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BOR - Papers in Press, published online ahead of print June 11, 2003.
Biol Reprod 2003, 10.1095/biolreprod.103.016162
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BIOLOGY OF REPRODUCTION 69, 1356–1361 (2003)
DOI: 10.1095/biolreprod.103.016162
© 2003 by the Society for the Study of Reproduction, Inc.

Pituitary

Evidence that Gonadotropin-Releasing Hormone (GnRH) II Stimulates Luteinizing Hormone and Follicle-Stimulating Hormone Secretion from Monkey Pituitary Cultures by Activating the GnRH I Receptor1

Yohei Okada3, Akiko Murota-Kawano3, Sham S. Kakar4, and Stephen J. Winters2,3

Division of Endocrinology and Metabolism3 James Graham Brown Cancer Center,4 University of Louisville, Louisville, Kentucky 40202


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Mammalian gonadotropin-releasing hormone (GnRH) I is the neuropeptide that regulates reproduction. In recent years, a second isoform of GnRH, GnRH II, and its highly selective type II GnRH receptor were cloned and identified in monkey brain, but its physiological function remains unknown. We sought to determine whether GnRH II stimulates LH and FSH secretion by activating specific receptors in primary pituitary cultures from male monkeys. Dispersed pituitary cells were maintained in steroid-depleted media and stimulated with GnRH I and/or GnRH II for 6 h. Cells were also treated with Antide (Bachem, King of Prussia, PA), a GnRH I antagonist, to block gonadotropin secretion. In monkey as well as rat pituitary cultures, GnRH II was a less effective stimulator of LH and FSH secretion than was GnRH I. In both cell preparations, Antide completely blocked LH and FSH release provoked by GnRH II as well as GnRH I. Furthermore, the combination of GnRH I and GnRH II was no more effective than either agonist alone. These results indicate that GnRH II stimulates FSH and LH secretion, but they also imply that this action occurs through the GnRH I receptor. The GnRH II receptors may have a unique function in the monkey brain and pituitary other than regulation of gonadotropin secretion.

follicle-stimulating hormone, gonadotropin-releasing hormone, gonadotropin-releasing hormone receptor, luteinizing hormone, pituitary


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Gonadotropin-releasing hormone (GnRH) is the primary hypothalamic signal peptide that governs reproductive function. It regulates the synthesis, glycosylation, and secretion of LH and FSH, which in turn stimulate gonadal steroidogenesis and gametogenesis.

The traditional view was that eutherian mammals express only a single form of GnRH, known as mammalian GnRH (GnRH I: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2). However, at least 16 novel decapeptides have now been identified as GnRH structural variants in lower vertebrates [1], and more than one form of GnRH is expressed in most species. Among these, a form of GnRH originally isolated from chicken brain (chicken GnRH II: pGlu-His-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2) [2] is universally conserved from fish to Homo sapiens [3–6]. GnRH II has been cloned from monkey brain [7, 8] and is expressed in a concentrated fashion in at least three distinct regions of the male rhesus monkey hypothalamus: the supraoptic and paraventricular nuclei and the medial basal hypothalamus. However, GnRH II is not coexpressed with GnRH I peptide [9], suggesting unique regulation and function.

Recently, a seven-transmembrane, G protein-coupled receptor that is highly selective for GnRH II was cloned and characterized from the monkey [10, 11] as well as from a number of fish and amphibians [12, 13]. Receptor mRNA was identified in the marmoset pituitary by polymerase chain reaction (PCR) [11] and by Northern blot analysis in the human pituitary using a cDNA to rhesus monkey pituitary GnRH II receptor based on the sequence of the human receptor [10]. In both human [10] and nonhuman primates [11], GnRH II receptor expression was found at similar levels in a wide variety of extrapituitary tissues. Unlike the type I GnRH receptor [14], the type II receptor has a C-terminal cytoplasmic tail that is phosphorylated when the receptor binds GnRH II, leading to receptor internalization and desensitization [15]. The type II GnRH receptor was identified by immunocytochemistry in the majority of ovine gonadotrophs [11], but to our knowledge, it so far has not been identified in gonadotrophs of primates. In rams, 10 µg of GnRH II i.v. stimulated LH and FSH secretion, although less effectively than GnRH I. Moreover, the ratio of FSH to LH secretion was higher following GnRH II than following GnRH I, suggesting that GnRH II could play a role in the differential secretion of FSH and LH [11]. In monkeys, a robust rise in LH secretion occurred after GnRH II administration, but FSH was not measured [7]. Because of the potential importance of GnRH II in the control of FSH and LH in primates, we studied FSH and LH secretion in pituitary cell cultures from adult male rhesus monkeys and compared the results with those from rat pituitary cell cultures, because rodents are not thought to express a selective GnRH II receptor [16].


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Reagents

Dulbecco minimum essential medium (DMEM), Dulbecco PBS (without CaCl2 and MgCl2), Hanks balanced salt solution (HBSS), Hepes, penicillin G, streptomycin sulfate, fetal calf serum (FCS), calf serum (CS), BSA fraction V, pancreatin, oligo dT primer, reverse transcription kit, and Super Script II RNase H-reverse transcriptase were purchased from Invitrogen (Carlsbad, CA). The FCS and CS were treated with dextran-charcoal (DCC) to remove steroids. Deoxyribonuclease (DNase) I was from Sigma (St. Louis, MO). Fluconazole was from Pfizer, Inc. (New York, NY). Collagenase was from Roche Molecular Biochemicals (Mannheim, Germany). The 100-base pair DNA ladder was from New England Biolabs (Beverly, MA). Prime RNase inhibitor was from Fisher Scientific (Pittsburgh, PA). Taq DNA polymerase and 10 mM dNTP Mix were from Promega (Madison, WI).

Hormones

The GnRH I (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), GnRH II (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2), and Antide (a GnRH I antagonist; N-Ac-D-Nal1-D-Cpa2-D-Pal3-Ser4-Lys(Nic)5-D-Lys(Nic)6-Leu7-Ilys8-Pro9-D-Ala10-NH2) were purchased from Bachem (King of Prussia, PA). All reagents were solubilized in distilled H2O.

Preparation of Anterior Pituitary Cells and Cell Cultures

Pituitary cultures were prepared using freshly removed anterior pituitary glands from normal adult male rhesus monkeys (Macaca mulatta) of approximately 5–15 yr of age that were obtained from Covance Research Primates (Alice, TX) and shipped on ice in HBSS containing 44 mM Hepes. Rat pituitary cells were prepared from 7-wk-old, male Sprague-Dawley rats (Harlan, Indianapolis, IN). The research was approved by the University of Louisville Animal Care and Use Committee.

The duration between removal of the pituitary and the start of the cell dispersal procedure was approximately 14 h for monkeys and 1 h for rats. All media contained 100 U/ml of penicillin G, 100 g/ml of streptomycin sulfate, and 2 mg/ml of fluconizole. The methods used for the preparation of pituitary cell cultures were similar to those described previously [17]. Briefly, anterior pituitaries were minced and treated for 60 min with 0.33% collagenase and 0.003% DNase in HBSS (pH 7.3) containing 0.4% BSA fraction V, 0.2% sucrose, and 44 mM Hepes. Cells were then treated with 0.25% pancreatin in HBSS for 8 min and washed three times with DMEM containing 5% DCC-FCS and 5% DCC-CS. Dispersed cells were cultured in DMEM with 10% DCC-FCS on 12-well plates at a density of 1.6–2.0 x 105 cells/well. Twenty-four hours after dispersal, media were changed, and some wells were treated with 100 nM Antide. After 16 h of preculture, media were changed to include increasing doses of GnRH I and/or GnRH II in the presence or absence of 100 nM Antide. After 6 h, spent culture media were collected, and cells were incubated for an additional 6 h to test the prolonged effect GnRH I or GnRH II.

Culture media were stored at -20°C for measurement of LH and FSH.

Immunoassays

The concentration of rat LH and FSH in the culture media was estimated using Biotrak rat LH and FSH enzyme immunoassay systems (Amersham Pharmacia Biotech, Piscataway, NJ) according to the manufacturer's protocol using a sample volume of 50 µl. The limit of detection was 0.2 and 1.0 ng/ml for LH and FSH, respectively. The within-assay coefficients of variation for sample pools were less than 10% and less than 5.8% for LH and FSH, respectively.

The concentration of LH and FSH in monkey pituitary culture media was determined in the Assay Core of the Center for Reproductive Physiology of the University of Pittsburgh (Pittsburgh, PA) using reagents supplied by the National Hormone and Pituitary Program, as described previously [18]. The RIA system uses 125I-labeled recombinant cynomolgus LH (AFP6936A), antirecombinant cynomolgus LH (AFP342994), and recombinant cynomolgus LH (rMoLH RP-1) as the standard. The average sensitivity was 15 pg rMoLH RP-1/tube. The within- and between-assay coefficients of variation were 7% and 15%, respectively. The concentration of monkey FSH in culture media was estimated using homologous RIA reagents [19]. Recombinant cynomolgus FSH (NICHHD Rec-MoFSH-RP-1, AFP-6940A) was the reference preparation and the radio-iodinated tracer, and a polyclonal rabbit antiserum (AFP782594) against recombinant cynomolgus FSH was used as the primary antibody. The within- and between-assay coefficients of variation were less than 7.4% and 5.4%, respectively.

The concentration of growth hormone (GH) in culture media was determined using an immunoassay kit from Diagnostic Products (Los Angeles, CA). The within-assay coefficient of variation for the unknown samples was less than 5%.

Data Analysis and Presentation

Statistical comparisons between two groups were performed using the Student t-test. Analysis of variance followed by the Dunnett or the Newman-Keuls test was used to compare results for multiple treatment groups. Values for the median effective concentration (EC50) were calculated using GraphPad Prism software version 4 (San Diego, CA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
GnRH II Stimulates LH and FSH Secretion by Primary Pituitary Cultures from Monkeys and Rats

To examine whether GnRH II directly stimulates LH and FSH secretion, dispersed pituitary cell monolayer cultures from monkeys and rats were maintained in steroid-depleted media and treated with GnRH I or GnRH II in increasing doses (0.1–100 nM) for 6 h.

As shown in Figure 1, in monkey pituitary cell cultures GnRH I increased LH secretion dose-dependently to a maximum value that was 5-fold higher than that in nonstimulated cultures. The EC50 was 0.10 nM. In addition, GnRH II stimulated LH release dose-dependently with an EC50 value of 0.37 nM. Maximum LH secretion following stimulation with GnRH II and GnRH I was similar.



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  		FIG. 1. LH and FSH secretion by pituitary cell cultures from adult male monkeys and rats. Cells were treated with GnRH I or GnRH II at a dose of 0.1–100 nM for 6 h. Culture media were collected and analyzed for LH and FSH. The experiment included two to three wells of cells per data point, and the LH and FSH concentration in each well was assayed in duplicate. The experiment was performed three times using pituitary cells from two monkeys for each experiment. The rat pituitary cells were from 10 seven-week-old animals. One representative experiment is presented.

Likewise, FSH secretion was increased 4-fold by maximum doses of both GnRH I and GnRH II. It has been suggested that GnRH II is a more effective stimulator of FSH than of LH when compared to GnRH I. In monkey pituitary cultures, however, the FSH and LH profiles in response to increasing concentrations of GnRH I and GnRH II were comparable (Fig. 1). The EC50 values for GnRH I- and GnRH II-stimulated FSH secretion were 0.10 and 0.59 nM, respectively, and both ligands at a dose of 0.1 nM increased (P < 0.05) FSH secretion.

In rat pituitary cultures, GnRH I and GnRH II also stimulated LH and FSH secretion comparably, and GnRH I was more potent than GnRH II. It is interesting to note that LH and FSH release from monkey pituitary cells was more responsive to GnRH I and GnRH II than that observed with rat pituitary cell cultures.

Antide, a GnRH I Antagonist, Blocks GnRH I-and GnRH II-stimulated LH and FSH Secretion

Antide, a potent GnRH I antagonist [20] with negligible binding affinity for the monkey GnRH II receptor (median inhibitory concentration, >10 000 nM) [21], was used to block LH and FSH release stimulated by GnRH I or GnRH II in monkey pituitary cultures. Cells were preincubated with 100 nM Antide or with control media for 16 h and then stimulated with GnRH I or GnRH II at doses of 1–100 nM for 6 h. As shown in Figure 2, Antide completely blocked LH and FSH secretion stimulated by either GnRH I or GnRH II at all doses tested.



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  		FIG. 2. Effect of a GnRH antagonist on LH and FSH secretion by monkey pituitary cell cultures stimulated with GnRH I or GnRH II. Cells were pretreated with vehicle (filled symbols) or 100 nM Antide (open symbols) for 16 h, and then GnRH I or GnRH II (1–100 nM) was added for 6 h. The experiment was replicated with two independent cell preparations from intact adult male rhesus monkey pituitary glands (two pituitaries per experiment) with similar results

GnRH I and GnRH II in Combination

We also examined the effects of cotreatment of monkey pituitary cultures with GnRH I and GnRH II on LH and FSH secretion. As shown in Figure 3, adding GnRH II in concentrations of 2 or 4 nM to a maximum stimulatory dose of GnRH I failed to increase LH or FSH secretion beyond the value for GnRH I alone.



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  		FIG. 3. Effects of cotreatment with GnRH I and GnRH II on LH and FSH secretion by monkey pituitary cultures. Cells were treated with GnRH I and/or GnRH II for 6 h. Culture media were collected and analyzed by RIA. All stimulated values are significantly different from vehicle (P < 0.05, ANOVA followed by the Tukey-Kramer multiple-comparison test). The experiment was replicated with two independent cell preparations from intact adult male rhesus monkey pituitary glands (two pituitaries per experiment) with similar results

Desensitization of Pituitary Cell Cultures to Stimulation by GnRH II or GnRH I

The mammalian GnRH II receptor has a C-terminal cytoplasmic tail that is important for rapid desensitization and that is absent in the GnRH I receptor. Accordingly, the idea that GnRH II-stimulated secretion would down-regulate more rapidly was tested. Early (first 6 h) and delayed (second 6 h) LH and FSH secretion stimulated by GnRH I and GnRH II were compared in monkey pituitary cultures treated with 1 nM or 4 nM GnRH I or GnRH II for 12 h; the results are shown in Table 1. As expected, 1 nM GnRH II was less potent than 1 nM GnRH I. The concentration of LH and FSH secreted during the first 6 h exceeded that in the second 6 h in cultures stimulated with either GnRH I or GnRH II.


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  		TABLE 1. Early and delayed stimulation of LH and FSH release by GnRH I and GnRH II.a

Effects of GnRH I or GnRH II on GH Secretion

We recently reported that the majority of LH-ß mRNA-positive cells in the pituitary of the male monkey also express GH mRNA [22]. Because GH levels rise with puberty in humans [23], the possibility that GnRH II stimulates gonadotrophs to release GH was studied by measuring GH in culture media. However, no significant effect on GH release by GnRH I or GnRH II in doses of 0.1 to 100 nM was found (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The expression of GnRH II in the monkey hypothalamus [7, 8] and the identification of a putative receptor for GnRH II in the human [10] and marmoset pituitary [11] raise the question of whether GnRH II activates this receptor to regulate gonadotropin synthesis and secretion in primates [24]. Our results in pituitary cell cultures from adult male rhesus monkeys reveal that GnRH II stimulates LH and FSH release but is less effective than GnRH I. Moreover, the gonadotropin-stimulatory actions of GnRH II, like those of GnRH I, were blocked by Antide, a GnRH I antagonist. Adding GnRH II failed to stimulate LH or FSH secretion beyond the effect of maximal stimulation by GnRH I alone, and both GnRH II and GnRH I stimulated the major portion of FSH and LH release within 6 h in plated cultures. Taken together, these data imply that GnRH II stimulates LH and FSH release from monkey pituitary cells by activating GnRH I receptors.

The finding in monkey pituitary cultures that GnRH II is less effective than GnRH I as a stimulator of FSH and LH secretion is consistent with previous results for sheep pituitary cell cultures in which GnRH II had 8% of the activity of GnRH I to release LH and FSH [25]. Likewise, in pituitary cell cultures from rats, in which the GnRH II receptor appears to be absent [16], GnRH II was approximately one-third as potent as GnRH I. In birds, on the other hand, GnRH II was 5- to 6-fold more potent than chicken type I GnRH in releasing LH from pituitary cell cultures from male chickens [26] and 2.5-fold more potent using perifused pituitary cells from male turkeys [27]. Thus, the GnRH II system in gonadotrophs is more active in nonmammalian species.

We next determined that the GnRH-antagonist Antide at a dose of 100 nM blocked completely LH and FSH secretion stimulated by GnRH II as well as GnRH I. Because the EC50 for Antide for the GnRH II receptor overexpressed in COS-1 cells was greater than 10 000 nM versus 1 nM for the GnRH I receptor [21], Antide is a highly selective GnRH I antagonist. We also found that the combination of GnRH I and GnRH II did not produce greater stimulation of LH or FSH release than did GnRH I alone. Large numbers of LH-positive cells in the sheep anterior pituitary express receptors for GnRH II [11], but to our knowledge, whether monkey gonadotrophs express type II GnRH receptor has not been investigated. If functional type II GnRH receptors are expressed in monkey gonadotrophs and separate signaling pathways are employed by each receptor, the effects of the two forms of GnRH should exceed those of either ligand alone. Taken together, these findings imply that GnRH II activates the type I GnRH receptor in monkey pituitary cells to stimulate gonadotropin secretion.

We reported recently that the majority of primate gonadotrophs express the GH gene [22]. This finding followed similar observations in rat pituitary cells [28]. Because GH secretion rises with puberty [23], we also tested whether GnRH II stimulates GH secretion, but we found no effect.

Substantial interest exists regarding the factors that differentially regulate FSH and LH. In early studies of pituitary cells from mature hens, chicken GnRH II was found to have 2-fold greater potency (EC50) to release FSH versus LH when compared to stimulation by chicken type I GnRH [25]. With rat hemipituitaries, on the other hand, chicken GnRH II was no more potent than mammalian GnRH I as a stimulator of FSH when compared to LH [29]. In rams, the mean ratio of circulating FSH to LH was approximately 2-fold higher following 10 µg i.v. doses of GnRH II compared with GnRH I [11]. Our results using pituitary cell cultures do not support the notion that GnRH II plays a role in the selective secretion of FSH in male primates.

Candidate sequences for the human GnRH II receptor are found on chromosomes 1 and 14. The chromosome 14 sequence is comprised of only exons 2 and 3, contains an intron, and is transcribed in the antisense orientation [30]. A second human type II receptor based on exon 1 expression was found by dot blotting in human sperm and faintly in central nervous system and peripheral tissues, but not in human pituitary. This gene contains a stop codon and a frame shift [31, 32], and it may be a pseudogene. Thus, whether a full-length functional GnRH II receptor is expressed in humans remains uncertain. The GnRH II receptor mRNA was identified in the marmoset pituitary by PCR using a cDNA from marmoset brain and in the preoptic area, amygdala, and periventicular region of the hypothalamus in the monkey by immunocytochemistry using an antiserum to a synthetic peptide from the human receptor [11].

Because GnRH 1 and GnRH II mRNA and peptide are not coexpressed in the monkey brain [9] and there is no evidence that GnRH II is found at high concentration in hypothalamic portal blood, the functions of these similar decapeptides may be quite dissimilar. GnRH II has been proposed to regulate sexual behavior [3]. The administration of GnRH II, but not of GnRH I, stimulated courtship behavior in female sparrows [33]. Recently, GnRH II administered into the cerebral ventricle of female musk shrews, a nocturnal mammal, was shown to stimulate sexual behavior if the animals were food-restricted for 48 h [34]. Although we currently have only a rudimentary understanding of the neuroendocrine control of behavior in male primates, GnRH II mRNA expression was found to be substantially greater in the mediobasal hypothalamus in adult compared with juvenile monkeys [35]. Thus, GnRH II may also influence sexual behavior in primates.

While this manuscript was being revised, Densmore and Urbanski [36] reported that Antide blocked the effect of GnRH II, but also that GnRH I and GnRH II produced similar elevations of circulating LH and FSH in female monkeys. Those authors concluded that the gonadotropin-stimulatory actions of GnRH II likely were mediated via the GnRH I receptor. Overall, it remains possible that the GnRH II receptor may have a unique function in the monkey brain and pituitary other than as a regulator of gonadotropin secretion; however, more studies are needed.


   ACKNOWLEDGMENTS
 
The authors wish to acknowledge the expert technical assistance provided by Mr. Dushan Ghooray and Mr. Alan Icard. We also thank Dr. Clifford R. Pohl and the staff of the Assay Core of the Center for Research in Reproductive Physiology of the University of Pittsburgh (U54-HD005610) for performing the monkey LH and FSH immunoassays.


   FOOTNOTES
 
1 Supported by NIH grants HD 19546, CA 60871 (to S.S.K.), the Walter F. and Avis Jacobs Foundation, and the Commonwealth of Kentucky Research Challenge Fund. Y.O. is an International Research Fellow from Tokyo Medical and Dental University (Tokyo, Japan). Back

2 Correspondence: Stephen J. Winters, Division of Endocrinology and Metabolism, University of Louisville Health Sciences Center, ACB-A3G11, 530 S. Jackson Street, Louisville, KY 40202. FAX: 502 852 4978; sjwint01{at}louisville.edu Back

Received: 10 February 2003.

First decision: 26 February 2003.

Accepted: 5 June 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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