Skip to main content

Advertisement

SpringerLink
Log in

Case Report: Adrenal LH/hCG Receptor Overexpression and Gene Amplification Causing Pregnancy-Induced Cushing’s Syndrome

  • Published:
Endocrine Pathology Aims and scope Submit manuscript

An Erratum to this article was published on 03 December 2009

Abstract

Transient pregnancy-induced Cushing’s syndrome (CS) is extremely rare, with only several cases reported in the literature. Ectopic LH/hCG-receptors (LHCGR) in the adrenal gland have been suggested to be involved in the pathogenesis of this condition. We report the clinical, molecular, and genetic features of a patient with pregnancy-induced CS. A 29-year-old female patient developed CS during multiple pregnancies, leading to repeated miscarriage. Signs and symptoms of hypercortisolism resolved soon after delivery or abortion, only to recur in subsequent pregnancies. In the non-pregnant state, hCG stimulation testing resulted in elevated cortisol levels. Serum cortisol was not suppressible with dexamethasone. The adrenals exhibited bilateral adrenal cortical nodular hyperplasia. Quantitative RT-PCR revealed a 2-fold increase in LHCGR and progesterone receptor mRNA expression and decreased estrogen receptor-beta expression in the patient’s adrenal tissue relative to normal adrenals. Higher intensity of immunostaining for LHCGR was observed, particularly within the nodular lesions, compared to controls. Quantitative PCR revealed a LHCGR-to-β-actin ratio of 1.5 in genomic DNA from adrenal and peripheral leukocytes, suggesting the presence of a germline duplication of the LHCGR gene. LHCGR overexpression resulting from germline gene duplication may be a potential pathogenic mechanism underlying this case of pregnancy-induced CS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing’s syndrome during pregnancy: personal experience and review of the literature. J Clin Endocrinol Metab 90:3077-3083, 2005.

    Article  PubMed  CAS  Google Scholar 

  2. Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hormone--dependent Cushing’s syndrome. N Engl J Med 341:1577-1581, 1999.

    Article  PubMed  CAS  Google Scholar 

  3. Wallace C, Toth EL, Lewanczuk RZ, Siminoski K. Pregnancy-induced Cushing’s syndrome in multiple pregnancies. J Clin Endocrinol Metab 81:15-21, 1996.

    Article  PubMed  CAS  Google Scholar 

  4. Wieland RG, Shaffer MB, Jr., Glove RP. Cushing’s syndrome complicating pregnancy. A case report. Obstet Gynecol 38:841-843, 1971.

    PubMed  CAS  Google Scholar 

  5. Hana V, Dokoupilova M, Marek J, Plavka R. Recurrent ACTH-independent Cushing’s syndrome in multiple pregnancies and its treatment with metyrapone. Clin Endocrinol (Oxf) 54:277-281, 2001.

    Article  CAS  Google Scholar 

  6. Close CF, Mann MC, Watts JF, Taylor KG. ACTH-independent Cushing’s syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone. Clin Endocrinol (Oxf) 39:375-379, 1993.

    Article  CAS  Google Scholar 

  7. Aron DC, Schnall AM, Sheeler LR. Spontaneous resolution of Cushing’s syndrome after pregnancy. Am J Obstet Gynecol 162:472-474, 1990.

    PubMed  CAS  Google Scholar 

  8. Reschini E, Giustina G, Crosignani PG, D’Alberton A. Spontaneous remission of Cushing syndrome after termination of pregnancy. Obstet Gynecol 51:598-602, 1978.

    Article  PubMed  CAS  Google Scholar 

  9. de Cremoux P, Rosenberg D, Goussard J, Bremont-Weil C, Tissier F, Tran-Perennou C, et al. Expression of progesterone and estradiol receptors in normal adrenal cortex, adrenocortical tumors, and primary pigmented nodular adrenocortical disease. Endocr Relat Cancer 15:465-474, 2008.

    Article  PubMed  CAS  Google Scholar 

  10. N’Diaye N, Tremblay J, Hamet P, De Herder WW, Lacroix A. Adrenocortical overexpression of gastric inhibitory polypeptide receptor underlies food-dependent Cushing’s syndrome. J Clin Endocrinol Metab 83:2781-2785, 1998.

    Article  PubMed  Google Scholar 

  11. Arnaldi G, Gasc JM, de Keyzer Y, Raffin-Sanson ML, Perraudin V, Kuhn JM, et al. Variable expression of the V1 vasopressin receptor modulates the phenotypic response of steroid-secreting adrenocortical tumors. J Clin Endocrinol Metab 83:2029-2035, 1998.

    Article  PubMed  CAS  Google Scholar 

  12. Lacroix A, Tremblay J, Touyz RM, Deng LY, Lariviere R, Cusson JR, et al. Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing’s syndrome, and orthostatic hypotension. J Clin Endocrinol Metab 82:2414-2422, 1997.

    Article  PubMed  CAS  Google Scholar 

  13. Lacroix A, Tremblay J, Rousseau G, Bouvier M, Hamet P. Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing’s syndrome. N Engl J Med 337:1429-1434, 1997.

    Article  PubMed  CAS  Google Scholar 

  14. Cartier D, Lihrmann I, Parmentier F, Bastard C, Bertherat J, Caron P, et al. Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing’s syndrome. J Clin Endocrinol Metab 88:248-254, 2003.

    Article  PubMed  CAS  Google Scholar 

  15. Feelders RA, Lamberts SW, Hofland LJ, van Koetsveld PM, Verhoef-Post M, Themmen AP, et al. Luteinizing hormone (LH)-responsive Cushing’s syndrome: the demonstration of LH receptor messenger ribonucleic acid in hyperplastic adrenal cells, which respond to chorionic gonadotropin and serotonin agonists in vitro. J Clin Endocrinol Metab 88:230-237, 2003.

    Article  PubMed  CAS  Google Scholar 

  16. Pabon JE, Li X, Lei ZM, Sanfilippo JS, Yussman MA, Rao CV. Novel presence of luteinizing hormone/chorionic gonadotropin receptors in human adrenal glands. J Clin Endocrinol Metab 81:2397-2400, 1996.

    Article  PubMed  CAS  Google Scholar 

  17. Wy LA, Carlson HE, Kane P, Li X, Lei ZM, Rao CV. Pregnancy-associated Cushing’s syndrome secondary to a luteinizing hormone/human chorionic gonadotropin receptor-positive adrenal carcinoma. Gynecol Endocrinol 16:413-417, 2002.

    Article  PubMed  CAS  Google Scholar 

  18. Mazzuco TL, Chabre O, Feige JJ, Thomas M. Aberrant expression of human luteinizing hormone receptor by adrenocortical cells is sufficient to provoke both hyperplasia and Cushing’s syndrome features. J Clin Endocrinol Metab 91:196-203, 2006.

    Article  PubMed  CAS  Google Scholar 

  19. Caticha O, Odell WD, Wilson DE, Dowdell LA, Noth RH, Swislocki AL, et al. Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia. J Clin Endocrinol Metab 77:494-497, 1993.

    Article  PubMed  CAS  Google Scholar 

  20. Foley EF, Jazaeri AA, Shupnik MA, Jazaeri O, Rice LW. Selective loss of estrogen receptor beta in malignant human colon. Cancer Res 60:245-248, 2000.

    PubMed  CAS  Google Scholar 

  21. Suzuki F, Akahira JI, Miura I, Suzuki T, Ito K, Hayashi SI, et al. Loss of estrogen receptor beta isoform expression and its correlation with aberrant DNA methylation of the 5′-untranslated region in human epithelial ovarian carcinoma. Cancer Sci 99:2365–2372, 2008.

    Article  PubMed  CAS  Google Scholar 

  22. Shimada M, Terada T. FSH and LH induce progesterone production and progesterone receptor synthesis in cumulus cells: a requirement for meiotic resumption in porcine oocytes. Mol Hum Reprod 8:612-618, 2002.

    Article  PubMed  CAS  Google Scholar 

  23. Chandrasekher YA, Brenner RM, Molskness TA, Yu Q, Stouffer RL. Titrating luteinizing hormone surge requirements for ovulatory changes in primate follicles. II. Progesterone receptor expression in luteinizing granulosa cells. J Clin Endocrinol Metab 73:584-589, 1991.

    Article  PubMed  CAS  Google Scholar 

  24. Park OK, Mayo KE. Transient expression of progesterone receptor messenger RNA in ovarian granulosa cells after the preovulatory luteinizing hormone surge. Mol Endocrinol 5:967-978, 1991.

    Article  PubMed  CAS  Google Scholar 

  25. Clemens JW, Robker RL, Kraus WL, Katzenellenbogen BS, Richards JS. Hormone induction of progesterone receptor (PR) messenger ribonucleic acid and activation of PR promoter regions in ovarian granulosa cells: evidence for a role of cyclic adenosine 3′,5′-monophosphate but not estradiol. Mol Endocrinol 12:1201-1214, 1998.

    Article  PubMed  CAS  Google Scholar 

  26. Kero J, Poutanen M, Zhang FP, Rahman N, McNicol AM, Nilson JH, et al. Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex. J Clin Invest 105:633-641, 2000.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Kelvin So and Wei Liu for technical assistance.

Author information

Authors and Affiliations

  1. Department of Pathology, University Health Network, 200 Elizabeth Street, 11th Floor, Toronto, ON, Canada, M5G 2C4

    Michael Herman Chui & Sylvia L. Asa

  2. Division of Endocrinology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, 34390 Capa, Istanbul, Turkey

    Nese Colak Özbey

  3. Department of Medicine, Division of Endocrinology, University Health Network and Mount Sinai Hospital, Toronto, ON, Canada

    Shereen Ezzat

  4. Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, 34390 Capa, Istanbul, Turkey

    Yersu Kapran

  5. Department of Surgery, Istanbul Faculty of Medicine, Istanbul University, 34390 Capa, Istanbul, Turkey

    Yesim Erbil

Authors
  1. Michael Herman Chui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nese Colak Özbey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shereen Ezzat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yersu Kapran
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yesim Erbil
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sylvia L. Asa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sylvia L. Asa.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s12022-009-9099-6

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herman Chui, M., Özbey, N.C., Ezzat, S. et al. Case Report: Adrenal LH/hCG Receptor Overexpression and Gene Amplification Causing Pregnancy-Induced Cushing’s Syndrome. Endocr Pathol 20, 256–261 (2009). https://doi.org/10.1007/s12022-009-9090-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12022-009-9090-2

Keywords

Search

Navigation