Original Article
Brief Report
Familial Gestational Hyperthyroidism Caused by a Mutant Thyrotropin Receptor Hypersensitive to Human Chorionic Gonadotropin
N Engl J Med 1998; 339:1823-1826December 17, 1998
- Article
Some degree of stimulation of the thyroid gland by human chorionic gonadotropin is common during early pregnancy.1-3 When serum chorionic gonadotropin concentrations are abnormally high — for example, in women with molar pregnancies — overt hyperthyroidism may ensue. The pathophysiologic mechanism is believed to be promiscuous stimulation of the thyrotropin receptor by the excess chorionic gonadotropin.4,5 The explanation for this stimulation is the close structural relations between chorionic gonadotropin and thyrotropin and between their receptors.6
Hyperemesis gravidarum is characterized by excessive vomiting in early pregnancy, leading to the loss of 5 percent or more of body weight.4 It is usually self-limited and therefore of little clinical consequence.5,7 Some women with the disorder have high serum thyroid hormone concentrations, and a few have sufficient clinical manifestations of hyperthyroidism to warrant short-term treatment with antithyroid drugs.8,9 Many but not all women with hyperemesis gravidarum and hyperthyroidism have high serum chorionic gonadotropin concentrations, raising the possibility that other factors contribute to the hyperthyroidism.3,8,9
We describe a woman and her mother who had recurrent gestational hyperthyroidism and normal serum chorionic gonadotropin concentrations. Both women were heterozygous for a missense mutation in the extracellular domain of the thyrotropin receptor. The mutant receptor was more sensitive than the wild-type receptor to chorionic gonadotropin, thus accounting for the occurrence of hyperthyroidism despite the presence of normal chorionic gonadotropin concentrations.
Case Report
The proband was a 27-year-old woman who was 10 weeks' pregnant when referred for the evaluation and treatment of hyperthyroidism. This was her third pregnancy, the first and second having resulted in early miscarriage accompanied by severe nausea and vomiting. She again reported severe nausea and vomiting and had recently lost 5 kg in weight. Physical examination revealed persistent tachycardia (heart rate, 120 beats per minute), excessive sweating, and tremor of the hands. There was a small, diffuse goiter and no ophthalmopathy. Laboratory studies revealed the following values: serum thyrotropin concentration, <0.07 μU per milliliter (normal, 0.2 to 6); serum free thyroxine concentration, 4.7 ng per deciliter (60 pmol per liter; normal, 0.8 to 1.9 ng per deciliter [11 to 24 pmol per liter]); and serum triiodothyronine concentration, 605 ng per deciliter (9.77 nmol per liter; normal, 65 to 170 ng per deciliter [1.05 to 2.75 nmol per liter]). No antibodies to thyroid peroxidase or the thyrotropin receptor were detected in serum.
The patient was treated with 450 mg of propylthiouracil per day for eight weeks, and the dose was then tapered to 150 mg per day. Her condition improved rapidly, and she remained clinically and biochemically euthyroid for the rest of her pregnancy. She delivered a normal girl at 38 weeks of gestation, at which time the propylthiouracil was discontinued. The patient did not return for a follow-up examination post partum.
Eighteen months later, after seven weeks of amenorrhea, she was referred for a recurrence of hyperthyroidism associated with hyperemesis gravidarum. The findings on examination were similar to those during the previous pregnancy. The patient denied having any symptoms during the intervening period. The results of laboratory studies were as follows: serum thyrotropin concentration, <0.07 μU per milliliter; serum free thyroxine concentration, 4.5 ng per deciliter (58 pmol per liter); and serum chorionic gonadotropin, 70 U per milliliter (normal range for the first trimester of pregnancy, 38 to 173). Serum thyroid-stimulating activity was undetectable.
The patient was treated with 250 mg of propylthiouracil per day for four weeks, and because her serum thyrotropin concentrations remained low, the dose was tapered to between 50 and 150 mg per day for the rest of the pregnancy (Figure 1Figure 1
Serum Free Thyroxine and Thyrotropin Concentrations during the Index Patient's Fourth Pregnancy.). She delivered a normal boy at 38 weeks of gestation, at which time the propylthiouracil was again discontinued. She was clinically and biochemically euthyroid when last examined four months after delivery.The patient's mother reported a similar history. She had given birth to the patient at the age of 27, two years after having a miscarriage. The pregnancy was complicated by nausea, vomiting, and weight loss of 7 kg during the first trimester. Delivery was without complications and occurred at term. The same symptoms recurred during a subsequent pregnancy, and the woman was treated with carbimazole for what was believed to be hyperthyroidism due to Graves' disease, despite the absence of goiter and ophthalmopathy. She delivered a normal boy at 40 weeks of gestation. Carbimazole was discontinued two months after delivery. Since that time she has remained euthyroid and has had no more pregnancies.
The study was approved by the local ethics committee, and both women gave informed consent.
Methods
Hormone Assays
Serum free thyroxine was measured by radioimmunoassay (Sorin Biomedica, Anthony, France), and serum thyrotropin and chorionic gonadotropin were measured by chemiluminescence assays (ACS180, Chiron, Cergy Pontoise, France). Thyroid-stimulating activity in the serum was assayed in cultures of Chinese-hamster–ovary cells, 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 the sequences of all exons of the thyrotropin-receptor gene and the intron–exon junctions were determined as described previously.11
Functional Characterization of the Mutant
The mutation identified in the thyrotropin-receptor gene of the patient and her mother was introduced in wild-type thyrotropin-receptor complementary DNA (cDNA) by site-directed mutagenesis based on the polymerase chain reaction (PCR). In brief, an Xho I–Afl III restriction fragment encompassing the mutated site was ligated to wild-type thyrotropin-receptor cDNA that had been inserted in the expression vector pSVL (Pharmacia, Roosendaal, the Netherlands). The sequence of the segment containing the mutation was verified on both strands.
Plasmids encoding wild-type or mutant thyrotropin receptors and wild-type luteinizing hormone or follicle-stimulating hormone receptors were transfected into COS-7 cells by the DEAE–dextran method.11 Cell-surface expression of the wild-type and mutant receptors was assessed by a FACScan flow cytometer (Becton Dickinson, San Diego, Calif.) with a mouse monoclonal antibody (BA-8) that recognizes a conformational epitope of the extracellular domain of the human thyrotropin receptor.12
The production of cyclic AMP (cAMP) was measured in the cells at base line and after incubation for 60 minutes11 with bovine thyrotropin (Sigma, Bornem, Belgium), chorionic gonadotropin from 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 DNA from the patient identified the substitution of guanine for adenine at codon 183 in exon 7 in one allele of the thyrotropin-receptor gene. This substitution results in the replacement of a lysine residue 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 characteristic that allows easy screening of the general population. None of 100 unrelated normal subjects carried the mutation, ruling out the possibility that it is a common polymorphism.
Functional Characterization of the Mutant Receptor
When transfected into COS-7 cells, the mutant cDNA was expressed at the cell surface at a concentration similar to that of the wild-type receptor (data not shown). Basal production of cAMP in cells expressing the mutant receptor was similar to that in cells expressing the wild-type receptor, as were the sensitivity and maximal responsiveness of the cells to bovine thyrotropin (Figure 2AFigure 2
Functional Characteristics of the Mutant Thyrotropin Receptor in COS-7 Cells.). In contrast, chorionic gonadotropin in concentrations of up to 1000 U per milliliter caused a dose-dependent increase in cAMP production by cells containing the mutant receptor, but only a minimal increase in cells containing the wild-type receptor (Figure 2B). Comparison of the stimulation of cAMP production by chorionic gonadotropin in cells containing the wild-type luteinizing hormone receptor or the mutant thyrotropin receptor indicated that the mutant was about 1000 times less responsive (Figure 2C).Serum from a pregnant woman with a high serum chorionic gonadotropin concentration (280 U per milliliter) was diluted to achieve a concentration (65 U per milliliter) that was similar to the values recorded during the first trimester of pregnancy. This concentration of chorionic gonadotropin caused cAMP production to increase by a factor of 3.5 in COS-7 cells expressing the mutant thyrotropin receptor, but it had no effect on cells expressing the wild-type receptor. Follicle-stimulating hormone (200 mU per milliliter) had no effect on cells expressing either the mutant or the wild-type receptor.
The results of assays of direct binding of radiolabeled chorionic gonadotropin or the displacement of radiolabeled thyrotropin by chorionic gonadotropin from the mutant receptors were negative (data not shown).
Discussion
The phenotype and genotype of our patient and her mother, together with the functional characteristics of the mutant thyrotropin receptor, led to a syndrome of hereditary gestational hyperthyroidism caused by hypersensitivity of the thyrotropin receptor to chorionic gonadotropin. The mutation is remarkable in that it broadens the ligand specificity of a G-protein–coupled receptor without altering sensitivity to the native ligand, thyrotropin.
The mechanism responsible for gestational hyperthyroidism in these women differs from that of the hyperthyroidism associated with molar pregnancies and, at least in some women, hyperemesis gravidarum. In women with the latter two conditions, hyperthyroidism results from the activation of the thyrotropin receptor by excessive quantities of chorionic gonadotropin or by chorionic gonadotropin molecules with increased thyrotropin-like activity.13-16 These two situations may be viewed as exaggerated forms of the thyroid stimulation that occurs at the time of maximal chorionic gonadotropin production in many normal pregnant women.1 In contrast, in our patient and her mother, both of whom were heterozygous for the K183R mutation, normal serum chorionic gonadotropin concentrations that would not stimulate the wild-type thyrotropin receptor excessively caused hyperthyroidism that was severe enough to necessitate antithyroid-drug therapy during pregnancy.
The relation between hyperemesis gravidarum and gestational hyperthyroidism is not clear. In some studies, high serum free thyroid hormone concentrations were found in 30 to 70 percent of women with hyperemesis gravidarum,5,7 but in other studies, few women had high values.17 Whether hyperemesis results from hyperthyroidism, from the hyperestrogenic state associated with hyperstimulation by chorionic gonadotropin, or from other mechanisms is not known.9,18-20 The finding of severe recurrent hyperemesis in the presence of normal serum chorionic gonadotropin concentrations in our patient suggests that hyperemesis is related to hyperthyroidism.
Considering its functional consequences, the mutation identified — the substitution of arginine for lysine at position 183 — is surprisingly conservative. This position is in a region of the receptor that constitutes the putative surface of interaction with thyrotropin.21,22 An arginine at position 183 may increase the stability of the illegitimate complex between chorionic gonadotropin and the thyrotropin receptor enough to cause signal transduction by the increased serum chorionic gonadotropin concentrations present in pregnant women.23 However, despite the fact that luteinizing hormone activates the wild-type thyrotropin receptor more easily than does chorionic gonadotropin,24 the serum luteinizing hormone concentrations after menopause would remain 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 function in the mutant thyrotropin receptor in response to stimulation by chorionic gonadotropin, in agreement with our inability to detect binding of chorionic gonadotropin.
Unlike other mammals, primates rely on chorionic gonadotropin for the maintenance of the corpus luteum in early pregnancy.25 Our data, together with the fact that thyrotropin secretion is often partially suppressed during the period when chorionic gonadotropin concentrations are maximal, suggest that evolution has led to the selection of physiologic mechanisms that operate close to the border of hyperthyroidism during normal pregnancy.
Supported by funds from the European Union Program for Training and Mobility (to Dr. Rodien); by the Belgian Program of University Poles of Attraction, Service for Sciences, Technology and Culture; and by grants from the Fonds de la Recherche Scientifique Médicale and the Fonds National de la Recherche Scientifique.
We are indebted to Dr. T. Minegishi (Maebashi, Japan) for the cDNA encoding the receptors for luteinizing hormone, chorionic gonadotropin, and follicle-stimulating hormone; to Dr. C. Gervy for the bovine thyrotropin assays; to Ms. Muriel Nguyen and Mr. Claude Massart for expert technical assistance; to Professor Samuel Refetoff for his critical reading of the manuscript; and to Organon for the generous gift of recombinant follicle-stimulating hormone.
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
References
1
Glinoer D . The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-433
CrossRef | Web of Science | Medline2
Burrow GN . Thyroid function and hyperfunction during gestation. Endocr Rev 1993;14:194-202
Web of Science | Medline3
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
CrossRef | Web of Science | Medline4
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
CrossRef | Web of Science | Medline5
Swaminathan R ,Chin RK ,Lao TT ,Mak YT ,Panesar NS ,Cockram CS . Thyroid function in hyperemesis gravidarum. Acta Endocrinol (Copenh) 1989;120:155-160
Medline6
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
CrossRef | Web of Science | Medline7
Bouillon R ,Naesens M ,Van Assche FA , et al. Thyroid function in patients with hyperemesis gravidarum. Am J Obstet Gynecol 1982;143:922-926
Web of Science | Medline8
Jeffcoate WJ ,Bain C . Recurrent pregnancy-induced thyrotoxicosis presenting as hyperemesis gravidarum: case report. Br J Obstet Gynaecol 1985;92:413-415
CrossRef | Medline9
Krentz AJ ,Redman H ,Taylor KG . Hyperthyroidism associated with hyperemesis gravidarum. Br J Clin Pract 1994;48:75-76
Medline10
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 | Web of Science | Medline11
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
CrossRef | Web of Science | Medline12
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
Web of Science | Medline13
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
CrossRef | Web of Science | Medline14
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
CrossRef | Web of Science | Medline15
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
CrossRef | Web of Science | Medline16
Goodwin TM ,Hershman JM . Hyperthyroidism due to inappropriate production of human chorionic gonadotropin. Clin Obstet Gynecol 1997;40:32-44
CrossRef | Web of Science | Medline17
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
CrossRef | Web of Science | Medline18
Evans AJ ,Li TC ,Selby C ,Jeffcoate WJ . Morning sickness and thyroid function. Br J Obstet Gynaecol 1986;93:520-522
Medline19
Rosenthal FD ,Jones C ,Lewis SI . Thyrotoxic vomiting. BMJ 1976;2:209-211
CrossRef | Web of Science | Medline20
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
Web of Science | Medline21
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
CrossRef | Web of Science | Medline22
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 | Web of Science | Medline23
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 | Web of Science | Medline24
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
CrossRef | Web of Science | Medline25
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
CrossRef | Medline
- Citing Articles (61)
Citing Articles
1
Robert P. Millar, Claire L. Newton, Antonia K. Roseweir. 2012. Neuroendocrine GPCR Signaling. , 21-53.
CrossRef2
Philippe Caron. (2011) Dysthyroïdies et grossesse. La Presse Médicale
CrossRef3
D. Führer. (2011) Schilddrüsenerkrankungen und Schwangerschaft. Der Internist 52:10, 1158-1166
CrossRef4
Alex Stagnaro-Green, Marcos Abalovich, Erik Alexander, Fereidoun Azizi, Jorge Mestman, Roberto Negro, Angelita Nixon, Elizabeth N. Pearce, Offie P. Soldin, Scott Sullivan, Wilmar Wiersinga. (2011) Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum. Thyroid 21:10, 1081-1125
CrossRef5
Gilbert Vassart, Sabine Costagliola. (2011) G protein-coupled receptors: mutations and endocrine diseases. Nature Reviews Endocrinology 7:6, 362-372
CrossRef6
Olaleye Sanu, Ronald F Lamont. (2011) Hyperemesis gravidarum: pathogenesis and the use of antiemetic agents. Expert Opinion on Pharmacotherapy 12:5, 737-748
CrossRef7
A. Delabaere, X. Tran, K. Jardon, J.-L. Pouly, N. Bourdel. (2011) Syndrome d’hyperstimulation ovarienne spontanée dans un contexte gravidique avec hypothyroïdie. Gynécologie Obstétrique & Fertilité 39:3, e64-e67
CrossRef8
Marlena S. Fejzo, Kimber W. MacGibbon, Roberto Romero, T. Murphy Goodwin, Patrick M. Mullin. (2011) Recurrence Risk of Hyperemesis Gravidarum. Journal of Midwifery & Women's Health 56:2, 132-136
CrossRef9
Alexander M. Goldman, Jorge H. Mestman. (2011) Transient Non-Autoimmune Hyperthyroidism of Early Pregnancy. Journal of Thyroid Research 2011, 1-11
CrossRef10
Virginia D. Sarapura, David F. Gordon, Mary H. Samuels. 2011. Thyroid-stimulating Hormone. , 167-203.
CrossRef11
H. Mönig, J. Hensen, H. Lehnert. (2010) Schilddrüsenerkrankungen und Schwangerschaft. Der Internist 51:5, 620-624
CrossRef12
S. F. Oosting, E. C. de Haas, T. P. Links, D. de Bruin, W. J. Sluiter, I. J. de Jong, H. J. Hoekstra, D. T. Sleijfer, J. A. Gietema. (2010) Prevalence of paraneoplastic hyperthyroidism in patients with metastatic non-seminomatous germ-cell tumors. Annals of Oncology 21:1, 104-108
CrossRef13
Komal Patil-Sisodia, Jorge H. Mestman. (2010) Graves Hyperthyroidism and Pregnancy: A Clinical Update. Endocrine Practice 16:1, 118-129
CrossRef14
Joachim Pohlenz, Guy Van Vliet. 2010. Developmental Abnormalities of the Thyroid. , 97-104.
CrossRef15
Stefan Karger, Dagmar Führer-Sakel. (2009) Schilddrüsenerkrankungen und Schwangerschaft. Medizinische Klinik 104:6, 450-456
CrossRef16
Mario Ascoli, David Puett. 2009. The Gonadotropin Hormones and Their Receptors. , 35-55.
CrossRef17
Marlena S. Fejzo, Sue Ann Ingles, Melissa Wilson, Wei Wang, Kimber MacGibbon, Roberto Romero, Thomas M. Goodwin. (2008) High prevalence of severe nausea and vomiting of pregnancy and hyperemesis gravidarum among relatives of affected individuals. European Journal of Obstetrics & Gynecology and Reproductive Biology 141:1, 13-17
CrossRef18
Onyebuchi E Okosieme, Helen Marx, John H Lazarus. (2008) Medical management of thyroid dysfunction in pregnancy and the postpartum. Expert Opinion on Pharmacotherapy 9:13, 2281-2293
CrossRef19
T. Murphy Goodwin. (2008) Hyperemesis Gravidarum. Obstetrics and Gynecology Clinics of North America 35:3, 401-417
CrossRef20
Niyati U. Chiniwala, Paul D. Woolf, Christopher P. Bruno, Sukhjinder Kaur, Harvey Spector, Kelli Yacono. (2008) Thyroid Storm Caused by a Partial Hydatidiform Mole. Thyroid 18:4, 479-481
CrossRef21
G. Meduri, A. Bachelot, M.P. Cocca, C. Vasseur, P. Rodien, F. Kuttenn, P. Touraine, M. Misrahi. (2008) Molecular pathology of the FSH receptor: New insights into FSH physiology. Molecular and Cellular Endocrinology 282:1-2, 130-142
CrossRef22
Anne De Leener, Gianluigi Caltabiano, Sanly Erkan, Mehmet Idil, Gilbert Vassart, Leonardo Pardo, Sabine Costagliola. (2008) Identification of the first germline mutation in the extracellular domain of the follitropin receptor responsible for spontaneous ovarian hyperstimulation syndrome. Human Mutation 29:1, 91-98
CrossRef23
ALAN M. RICE, SCOTT A. RIVKEES. 2008. Receptor Transduction of Hormone Action. , 26-73.
CrossRef24
Bindu Nayak, Steven P. Hodak. (2007) Hyperthyroidism. Endocrinology & Metabolism Clinics of North America 36:3, 617-656
CrossRef25
Anat Ben-Shlomo, Shlomo Melmed. (2007) Pituitary hormone receptors and tumorigenesis. Nature Reviews Cancer 7:9,
CrossRef26
G. Ducarme, J. Bertherat, E. Vuillard, M. Polak, J. Guibourdenche, D. Luton. (2007) Pathologies thyroïdiennes et grossesse. La Revue de Médecine Interne 28:5, 314-321
CrossRef27
CAROLYN A. LANE. (2007) Nausea and Vomiting of Pregnancy: A Tailored Approach to Treatment. Clinical Obstetrics and Gynecology 50:1, 100-111
CrossRef28
Andrea G Lania, Giovanna Mantovani, Anna Spada. (2006) Mechanisms of Disease: mutations of G proteins and G-protein-coupled receptors in endocrine diseases. Nature Clinical Practice Endocrinology & Metabolism 2:12, 681-693
CrossRef29
Benjamin U. Nwosu, Loukas Gourgiotis, Marvin C. Gershengorn, Susanne Neumann. (2006) Case History: A Novel Activating Mutation in Transmembrane Helix 6 of the Thyrotropin Receptor as Cause of Hereditary Nonautoimmune Hyperthyroidism. Thyroid 16:5, 505-512
CrossRef30
Marian Ludgate, Dagmar Fuhrer. 2006. Thyroid Dysfunction: Molecular Genetics. .
CrossRef31
Su-Chin Ho, Sui-Sin Goh, Qing Su, Daphne Hsu-Chin Khoo. (2005) Cysteine 390 mutation of the TSH receptor modulates its ectodomain as an inverse agonist on the serpentine domain with decrease in basal constitutive activity. Molecular and Cellular Endocrinology 245:1-2, 158-168
CrossRef32
Rui Lu, Kenneth D. Burman, Jacqueline Jonklaas. (2005) Transient Graves' Hyperthyroidism During Pregnancy in a Patient with Hashimoto's Hypothyroidism. Thyroid 15:7, 725-729
CrossRef33
Catarina Brasil d’Alva, Paulo Serafini, Eduardo Motta, Maria Beatriz da Fonte Kohek, Ana Claudia Latronico, Berenice Bilharinho Mendonca. (2005) Absence of follicle-stimulating hormone receptor activating mutations in women with iatrogenic ovarian hyperstimulation syndrome. Fertility and Sterility 83:6, 1695-1699
CrossRef34
Jan Bogerd, Joke C.M. Granneman, Rüdiger W. Schulz, Henry F. Vischer. (2005) Fish FSH receptors bind LH: How to make the human FSH receptor to be more fishy?. General and Comparative Endocrinology 142:1-2, 34-43
CrossRef35
John H Lazarus. (2005) Thyroid Disorders Associated with Pregnancy. Treatments in Endocrinology 4:1, 31-41
CrossRef36
André Lacroix, Valérie Baldacchino, Isabelle Bourdeau, Pavel Hamet, Johanne Tremblay. (2004) Cushing's syndrome variants secondary to aberrant hormone receptors. Trends in Endocrinology & Metabolism 15:8, 375-382
CrossRef37
Jerome M. Hershman. (2004) Physiological and pathological aspects of the effect of human chorionic gonadotropin on the thyroid. Best Practice & Research Clinical Endocrinology & Metabolism 18:2, 249-265
CrossRef38
S NADER. (2004) Thyroid disease and other endocrine disorders in pregnancy. Obstetrics and Gynecology Clinics of North America 31:2, 257-285
CrossRef39
R Navaneethakrishnan, SW Lindow, EA Masson, B Allan. (2004) Recurrent gestational thyrotoxicosis presenting as recurrent hyperemesis gravidarum--report of two cases. Journal of Obstetrics & Gynaecology 24:7, 774-775
CrossRef40
Dagmar Führer, Peter Lachmund, Istvan-Tibor Nebel, Ralf Paschke. (2003) The Thyrotropin Receptor Mutation Database: Update 2003. Thyroid 13:12, 1123-1126
CrossRef41
Samir A. Kouzi. (2003) Nausea and Vomiting of Pregnancy. American Journal of Pharmaceutical Education 67:2, 66
CrossRef42
Smits, Guillaume, Olatunbosun, Olufemi, Delbaere, Anne, Pierson, Roger, Vassart, Gilbert, Costagliola, Sabine, . (2003) Ovarian Hyperstimulation Syndrome Due to a Mutation in the Follicle-Stimulating Hormone Receptor. New England Journal of Medicine 349:8, 760-766
Full Text43
Vasseur, Claudine, Rodien, Patrice, Beau, Isabelle, Desroches, Agnès, Gérard, Capucine, de Poncheville, Loïc, Chaplot, Stéphanie, Savagner, Frédérique, Croué, Anne, Mathieu, Elisabeth, Lahlou, Najiba, Descamps, Philippe, Misrahi, Micheline, . (2003) A Chorionic Gonadotropin–Sensitive Mutation in the Follicle-Stimulating Hormone Receptor as a Cause of Familial Gestational Spontaneous Ovarian Hyperstimulation Syndrome. New England Journal of Medicine 349:8, 753-759
Full Text44
David S Cooper. (2003) Hyperthyroidism. The Lancet 362:9382, 459-468
CrossRef45
Daniel Glinoer. (2003) Management of hypo- and hyperthyroidism during pregnancy. Growth Hormone & IGF Research 13, S45-S54
CrossRef46
Frederique Ruf, Marc Y. Fink, Stuart C. Sealfon. (2003) Structure of the GnRH receptor-stimulated signaling network: insights from genomics. Frontiers in Neuroendocrinology 24:3, 181-199
CrossRef47
Viktória Kaczur, László G Puskás, Mária Takács, István András Rácz, Andrea Szendrői, Sára Tóth, Zsuzsanna Nagy, Csaba Szalai, Csaba Balázs, András Falus, Bjarne Knudsen, Nadir R Farid. (2003) Evolution of the thyrotropin receptor: a G protein coupled receptor with an intrinsic capacity to dimerize. Molecular Genetics and Metabolism 78:4, 275-290
CrossRef48
Roy E. Weiss, Peter M. Sadow. 2003. Thyroid Hormone Receptor, TSH and TSH Receptor Mutations. , 477-483.
CrossRef49
U. Neeb, A. Niesel, F. Schuppert. 2002. , 321-327.
CrossRef50
Kanakasabai L. Narasimhan, Michel W. Ghobrial, Edward B. Ruby. (2002) Hyperthyroidism in the Setting of Gestational Trophoblastic Disease. The American Journal of the Medical Sciences 323:5, 285-287
CrossRef51
Chin Pin Yeo, Daphne Hsu Chin Khoo, Peter Hsi Ko Eng, Hak Koon Tan, Sui Lan Yo, Edward Jacob. (2001) Prevalence of gestational thyrotoxicosis in Asian women evaluated in the 8th to 14th weeks of pregnancy: correlations with total and free beta human chorionic gonadotrophin. Clinical Endocrinology 55:3, 391-398
CrossRef52
Mary P. Gillam, Peter Kopp. (2001) Genetic defects in thyroid hormone synthesis. Current Opinion in Pediatrics 13:4, 364-372
CrossRef53
B. Corvilain, J. Van Sande, J. E. Dumont, G. Vassart. (2001) Somatic and germline mutations of the TSH receptor and thyroid diseases. Clinical Endocrinology 55:2, 143-158
CrossRef54
N. de Roux, E. Milgrom. (2001) Inherited disorders of GnRH and gonadotropin receptors. Molecular and Cellular Endocrinology 179:1-2, 83-87
CrossRef55
Colin M Dayan. (2001) Interpretation of thyroid function tests. The Lancet 357:9256, 619-624
CrossRef56
Arthur D. Conigrave. (2001) Molecular mechanisms of receptor dysfunction: implications for endocrine disorders. Current Opinion in Endocrinology & Diabetes 8:1, 41-46
CrossRef57
Dagmar Fuhrer, Ralf Paschke. (2000) Thyroid-stimulating hormone receptor mutations: update and clinical implications. Current Opinion in Endocrinology & Diabetes 7:5, 288-294
CrossRef58
John H. Lazarus, Amal Kokandi. (2000) Thyroid disease in relation to pregnancy: A decade of change. Clinical Endocrinology 53:3, 265-278
CrossRef59
Paul Atkins, S. Bernard Cohen, Brenda Joyce Phillips. (2000) Drug Therapy for Hyperthyroidism in Pregnancy. Drug Safety 23:3, 229-244
CrossRef60
JEROME M. HERSHMAN. (1999) Human Chorionic Gonadotropin and the Thyroid: Hyperemesis Gravidarum and Trophoblastic Tumors. Thyroid 9:7, 653-657
CrossRef61
Jorge H. Mestman. (1999) Diagnosis and management of maternal and fetal thyroid disorders. Current Opinion in Obstetrics and Gynaecology 11:2, 167-175
CrossRef
