Download PDF
Horm Metab Res 2018; 50(02): 124-132
DOI: 10.1055/s-0043-122074
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Successful Treatment of Estrogen Excess in Primary Bilateral Macronodular Adrenocortical Hyperplasia with Leuprolide Acetate

Fady Hannah-Shmouni   *
1   Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
,
Andreas G. Moraitis   *
1   Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
2   Corcept Therapeutics Incorporated, Drug Research and Development, MI, USA (Current address)
,
Vladimir Valera Romero
3   Laboratory of Pathology, National Cancer Institute (NCI), NIH, Bethesda, MD, USA
,
Fabio R. Faucz
1   Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
,
Spyridon A. Mastroyannis
1   Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
,
Annabel Berthon
1   Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
,
Richard A. Failor
4   Division of Endocrinology, Metabolism, & Nutrition University of Washington, Seattle, WA, USA
,
Maria Merino
3   Laboratory of Pathology, National Cancer Institute (NCI), NIH, Bethesda, MD, USA
,
Andrew P. Demidowich
1   Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
,
Constantine A. Stratakis
1   Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
› Author Affiliations
Further Information

Publication History

received 08 July 2017

accepted 16 October 2017

Publication Date:
28 November 2017 (online)

Also available at
    Permissions and Reprints

Abstract

Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is an uncommon cause of adrenal Cushing syndrome (CS) in which cortisol and occasionally other steroid hormones can be secreted under the influence of aberrantly expressed G-protein coupled receptors (GPCRs) in the adrenal cortex. We describe the unique case of a 64-year-old postmenopausal female with PBMAH whose adrenal lesions expressed luteinizing hormone receptors (LHr). She presented initially with CS and underwent right adrenalectomy; a few years later she presented with macromastia and mastodynia, possibly due to estrogen excess from her remaining left adrenocortical masses. Testing before and after treatment with quarterly leuprolide acetate therapy and immunohistochemistry on tissue and targeted sequencing of the genes of interest were performed. Tissue from the patient’s right adrenal was tested for P450 aromatase (CYP19A1) and LHr expression; both were expressed throughout the hyperplastic cortex, although expression was more intense in the adenomatous areas. Targeted sequencing revealed a pathogenic PDE11A mutation, as well as variants in the ARMC5 and INHA genes. PDE11A expression was decreased in the adenoma but there was no loss of heterozygosity for the PDE11A locus. Because of the clinical presentation and LHr expression, quarterly leuprolide acetate therapy was started. Shortly after initiation of therapy, the patient reported decreased breast size and pain; she remains well controlled to date, after 10 years of treatment. This is the first description of a patient with PBMAH presenting with severe macromastia and mastodynia from what appears to be excess estrogen production from her adrenal tumor. The patient had a long-lasting response to chronic leuprolide acetate treatment, showing that drug therapy exploiting the aberrant receptor expression in PBMAH is possible even in the absence of cortisol overproduction.

Key words

adrenocortical tumors - Cushing syndrome - genetics - mastodynia - macromastia - phosphodiesterase - leuprolide

* Co-first authors


Supplementary Material

 

  • References

  • 1 Assie G, Libe R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, Barreau O, Lefevre L, Sibony M, Guignat L, Rodriguez S, Perlemoine K, Rene-Corail F, Letourneur F, Trabulsi B, Poussier A, Chabbert-Buffet N, Borson-Chazot F, Groussin L, Bertagna X, Stratakis CA, Ragazzon B, Bertherat J. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome. N Engl J Med 2013; 369: 2105-2114
    CrossrefPubMedGoogle Scholar
  • 2 Yu B, Ragazzon B, Rizk-Rabin M, Bertherat J. Protein kinase A alterations in endocrine tumors. Horm Metab Res 2012; 44: 741-748
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hormone--dependent Cushing's syndrome. N Engl J Med 1999; 341: 1577-1581
    CrossrefPubMedGoogle Scholar
  • 4 Carlson HE. Human adrenal cortex hyperfunction due to LH/hCG. Mol Cell Endocrinol 2007; 269: 46-50
    CrossrefPubMedGoogle Scholar
  • 5 Bertherat J, Contesse V, Louiset E, Barrande G, Duparc C, Groussin L, Emy P, Bertagna X, Kuhn JM, Vaudry H, Lefebvre H. In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism. J Clin Endocrinol Metab 2005; 90: 1302-1310
    CrossrefPubMedGoogle Scholar
  • 6 Bourdeau I, D'Amour P, Hamet P, Boutin JM, Lacroix A. Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing's syndrome. J Clin Endocrinol Metab 2001; 86: 5534-5540
    PubMedGoogle Scholar
  • 7 Horiba N, Suda T, Aiba M, Naruse M, Nomura K, Imamura M, Demura H. Lysine vasopressin stimulation of cortisol secretion in patients with adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab 1995; 80: 2336-2341
    PubMedGoogle Scholar
  • 8 Gagliardi L, Hotu C, Casey G, Braund WJ, Ling KH, Dodd T, Manavis J, Devitt PG, Cutfield R, Rudzki Z, Scott HS, Torpy DJ. Familial vasopressin-sensitive ACTH-independent macronodular adrenal hyperplasia (VPs-AIMAH): clinical studies of three kindreds. Clin Endocrinol (Oxf) 2009; 70: 883-891
    CrossrefPubMedGoogle Scholar
  • 9 Hofland J, Hofland LJ, van Koetsveld PM, Steenbergen J, de Herder WW, van Eijck CH, de Krijger RR, van Nederveen FH, van Aken MO, de Groot JW, Links TP, de Jong FH, Feelders RA. ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11b-hydroxylase. Orphanet J Rare Dis 2013; 8: 142
    CrossrefPubMedGoogle Scholar
  • 10 Lacroix A, Bolte E, Tremblay J, Dupre J, Poitras P, Fournier H, Garon J, Garrel D, Bayard F, Taillefer R, Flanagan RJ, Hamet P. Gastric inhibitory polypeptide-dependent cortisol hypersecretion–a new cause of Cushing's syndrome. N Engl J Med 1992; 327: 974-980
    CrossrefPubMedGoogle Scholar
  • 11 Preumont V, Mermejo LM, Damoiseaux P, Lacroix A, Maiter D. Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome. Horm Metab Res 2011; 43: 287-291
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Feelders RA, Lamberts SW, Hofland LJ, van Koetsveld PM, Verhoef-Post M, Themmen AP, de Jong FH, Bonjer HJ, Clark AJ, van der Lely AJ, de Herder WW. 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 2003; 88: 230-237
    CrossrefPubMedGoogle Scholar
  • 13 Stratakis CA, Sarlis N, Kirschner LS, Carney JA, Doppman JL, Nieman LK, Chrousos GP, Papanicolaou DA. Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Ann Intern Med 1999; 131: 585-591
    PubMedGoogle Scholar
  • 14 Hsiao HP, Kirschner LS, Bourdeau I, Keil MF, Boikos SA, Verma S, Robinson-White AJ, Nesterova M, Lacroix A, Stratakis CA. Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J Clin Endocrinol Metab 2009; 94: 2930-2937
    CrossrefPubMedGoogle Scholar
  • 15 Horvath A, Boikos S, Giatzakis C, Robinson-White A, Groussin L, Griffin KJ, Stein E, Levine E, Delimpasi G, Hsiao HP, Keil M, Heyerdahl S, Matyakhina L, Libe R, Fratticci A, Kirschner LS, Cramer K, Gaillard RC, Bertagna X, Carney JA, Bertherat J, Bossis I, Stratakis CA. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet 2006; 38: 794-800
    CrossrefPubMedGoogle Scholar
  • 16 Libe R, Fratticci A, Coste J, Tissier F, Horvath A, Ragazzon B, Rene-Corail F, Groussin L, Bertagna X, Raffin-Sanson ML, Stratakis CA, Bertherat J. Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors. Clin Cancer Res 2008; 14: 4016-4024
    CrossrefPubMedGoogle Scholar
  • 17 Longui CA, Lemos-Marini SH, Figueiredo B, Mendonca BB, Castro M, Liberatore Jr. R, Watanabe C, Lancellotti CL, Rocha MN, Melo MB, Monte O, Calliari LE, Guerra-Junior G, Baptista MT, Sbragia-Neto L, Latronico AC, Moreira A, Tardelli AM, Nigri A, Taymans SE, Stratakis CA. Inhibin alpha-subunit (INHA) gene and locus changes in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers. J Med Genet 2004; 41: 354-359
    CrossrefPubMedGoogle Scholar
  • 18 Rothenbuhler A, Horvath A, Libé R, Faucz FR, Fratticci A, Raffin Sanson ML, Vezzosi D, Azevedo M, Levy I, Almeida MQ, Lodish M, Nesterova M, Bertherat J, Stratakis CA. Identification of novel genetic variants in phosphodiesterase 8B (PDE8B), a cAMP-specific phosphodiesterase highly expressed in the adrenal cortex, in a cohort of patients with adrenal tumours. Clin Endocrinol (Oxf) 2012; 77: 195-199
    CrossrefPubMedGoogle Scholar
  • 19 Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37: e67
    CrossrefPubMedGoogle Scholar
  • 20 Moreno S, Guillermo M, Decoulx M, Dewailly D, Bresson R, Proye C. Feminizing adreno-cortical carcinomas in male adults. A dire prognosis. Three cases in a series of 801 adrenalectomies and review of the literature. Ann Endocrinol (Paris) 2006; 67: 32-38
    CrossrefPubMedGoogle Scholar
  • 21 Millington DS, Golder MP, Cowley T, London D, Roberts H, Butt WR, Griffiths K. In vitro synthesis of steroids by a feminising adrenocortical carcinoma: effect of prolactin and other protein hormones. Acta Endocrinol (Copenh) 1976; 82: 561-571
    PubMedGoogle Scholar
  • 22 Phornphutkul C, Okubo T, Wu K, Harel Z, Tracy Jr. TF, Pinar H, Chen S, Gruppuso PA, Goodwin G. Aromatase p450 expression in a feminizing adrenal adenoma presenting as isosexual precocious puberty. J Clin Endocrinol Metab 2001; 86: 649-652
    CrossrefPubMedGoogle Scholar
  • 23 Gabrilove JL, Sharma DC, Wotiz HH, Dorfman RI. Feminizing adrenocortical tumors in the male. A review of 52 cases including a case report. Medicine (Baltimore) 1965; 44: 37-79
    CrossrefPubMedGoogle Scholar
  • 24 Wotiz HH, Chattoraj SC, Gabrilove JL. Urinary estrogen titers in a patient with feminizing adrenocortical carcinoma. J Clin Endocrinol Metab 1968; 28: 192-197
    CrossrefPubMedGoogle Scholar
  • 25 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 1996; 81: 2397-2400
    PubMedGoogle Scholar
  • 26 Goodarzi MO, Dawson DW, Li X, Lei Z, Shintaku P, Rao CV, Van Herle AJ. Virilization in bilateral macronodular adrenal hyperplasia controlled by luteinizing hormone. J Clin Endocrinol Metab 2003; 88: 73-77
    CrossrefPubMedGoogle Scholar
  • 27 Bovenberg SA, Pieters GF, Hofland LJ, Hermus AR. Leuprolide acetate therapy in LH-dependent Cushing's syndrome: In vivo and in vitro observations. Neth J Med 2004; 62: 456-458
    PubMedGoogle Scholar
  • 28 Nishii M, Nomura M, Sekine Y, Koike H, Matsui H, Shibata Y, Ito K, Oyama T, Suzuki K. Luteinizing hormone (LH)-releasing hormone agonist reduces serum adrenal androgen levels in prostate cancer patients: Implications for the effect of LH on the adrenal glands. J Androl. 2012; 33: 1233-1238
    CrossrefPubMedGoogle Scholar
  • 29 Young J, Bulun SE, Agarwal V, Couzinet B, Mendelson CR, Simpson ER, Schaison G. Aromatase expression in a feminizing adrenocortical tumor. J Clin Endocrinol Metab 1996; 81: 3173-3176
    PubMedGoogle Scholar
  • 30 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 2006; 91: 196-203
    CrossrefPubMedGoogle Scholar
  • 31 Kero J, Poutanen M, Zhang FP, Rahman N, McNicol AM, Nilson JH, Keri RA, Huhtaniemi IT. Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex. J Clin Invest 2000; 105: 633-641
    CrossrefPubMedGoogle Scholar
  • 32 Saner-Amigh K, Mayhew BA, Mantero F, Schiavi F, White PC, Rao CV, Rainey WE. Elevated expression of luteinizing hormone receptor in aldosterone-producing adenomas. J Clin Endocrinol Metab 2006; 91: 1136-1142
    CrossrefPubMedGoogle Scholar
  • 33 Ye P, Mariniello B, Mantero F, Shibata H, Rainey WE. G-protein-coupled receptors in aldosterone-producing adenomas: A potential cause of hyperaldosteronism. J Endocrinol 2007; 195: 39-48
    CrossrefPubMedGoogle Scholar
  • 34 Mircescu H, Jilwan J, N'Diaye N, Bourdeau I, Tremblay J, Hamet P, Lacroix A. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing's syndrome?. J Clin Endocrinol Metab 2000; 85: 3531-3536
    PubMedGoogle Scholar
  • 35 Christopoulos S, Bourdeau I, Lacroix A. Aberrant expression of hormone receptors in adrenal Cushing's syndrome. Pituitary 2004; 7: 225-235
    CrossrefPubMedGoogle Scholar
  • 36 Szarek E, Stratakis CA. Phosphodiesterases and adrenal Cushing in mice and humans. Horm Metab Res 2014; 46: 863-868
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Horvath A, Giatzakis C, Robinson-White A, Boikos S, Levine E, Griffin K, Stein E, Kamvissi V, Soni P, Bossis I, de Herder W, Carney JA, Bertherat J, Gregersen PK, Remmers EF, Stratakis CA. Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population. Cancer Res 2006; 66: 11571-11575
    CrossrefPubMedGoogle Scholar