI animals, viral labeling completely disappeared at the T5 levels (i.e. above cord transection), in the substantia nigra, in the NTS, and in the cortex, whereas many labeled cells were observed in sham-operated animals. These results indicate that the proposed pathway exits the cord below T8. Although in theory this circuit might include splanchnic nerves and the inferior mesenteric ganglion (which originate in the sacral and lumbar cord, respectively), this is highly unlikely because, as mentioned above, surgical transection of the rat superior spermatic nerves significantly lowers Leydig cell LH receptor numbers (4, 21). However, SCI rats showed a significant T response to hCG and therefore have adequate testicular LH receptors.
The only central area in which we found viral staining in SCI rats was the PVN. The presence in spine-intact rats, during very early stages of infection, of virus-positive neurons in the NTS, when other labeled perikarya could only be observed in the A5 cell group and the raphe obscurus, had led Gerendai et al. (29) to propose that infection had reached the NTS along afferent vagal fibers. As these fibers remained intact in SCI rats, it was theoretically possible that PVN labeling found in this report (29) was indeed at least in part due to passage of the virus from the vagus to the PVN via the NTS. However, our finding that there were no PRV-labeled cells in the NTS following cord severance argues against this hypothesis. It is important to point out here that the question is not whether leakage of viral particles into the abdominal cavity would stain the PVN. Our finding that placement of 15 µl PRV on, rather than in the testis, resulted in PVN staining was not surprising as PRV was undoubtedly taken up by other visceral organs previously reported to be neurally connected to this brain nucleus (see, for example, Refs. 25 and 46, 47, 48, 49). However, the injection of 3 µl PRV, a volume significantly larger than the one expected to leak out of the testis, did not stain the PVN. Nevertheless, whereas it seemed highly unlikely that viral leakage caused PVN staining in SCI rats, one could still argue that we did not prove that leakage did not take place and therefore did not provide unequivocal anatomical information regarding the presence of a specific brain-testicular pathway. Consequently, we thought it critically important to establish the physiological relevance of this pathway. As indicated above, we had reported that the icv injection of CRF or IL-1ß inhibited the T response to hCG independently of the pituitary (7, 21, 22). We reasoned that, if this inhibitory effect depended on the integrity of the neural circuit we had uncovered, it would not be present in SCI rats. Despite the possibility that cutting the cord might disrupt not only spinal pathways connecting the brain to the testes, but also the sympathetic innervation of the gonads that is important for testicular LH receptors (4, 21), SCI rats retained a significant T response to hCG. We then showed that the icv injection of IL-1ß or CRF did not significantly alter the hCG-induced T response of SCI rats. These results demonstrate that CRF and IL-1ß were unable to modify testicular responsiveness to hCG in the absence of an intact neural circuit that connected the brain and the testes. We therefore concluded that these treatments inhibit testicular activity by stimulating a descending pathway that travels through the spinal cord. Our findings also rule out a participation of vagal fibers in the ability of icv CRF or IL-1ß to blunt the T response to hCG. As mentioned earlier, these fibers, which innervate the testis, had been suggested by Gerendai et al. (29) as providing a route through which PRV traveled to the brain.
As indicated above, sympathetic innervation is crucial for the maintenance of testicular LH receptors and the control of blood flow. Additional evidence for the importance of peripheral testicular efferents in regulating T release comes in particular from studies by Huang et al. (39), who had proposed that the inability of exogenous testosterone therapy to restore spermatogenesis in the majority of SCI rats implicated nonendocrine factors in this defect because these animals exhibited relatively normal LH and T levels, although in a later another article they reported that T capsules were able to maintain spermatogenesis (30). By comparing changes in LH, FSH, T, and Sertoli protein levels, these authors furthermore showed that reasons other than hormone deficiency needed to be invoked to explain impaired spermatogenesis (50). The question is, is the neural innervation of Sertoli cells that Huang et al. (39) believe to be defective in their SCI model part of the brain testicular pathway that we propose, or is it distinct from it? The work of Mayerhofer et al. (5, 51) had indicated that the peripheral influence of ß-adrenergic agonists was stimulatory for androgen production. On the other hand, our finding that the iv injection of -adrenergic antagonists completely blocked the ability of hCG to release T (7) had shown that with regard to peripheral innervation, Leydig cell function is (also?) under the stimulatory control of -adrenergic pathways. In contrast, the ability of icv injected isoproterenol to block the T response to hCG (7) argues that the proposed neural brain-testicular pathway inhibits Leydig cell activity through mechanisms mediated by ß-adrenergic receptors. It should be mentioned, however, that in the rat the neural control of ovarian steroidogenesis is excitatory through the stimulation of ß-adrenergic receptors and inhibitory through the stimulation of -receptors (52). These observations indicate a complex influence of catecholamines on rat steroidogenesis that may depend on the gender and the type of animal model used. Consequently, comparison between the influence of various adrenergic agonists and antagonists on T secretion may not help us in differentiating between the sympathetic testicular nerves whose cell bodies are in the prevertebral nerve plexus around the major arteries, the so-called classical sympathetic testicular innervation, and a neural brain-testicular pathway. Another set of data that needs to be taken into consideration pertains to the fact that the pelvic ganglia that innervate the testes are supplied, in part, by the vagus nerve (53). However, as mentioned above, the absence of PRV-labeled cells in the NTS of rats with spinal cord injury does not support the hypothesis that vagal afferents represent an important component of our proposed pathway. Finally, we observed that the local application of lidocaine on testicular nerves completely abolished the T response to hCG (21), which corresponds to the influence of testicular denervation (4, 54). SCI rats, however, showed significant T responses to hCG despite a shift of their curve to the right, compared with sham-operated controls. This means that, whereas it may have reduced LH receptors binding affinity and/or number, severing the spinal cord remained compatible with significant Leydig cell responsiveness. Consequently, whereas we do not know where the hypothalamic neurons that modulate Leydig cell responsiveness to gonadotropin join the descending sympathetic circuitry, presently available results do not seem to be compatible with the hypothesis that classical testicular innervation and a neural brain-testicular pathway are identical.
In conclusion, our work suggests that the present view of the hypothalamic-pituitary-gonadal axis requires revision to take into account a central neural mechanism that controls Leydig cell function. In particular, it will be important to establish the respective role of the known LHRH-LH axis, and the hypothalamic-testicular axis described here in modulating the influence of specific stressors on T release. Although it may sound surprising that the existence of this pathway had attracted little attention until now, the fact that terminals for autonomic nerves are found in the testicular capsule, but not in close proximity to Leydig cells (see Ref. 5), coupled with the relatively sparse innervation of the rat testis (5), has been difficult to reconcile with a major importance of innervation for T release. Our present results indicate the existence of a neural pathway that originates in the brain and travels through the spinal cord, and that plays a crucial role in Leydig cell function. This conclusion agrees with the finding that SCI causes prolonged deterioration of spermatogenesis in rats despite relatively normal LH levels (50), but that sperm formation can be restored by exogenous testosterone (30). It is true that spermatogenesis and steroidogenesis can eventually recover in some patients with long-term spinal cord injury (55). However, only a subgroup of these patients has viable sperm, whereas most others are characterized with permanently impaired testicular activity (55). As the completeness of cord transection has not been ascertained in any of these patients, it is possible that when steroidogenesis is (partially) restored, it may be due to incomplete lesions.
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Acknowledgments |
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Footnotes |
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Abbreviations: CRF, Corticotropin-releasing factor; hCG, human chorionic gonadotropin; icv, intracerebroventricular; LHRH, LH-releasing hormone; NTS, nucleus of the solitary tract; PRV, pseudorabies virus; PVN, paraventricular nucleus; rh, recombinant human; r/h, rat/human; SCI, spinal cord injury; T, testosterone.
Received April 10, 2002.
Accepted for publication July 2, 2002.
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-hydroxylase and 17, 20-lyase without affecting the binding of LH/hCG receptors. J Androl 15:302–308This article has been cited by other articles:
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M. Herman and C. Rivier Activation of a Neural Brain-Testicular Pathway Rapidly Lowers Leydig Cell Levels of the Steroidogenic Acute Regulatory Protein and the Peripheral-Type Benzodiazepine Receptor while Increasing Levels of Neuronal Nitric Oxide Synthase Endocrinology, January 1, 2006; 147(1): 624 - 633. [Abstract] [Full Text] [PDF]
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P. Y. Liu, P. Y. Takahashi, P. D. Roebuck, A. Iranmanesh, and J. D. Veldhuis Age-specific changes in the regulation of LH-dependent testosterone secretion: assessing responsiveness to varying endogenous gonadotropin output in normal men Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R721 - R728. [Abstract] [Full Text] [PDF]
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D. R. Simorangkir, S. Ramaswamy, G. R. Marshall, and T. M. Plant In the Adult Male Rhesus Monkey (Macaca mulatta), Unilateral Orchidectomy in the Face of Unchanging Gonadotropin Stimulation Results in Partial Compensation of Testosterone Secretion by the Remaining Testis Endocrinology, November 1, 2004; 145(11): 5115 - 5120. [Abstract] [Full Text] [PDF]
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D. J. Selvage, S. Y. Lee, L. H. Parsons, D. O. Seo, and C. L. Rivier A Hypothalamic-Testicular Neural Pathway Is Influenced by Brain Catecholamines, But Not Testicular Blood Flow Endocrinology, April 1, 2004; 145(4): 1750 - 1759. [Abstract] [Full Text] [PDF]
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D. J. Selvage and C. Rivier Importance of the Paraventricular Nucleus of the Hypothalamus as a Component of a Neural Pathway between the Brain and the Testes that Modulates Testosterone Secretion Independently of the Pituitary Endocrinology, February 1, 2003; 144(2): 594 - 598. [Abstract] [Full Text] [PDF]
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