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Division of Neuroscience (V.S.D., H.F.U.), Oregon National Primate Research Center, Beaverton, Oregon 97006; and Department of Physiology and Pharmacology (H.F.U.), Oregon Health and Science University, Portland, Oregon 97239
Address all correspondence and requests for reprints to: Henryk F. Urbanski, Division of Neuroscience, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, Oregon 97006. E-mail: urbanski{at}ohsu.edu.
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Abstract |
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Introduction |
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Most nonmammalian vertebrates appear to express at least 2 of the 14 different forms of GnRH that are known to exist. In contrast, mammals have generally been thought to express only one form of GnRH, commonly referred to as mammalian GnRH or GnRH-I. However, on the basis of recent evidence from HPLC (3), immunohistochemistry (4, 5, 6), Northern blots (7), and in situ hybridization (8), it is now clear that a second form of GnRH (GnRH-II) also exists in the brain of many mammals and has been cloned from humans (7) and rhesus monkeys (8, 9).
GnRH-II is regarded as the most ancient and conserved member of the GnRH family, because it has been found in representative members of every vertebrate class (10, 11, 12, 13). First cloned and sequenced from the chicken in 1984 (12), its amino acid sequence (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2) only differs from mammalian GnRH, or GnRH-I (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), at positions 5, 7, and 8. Despite the peptide similarity, a distinct gene is known to encode GnRH-II (2) in humans, and separate cell populations express GnRH-I and GnRH-II in the rhesus monkey (Macaca mulatta) (8, 14). Mapping the GnRH-II distribution also revealed that the rhesus monkey hypothalamus expresses GnRH-II in the supraoptic and paraventricular nuclei and the medial basal hypothalamus, which may allow GnRH-II to reach the pituitary gonadotropes and stimulate LH and/or FSH release (8). This is underscored by the recent finding that specific GnRH-II receptors are expressed in the anterior pituitary of several mammalian species (15, 16). Taken together, these findings suggest that GnRH-II may contribute to regulating the primate reproductive system and may be under separate neuroendocrine control from GnRH-I. However, although it is known that GnRH-II can stimulate LH release in vivo (9), less is known about its potency compared with GnRH-I or its ability to stimulate FSH release. Moreover, it is unclear whether the gonadotropin-releasing abilities of GnRH-II have physiological relevance. To help resolve this issue, the present study involved administration of GnRH-I or GnRH-II in vivo at various doses to adult female rhesus monkeys. A GnRH-I receptor antagonist was also given to examine which GnRH receptor subtype mediates the effect of GnRH-II on gonadotropin release. Preliminary findings from this study have been published in abstract form (17).
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Materials and Methods |
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The study was approved by the Institutional Animal Care and Use Committee at the Oregon National Primate Research Center (ONPRC), and animal care was provided by the ONPRC in accordance with the NIH Guide for the Care and Use of Laboratory Animals. For the in vivo experiments, seven regularly cycling female rhesus monkeys (M. mulatta) were used to compare the gonadotropin-releasing ability of GnRH-I and GnRH-II; three of the animals were young adults (8–12 yr old), and four were old but still premenopausal (21–23 yr old). Each animal was surgically fitted with an indwelling subclavian catheter as previously described (18) to enable iv administration of GnRH as well as remote blood sampling from an adjacent room.
For the in vitro experiments, pituitaries were obtained from adult female rhesus monkeys that were euthanized as part of the ONPRC Tissue Distribution Program to provide tissue for this and other studies. The animals were deeply anesthetized using ketamine/pentobarbital and painlessly killed, according to procedures established by the Panel on Euthanasia of the American Veterinary Society.
Effects of GnRH on LH and FSH release in vivo
Experiment 1.
Animals were determined to be in their midluteal phase (d 18–24 of an 
28-d cycle) based on detailed menstruation records and by analyzing blood samples for estrogen and progesterone concentrations. The luteal phase was chosen because the endogenous pulse frequency was infrequent (1 pulse per 4 h), allowing animals to be tested without interference from endogenous GnRH secretion. They were given a bolus iv injection of saline, as negative control, or GnRH-I or GnRH-II at four doses: 0.01 µg, 0.1 µg, 1 µg, or 10 µg/kg body weight. Blood samples (0.5 ml) were collected in glass tubes coated with EDTA (50 µl of a 10% wt/vol; Ricca Chemical, Arlington, TX) at -10, 0, 10, 20, 30, 60, and 120 min after administration, and then centrifuged; the plasma supernatant was removed and stored at -20 C until assay for LH and FSH.
Experiment 2.
Animals were determined to be in their midfollicular phase (d 4–10 of an 28-d cycle) on the basis of detailed menstruation records and by analyzing blood samples for estrogen and progesterone concentrations. They were given a bolus iv injection of saline, as negative control, or GnRH-I or GnRH-II at four doses: 0.01 µg, 0.1 µg, 1 µg, or 10 µg/kg body weight. Blood samples (0.5 ml) were collected, as before, at -10, 0, 10, 20, 30, 60, and 120 min after administration and then centrifuged; the plasma supernatant was removed and stored at -20 C until assay. Samples were only assayed for FSH concentration to determine whether the FSH response was more pronounced during the follicular, rather than the luteal, phase.
Experiment 3. Because a single injection of GnRH-I or GnRH-II failed to elicit a significant increase in plasma FSH during either the midluteal or midfollicular phase (experiments 1 and 2, respectively), an additional experiment was performed to assess the effectiveness of repeated GnRH administrations. Four of the animals were treated with either GnRH-I or GnRH-II (1 µg/kg body weight, iv) every 2 h for 24 h, or with saline vehicle; the same animals were used for each of the tests, in a randomized order, spread across 1 month. Blood samples (0.5 ml) were collected, as before, at 0 min before the initial treatment and 10 min after the last administration. They were then centrifuged, and the plasma supernatant was removed and stored at -20 C until assay for LH and FSH.
Experiment 4. To determine whether GnRH-II required the mammalian GnRH receptor (GnRH-I receptor) to stimulate LH release, animals were treated with antide (Bachem; Torrance, CA), a potent GnRH-I receptor antagonist (19), either alone or in combination with GnRH-I and GnRH-II during the midluteal phase, determined as described in experiment 1. GnRH forms were administered iv at a 1-µg/kg body weight dose, and antide was administered iv at 100 µg/kg body weight. Blood samples (0.5 ml) were collected, processed, stored, assayed for LH, and analyzed as described in experiment 1.
Experiment 5. To determine the interaction of GnRH-I and GnRH-II, each animal received four different GnRH treatments: GnRH-I and GnRH-II both at 0.1 µg/kg body weight, GnRH-I at 0.1 µg and GnRH-II at 1 µg/kg body weight, GnRH-I at 1 µg and GnRH-II at 0.1 µg/kg body weight, and GnRH-I and GnRH-II both at 1 µg/kg body weight. All treatments were administered iv during the midluteal phase, and blood samples (0.5 ml) were collected, processed, and stored as described in experiment 1.
Effect of GnRH on LH and FSH release in vitro
The anterior pituitary gland was separated from the posterior pituitary gland, and the cells were dispersed as previously described in rats (20). Briefly, the tissue was incubated in 0.3% type IV collagenase (wt/vol, Sigma, St. Louis, MO) and 0.1% DNase (wt/vol, Sigma) in calcium- and magnesium-free Hanks’ balanced salt solution (HBSS; Life Technologies, Inc., Carlsbad, CA) at 37 C for 1 h, centrifuged at 3000 rpm for 5 min, and then washed twice in HBSS followed by centrifugation as before. Next, the tissue was incubated in 0.15% pancreatin (wt/vol; Sigma) and 0.1% DNase in HBSS at 37 C for 30 min, and centrifuged and washed as before. It was then triturated in 0.2% DNase in HBSS using a sterilized Pasteur pipette, centrifuged, washed, and resuspended in 1 ml DMEM/F12 (Sigma) containing 10% fetal calf serum (Sigma). The dispersed cells were counted using a hemacytometer, transferred to coated 48-well tissue culture plates (Fisher Scientific, Auburn, WA) at 1.5 x 105 cells per well, and incubated at 37 C with 5% CO2 for 48 h to allow them to adhere to the plate. They were then incubated for 1 h and washed in serum-free DMEM/F12 media, and subsequently treated with GnRH-I or GnRH-II at doses ranging from 10-11 to 10-8 in serum-free media for 2 h at 37 C. The culture media were collected, centrifuged to remove any cells, and stored at -20 C until assay for LH and FSH concentration. After media collection, cells were exposed to trypan blue, and an average of 95% were able to exclude the dye, indicating their viability.
Hormone assay
Samples were assayed for LH using a previously described mouse Leydig cell bioassay involving RIA for testosterone (21); results are expressed in terms of a cynomolgus LH-RP1 standard (21). FSH was measured by RIA using an antirecombinant monkey FSH (NIDDK lot no. AFP782594) antibody; results are expressed in terms of the recombinant monkey FSH-RP1 (NIDDK lot no. AFP6940A) standard.
Analytical methods
In vivo analyses. GnRH administrations were randomized and spaced 24–48 h apart to prevent an interaction occurring between separate treatments. LH and FSH values from -10 and 0 min were analyzed for homogenity of variance using Systat software (version 10; Systat Software, Inc., Richmond, CA), and only animals that had basal gonadotropin concentrations were considered to be between endogenous GnRH pulses and were analyzed further. Baseline LH and FSH concentrations were then determined by averaging the values obtained at -10 and 0 min before GnRH treatment; these baseline concentrations were then subtracted from experimental values to obtain the net LH and FSH concentrations at each time point. Net LH and FSH values over time for each GnRH dose were analyzed using Systat and two-factor repeated measures ANOVA, the two factors being time and treatment. The Huynh-Feldt (H-F) factor was used in lieu of the P value to minimize error due to nonuniform variance-covariance matrices (22); a value of less than 0.05 was considered to be statistically significant. The data were also analyzed across the two age groups using two-factor ANOVA, and a P value less than 0.05 was considered to be statistically significant.
For the repeated treatments with saline, GnRH-I, or GnRH-II (experiment 3), the net saline values were analyzed for homogenity of variance using Systat software. Due to the small number of animals used, the results from this test indicated that nonparametric statistics should be used, so the net LH and FSH values for GnRH-I and GnRH-II were compared with saline values using the Mann-Whitney U test. The P value was used to indicate any statistical significance.
In vitro analysis. Basal LH levels were obtained using media treatment alone and subtracted from experimental values to determine net LH release. Each dose of GnRH was tested in duplicate or triplicate to obtain a mean value per pituitary; the overall mean level of LH release was then calculated from four pituitaries. The net LH release for each pituitary was analyzed using Systat software and two-way ANOVA, and the P value was used to indicate any statistical significance.
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Results |
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The LH response to different bolus doses of GnRH-I is shown in Fig. 1A
. All four doses (0.01 µg, 0.1 µg, 1 µg, and 10 µg) of GnRH-I produced a significant increase in LH compared with saline treatment (H-F < 0.05), but the 0.01-µg dose was significantly less effective than all other doses, which were not statistically different from one another. Circulating LH levels peaked by approximately 10 min after each dose and then declined gradually, although the 1-µg dose of GnRH-I had not yet reached baseline concentrations by 120 min.
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). After treatment, circulating LH levels rose within 10 min, remained elevated for 20 min, and then fell gradually to baseline levels by 120 min. The lowest dose, 0.01 µg, stimulated an LH release pattern that was qualitatively similar to that produced by the other GnRH-II doses, but the comprehensive amount of LH released was not significantly different from saline alone (H-F > 0.05). Overall, the LH response pattern to GnRH-II treatment (Fig. 1B) was similar to that seen for GnRH-I (Fig. 1A), and GnRH-I did not release significantly more LH than GnRH-II at any dose (Fig. 1C).
In experiments 1 and 2, none of the GnRH-I or GnRH-II bolus treatments stimulated a significant increase in the level of FSH release, during either the follicular phase (Fig. 2) or the luteal phase (data not shown). However, experiment 3 showed that repeated treatment with either GnRH-I or GnRH-II (1 µg/kg body weight, every 2 h for 24 h) does eventually result in a significant (P < 0.05) increase in plasma FSH concentrations (Fig. 3B); equally important, a similar response was produced by GnRH-II and GnRH-I (Fig. 3B). In addition, the multiple-GnRH administration regimen significantly (P < 0.01) stimulated LH secretion (Fig. 3A); the resulting plasma LH concentrations were not statistically different from those produced by a single bolus dose (1 µg/kg) of GnRH-I or GnRH-II.
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The ability of age to influence gonadotropin response was also analyzed for both GnRH-I and GnRH-II. Three of the seven rhesus monkeys used were young adults (8–12 yr old), and the remaining four were old but still premenopausal (21–23 yr old). Figure 4 shows the responses of the two age groups to GnRH-I and GnRH-II treatment. Two-factor repeated measures ANOVA was performed using age as a grouping factor and suggests that the older animals were less sensitive to both GnRH-I (Fig. 4A) and GnRH-II (Fig. 4B) treatment than the young animals, at the 0.1 µg/kg dose (P < 0.05).
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The time-course of response to GnRH-II (Fig. 1B) suggests that GnRH-II may act at the same level as GnRH-I, namely at the pituitary gonadotropes. To confirm that GnRH-II was not acting upstream of the pituitary and modulating GnRH-I release, GnRH-II was administered in vitro to primary cultures of dispersed anterior pituitary cells. After a 2-h static incubation in media containing GnRH-I or GnRH-II at doses ranging between 10-11 and 10-8 M, the media was removed and assayed for LH and FSH concentrations. GnRH-I is known to directly stimulate the pituitary gonadotropes to release LH, so it was used comparatively to assess the relative ability of GnRH-II to act at the pituitary level. As shown in Fig. 5, GnRH-II stimulated LH and FSH release in vitro with similar potency to GnRH-I.
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Recently, a second GnRH receptor was discovered in mammals and found to have a high selectivity for GnRH-II over GnRH-I. This provoked the question whether the ability of GnRH-II to release LH is mediated by its own receptor or by cross-reactivity at the GnRH-I receptor. Therefore, a 100-µg/kg dose of antide, a potent GnRH-I receptor antagonist, was administered with either GnRH-I or GnRH-II at 1 µg/kg or alone as a negative control. Administered with GnRH-I, antide attenuated the cumulative LH release but did not affect the time-course of the response (Fig. 6A). This treatment paradigm did not completely inhibit GnRH-I-stimulated LH release, likely because of the relative dissociation constants of antide and GnRH-I. However, when administered with GnRH-II, antide was able to completely block both the time-course and cumulative LH response (Fig. 6B).
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Because exogenous GnRH-II was able to stimulate LH release through pituitary GnRH-I receptors and a population of GnRH-II-containing cells exists in the primate medial basal hypothalamus, it is possible that GnRH-II is released into the portal vasculature and may modulate the response of pituitary gonadotropes to GnRH-I stimulation. Therefore, GnRH-I and GnRH-II were administered concomitantly at two different doses to determine whether GnRH-II exposure would potentiate or attenuate GnRH-I-stimulated LH release or whether the time-course of LH secretion would be altered by exposure to GnRH-II. Because the 1-µg dose appeared most effective for both forms, 1 µg was used as the optimal dose and 0.1 µg as the suboptimal dose for both forms.
As indicated in Fig. 7, the most effective treatments included GnRH-I at the optimal, 1-µg, dose. Therefore, GnRH-I at 1 µg and GnRH-II at 0.1 µg were more effective than GnRH-I at 0.1 µg and GnRH-II at 1 µg. However, combining both GnRH forms at optimal doses did not produce a statistically additive effect over either GnRH-I or GnRH-II alone at the 1-µg dose. Likewise, combining GnRH-II treatment with GnRH-I did not produce a subtractive effect from either form alone. In addition, the time-course of LH secretion more closely resembled that seen with GnRH-I.
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Discussion |
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GnRH-II and GnRH-I elicited an equivalent LH response when they were administered iv at three different bolus doses to adult, luteal-phase rhesus monkeys. Because a previous study reported that the mammalian GnRH-I receptor had a 10-fold higher affinity for GnRH-I compared with GnRH-II (21), these results suggest that GnRH-II does not act directly at the GnRH-I receptor to stimulate LH secretion. Alternatively, GnRH-II might stimulate nerve terminals in the median eminence to release GnRH-I into the portal vasculature, or GnRH-II might act through the recently discovered GnRH-II receptor (15, 16), which is known to colocalize with LH in pituitary gonadotropes (16).
To distinguish between these two possibilities, it was prudent to initially determine whether GnRH-II could stimulate LH release directly from the pituitary. After static incubation of freshly dispersed anterior pituitary cells with GnRH-II, LH concentrations were significantly elevated compared with treatment with medium alone. Furthermore, the LH response to different doses of either GnRH-I or GnRH-II was similar, indicating that exogenous GnRH-II acted directly at the pituitary to stimulate LH secretion. In combination with the previous finding of Millar et al. (16) that a population of LH gonadotropes expresses the GnRH-II receptor, these data suggest that the stimulatory action of GnRH-II on LH release might be mediated through its own distinct receptor.
The GnRH-II receptor that was recently discovered in mammals has approximately a 400-fold selectivity for GnRH-II over GnRH-I (15, 16, 28). This is in contrast to the 10-fold selectivity of the mammalian GnRH-I receptor for GnRH-I over GnRH-II (21). Taken together, this evidence is in harmony with the idea that GnRH-II stimulates LH release through the GnRH-II receptor. On the other hand, in the present study antide (a potent GnRH-I receptor antagonist) completely blocked the GnRH-II-induced increase in plasma LH concentrations in vivo. Because the GnRH-II receptor has little to no affinity (IC50 > 10,000 nM) for antide (28), it is unlikely that this blocking effect was mediated at the level of the GnRH-II receptor, despite the pharmacological dose of antide (100 µg/kg body weight) used. Therefore, this finding indicates that a bolus dose of GnRH-II requires the GnRH-I receptor to stimulate LH release directly from the pituitary gland in vivo.
GnRH-I and GnRH-II failed to stimulate FSH secretion in vivo when they were administered as a single treatment, although GnRH-I and GnRH-II were equally effective at stimulating FSH secretion in vitro. However, a few factors complicate the interpretation of these results. Among them, it is questionable whether the existing assay is entirely reliable to accurately detect FSH (29). Although the assay is reproducible with a standard curve, multiple isoforms of FSH are known to exist (30). Furthermore, baseline concentrations of FSH are markedly elevated compared with LH, and it is unclear whether this is due to an enhanced tonic release pattern, a longer circulating half-life, or another unknown factor. As a result, determining the FSH response is, at best, a relative measurement. However, a recent study in sheep demonstrated that administering GnRH-I or GnRH-II every 2 h for 24 h stimulated FSH release in vivo (31). In the present study, we corroborate these findings by demonstrating that similar repeated injections of GnRH increased plasma FSH levels in the rhesus monkey. Furthermore, both forms of GnRH showed equal effectiveness at the dose tested (1 µg/kg body weight). Taken together, these data suggest that a single exposure to GnRH-I or GnRH-II is not sufficient to elevate plasma FSH concentrations, although this treatment paradigm significantly stimulates LH release. However, 24 h of multiple GnRH administrations is sufficient to stimulate FSH release. Therefore, although the present data fail to distinguish either form as a definitive FSHRH, they emphasize that the neuroendocrine control of LH and FSH secretion is not identical.
The LH and FSH data call into question the physiological relevance of GnRH-II as a gonadotropin-releasing hormone. For example, does endogenous GnRH-II simply duplicate the known action of GnRH-I, or does it have another unique function that was not disclosed by the present treatment paradigm? One possibility is that GnRH-II plays a role in modulating pituitary responsiveness to GnRH-I. Previous studies have shown that the GnRH-I receptor becomes desensitized when exposed to continuous, rather than episodic, GnRH-I (32, 33, 34). In addition, GnRH-II has a substantially longer circulating half-life than GnRH-I (35, 36). Therefore, if GnRH-II remains bound to the GnRH-I receptor for a longer period, it is possible that GnRH-II treatment would eventually result in a more pronounced desensitization of the GnRH-I receptor. Alternatively, episodic GnRH-I exposure has been shown to prime the GnRH-I receptor and potentiate the LH response to a bolus GnRH-I treatment (37). However, it is unclear whether GnRH-II might also act to prime the GnRH-I receptor.
To address this, GnRH-I and GnRH-II were administered together at two different doses to determine whether GnRH-II exposure has an inhibitory or stimulatory effect on GnRH-I-stimulated LH release. GnRH-II did not potentiate or attenuate GnRH-I-stimulated LH secretion, which suggests that the only interaction between the GnRH-I and GnRH-II treatments resulted from competition at the GnRH-I receptor. These results corresponded to the earlier findings that GnRH-II required the GnRH-I receptor to stimulate LH secretion. However, because previous investigations found that the GnRH-I receptor has a higher affinity for GnRH-I than GnRH-II (16, 21, 28), GnRH-II might not affect GnRH-I signaling unless the pituitary is exposed to the two forms sequentially, rather than simultaneously. Alternatively, endogenous GnRH-II might signal to GnRH-I cell bodies to alter GnRH-I secretion, but the present experimental design did not address this possibility. Taken together, these data indicate that exogenous GnRH-II most likely exerts its physiological action via the established GnRH-I pathway rather than through a unique neuroendocrine pathway.
In addition to the relative potency of GnRH-I and GnRH-II, the effect of age on the LH response to GnRH treatment was also examined. Unexpectedly, the results demonstrated that old regularly cycling rhesus monkeys secreted less LH after GnRH treatment than young adult rhesus monkeys. This was observed for both GnRH-I and GnRH-II at the 10-ng/kg and 100-ng/kg doses, but was not noticeable at 1 µg/kg, which appeared to be the most effective dose for both GnRH forms. It is possible that these results stem from a change in GnRH receptor numbers or a smaller releasable pool of LH stored in the gonadotropes. However, we are hesitant to make more than a preliminary conclusion due to the small number of animal subjects per group.
In summary, the present study finds that exogenous GnRH-II is able to stimulate LH release from the anterior pituitary using the GnRH-I receptor. Furthermore, GnRH-II demonstrates equal potency to GnRH-I at stimulating LH release, although a single dose of either form failed to stimulate FSH release in vivo. Therefore, it is possible that neither GnRH-II nor GnRH-I plays a significant physiological role as an FSHRH in primates. Moreover, because the hypothalamo-pituitary axis of rhesus monkeys closely resembles that of humans, these results may provide further understanding of the neuroendocrine mechanisms that regulate human reproduction.
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Acknowledgments |
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Footnotes |
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Abbreviations: FSHRH, FSH-releasing hormone; HBSS, Hanks’ balanced salt solution; H-F, Huynh-Feldt.
Received August 26, 2002.
Accepted February 2, 2003.
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References |
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-Adrenergic receptor antagonism and N-methyl-D-aspartate (NMDA) induced luteinizing hormone release in female rhesus macaques. Brain Res 744:96–104[CrossRef][Medline]
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