Some degree of stimulation of the thyroid gland by human chorionicgonadotropin is common during early pregnancy.1,2,3 When serumchorionic gonadotropin concentrations are abnormally high for example, in women with molar pregnancies overt hyperthyroidismmay ensue. The pathophysiologic mechanism is believed to bepromiscuous stimulation of the thyrotropin receptor by the excesschorionic gonadotropin.4,5 The explanation for this stimulationis the close structural relations between chorionic gonadotropinand thyrotropin and between their receptors.6
Hyperemesis gravidarum is characterized by excessive vomitingin early pregnancy, leading to the loss of 5 percent or moreof body weight.4 It is usually self-limited and therefore oflittle clinical consequence.5,7 Some women with the disorderhave high serum thyroid hormone concentrations, and a few havesufficient clinical manifestations of hyperthyroidism to warrantshort-term treatment with antithyroid drugs.8,9 Many but notall women with hyperemesis gravidarum and hyperthyroidism havehigh serum chorionic gonadotropin concentrations, raising thepossibility that other factors contribute to the hyperthyroidism.3,8,9
We describe a woman and her mother who had recurrent gestationalhyperthyroidism and normal serum chorionic gonadotropin concentrations.Both women were heterozygous for a missense mutation in theextracellular domain of the thyrotropin receptor. The mutantreceptor was more sensitive than the wild-type receptor to chorionicgonadotropin, thus accounting for the occurrence of hyperthyroidismdespite the presence of normal chorionic gonadotropin concentrations.
Case Report
The proband was a 27-year-old woman who was 10 weeks' pregnantwhen referred for the evaluation and treatment of hyperthyroidism.This was her third pregnancy, the first and second having resultedin early miscarriage accompanied by severe nausea and vomiting.She again reported severe nausea and vomiting and had recentlylost 5 kg in weight. Physical examination revealed persistenttachycardia (heart rate, 120 beats per minute), excessive sweating,and tremor of the hands. There was a small, diffuse goiter andno ophthalmopathy. Laboratory studies revealed the followingvalues: serum thyrotropin concentration, <0.07 µU permilliliter (normal, 0.2 to 6); serum free thyroxine concentration,4.7 ng per deciliter (60 pmol per liter; normal, 0.8 to 1.9ng per deciliter [11 to 24 pmol per liter]); and serum triiodothyronineconcentration, 605 ng per deciliter (9.77 nmol per liter; normal,65 to 170 ng per deciliter [1.05 to 2.75 nmol per liter]). Noantibodies to thyroid peroxidase or the thyrotropin receptorwere detected in serum.
The patient was treated with 450 mg of propylthiouracil perday for eight weeks, and the dose was then tapered to 150 mgper day. Her condition improved rapidly, and she remained clinicallyand biochemically euthyroid for the rest of her pregnancy. Shedelivered a normal girl at 38 weeks of gestation, at which timethe propylthiouracil was discontinued. The patient did not returnfor a follow-up examination post partum.
Eighteen months later, after seven weeks of amenorrhea, shewas referred for a recurrence of hyperthyroidism associatedwith hyperemesis gravidarum. The findings on examination weresimilar to those during the previous pregnancy. The patientdenied having any symptoms during the intervening period. Theresults of laboratory studies were as follows: serum thyrotropinconcentration, <0.07 µU per milliliter; serum freethyroxine concentration, 4.5 ng per deciliter (58 pmol per liter);and serum chorionic gonadotropin, 70 U per milliliter (normalrange for the first trimester of pregnancy, 38 to 173). Serumthyroid-stimulating activity was undetectable.
The patient was treated with 250 mg of propylthiouracil perday for four weeks, and because her serum thyrotropin concentrationsremained low, the dose was tapered to between 50 and 150 mgper day for the rest of the pregnancy (Figure 1). She delivereda normal boy at 38 weeks of gestation, at which time the propylthiouracilwas again discontinued. She was clinically and biochemicallyeuthyroid when last examined four months after delivery.
Figure 1. Serum Free Thyroxine and Thyrotropin Concentrations during the Index Patient's Fourth Pregnancy.
To convert values for serum free thyroxine to picomoles per liter, multiply by 12.9.
The patient's mother reported a similar history. She had givenbirth to the patient at the age of 27, two years after havinga miscarriage. The pregnancy was complicated by nausea, vomiting,and weight loss of 7 kg during the first trimester. Deliverywas without complications and occurred at term. The same symptomsrecurred during a subsequent pregnancy, and the woman was treatedwith carbimazole for what was believed to be hyperthyroidismdue to Graves' disease, despite the absence of goiter and ophthalmopathy.She delivered a normal boy at 40 weeks of gestation. Carbimazolewas discontinued two months after delivery. Since that timeshe has remained euthyroid and has had no more pregnancies.
The study was approved by the local ethics committee, and bothwomen gave informed consent.
Methods
Hormone Assays
Serum free thyroxine was measured by radioimmunoassay (SorinBiomedica, Anthony, France), and serum thyrotropin and chorionicgonadotropin were measured by chemiluminescence assays (ACS180,Chiron, Cergy Pontoise, France). Thyroid-stimulating activityin the serum was assayed in cultures of Chinese-hamsterovarycells, stably transfected with the human thyrotropin receptor.10
Sequencing of the Thyrotropin-Receptor Gene
To determine the sequence of the thyrotropin-receptor gene,DNA was extracted from peripheral-blood leukocytes, and thesequences of all exons of the thyrotropin-receptor gene andthe intronexon junctions were determined as describedpreviously.11
Functional Characterization of the Mutant
The mutation identified in the thyrotropin-receptor gene ofthe patient and her mother was introduced in wild-type thyrotropin-receptorcomplementary DNA (cDNA) by site-directed mutagenesis basedon the polymerase chain reaction (PCR). In brief, an Xho IAflIII restriction fragment encompassing the mutated site was ligatedto wild-type thyrotropin-receptor cDNA that had been insertedin the expression vector pSVL (Pharmacia, Roosendaal, the Netherlands).The sequence of the segment containing the mutation was verifiedon both strands.
Plasmids encoding wild-type or mutant thyrotropin receptorsand wild-type luteinizing hormone or follicle-stimulating hormonereceptors were transfected into COS-7 cells by the DEAEdextranmethod.11 Cell-surface expression of the wild-type and mutantreceptors was assessed by a FACScan flow cytometer (Becton Dickinson,San Diego, Calif.) with a mouse monoclonal antibody (BA-8) thatrecognizes a conformational epitope of the extracellular domainof the human thyrotropin receptor.12
The production of cyclic AMP (cAMP) was measured in the cellsat base line and after incubation for 60 minutes11 with bovinethyrotropin (Sigma, Bornem, Belgium), chorionic gonadotropinfrom the urine of pregnant women (Intervet, Chorulon, Turnhout,Belgium), and recombinant follicle-stimulating hormone (Organon,Brussels, Belgium).
Results
Sequence Determination
Direct sequencing of PCR products amplified from genomic DNAfrom the patient identified the substitution of guanine foradenine at codon 183 in exon 7 in one allele of the thyrotropin-receptorgene. This substitution results in the replacement of a lysineresidue with an arginine (K183R) at position 183 of the receptor,which is in the middle of its extracellular N-terminal domain.The patient's mother was heterozygous for the same mutation.The mutation nullifies an Alu I restriction site, a characteristicthat allows easy screening of the general population. None of100 unrelated normal subjects carried the mutation, ruling outthe possibility that it is a common polymorphism.
Functional Characterization of the Mutant Receptor
When transfected into COS-7 cells, the mutant cDNA was expressedat the cell surface at a concentration similar to that of thewild-type receptor (data not shown). Basal production of cAMPin cells expressing the mutant receptor was similar to thatin cells expressing the wild-type receptor, as were the sensitivityand maximal responsiveness of the cells to bovine thyrotropin(Figure 2A). In contrast, chorionic gonadotropin in concentrationsof up to 1000 U per milliliter caused a dose-dependent increasein cAMP production by cells containing the mutant receptor,but only a minimal increase in cells containing the wild-typereceptor (Figure 2B). Comparison of the stimulation of cAMPproduction by chorionic gonadotropin in cells containing thewild-type luteinizing hormone receptor or the mutant thyrotropinreceptor indicated that the mutant was about 1000 times lessresponsive (Figure 2C).
Figure 2. Functional Characteristics of the Mutant Thyrotropin Receptor in COS-7 Cells.
Panel A shows the effect of stimulation of cAMP production by graded concentrations of bovine thyrotropin in cells transfected with wild-type or mutant thyrotropin receptor. The median (±SE) effective concentration of bovine thyrotropin was 0.76±0.24 µU per milliliter in cells transfected with the wild-type receptor and 0.75±0.08 µU per milliliter in cells transfected with the mutant receptor. Panel B shows the effect of stimulation of cAMP production by graded concentrations of chorionic gonadotropin in cells transfected with wild-type or mutant thyrotropin receptor. Panel C shows the effect of stimulation of cAMP production by graded concentrations of chorionic gonadotropin in cells transfected with wild-type luteinizing hormone receptor or mutant thyrotropin receptor. Cells were incubated with bovine thyrotropin or chorionic gonadotropin for 60 minutes. Transfections were performed in triplicate. Representative results are shown for one of three separate experiments in the case of Panels B and C and for one of four separate experiments in the case of Panel A. The I bars indicate the standard errors.
Serum from a pregnant woman with a high serum chorionic gonadotropinconcentration (280 U per milliliter) was diluted to achievea concentration (65 U per milliliter) that was similar to thevalues recorded during the first trimester of pregnancy. Thisconcentration of chorionic gonadotropin caused cAMP productionto increase by a factor of 3.5 in COS-7 cells expressing themutant thyrotropin receptor, but it had no effect on cells expressingthe wild-type receptor. Follicle-stimulating hormone (200 mUper milliliter) had no effect on cells expressing either themutant or the wild-type receptor.
The results of assays of direct binding of radiolabeled chorionicgonadotropin or the displacement of radiolabeled thyrotropinby chorionic gonadotropin from the mutant receptors were negative(data not shown).
Discussion
The phenotype and genotype of our patient and her mother, togetherwith the functional characteristics of the mutant thyrotropinreceptor, led to a syndrome of hereditary gestational hyperthyroidismcaused by hypersensitivity of the thyrotropin receptor to chorionicgonadotropin. The mutation is remarkable in that it broadensthe ligand specificity of a G-proteincoupled receptorwithout altering sensitivity to the native ligand, thyrotropin.
The mechanism responsible for gestational hyperthyroidism inthese women differs from that of the hyperthyroidism associatedwith molar pregnancies and, at least in some women, hyperemesisgravidarum. In women with the latter two conditions, hyperthyroidismresults from the activation of the thyrotropin receptor by excessivequantities of chorionic gonadotropin or by chorionic gonadotropinmolecules with increased thyrotropin-like activity.13,14,15,16These two situations may be viewed as exaggerated forms of thethyroid stimulation that occurs at the time of maximal chorionicgonadotropin production in many normal pregnant women.1 In contrast,in our patient and her mother, both of whom were heterozygousfor the K183R mutation, normal serum chorionic gonadotropinconcentrations that would not stimulate the wild-type thyrotropinreceptor excessively caused hyperthyroidism that was severeenough to necessitate antithyroid-drug therapy during pregnancy.
The relation between hyperemesis gravidarum and gestationalhyperthyroidism is not clear. In some studies, high serum freethyroid hormone concentrations were found in 30 to 70 percentof women with hyperemesis gravidarum,5,7 but in other studies,few women had high values.17 Whether hyperemesis results fromhyperthyroidism, from the hyperestrogenic state associated withhyperstimulation by chorionic gonadotropin, or from other mechanismsis not known.9,18,19,20 The finding of severe recurrent hyperemesisin the presence of normal serum chorionic gonadotropin concentrationsin our patient suggests that hyperemesis is related to hyperthyroidism.
Considering its functional consequences, the mutation identified the substitution of arginine for lysine at position183 is surprisingly conservative. This position is ina region of the receptor that constitutes the putative surfaceof interaction with thyrotropin.21,22 An arginine at position183 may increase the stability of the illegitimate complex betweenchorionic gonadotropin and the thyrotropin receptor enough tocause signal transduction by the increased serum chorionic gonadotropinconcentrations present in pregnant women.23 However, despitethe fact that luteinizing hormone activates the wild-type thyrotropinreceptor more easily than does chorionic gonadotropin,24 theserum luteinizing hormone concentrations after menopause wouldremain too low to cause activation of the mutant receptor. Indeed,the mother of our patient remained euthyroid after menopause.This finding is compatible with a relatively small gain of functionin the mutant thyrotropin receptor in response to stimulationby chorionic gonadotropin, in agreement with our inability todetect binding of chorionic gonadotropin.
Unlike other mammals, primates rely on chorionic gonadotropinfor the maintenance of the corpus luteum in early pregnancy.25Our data, together with the fact that thyrotropin secretionis often partially suppressed during the period when chorionicgonadotropin concentrations are maximal, suggest that evolutionhas led to the selection of physiologic mechanisms that operateclose to the border of hyperthyroidism during normal pregnancy.
Supported by funds from the European Union Program for Trainingand Mobility (to Dr. Rodien); by the Belgian Program of UniversityPoles of Attraction, Service for Sciences, Technology and Culture;and by grants from the Fonds de la Recherche Scientifique Médicaleand the Fonds National de la Recherche Scientifique.
We are indebted to Dr. T. Minegishi (Maebashi, Japan) for thecDNA encoding the receptors for luteinizing hormone, chorionicgonadotropin, and follicle-stimulating hormone; to Dr. C. Gervyfor the bovine thyrotropin assays; to Ms. Muriel Nguyen andMr. Claude Massart for expert technical assistance; to ProfessorSamuel Refetoff for his critical reading of the manuscript;and to Organon for the generous gift of recombinant follicle-stimulatinghormone.
Source Information
From the Institut de Recherche Interdisciplinaire (P.R., J.P., J.V., S.C., G.V., L.D.) and Service de Génétique Médicale (J.P., G.V.), Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium; the Service d'Endocrinologie Maladies Métaboliques, Hôpital Cochin, Paris (P.R., C.B., J.-P.L.); and the Centre National pour la Recherche Scientifique, Unité Propre de Recherche 1524, Paris (M.-L.R.S.).
Address reprint requests to Dr. Vassart at IRIBHN, Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium.
References
Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-433. [Free Full Text]
Burrow GN. Thyroid function and hyperfunction during gestation. Endocr Rev 1993;14:194-202. [Free Full Text]
Harada A, Hershman JM, Reed AW, et al. Comparison of thyroid stimulators and thyroid hormone concentrations in the sera of pregnant women. J Clin Endocrinol Metab 1979;48:793-797. [Free Full Text]
Goodwin TM, Montoro M, Mestman JH, Pekary AE, Hershman JM. The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum. J Clin Endocrinol Metab 1992;75:1333-1337. [Abstract]
Swaminathan R, Chin RK, Lao TT, Mak YT, Panesar NS, Cockram CS. Thyroid function in hyperemesis gravidarum. Acta Endocrinol (Copenh) 1989;120:155-160. [Free Full Text]
Grossmann M, Weintraub BD, Szkudlinski MW. Novel insights into the molecular mechanisms of human thyrotropin action: structural, physiological, and therapeutic implications for the glycoprotein hormone family. Endocr Rev 1997;18:476-501. [Free Full Text]
Bouillon R, Naesens M, Van Assche FA, et al. Thyroid function in patients with hyperemesis gravidarum. Am J Obstet Gynecol 1982;143:922-926. [Medline]
Jeffcoate WJ, Bain C. Recurrent pregnancy-induced thyrotoxicosis presenting as hyperemesis gravidarum: case report. Br J Obstet Gynaecol 1985;92:413-415. [Medline]
Krentz AJ, Redman H, Taylor KG. Hyperthyroidism associated with hyperemesis gravidarum. Br J Clin Pract 1994;48:75-76. [Medline]
Ludgate M, Perret J, Parmentier M, et al. Use of the recombinant human thyrotropin receptor (TSH-R) expressed in mammalian cell lines to assay TSH-R autoantibodies. Mol Cell Endocrinol 1990;73:R13-R18. [CrossRef][Medline]
Parma J, Duprez L, Van Sande J, et al. Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic thyroid adenomas. J Clin Endocrinol Metab 1997;82:2695-2701. [Free Full Text]
Costagliola S, Rodien P, Many MC, Ludgate M, Vassart G. Genetic immunization against the human thyrotropin receptor causes thyroiditis and allows production of monoclonal antibodies recognizing the native receptor. J Immunol 1998;160:1458-1465. [Free Full Text]
Hoermann R, Keutmann HT, Amir SM. Carbohydrate modifications transform human chorionic gonadotropin into a potent stimulator of adenosine 3',5'-monophosphate and growth responses in FRTL-5 thyroid cells. Endocrinology 1991;128:1129-1135. [Free Full Text]
Tsuruta E, Tada H, Tamaki H, et al. Pathogenic role of asialo human chorionic gonadotropin in gestational thyrotoxicosis. J Clin Endocrinol Metab 1995;80:350-355. [Abstract]
Kimura M, Amino N, Tamaki H, et al. Gestational thyrotoxicosis and hyperemesis gravidarum: possible role of hCG with higher stimulating activity. Clin Endocrinol (Oxf) 1993;38:345-350. [Medline]
Goodwin TM, Hershman JM. Hyperthyroidism due to inappropriate production of human chorionic gonadotropin. Clin Obstet Gynecol 1997;40:32-44. [CrossRef][Medline]
Wilson R, McKillop JH, MacLean M, et al. Thyroid function tests are rarely abnormal in patients with severe hyperemesis gravidarum. Clin Endocrinol (Oxf) 1992;37:331-334. [Medline]
Evans AJ, Li TC, Selby C, Jeffcoate WJ. Morning sickness and thyroid function. Br J Obstet Gynaecol 1986;93:520-522. [Medline]
Rosenthal FD, Jones C, Lewis SI. Thyrotoxic vomiting. BMJ 1976;2:209-211.
Depue RH, Bernstein L, Ross RK, Judd HL, Henderson BE. Hyperemesis gravidarum in relation to estradiol levels, pregnancy outcome, and other maternal factors: a seroepidemiologic study. Am J Obstet Gynecol 1987;156:1137-1141. [Medline]
Kajava AV, Vassart G, Wodak SJ. Modeling of the three-dimensional structure of proteins with the typical leucine-rich repeats. Structure 1995;3:867-877. [Medline]
Nagayama Y, Russo D, Chazenbalk GD, Wadsworth HL, Rapoport B. Extracellular domain chimeras of the TSH and LH/CG receptors reveal the mid-region (amino acids 171-260) to play a vital role in high affinity TSH binding. Biochem Biophys Res Commun 1990;173:1150-1156. [CrossRef][Medline]
Mrabet NT, Van den Broeck A, Van den brande I, et al. Arginine residues as stabilizing elements in proteins. Biochemistry 1992;31:2239-2253. [CrossRef][Medline]
Yoshimura M, Hershman JM, Pang XP, Berg L, Pekary AE. Activation of the thyrotropin (TSH) receptor by human chorionic gonadotropin and luteinizing hormone in Chinese hamster ovary cells expressing functional human TSH receptors. J Clin Endocrinol Metab 1993;77:1009-1013. [Abstract]
Stewart HJ, Jones DSC, Pascall JC, Popkin RM, Flint APF. The contribution of recombinant DNA techniques to reproductive biology. J Reprod Fertil 1988;83:1-57. [Free Full Text]
Oosting, S. F., de Haas, E. C., Links, T. P., de Bruin, D., Sluiter, W. J., de Jong, I. J., Hoekstra, H. J., Sleijfer, D. T., Gietema, J. A.
(2009). Prevalence of paraneoplastic hyperthyroidism in patients with metastatic non-seminomatous germ-cell tumors. Ann Oncol
0: mdp265v1-mdp265
[Abstract][Full Text]
Kleinau, G., Krause, G.
(2009). Thyrotropin and Homologous Glycoprotein Hormone Receptors: Structural and Functional Aspects of Extracellular Signaling Mechanisms. Endocr. Rev.
30: 133-151
[Abstract][Full Text]
Royer, J., Lefevre-Minisini, A., Caltabiano, G., Lacombe, T., Malthiery, Y., Savagner, F., Pardo, L., Rodien, P.
(2008). The Cloned Equine Thyrotropin Receptor Is Hypersensitive to Human Chorionic Gonadotropin; Identification of Three Residues in the Extracellular Domain Involved in Ligand Specificity. Endocrinology
149: 5088-5096
[Abstract][Full Text]
Haddow, J. E., McClain, M. R., Lambert-Messerlian, G., Palomaki, G. E., Canick, J. A., Cleary-Goldman, J., Malone, F. D., Porter, T. F., Nyberg, D. A., Bernstein, P., D'Alton, M. E., for the First and Second Trimester Evaluation of R,
(2008). Variability in Thyroid-Stimulating Hormone Suppression by Human Chronic Gonadotropin during Early Pregnancy. J. Clin. Endocrinol. Metab.
93: 3341-3347
[Abstract][Full Text]
Abalovich, M., Amino, N., Barbour, L. A., Cobin, R. H., De Groot, L. J., Glinoer, D., Mandel, S. J., Stagnaro-Green, A.
(2007). Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab.
92: s1-s47
[Abstract][Full Text]
Nagasaki, H., Wang, Z., Jackson, V. R, Lin, S., Nothacker, H.-P., Civelli, O.
(2006). Differential expression of the thyrostimulin subunits, glycoprotein {alpha}2 and {beta}5 in the rat pituitary.. J Mol Endocrinol
37: 39-50
[Abstract][Full Text]
De Leener, A., Montanelli, L., Van Durme, J., Chae, H., Smits, G., Vassart, G., Costagliola, S.
(2006). Presence and Absence of Follicle-Stimulating Hormone Receptor Mutations Provide Some Insights into Spontaneous Ovarian Hyperstimulation Syndrome Physiopathology. J. Clin. Endocrinol. Metab.
91: 555-562
[Abstract][Full Text]
Themmen, A. P N
(2005). An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms. Reproduction
130: 263-274
[Abstract][Full Text]
Costagliola, S., Urizar, E., Mendive, F., Vassart, G.
(2005). Specificity and promiscuity of gonadotropin receptors. Reproduction
130: 275-281
[Abstract][Full Text]
Mullenbach, R, Bennett, A, Tetlow, N, Patel, N, Hamilton, G, Cheng, F, Chambers, J, Howard, R, Taylor-Robinson, S D, Williamson, C
(2005). ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy. Gut
54: 829-834
[Abstract][Full Text]
Sealfon, S. C.
(2005). G Protein-Coupled Receptors. Sci Signal
2005: tr11-tr11
[Abstract][Full Text]
Montanelli, L., Van Durme, J. J. J., Smits, G., Bonomi, M., Rodien, P., Devor, E. J., Moffat-Wilson, K., Pardo, L., Vassart, G., Costagliola, S.
(2004). Modulation of Ligand Selectivity Associated with Activation of the Transmembrane Region of the Human Follitropin Receptor. Mol. Endocrinol.
18: 2061-2073
[Abstract][Full Text]
Rodien, P., Jordan, N., Lefevre, A., Royer, J., Vasseur, C., Savagner, F., Bourdelot, A., Rohmer, V.
(2004). Abnormal stimulation of the thyrotrophin receptor during gestation. Hum Reprod Update
10: 95-105
[Abstract][Full Text]
Delbaere, A., Smits, G., Olatunbosun, O., Pierson, R., Vassart, G., Costagliola, S.
(2004). New insights into the pathophysiology of ovarian hyperstimulation syndrome. What makes the difference between spontaneous and iatrogenic syndrome?. Hum Reprod
19: 486-489
[Abstract][Full Text]
Vasseur, C., Rodien, P., Beau, I., Desroches, A., Gerard, C., de Poncheville, L., Chaplot, S., Savagner, F., Croue, A., Mathieu, E., Lahlou, N., Descamps, P., Misrahi, M.
(2003). A Chorionic Gonadotropin-Sensitive Mutation in the Follicle-Stimulating Hormone Receptor as a Cause of Familial Gestational Spontaneous Ovarian Hyperstimulation Syndrome. NEJM
349: 753-759
[Full Text]
Smits, G., Olatunbosun, O., Delbaere, A., Pierson, R., Vassart, G., Costagliola, S.
(2003). Ovarian Hyperstimulation Syndrome Due to a Mutation in the Follicle-Stimulating Hormone Receptor. NEJM
349: 760-766
[Full Text]
Schubert, R. L., Narayan, P., Puett, D.
(2003). Specificity of Cognate Ligand-Receptor Interactions: Fusion Proteins of Human Chorionic Gonadotropin and the Heptahelical Receptors for Human Luteinizing Hormone, Thyroid-Stimulating Hormone, and Follicle-Stimulating Hormone. Endocrinology
144: 129-137
[Abstract][Full Text]
Smits, G., Govaerts, C., Nubourgh, I., Pardo, L., Vassart, G., Costagliola, S.
(2002). Lysine 183 and Glutamic Acid 157 of the TSH Receptor: Two Interacting Residues with a Key Role in Determining Specificity toward TSH and Human CG. Mol. Endocrinol.
16: 722-735
[Abstract][Full Text]
Kuscu, N K, Koyuncu, F
(2002). Hyperemesis gravidarum: current concepts and management. Postgrad. Med. J.
78: 76-79
[Abstract][Full Text]
Winter, W. E., Signorino, M. R.
(2001). Molecular Thyroidology. Annals of Clinical & Laboratory Science
31: 221-244
[Abstract][Full Text]
Lacroix, A., N'Diaye, N., Tremblay, J., Hamet, P.
(2001). Ectopic and Abnormal Hormone Receptors in Adrenal Cushing's Syndrome. Endocr. Rev.
22: 75-110
[Abstract][Full Text]
Fantz, C. R., Dagogo-Jack, S., Ladenson, J. H., Gronowski, A. M.
(1999). Thyroid Function during Pregnancy. Clin. Chem.
45: 2250-2258
[Abstract][Full Text]
Bhowmick, N., Narayan, P., Puett, D.
(1999). Identification of Ionizable Amino Acid Residues on the Extracellular Domain of the Lutropin Receptor Involved in Ligand Binding. Endocrinology
140: 4558-4563
[Abstract][Full Text]