The glycoprotein hormones form a family of structurally related trophic factors that regulate the gonads and the thyroid(1) . In humans these include the placental hormone hCG ()and the pituitary hormones hLH, hFSH, and human thyroid-stimulating hormone. Each is an heterodimer containing a common -subunit and a hormone-specific -subunit. Hormone function is initiated by binding of the hormones to a plasma membrane receptor that contains a large extracellular domain and a plasma membrane domain composed of seven hydrophobic -helices(2, 3) . This leads to activation of G-proteins and subsequent production of second messengers.

The mechanism by which hormone-receptor interaction leads to signal transduction is not known. In a widely assumed model of hCG-receptor interaction that we term the ``tether'' model, hCG binds with high affinity to the extracellular domain of the LH receptor(4) . Because the extracellular domain is tethered to the transmembrane domain, this brings the hormone close to the transmembrane domain. Signal transduction starts when a second site on the hormone binds to the transmembrane domain. Support for this model is based on the observations that the extracellular domain has high affinity for hCG (4, 5, 6, 7) and the report that hCG can elicit signal transduction from an LH receptor analog containing only the transmembrane domain(7, 8) . The tether model predicts that one large or two smaller regions of hCG on at least two faces of the protein would interact with the receptor. The portions of hCG that interact with the LH receptor are unknown.

One way to test the model would be to identify portions of the hormone that contact specific parts of the receptor. Most putative contact sites have been identified by scanning the hormone to find amino acid substitutions that cause a loss in hormone function or by measuring the abilities of synthetic hormone peptides to block hormone activity (9, 10, 11) . As noted in a companion study(53) , the complexity of these hormones may confound interpreting the results of these studies. For example, truncation of the -subunit at residue 87 leads to a hormone analog with very low affinity for the LH receptor, suggesting that this region may be involved in receptor contacts(1, 12) . However, as will be shown here, this analog is recognized better than hCG by antibodies that have higher affinities for the free -subunit than for hCG. This implies that the mutation has altered the interaction between the subunits and that it will be impossible to distinguish effects on hormone conformation from those on receptor binding without using high resolution techniques such as x-ray crystallography or NMR spectroscopy.

Another way to test the tether model is to identify portions of the hormone that are exposed in the hormone-receptor complex. We have used this approach because it does not depend on loss of function mutants and provides data that are more easily interpreted. The tether model predicts that more than one surface of hCG would be hidden in the hormone-receptor complex. Thus, it can be tested by scanning the surface of the hormone to find regions that are exposed or that are hidden in the hormone-receptor complex. This can be accomplished by identifying hormone epitopes that are recognized by monoclonal antibodies after hCG binds to LH receptors. Since antibodies are much larger molecules than hCG, they will bind to only those surfaces of hCG that do not contact the receptor or other nearby proteins.

In a companion study(53) , we showed that a large portion of the hormone -subunit is exposed in the hormone-receptor complex and that the conformation of the region most likely to make high affinity contacts with the receptor is changed following hormone binding. Here we report that a similar large portion of the -subunit can also be detected in the hormone-receptor complex. The crystal structure of deglycosylated hCG (13) shows that the -subunit is formed from three large loops held together by a cysteine knot (Fig. 1). Loops one and three are adjacent, and loop two is found at the other end of the protein. Loop two is the most conserved part of the -subunit and is located near -subunit loops one and three. To identify -subunit residues involved in -subunit antibody binding sites, we measured the abilities of the antibodies to bind heterodimers composed of hCG -subunit and bovine/human -subunit chimeras. Because bovine -subunit had low affinity for many antibodies made against the human -subunit, chimeras having human -subunit residues at an antibody binding site would be expected to bind an antibody much better than chimeras with bovine -subunit residues at these same sites. By comparing the sequences of analogs that bound antibodies with those that did not, we identified key residues likely to be involved in binding of a large panel of anti--subunit antibodies. The relative locations of these residues determined in epitope maps were consistent with the crystal structure of deglycosylated hCG(13) . The -subunit residues that are exposed in the hormone-receptor complex include residues in the N terminus and portions of the first and third loops. In combination with data for the -subunit in a companion study (53) and knowledge of residues that can be changed without disrupting hormone function, these observations enabled us to devise a model that explains how hCG interacts with LH receptors and initiates signal transduction.

Figure 1: Ribbon diagram of the -subunit. This figure illustrates the location of the three -subunit loops (dark blue) and the two oligosaccharide chains (red sticks). In the heterodimer, loop two of the -subunit is located near the front of loops one and three of the -subunit(13) . The -subunit seat belt loop that surrounds the second -subunit loop passes over the second loop midway down its length. The oligosaccharide shown at the bottom (Asn), but not the top (Asn) is essential for full signal transduction. Residues noted on the figure illustrate the relative locations of key antibody binding sites summarized in Table 2. Red, green, blue, and orange labels refer to some of the key residues in the epitopes of type I, II, IV, and V antibodies, respectively.

MATERIALS AND METHODS

Antibodies and Hormones

Mutagenesis

Figure 2: Diagram of the chimeras and analogs used in these studies. These analogs were produced by a combination of cassette and polymerase chain reaction mutagenesis as outlined in the text. The nomenclature refers to the locations of residues derived from the human -subunit. The amino acid sequence of the bovine and human -subunits are FPDGEFTMQGCPECKLKENKYFSKPDAPIYQCMGCCFSRAYPTPARSKKTMLVPKNITSEATCCVAKAFTKATVMGNVRVENHTECHCSTCYYHKS and APDVQDCPECTLQENPFFSQPGAPILQCMGCCFSRAYPTPLRSKKTMLVQKNVTSESTCCVAKSYNRVTVMGGFKVENHTACHCSTCYYHKS, respectively. Solid bars are residues derived from bovine -subunit and stippled bars are from human -subunit.

Production and Characterization of Recombinant -Subunit Chimeras

Receptor Binding Studies

Model of hCG-Antibody and hCG-Receptor Complexes

Modeling of hCG-receptor complexes will be described in detail elsewhere. Briefly, we modeled the LH receptor on the crystal structure of of porcine ribonuclease inhibitor (30) obtained from the Protein Data Bank (i.e. 1bnh.ent). We aligned the sequences of the leucine repeats in the LH receptor with those of the crystal structure of ribonuclease inhibitor. In this alignment residues encoded by the intron-exon junctions of the receptor become located in solvent exposed loops furthest from the portion of the extracellular domain that contacts the transmembrane domain. Five of the six glycosylation signals found in the LH receptor are also located in these loops. After adding oligosaccharides, we subjected the structure to energy minimization and molecular dynamics at 300 K using the modeling package Sybyl (Tripos, St. Louis, MO). The crystal structure of hCG was ``docked'' to this model of the extracellular domain of the receptor using biological information on the parts of the hormone that are exposed in the hormone-receptor complex reported in this and in a companion study(53) . The groove of the hormone between the - and -subunits thought to make the high affinity contacts identified in the companion study (53) was placed over receptor residues 93-170 which have been shown to control LH receptor binding specificity(31) . The hormone was rotated slightly around this putative contact until the exposed and hidden surfaces of the hormone were in positions that agreed sterically with the observations on antibody binding made in this and a companion study(53) . The fully glycosylated complex was then subjected to energy minimization and molecular dynamics until it reached a stable minimum energy. Finally, to illustrate the transmembrane domain, we visually docked the structure of rhodopsin (i.e. 1bac.ent from the Protein Data Bank) to the plasma membrane side of the hormone-receptor complex. During docking, the N-terminal end of the first -helix was placed beneath the C-terminal end of the extracellular domain. The structure of rhodopsin was then rotated until the helices were perpendicular to the central cavity of the extracellular domain. In this configuration helices 1-5 of rhodopsin made a direct contact with the extracellular domain of the receptor while helices 6 and 7 were under the open space created by the ``U'' shape of the extracellular domain.

RESULTS

A Portion of the -Subunit Is Exposed after hCG Binds to Membrane LH Receptors

Figure 3: Ability of antibodies to inhibit binding of I-hCG to LH receptors. Increasing amounts of antibodies as shown on the abscissa were incubated with radiolabeled hCG for 30 min at 37 °C. After the antibody had bound to the hormone, the mixture was added to homogenates of ovarian corpora lutea and the binding of I-hCG to LH receptors was measured as described in the text. Radiolabel that became bound to the membrane receptors is illustrated here. Values are means of closely agreeing duplicates (all antibodies except A101) or triplicates (A101).

Previous studies including those using antisera to hCG -subunit have failed to detect exposed residues of the -subunit and led to models of hormone binding in which the entire -subunit is close to the receptor(32) . The observations that two -subunit antibodies bound to hormone-receptor complexes show that these models are incorrect. However, we have also found that hCG can bind to membranes and other surfaces ``nonspecifically''(23) . Binding of A407 was readily detected with virtually every preparation of radiolabeled antibody; binding of A105 to receptor complexes was seen only with freshly iodinated preparations. To be certain that we were not observing the binding of A105 to hCG that became bound ``nonspecifically'' to the membranes, we repeated the studies using analogs of hCG that had related structures but different abilities to bind to LH receptors. A105 bound to receptor complexes prepared by incubating membrane receptors with hCG analogs having lutropin activity. It did not bind receptor preparations that had been incubated with similar amounts of closely related analogs that have low LH activity (Table 1). This showed that A105 recognized an exposed portion of the -subunit of hCG after the hormone was specifically bound to LH receptors.

Epitope Maps Show That Two Different Regions of the -Subunit Are Exposed in hCG-Receptor Complexes

Figure 4: Epitope map describing the binding sites of the antibodies used in these studies. These maps illustrate the relative properties of the antibodies to bind to hCG as discussed in the text. They were determined by measuring the abilities of the antibodies to bind to hCG at the same time.

Identification of Key Residues in the Antibody Binding Sites

Type Ia Antibodies Bind to the First Loop of the -Subunit Near the -Subunit Interface

Type Ib Antibodies Bind to a Surface on the First and Third Loops of the -Subunit That Faces the -Subunit

Type II Antibodies Bind to a Part of the Third -Subunit Loop

The Type III Antibody Binds to a Part of the Third Loop Near the Sites for the Type I and Type II Antibodies

The Type IV Antibody Binds to a Conformational Epitope Derived from the N Terminus and Regions of the -Subunit Derived from Loops One and Three Furthest from the -Subunit Interface

The Type V Antibody Binds to a Highly Conserved Portion of the Third -Subunit Loop Near the Cysteine Knot

Deletion of -Subunit Residues 88

Heterodimers lacking the C terminus of the -subunit have low affinities for their receptors and this has been interpreted as support for the idea that C terminus of the -subunit has a role in hormone binding(1) . To learn if the C terminus of the -subunit was involved in the binding sites of any of the -subunit antibodies, we tested the abilities of each antibody to bind an analog lacking -subunit residues 88-92. All of these antibodies bound to this analog indicating that residues 88-92 were not part of their binding sites (Table 5). Unexpectedly, antibodies that had higher affinity for the heterodimer recognized the analog lacking the C terminus better than hCG (Table 5). This suggested that this mutation distorted the interaction between the subunits without causing them to dissociate. We also found that deletion of the C terminus led to an increased ability of hCG to be recognized by A105, an antibody that bound to hormone-receptor complexes (Table 4). The binding site for A105 appears to be near the C terminus, and we anticipate that the mobility of the C terminus that prevents it from being seen in the crystal structure (13) also interferes with binding of A105. These observations indicate that it may be premature to conclude that the C terminus of the -subunit contacts the LH receptor based on the reduced abilities of analogs with mutations in this region to bind to LH receptors. In addition, these observations suggested that the ability of mutant subunits to combine into a heterodimer is not sufficient to detect the influences of mutations on hormone conformation.

DISCUSSION

The Identity of -Subunit Residues in Antibody Binding Sites Is Consistent with the Epitope Map and with the Crystal Structure of Deglycosylated hCG

The locations of all the antibody binding sites are consistent with the crystal structure of deglycosylated hCG(13) . This is most convincingly illustrated by predictions about the locations of residues in the twin loops of the -subunit made on the basis of the A109 and A407 binding sites. For example, as predicted from the ability of A109 to bind to chimeras(33) , residues 14-17 and 73-75 were found to be adjacent in the crystal structure. Also, the proximity of residues near the N terminus of the protein and residue 81 had been predicted from the A407 binding site prior to the crystal structure(33) . This suggested that the locations of the antibody binding sites have been correctly identified.

The Abilities of Hormones to Form Heterodimers Is Not Always a Good Indication That the Subunits Have Combined Correctly

()

Antibodies to the -Subunit Recognize Most of the Exposed Surfaces of Loops One and Three

Figure 5: Composite figure illustrating the relative binding sites of several anti--subunit antibodies. The -subunit is illustrated in white and the -subunit is shown in yellow. The oligosaccharides are illustrated in red. The relative locations of the antibody binding sites are shown by the positions of the space filled coordinates of the crystal structure of anti-lysozyme Fab fragments that have been placed visually. This was done by docking a high resolution structure for a lysozyme-anti-lysozyme Fab fragment complex perpendicular to hCG over residues that were identified as being in the antibody binding sites (Table 2). The view shown in the upper panel explains the relative abilities of the antibodies to bind to hCG at the same time (cf. epitope map, Fig. 4). Top panel, view from above the -subunit looking down on the tips of the first and third loops. Lower panel, view of molecule turned 90° and illustrating the second loop of the -subunit and the -subunit. Color code: -subunit, white; -subunit, yellow; oligosaccharides, red; type IV site, orange; type V site, blue; type II site, green; and type I site, purple.

Aside from monoclonal antibodies made against synthetic peptides, the binding sites for most anti--subunit antibodies have not been determined. The identification of key residues in the binding sites of antibodies we report here should have several practical applications. Many of the antibodies we have used in these studies are widely used for research and clinical diagnoses. Knowledge of the portions of hCG recognized by these antibodies will facilitate identifying unknown analytes present in serum or that are produced by tissues. Epitope maps prepared with these antibodies as reference compounds can also be used to predict the binding sites of other antibodies. Finally, since their binding sites are now known, these antibodies can be used to study the influence of mutations on specific regions of the protein and to detect changes in hormone conformation that may influence receptor binding (cf. Table 2and Table 5).

Model to Explain Hormone-Receptor Interaction and Gonadotropin-induced Signal Transduction

Figure 6: Model of hCG binding to the extracellular domain of the LH receptor that illustrates a mechanism of signal transduction. Note, panels in the left column illustrate a side view of the receptor and those in the right column illustrate the corresponding top view obtained by rotating the side view forward 90°. The free LH receptor (top left and right panels) ribbon model is based on the structure of RNase inhibitor (2) and was prepared by replacing residues in the leucine-rich repeats of RNase inhibitor with those of the corresponding repeats found in the LH receptor. Following extensive energy minimization and molecular dynamics, the receptor model was ``docked'' onto the structure of bacteriorhodopsin (52) to obtain a view illustrating the approximate sizes and orientations of the extracellular and transmembrane domains. The extracellular and cytoplasmic loops of the transmembrane domain are not shown. During docking, the C-terminal residue of the extracellular domain (Arg) was placed adjacent to the N-terminal end of the first -helix of rhodopsin (white). The remaining six helices of rhodopsin (shown in the order green, red, yellow, purple, orange, and magenta) were rotated to make maximal contact with the extracellular domain. The extracellular domain of the receptor is illustrated in blue (residues 1-93 and 170-341) and orange (residues 94-169). The orange-colored section of the extracellular domain illustrates a portion of the LH receptor that appears to control its ligand binding specificity. When this section of the LH receptor was substituted for the homologous region of the FSH receptor, the resulting chimera bound both hCG and hFSH with high affinity(31) . Five of the six receptor oligosaccharides are illustrated in yellow. In the hormone-receptor complex (middle left and right panels) note that, to improve the clarity of these panels, we have omitted the oligosaccharides and the transmembrane domain of the receptor. To dock the hormone to the receptor we moved the groove in hCG formed by -subunit loop two, -subunit loop three, and, to a lesser extent, -subunit loop one (13) over the orange-colored portion of the receptor (-subunit, red ribbon; -subunit, green ribbon; hormone oligosaccharides, red sticks). We then rotated the hormone about this intersection with the receptor to expose hormone residues found to be exposed and hidden based on the antibody binding data described in this and a companion study(53) . Finally, all the atoms in the hormone and extracellular domain of the receptor including those in their oligosaccharides were subjected to energy minimization and molecular dynamics at 300 K to eliminate bad contacts and optimize side chain interactions. This occurred without major structural changes in either the hormone or the receptor and led to the stable complex shown here. hCG -subunit loops one and three are immediately above the portion of the receptor known to convey lutropin binding specificity (i.e. colored orange). The second -subunit loop contacts the concave portion of this region of the extracellular domain on its inner surface. hCG -subunit loops one and three and -subunit loop two project into the large cavity formed by the U shape of the receptor extracellular domain and are nearest its C-terminal arm. The N-terminal ends of both hormone subunits (free ends of the - and -subunit ribbons shown in middle left panel) and the oligosaccharides of the -subunit (red oligosaccharide chains that point upward in middle left panel) are on the surface of the hormone furthest from the plasma membrane. Only those oligosaccharides on the -subunit are shown in the top view (middle right panel). Note the proximity of the oligosaccharide needed for signal transduction (i.e. that at Asn) and the N terminus of the extracellular domain of the receptor (middle right panel). Signal transduction results from the steric effect of the oligosacharide at Asn on the N-terminal end of the extracellular domain to widen the distance between its N- and C-terminal arms. This may be accentuated by steric interaction of -subunit loops one and three with the C-terminal end of the extracellular domain. The model does not require a direct interaction between the hormone and the transmembrane domain for signal transduction. Given the proximity of the hormone and the transmembrane domain in this model, these cannot be excluded. In antibody-hCG receptor complexes (lower left and right panels) the crystal structure of an Fab fragment-lysozyme complex was ``docked'' to residues of epitopes known to be exposed in hCG-receptor complexes. To minimize complexity, we illustrate only four of the five known antibody binding sites and none of the oligosaccharides on the hormone or the receptor. The orange and yellow ribbons correspond to Fab fragments docked over exposed residues of the -subunit (i.e. A105, yellow; A407, orange; cf. Table 2). The red and blue ribbons correspond to Fab fragments docked over exposed residues of the -subunit (i.e. B111, red; B112, blue). Key residues in the binding sites of these antibodies include 108-114 and 77, respectively. Not shown is the binding site of B105, an antibody that recognizes a portion of hCG containing residue 74 (cf. (53) ). The binding site for this antibody is most easily visualized as lying between that of the red and blue ribbons on the lower left panel.

There are few other configurations of the receptor that would account for the portions of the hormone in the receptor complex that can be detected by antibodies and that would also permit the hormone to be near the transmembrane domain. As discussed later, the conformation of another leucine-rich repeat protein, RNase inhibitor is horseshoe-shaped(30) . This provides considerable precedent for the model we have proposed. In addition, the model is consistent with the known interactions between hCG and the LH receptor discussed as follows.

First, the model of hCG-receptor interaction accounts for portions of the hormone that can be recognized by antibodies that bind to hormone-receptor complexes described here and in a companion study (53) (Fig. 6). In the -subunit this includes residues near the N terminus and most of the portions of the first and third -subunit loops furthest from the -subunit interface. In the -subunit this includes residues on the surfaces of the first and third loops that are furthest from the -subunit interface. Surfaces recognized by antibodies face away from all parts of the receptor and are not likely to be near other proteins in the cell membrane.

Second, the model explains why many residues in both - and -subunits usually proposed to be near the receptor interface can be replaced without altering receptor binding or hormone activity(24, 31) . In the -subunit these include most of the residues found in loops one and three near the -subunit interface, a few residues in the second loop including Arg-Lys(38) , and a residue that can be cross-linked to the -subunit (i.e. that corresponding to human -subunit Lys in pig and bovine LH)(39, 40) . In the -subunit these residues include nearly all the amino acids found in the second loop (24) and in the seat belt, the region that has the major influence on receptor binding specificity (24, 31) . The model suggests that the side chains of these residues do not make specific contacts with the receptor even though many of these residues are in the large groove of the extracellular domain. Their functions in signal transduction, if any, occurs primarily by steric effects. Mutations of residues that are found in this groove have relatively little influence on hormone function unless they disrupt the structure of the hormone.

Portions of the - and -subunits that become located between the arms of the receptor extracellular domain lose their abilities to be recognized by antibodies after they bind to LH receptors. These epitopes appear to be obscured by the receptor. Antibodies that bind to these regions are very effective in blocking hormone binding, a phenomenon that appears due in part to their abilities to prevent this region of the hormone from entering the space between the arms of the receptor. As noted earlier, Pantel et al.(41) have found that these antibodies can recognize hCG that is bound to truncated LH receptors, an observation that is consistent with this view.

Third, the structure of a U- or J-shaped extracellular domain could readily create a narrow projection that fits into the hormone groove created by the apposition of the second -subunit loop and portions of the first and third -subunit loops. Entry of a portion of the receptor into this groove could also account for the change in conformation of the -subunit that occurs on binding to receptors (28, 53) .

Fourth, the model of hCG-receptor interaction explains why the oligosaccharides are essential for signal transduction. In the model, binding of hormone to the receptor is distinct from signal transduction. Signal transduction occurs by an influence of the hormone on the distance between the arms of the extracellular domain. While it is possible that the hormone reduces this distance by binding to both arms of the extracellular domain, we think this is very unlikely since the residues in the portion of the hormone near the arms of the extracellular domain (24) and the leucine-rich receptor repeats in these arms (31) can be changed without disrupting signal transduction. More likely, we anticipate that the hormone will increase the distance between the two arms and we propose that this is the role played by the oligosaccharides in signal transduction. The sugars appear to function primarily by their bulk rather than by a specific interaction with the receptor, an idea that is consistent with the following observations. (a) It explains why both hLH and hCG are potent lutropins even though their sugars are quite different(42) . It also explains the full efficacy of hormones having high mannose sugars that have been expressed in Baculovirus(43) . (b) The bulk of the sugars resolves the differences in the influence of the oligosaccharides on efficacy(44) . That on the -subunit at Asn has the least effect on hormone efficacy because it extends beyond the arms of the receptor. The -subunit oligosaccharide at Asn has the greatest influence on efficacy because it is closest to the receptor. The oligosaccharides on the -subunit have an intermediate influence on efficacy. These project away from the hormone-receptor complex but are sufficiently near the arms of the extracellular domain that they could interact with them. (c) The influence of bulk accounts for the observations that sequential removal of the oligosaccharides from hCG using exoglycosidases is accompanied by a graded loss in efficacy(45) . (d) Finally, the observation that antibodies to hCG can restore efficacy to deglycosylated hCG (46, 47) is also consistent with the idea that the oligosaccharides function primarily by steric effects. Binding of antibodies to the exposed region of the -subunit would increase the bulk of the portion of the hormone that is found between the arms of the receptor extracellular domain.

Fifth, the model explains the observation that hCG will bind and activate FSH receptor analogs that have relatively few residues derived from the LH receptor(31) . Because the arms of the extracellular domain make few specific high affinity contacts with the side chains of the hormone, hCG analogs bind with high affinity to LH/FSH receptor chimeras that are derived mostly from the FSH receptor(31) . Further, because the ``contacts'' needed for signal transduction are ``steric'' in nature, both hCG and hFSH can elicit signal transduction from LH/FSH receptor chimeras(31) . Only a small part of the extracellular domain of the receptor appears essential for hormone binding. Thus, the model also explains why LH receptors that have been truncated at amino acid 206 are able to bind hCG with high affinity (4) .

Sixth, the model does not require the hormone to interact with the transmembrane domain of the receptor. However, since much of the hormone is present in the space between the arms of the extracellular domain, these interactions are not precluded. This would account for the reports that hCG can bind and activate the transmembrane domain of the LH receptor (7, 8) and that a synthetic peptide corresponding to the C terminus of the -subunit can stimulate cyclic AMP accumulation (48) . The interaction of a portion of the hormone with the transmembrane domain might also serve to attract the hormone into the groove in the extracellular domain and potentiate its effect on the conformation of the receptor. This would explain the observation that binding of hCG to a membrane bound receptor occurs with higher affinity than to soluble receptors.

Leucine-rich Domains Have Horseshoe Shapes Similar to the Shape Proposed for the Extracellular Domain of the LH Receptor

Signal Transduction by the Glycoprotein Hormones Is Fundamentally Similar to That Thought to Occur in Other G-protein-coupled Receptors

FOOTNOTES

*

These studies were supported in part by National Institutes of Health Grants HD14907, HD24650, and HD15454. A preliminary account describing how the antibody binding site data illustrated here can be used to devise protein models using distance geometry algorithms has been published elsewhere (33). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence should be addressed: Dept. of Obstetrics/Gynecology, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. Tel.: 908-235-4224; Fax: 908-235-4225.

¶

Present address: Ares Advanced Technology, Inc., 280 Pond Street, Randolph, MA 02368.

()

The abbreviations are: hCG, human chorionic gonadotropin; LH, lutropin; hLH, human LH; FSH, follitropin; hFSH, human follitropin.

()

Slaughter, S., Wang, Y., Myers, R. V., and Moyle, W. R. (1995) Mol. Cell. Endocrinol., in press.

ACKNOWLEDGEMENTS

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