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CC BY 4.0 · Journal of Diabetes and Endocrine Practice
DOI: 10.1055/s-0045-1813714
Case Report

Cyclophosphamide-Induced SIADH in a Breast Cancer Patient: A Serious Complication

Authors

  • Faryal Ashfaq

    1   Endocrinology Department, Dubai Hospital, Dubai, United Arab Emirates

  • Faizal Ahamed

    1   Endocrinology Department, Dubai Hospital, Dubai, United Arab Emirates

  • Maryam Sayeed

    2   Department of Medicine, Dubai Medical College, Dubai, United Arab Emirates
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Abstract

Cyclophosphamide is an antineoplastic agent commonly used to treat several malignancies. While it can cause a range of common side effects, including immunosuppression and alopecia, in rare instances, it has been found to cause severe hyponatremia. The probable mechanism by which it causes hyponatremia is by inducing the syndrome of inappropriate antidiuretic hormone secretion. This case report discusses the case of a 66-year-old female diagnosed with grade 3 breast cancer, who showed drastic improvement in her sodium levels with fluid restriction. Her subsequent chemotherapy regimen was changed to doxorubicin monotherapy while cyclophosphamide was omitted, to which she responded favorably without any hyponatremia. Early recognition and prompt treatment of this life-threatening complication are important.


Keywords

cyclophosphamide - doxorubicin - headache - hyponatremia - SIADH

Introduction

Cyclophosphamide is a common chemotherapeutic agent that is used in the treatment of several types of cancers, including breast cancer, lymphoma, and multiple myeloma.[1] This medication exerts its therapeutic effect by alkylating DNA, which eventually leads to programmed cell death.

As with many antineoplastic drugs, cyclophosphamide can cause a range of side effects, the most common being hemorrhagic cystitis, amenorrhea, myelosuppression, alopecia, nausea, and vomiting. Rarer side effects include cardiotoxicity, pulmonary toxicity, veno-occlusive liver disease, secondary malignancies, as well as syndrome of inappropriate antidiuretic hormone secretion (SIADH).[1] In this case report, we discuss a case of severe hyponatremia induced in a patient after receiving one cycle of cyclophosphamide.


Case Description

A 66-year-old patient, with a history of hypertension, stage 3 chronic kidney disease, and recent diagnosis of estrogen receptor–positive left breast cancer, was brought to the emergency department 3 days after her first chemotherapy cycle with doxorubicin and cyclophosphamide adjuvant therapy. She complained of severe nausea, vomiting, and headache associated with dizziness. Her vital signs were stable. Systemic examination was unremarkable. Investigation showed low sodium ([Fig. 1]). She was started on supportive treatment with continuous 0.9% normal saline infusion. The patient was discharged on request the next day in stable condition.

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Fig. 1 Trend of Hyponatremia before and after fluid restriction.

She returned to the emergency department 1 day later with the worsening of her symptoms, now accompanied by anorexia. Laboratory investigations revealed severe hyponatremia ([Table 1]). She was admitted and started on hypertonic saline and later switched to 0.9% normal saline. Her thyroid function tests were within normal limits ([Table 1]). Cortisol level was normal ([Table 1]). Her plasma osmolality was low, and urine osmolality and random urinary sodium were elevated ([Table 1]).

Table 1

Workup for hyponatremia

Component

Result

Reference range

Free T4

20 pmol/L

12–22 pmol /L

TSH

1.230 mIU/L

0.2–4.4 mIU/L

Cortisol (am)

630 nmol/L

133–537 nmol/L

Serum creatinine

0.85 mg/dL

0.5–0.90 mg/dL

Plasma osmolality

237 mOsm/kg H2O

275–295 mOsm/kg H2O

Urine osmolality

489 mOsm/kg H2O

50–1,200 mOsm/kg H2O

Urinary sodium, random

116 mmol/L

40–220 mmol/L as per patient dietary intake

The above lab results were consistent with the diagnosis of SIADH, and she was started on fluid restriction of 1 to 1.5 liters per day. On the following days, her sodium started to improve and later normalized ([Fig. 1]).

Given the suspicion that cyclophosphamide was the offending agent, her chemotherapy regimen was adjusted to doxorubicin monotherapy, with discontinuation of cyclophosphamide. Two months later, she completed four cycles of this treatment plan without any further complications.


Discussion

SIADH is a condition defined by excessive release of the antidiuretic hormone (ADH) from the pituitary gland or other nonpituitary sources. ADH exerts its effects by increasing water reabsorption in the renal collecting ducts and by constricting peripheral arterioles. This in turn affects the fluid volume, blood pressure, and plasma sodium concentration. SIADH primarily presents with low sodium levels, which is the underlying cause of all the symptoms and signs seen in affected patients. The initial presentation of low sodium, when it falls below 125 to 130 mmol/L, includes nausea and malaise. Other symptoms, such as headache, lethargy, obtundation, and finally seizures, occur with further drops in sodium levels. Neurological signs usually indicate the development of cerebral edema.

Common causes of SIADH include central nervous system disturbances, such as stroke, infections, or hemorrhage, recent surgeries, and use of certain drugs. The most common drugs include carbamazepine, oxcarbazepine, chlorpropamide, cyclophosphamide, and selective serotonin reuptake inhibitors.[1]

While some drugs, such as carbamazepine, are known to increase ADH activity by enhancing receptor sensitivity to the hormone, the exact mechanism through which cyclophosphamide can induce SIADH is still unknown.

Hyponatremia, albeit rare, is a well-documented side effect of cyclophosphamide therapy. Most patients, when given high doses intravenously, also receive a high load of fluids to avoid the risk of developing hemorrhagic cystitis. This often results in a fluid overload state and hyponatremia. A few studies have also shown that it can induce low sodium levels through the development of SIADH. The exact mechanism is unknown, but a proposed mechanism is that cyclophosphamide or its active metabolite 4-hydroperoxycyclophosphamide (4-HC) expresses vasopressor-like activity on the kidney.[2] Steinman et al and Campbell et al both reported patients who were known to have diabetes insipidus and still developed SIADH following the use of cyclophosphamide.[2] [3] This suggests that cyclophosphamide does not increase vasopressin release, as the patients reported could not secrete vasopressin, but rather, causes a drug-induced nephrogenic syndrome of inappropriate diuresis.[4]

The earliest correlation between cyclophosphamide use and SIADH was described in a case by Harlow et al. This was a case of fatally severe hyponatremia in a 5-year-old patient after a high dose of cyclophosphamide administration. Postmortem examination of this patient showed loss of Herring's bodies and degranulation of various hypothalamic neurosecretory organelles.[4]

Several case reports have been published that have shown evidence of hyponatremia post-cyclophosphamide use. Bruining et al reported a case of a 64-year-old woman who was due to receive three cycles of adjuvant chemotherapy containing 5-fluouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 (FEC) for her breast cancer. She had a previous history of use of low-dose citalopram 7 years prior, with no reported side effects, which was reinstated 3 months before starting chemotherapy. She developed severe hyponatremia following her second chemotherapy cycle despite the use of low-dose cyclophosphamide (<15 mg/kg). The patient, however, had been consuming excessive fluids after her first cycle, which may have triggered the hyponatremia episode after her second cycle.[5] Few published reports also describe hyponatremia following low-dose cyclophosphamide use in patients with various diseases, including multiple myeloma and systemic lupus erythematosus.[6] [7] [8] [9] [10] [11] Interestingly, a prospective observational study by Geng et al showed an 18.6% incidence of hyponatremia following the first cycle of low-dose cyclophosphamide in breast cancer patients.[11] However, none of the patients in this study developed hyponatremia of less than 125 mEq/L, and all patients recovered without specific management. Baker et al also reported two cases of severe hyponatremic encephalopathy in patients with breast cancer, one of whom had a similar course to our patient. She presented with hyponatremia of 117 mEq/L approximately 48 to 72 hours after completing her first chemotherapy cycle. However, unlike our patient, the patient described in this study continued to deteriorate over the next 3 days severely, finally developing altered sensorium.[12] Our patient developed severe hyponatremia, with the lowest value being 107 mEq/L. Despite such dangerously low levels of sodium, she did not develop any neurological signs or altered sensorium.


Conclusion

Hyponatremia following cyclophosphamide use is a well-known but rare side effect. Although it is important to ensure that patients consume a large amount of fluids and are administered Mesna to prevent hemorrhagic cystitis, it is necessary to ensure that the fluid intake is controlled to prevent SIADH. High-risk patients must be monitored for the development of any electrolyte abnormalities following their cycle of chemotherapy with cyclophosphamide to avoid any preventable complications. More research and further studies are still needed to elucidate the exact mechanism that could correlate SIADH with cyclophosphamide use.



Conflict of Interest

None declared.

Financial Disclosure

None.



Address for correspondence

Faizal Ahamed, MBBS, MD, DM
Endocrinology Department, Dubai Hospital
Dubai
United Arab Emirates   

Publication History

Article published online:
02 December 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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Fig. 1 Trend of Hyponatremia before and after fluid restriction.