Journal of Endocrinological Investigation

, Volume 26, Issue 11, pp 1128–1135 | Cite as

Hypothyroidism associated with anti-human chorionic gonadotropin antibodies secondarily produced by gonadotropin therapy in a case of idiopathic hypothalamic hypogonadism

  • T. Ogura
  • Y. Mimura
  • Fumio Otsuka
  • M. Kishida
  • K. Yokota
  • J. Suzuki
  • A. Nagai
  • S. Hirakawa
  • H. Makino
  • K. Tobe
Case Report


We report a 22-yr-old male patient with idiopathic hypothalamic hypogonadism who showed secondary resistance to gonadotropin (Gn) therapy over 3 yr after successful treatment with hCG combined with human menopausal Gn. The patient simultaneously developed subclinical hypothyroidism. Endocrine examination revealed low levels of testosterone (0.3 ng/ml), free T4 (0.91 ng/dl), and increased levels of TSH (31.1 μU/ml) in the serum. Serum autoantibodies to thyroid gland were all negative. Interestingly, thyroid function was improved after discontinuation of Gn therapy. In vitro assays by immunoprecipitation using 125I-hCG or 125I-TSH elucidated the presence of anti-hCG antibody in the serum 13 months after commencement of Gn therapy but anti-TSH antibody was not detected in the serum. Furthermore, the anti-hCG antibody specifically bound to hCG but not to other glycoproteins including TSH and FSH based on a competitive displacement assay. Bioassays using porcine thyroid cells revealed that the serum γ-globulin fraction enables the suppression of cyclic AMP (cAMP) synthesis stimulated by TSH. Our findings suggest that anti-hCG and/or anti-idiotypic hCG antibodies induced by hCG therapy impaired TSH-dependent cAMP production through interfering with binding of TSH to its receptor, and this resulted in subclinical hypothyroidism in this patient.


Anti-hCG antibody gonadotropin hypothyroidism idiopathic hypothalamic hypogonadism immunoprecipitation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Sokol RZ, McClure RD, Peterson M, Swerdloff RS. Gonadotropin therapy failure secondary to human chorionic gonadotropin-induced antibodies. J Clin Endocrino Metab 1981, 52: 929–32.CrossRefGoogle Scholar
  2. 2.
    Claustrat B, David L, Faure A, Francois R. Development of anti-human chorionic gonadotropin antibodies in patients with hypogonadotropic hypogonadism. A study of four patients. J Clin Endocrinol Metab 1983, 57: 1041–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Thau RB, Goldstein M, Yamamoto Y, Burrow GN, Phillips D, Bardin CW. Failure of gonadotropin therapy secondary to chorionic gonadotropin-induced antibodies. J Clin Endocrinol Metab 1988, 66: 862–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Hidaka A, Ban T, Panesar NS, Minegishi T, Kohn LD, Tahara K. Thyrotropin stimulation of the lutropin/choriogonadotropin receptor: Different sites mediate agonist activity and high affinity binding. Thyroid 1994, 4: 447–57.PubMedCrossRefGoogle Scholar
  5. 5.
    Kenimer JG, Hershman JM, Higgins HP. The thyrotropin in hydatidiform moles is human chorionic gonadotropin. J Clin Endocrinol Metab 1975, 40: 482–91.PubMedCrossRefGoogle Scholar
  6. 6.
    Kitahara S, Yoshida K, Ishizaka K, Higashi Y, Takagi K, Oshima H. Secondary treatment failure without anti-chorionic gonadotropin antibodies in a patient with Kallmann syndrome. Int J Urol 1998, 5: 398–400.PubMedCrossRefGoogle Scholar
  7. 7.
    Ogura T, Tobe K, Mimura Y, et al. Testosterone modulates serum leptin concentrations in a male patient with hypothalamic hypogonadism. J Endocrinol Invest 2000, 23: 246–50.PubMedCrossRefGoogle Scholar
  8. 8.
    Yoshimura M, Hershman JM, Pang XP, Berg L, Pekary AE. Activation of the thyrotropin (TSH) receptor by human chorionic gonadotropin and leutenizing hormones in Chinese hamster ovary cells expressing functional human TSH receptors. J Clin Endocrinol Metab 1993, 77: 1009–13.PubMedGoogle Scholar
  9. 9.
    Baker JR Jr, Lukes YG, Smallridge RC, Berger M, Burman KD. Partial characterization and clinical correlation of circulating human immunoglobulins directed against thyrotropin binding sites in guinea pig fat cell membrane. Development of a direct enzyme immunoassay. J Clin nvest 1983, 72: 1487–97.CrossRefGoogle Scholar
  10. 10.
    Biro J. Specific binding of thyroid-stimulating hormone by human serum globulins. J Endocrinol 1981, 88: 339–49.PubMedCrossRefGoogle Scholar
  11. 11.
    Akamizu T, Ishii H, Mori T, Ishihara T, Ikekubo K, Imura H. Abnormal thyrotropin-binding immunoglobulins in two patients with Graves’ disease. J Clin Endocrinol Metab 1984, 59: 240–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Kajita Y, Nakajima Y, Ishida M, et al. Characteristics of auto-antibodies to bovine TSH in the serum of two patients with Graves’ disease. Acta Endocrinol (Copenh) 1983, 104: 423–30.Google Scholar
  13. 13.
    Karlsson FA, Dahlberg PA, Alm J, Larsson A, Felding I. Maternal TSH-receptor antibodies and TSH antibodies in screening for congenital hypothyroidism. Acta Paediatr Scand 1986, 75: 756–61.PubMedCrossRefGoogle Scholar
  14. 14.
    Ochi Y, Nagamune Y, Nakajima Y, et al. Anti-TSH antibodies in Graves’ disease and their failure to interact with TSH receptor antibodies. Acta Endocrinol (Copenh) 1989, 120: 773–7.Google Scholar
  15. 15.
    Benkirane M, Bon D, Bellot F, et al. Characterization of monoclonal antibodies against human thyrotropin and use in an immunoradiometric assay and immunohistochem-istry. J Immunol Methods 1987, 98: 173–81.PubMedCrossRefGoogle Scholar
  16. 16.
    Yamazaki K, Sato K, Shizume K, et al. Potent thyrotropic activity of human chorionic gonadotropin variants in terms of 125I incorporation and de novo synthesized thyroid hormone release in human thyroid follicles. J Clin Endocrinol Metab 1995, 80: 473–9.PubMedGoogle Scholar
  17. 17.
    Mann K, Hoermann R. Thyroid stimulation by placental factors. J Endocrinol Invest 1993, 16: 378–84.PubMedCrossRefGoogle Scholar
  18. 18.
    Hoermann R, Amir SM, Nomura T, Ingbar SH. Design of a long-lived thyrotropin antagonist from derivatives of human chorionic gonadotropin. Endocrinology 1989, 124: 223–32.PubMedCrossRefGoogle Scholar
  19. 19.
    Desai RK, Dallas JS, Gupta MK, et al. Dual mechanism of perturbation of thyrotropin-mediated activation of thyrotropin receptor (TSHR) and TSHR-derived peptides. J Clin Endocrinol Metab 1993, 77: 658–63.PubMedGoogle Scholar
  20. 20.
    Sakata S, Ogawa T, Matsui I, Manshouri T, Atassi MZ. Biological activities of rabbit antibodies against synthetic human thyrotropin receptor peptides representing thyrotropin binding regions. Biochem Biophys Res Commun 1992, 182: 1369–75.PubMedCrossRefGoogle Scholar
  21. 21.
    Wallaschofski H, Kaczmarek M, Miehle K, Hentshel B, Paschke R. Differences between thyrotropin receptor antibody bioactivity and inhibition of 125I-bovine thyrotropin binding. Thyroid 2000, 10: 897–907.PubMedCrossRefGoogle Scholar
  22. 22.
    Jerne NK. Towards a network theory of the immune system. Ann Immunol (Paris) 1974, 125C: 373–89.Google Scholar
  23. 23.
    Islam MN, Pepper BM, Briones-Urbina R, Farid NR. Biological activity of anti-thyrotropin anti-idiotypic antibody. Eur J Immunol 1983, 13: 57–63.PubMedCrossRefGoogle Scholar
  24. 24.
    Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002, 346: 1692–8.PubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2003

Authors and Affiliations

  • T. Ogura
    • 1
  • Y. Mimura
    • 2
  • Fumio Otsuka
    • 3
  • M. Kishida
    • 3
  • K. Yokota
    • 3
  • J. Suzuki
    • 3
  • A. Nagai
    • 4
  • S. Hirakawa
    • 5
  • H. Makino
    • 3
  • K. Tobe
    • 1
  1. 1.Health and Medical CenterOkayama UniversityJapan
  2. 2.Faculty of EducationOkayama UniversityJapan
  3. 3.Department of Medicine and Clinical ScienceOkayama University Graduate School of Medicine and DentistryOkayamaJapan
  4. 4.Department of UrologyOkayama University Graduate School of Medicine and DentistryOkayamaJapan
  5. 5.Hirakawa ClinicSoujaJapan

Personalised recommendations