General Family Medicine No.1.2025
Progesterone Receptor Antagonists - A Novel
Treatment for Severe Hyponatremia from the Endocrine
Paraneoplastic Syndrome
Jerome H. Check1,2* Diane L. Check2 Michael P. Dougherty3
1.Cooper Medical School of Rowan University, Dept. OB/GYN, Div. Reproductive Endocrinology & Infertility, Camden, NJ, USA
2.Cooper Institute for Reproductive Hormonal Disorders, P.C., MT. Laurel, NJ, USA
3.Augusta University, Augusta, Georgia, USA
ABSTRACT
Hyponatremia related to ectopic secretion of cancer cells of arginine vasopressin (AVP) or atrial natriuretic peptide (ANP) is most commonly caused by small cell lung cancer. The ideal treatment would be one that not only corrects the hyponatremia, especially if it is life threatening, but at the same time causes regression of the cancer, and thus improves both quality and length of life. As one is waiting for chemotherapy, surgery, or radiotherapy to decrease the cancer burden, tolvaptan has been used to correct the hyponatremia to improve symptoms or prevent death. Mifepristone, a progesterone receptor modulator/antagonist has been used to treat various cancers. The oral 200mg tablet was given to an 80-year-old woman who developed sudden extensive lung cancer with a serum sodium of 118 mmol/L. She refused chemotherapy but agreed to take mifepristone. The hyponatremia was completely corrected (145 mmol/L) within one month of treatment. She was in complete remission for 5 years and died not from lung cancer, but an acute myocardial infarction. Mifepristone may serve the purpose to not only quickly correct hyponatremia when it is related to an endocrine paraneoplastic syndrome, but also to provide improved quality and length of life.
Keywords:Arginine vasopressor (AVN); Atrial natriuretic peptide (ANP); Lung cancer;
Syndrome of inappropriate anti-diuretic hormone (SIADH);Mifepristone;
1.Introduction
Lung cancer is one of the most common cancers to cause endocrine paraneoplastic syndromes. When paraneoplastic syndrome occurs, the associated metabolic or endocrine disorder is related to the malignant tumor secreting hormones or peptides. One of these paraneoplastic syndromes is hyponatremia related to inappropriate secretion of the anti-
diuretic hormone (ADH), and thus the condition is called the syndrome of inappropriate anti- diuretic hormone (SIADH).
The most common type of lung cancer associated with SIADH is small-cell lung cancer (SCLC) representing about 70% of the lung cancer cases (1). SIADH may be present in 7-16% of patients with SCLC. Though non- SCLC (NSCLC) has also been associated with SIADH, it only accounts for 1% of the cases
of SIADH resulting from a paraneoplastic syndrome .
Another paraneoplastic etiology for hyponatremia associated with lung cancer is the ectopic secretion of the atrial natriuretic peptide (ANP) . Studies of SCLC cell lines have demonstrated that ectopic ADH, and ANP, are equally likely to be the cause of the hyponatremia, and not uncommonly both may be increased at the same time.
The prognosis for patients with lung cancer with hyponatremia is worse than those with normal serum sodium levels . Serum sodium levels <125 mEq/L are associated with an extremely poor prognosis, with death generally within two weeks associated with severe brain edema that is associated with very low sodium levels with the resulting low plasma hypo osmolarity leading to headache, memory impairment, generalized muscle weakness and associated fatigue, seizures, nausea, and psychiatric dysfunction progressing to coma and death.
Chemotherapy, po ssibly combined with surgery or radiotherapy, and supportive measures are the main treatment modality for hyponatremia associated with lung cancer. If one achieves a remission following chemotherapy, there is a high success rate in correcting the hyponatremia. However, with tumor recurrence, the hyponatremia generally also returns. In very rare circumstances, aggressive chemotherapy may be associated with marked hyponatremia related to sudden excessive release of stored ADH (otherwise known as arginine vasopressin AVP)) andANP.
A case is reported of probable rapid
onset very aggressive SCLC, with marked hyponatremia, who had quick resolution of the hyponatremia, not with chemotherapy, but with a progesterone modulator/antagonist.
2.Case Report
A 78-year-old woman was first diagnosed with chronic lymphocytic leukemia (CLL) . Since she was asymptomatic, she was given no therapy but continued observation and evaluation by blood studies. With continued slow progression of leukocytosis (38,000) and mild thrombocytopenia, and with the development of some symptoms of dyspnea on exertion and weakness, her hematologist when she was age 80 decided to try treatment with oral chlorambucil.
Three days after starting the chlorambucil her clinical status significantly deteriorated with confusion, extreme weakness, and severe respiratory distress. Three months prior to her admission to the hospital for this acute decline in her health status, it was noted that she had mild hyponatremia of 130 mmol/L. On admission her serum sodium was life threatening at 118 mmol/L. By manipulating fluid intake and administration of electrolytes intravenously, her serum sodium increased to 122 mmol/L. Her serum PO2 on admission was 72 mmHg.
A chest x-ray revealed extensive pulmonary nodules with the radiologic diagnosis of metastatic lung cancer,or less likely, rapidly advancing lymphoma, as opposed to rapid progression of her CLL to a more acute leukemia process.
A biopsy of a pulmonary lesion with possible chemo- therapy was recommended, but she refused this management. However, after a
brief discussion, she agreed to be treated with oral mifepristone 200 mg/day as an outpatient. A compassionate use investigational drug approval (IND) was obtained from the United States Food and Drug Administration and her treatment was approved by the Western Institutional Review Board.
She clinically was much improved after two weeks of treatment. After one month of treatment her PO2 was 99- 100 mmHg without supplemental oxygen. Her serum sodium level was normal at 145 mmol/L.
After 2 months of treatment her computerized axial tomography (CT-scan) showed mostly complete resolution of all of her lung nodules with those remaining much smaller.
Subsequent chest x-rays over the next 5 years continued to demonstrate no pulmonary nodules just a ground glass appearance to the lungs. Her PO2 and serum sodium were continually normal. Her CLL did seem to respond to the very short course of chlorambucil and the CLL just slowly progressed over these 5-year period requiring no additional therapy.
At age 85 while sleeping she had an acute myocardial infarction, and she was pronounced dead when she arrived by rescue squad to the hospital’s emergency room.
3.Discussion
The radiologists and oncologist based on chest x-ray and CT scan were convinced that the woman was suffering from lung cancer, but rapidly advancing lymphoma was a much less likely possibility. However, without a pathological diagnosis, they could not determine if the woman was suffering from SCLC or
NSCLC. However, based on the very rapid aggressive onset, and the fact that hyponatremia related to excessive secretion of AVP or ANP is much more common in SCLC vs. NSCLC (or lymphoma), her oncologist favored SCLC as her diagnosis.
It is not clear if the severe sudden drop in serum sodium was related to rapid advancing lung cancer, or did the chlorambucil treatment, which was given for CLL (and would not be a very effective treatment for lung cancer), caused cell lysis with acute release of AVP or ANP further exacerbating preexisting SIADH from mild ectopic AVP or ANP release from lung cancer cells?
Mifepristone has been proven to be an effective treatment for advanced lung cancer providing significant improved quality and extension of life. Mifepristone has provided similar benefits in patients with a variety of different advanced cancers. The mechanism of action is thought to be secondary to its effect on blocking membrane progesterone receptors that are needed to make a protein called the progesterone induced blocking factor (PIBF) . This PIBF protein is unique with no amino acid homology to any known protein, is needed by both the fetal-placental unit and cancer cells to proliferate, invade, tissue and escape immune surveillance, but is not essential for everyday life in people that are healthy.
Tolvaptan has been used to treat cancer patients with hyponatremia due to SIADH. Tolvaptan is an oral selective V2-receptor antagonist. AVP normally acts on V2 receptors in the renal collecting duct to promote free water absorption, thereby increasing extracellular fluid
volume. The continued upregulated expression of AVP in paraneoplastic SIADH leads to excessive dilution of free sodium which leads to the state of hyponatremia.
In the post-hoc analysis of the SALT- 1 and SALT-2 trials, 7 of 8 taking tolvaptan normalized their serum sodium vs . 2 of 16 placebo controls. A previous study found similar results. Tolvaptan could be used concomitantly with mifepristone to try to get the hyponatremia corrected in case the mifepristone is not able to cause regression of that particular patient’s cancer. In that case, the tolvaptan could be used with the drug of choice for treating that cancer.
Nevertheless, the best treatment for the hyponatremia is to correct the cause of ectopic production by cancer cells ofAVP or ANP, since the obvious goal is to prolong and improve quality of life. Nevertheless, tolvaptan seems to be a reasonable short-term solution in case the person could die from the hyponatremia before regression of the cancer is obtained by mifepristone, chemotherapy, radiotherapy or immune therapy. Nevertheless, in the case reported here, rapid correction of the severe life- threatening hyponatremia related to SIADH was solely related to mifepristone therapy.
References
[1 ]Maz z one PJ, Ar ro liga AC . Endocrin e paraneoplastic syndromes in lung cancer. Curr Opin Pulm Med. 2003 Jul;9(4):313-20.
[2]Efthymiou C, Spyratos D, Kontakiotis T. Endocrine paraneoplastic syndromes in lung cancer. Hormones (Athens). 2018 Sep;17(3):351-358.
[3]Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med. 1957 Oct;23(4):529-42.
[4]Vorherr H, Massry SG, Utiger RD, Kleeman
CR. Antidiuretic principle in malignant tumor extracts from patients with inappropriate ADH syndrome. J Clin Endocrinol Metab. 1968 Feb;28(2):162-8.
[5]Amatruda TT Jr, Mulrow PJ, Gallagher JC, Sawyer WH. Carcinoma of the lung with inappropriate antidiuresis. Demonstration of antidiuretic hormone like- hormone activity in tumor extract. N Engl J 1963269:544- 9.
[6]List AF, Hainsworth JD, Davis BW, Hande KR, Greco FA, Johnson DH. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer. J Clin Oncol. 1986 Aug;4(8):1191-8.
[7]Lokich JJ. The frequency and clinical biology of the ectopic hormone syndromes of small cell carcinoma. Cancer. 1982 Nov 15;50(10):2111-4.
[8]Monsieur I, Meysman M, Noppen M, de Greve J, Delhove O, Velckeniers B, Jacobvitz D, Vincken W. Non-small-cell lung cancer with multiple paraneoplastic syndromes. Eur Respir J. 1995 Jul;8(7):1231-4.
[9]Tho LM, Ferry DR . Is the paraneoplastic syndrome of inappropriate antidiuretic hormone secretion in lung cancer always attributable to the small cell variety? Postgrad Med J. 2005 Nov;81(961):e17.
[10]Kamoi K, Ebe T, Hasegawa A, Sato F, Takato H, Iwamoto H, Kaneko H, Ishibashi M, Yamaji T. Hyponatremia in small cell lung cancer. Mechanisms not involving inappropriate ADH secretion. Cancer. 1987 Sep 1;60(5):1089-93.
[11]Cogan E, Debiève MF, Philipart I, Pepersack T, Abramow M. High plasma levels of atrial natriuretic factor in SIADH. N Engl J Med. 1986 May 8;314(19):1258-9.
[12]Donckier JE, Meunier HT, Ketelslegers JM, Lambert AE. Atrial natriuretic peptide and the syndrome of inappropriate secretion of antidiuretic hormone. Ann Intern Med. 1986 Nov;105(5):795-6.
[13]Hansen O, Sørensen P, Hansen KH . The occurrence of hyponatremia in SCLC and the influence on prog- nosis: a retrospective study of 453 patients treated in a single institution in a 10-year period. Lung Cancer. 2010 Apr;68(1):111-4.
[14]Yeung SC, Habra MA, Thosani SN. Lung cancer-induced paraneoplastic syndromes. Curr Opin Pulm Med. 2011 Jul;17(4):260-8.
[15]Hainsworth JD, Workman R, Greco FA . Management of the syndrome of inappropriate antidiuretic hormone secretion in small cell lung cancer. Cancer. 1983 Jan 1;51(1):161-5.
[16]Saintigny P, Chouahnia K, Cohen R, Pailler
MC, Brechot JM, Morere JF, Breau JL. Tumor lysis associated with sudden onset of syndrome of inappropriate antidiuretic hormone secretion. Clin Lung Cancer. 2007 Jan;8(4):282-4.
[17]Check DL, Check JH: Significant palliative benefits of single agent mifepristone for advanced lung cancer that previously failed standard therapy. Med Clin Sci 2019;1(2):1-5.
[18]Check JH, Check D, Poretta T: Mifepristone extends both length and quality of life in a patient with advanced non-small cell lung cancer that has progressed despite chemotherapy and a check-point inhibitor. Anticancer Res 2019;39:1923-1926.
[19]Check DL, Check JH, Poretta T, Aikins J, Wilson C: Prolonged high-quality life in patients with non- small cell lung cancer treated with mifepristone who advanced despite osimertinib. Cancer Sci Res 2020;3(2):1-5.
[20]Check JH, Dix E, Cohen R, Check D, Wilson C: Efficacy of the progesterone receptor antagonist mifepristone for palliative therapy of patients with a variety of advanced cancer types . Anticancer Res 2010;30:623-628.
[21]Check JH, Dix E, Sansoucie L, Check D: Mifepristone may halt progression of extensively metastatic human adenocarcinoma of the colon – case report. Anticancer Res 2009 May;29(5):1611-1613.
[22]Check JH, Wilson C, Cohen R, Sarumi M: Evidence that mifepristone, a progesterone receptor antagonist can cross the blood brain barrier and provide palliative benefits for glioblastoma multiforme grade IV. Anticancer Res 2014;34:2385-2388.
[23]Check DL, Check JH, Poretta T: Conservative laparoscopic surgery plus mifepristone for treating multifocal renal cell carcinoma . Cancer Sci Res 2020;3(2):1-4.
[24]Check JH, Check D, Srivastava MD, Poretta T, Aikins JK: Treatment with mifepristone allows a patient with end-stage pancreatic cancer in hospice on a morphine drip to restore a decent quality of life. Anticancer Res 2020;40:6997-7001.
[25]Check JH, Check D, Poretta T, Wilson C: Palliative benefits of oral mifepristone for the treatment of metastatic fibroblastic osteosarcoma. Anticancer Res 2021;41:2111-2115.
[26]Check JH, Check D: Mifepristone may be the best single pharmaceutical agent for treatment of a variety of advanced cancers. Cancer Sci Res 2021;4:1-6.
[27]Check JH, Nazari P, Goldberg J, Yuen W, Angotti D: A model for potential tumor immunotherapy based on knowledge of immune mechanisms responsible for spontaneous abortion. Med Hypoth 57:337-343, 2001.
[28]Check JH, Dix E, Sansoucie L: Support for the hypothesis that successful immunotherapy of various cancers can be achieved by inhibiting a progesterone associated immunomodulatory protein. Med Hypoth 2009;72:87-90.
[29]Check JH, Cohen R: The role of progesterone and the progesterone receptor in human reproduction and cancer. Exp Rev Endocrinol Metab 2013;8:469-484.
[30]Check JH: The role of progesterone and the progesterone receptor in cancer. Expert Review Endo Metab 2017;12:187-197.
[31]Check JH, Check D: Therapy aimed to suppress the production of the immunosuppressive protein progesterone induced blocking factor (PIBF) may provide palliation and/or increased longevity for patients with a variety of different advanced cancers – A review. Anticancer Res 2019;39:3365-3372.
[32]Gralla RJ, Ahmad F, Blais JD, Chiodo J 3rd, Zhou W, Glaser LA, Czerwiec FS. Tolvaptan use in cancer patients with hyponatremia due to the syndrome of inappropriate antidiuretic hormone: a post hoc analysis of the SALT-1 and SALT-2 trials. Cancer Med. 2017 Apr;6(4):723-729.
[33]Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C; SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006 Nov 16;355(20):2099-112.
[34]Schrier RW. Vasopressin and aquaporin 2 in clinical disorders of water homeostasis. Semin Nephrol. 2008 May;28(3):289-96.
[35]Petereit C, Zaba O, Teber I, Lüders H, Grohé C. A rapid and efficient way to manage hyponatremia in patients with SIADH and small cell lung cancer: treatment with tolvaptan. BMC Pulm Med. 2013 Aug 29;13:55.
