Cushing’s syndrome with diabetes insipidus in pregnancy: a case report

Abstract

Background

Cushing’s syndrome (CS) during pregnancy is a rare condition associated with significant maternal and fetal complications, including hypertension, diabetes, preeclampsia, and preterm birth. Diabetes insipidus (DI) in pregnancy is a rare but often diagnosed condition, and its effective management is crucial for maintaining maternal health during pregnancy and childbirth. This case report describes the rare coexistence of DI and CS during pregnancy, highlighting the unique complexities in diagnosis and management.

Case presentation

A 29-year-old woman with a history of pregnancy-induced hypertension developed severe hypertension, hypokalemia, and polyuria (6.6 L/day) during her 7th pregnancy. Laboratory findings showed elevated cortisol, suppressed adrenocorticotropic hormone (ACTH), and a 30-mm left adrenal mass, confirming adrenal CS. Despite potassium supplementation, persistent polyuria and fluid imbalance necessitated initiating desmopressin therapy at 27 weeks of gestation. The patient subsequently developed preeclampsia and underwent emergency cesarean section at 29 weeks, delivering a 1197-g infant with a very low birth weight. Polyuria resolved postpartum, and she underwent left adrenalectomy after discharge.

Conclusions

This case illustrates the complexity of managing coexisting CS and GDI during pregnancy, emphasizing the importance of considering alternative mechanisms, such as cortisol-induced antidiuretic hormone resistance, in polyuria. Multidisciplinary approaches are crucial to optimizing maternal and fetal outcomes in rare endocrine conditions, and help contribute to the understanding of CS and DI interactions during pregnancy.

Background

Cushing’s syndrome (CS) during pregnancy is a rare but serious condition that can significantly affect both maternal and fetal health. Elevated cortisol levels associated with CS can lead to complications such as hypertension, gestational diabetes mellitus (GDM), preeclampsia, and cardiac issues in the mother [1]. For the fetus, the risks include prematurity, growth retardation, and increased mortality [2]. Diagnosing CS during pregnancy is challenging owing to symptoms overlapping with normal pregnancy changes, such as weight gain and hypertension [3]. Diagnosis typically involves measuring urine-free or midnight salivary cortisol levels [4]. Early diagnosis and treatment are crucial to improve maternal and fetal outcomes [5].

Diabetes insipidus (DI) during pregnancy is another rare but significant condition, which presents both diagnostic and management challenges. Its symptoms, such as polyuria and polydipsia, often overlap with normal physiological changes during pregnancy, complicating timely diagnosis [6]. If left untreated, DI can result in severe maternal and fetal complications, including oligohydramnios and electrolyte imbalances [7]. Early recognition and treatment with desmopressin can significantly improve outcomes, underscoring the importance of heightened clinical awareness [8].

Recently, there has been a movement toward renaming diseases using terms that accurately reflect their nature. Central DI, which is caused by insufficient secretion of the antidiuretic hormone arginine vasopressin (AVP), has been renamed Arginine Vasopressin Deficiency (AVP-D) [9]. In contrast, nephrogenic DI, which results from reduced responsiveness to AVP, has been renamed Arginine Vasopressin Resistance (AVP-R) [9]. However, as these new terms have not yet been widely adopted, the term “diabetes insipidus” is used in this report.

This case report aims to highlight the diagnostic and management complexities of coexisting CS and DI during pregnancy, emphasizing the importance of considering alternative mechanisms in polyuria and a multidisciplinary approach to optimize maternal and fetal outcomes.

Case presentation

A 29-year-G7P3 (three vaginal deliveries, three spontaneous abortions) presented with systolic blood pressure consistently exceeding 150 mmHg from the early stages of her 7 th pregnancy. She was transferred to the obstetrics department of our hospital at 26 weeks and 2 days of the 7 th gestation. Serum electrolyte analysis demonstrated normal sodium levels (139 mEq/L) and decreased potassium levels (2.4 mEq/L). Polyuria (6.6 L/day) was observed immediately before transfer, prompting a referral to our department for further investigation of the hypokalemia and polyuria. Her weight and height were 58.2 kg and 144.7 cm (body mass index, 27.8), respectively. Her body temperature was 37.7 °C, and pulse rate was 80 beats per minute. SpO₂ was 98%, and blood pressure was 150/94 mmHg. Two years prior to hospitalization, the patient gained 20 kg and developed central obesity, accompanied by facial rounding and supraclavicular fat accumulation. The patient had no family history of parathyroid or adrenal tumors and no significant medical history, apart from increased urine output and hypertensive disorders of pregnancy (HDP) during the late stages of her previous pregnancy, which necessitated an induced delivery. The patient was not on any chronic medication before the current pregnancy and was taking nifedipine and ferric citrate hydrate prior to her transfer. Endocrinological evaluation conducted after transfer to our hospital revealed the following: ACTH levels < 0.3 pmol/L; morning cortisol, 738.7 nmol/L; cortisol following a 1 mg dexamethasone suppression test (DST), 831.6 nmol/L; 24-h urinary free cortisol (UFC), 413.9 nmol/day; serum osmolality, 283 mOsm/L; and urinary osmolality, 274 mOsm/L. AVP was 1.1 pmol/L when serum sodium was 139 mmol/L. Fasting plasma glucose was 6.8 mmol/L and HbA1c levels were 44.0 mmol/mol, leading to the diagnosis of GDM (Table 1).

Table 1.

Laboratory findings on admission

Component	Value	Reference value and range
AST	15 IU	13–33 IU
ALT	16 IU	6–27 IU
T-Bil	0.5 mg/dL (8.55 μmol/L)	0.3–1.2 mg/dL (3.4–17.1 μmol/L)
Creatinine	0.58 mg/dL (51.27 μmol/L)	0.46–0.79 (40.7–69.8 μmol/L)
Sodium	139 mmol/L	138–145 mmol/L
Chloride	101 mmol/L	101–108 mmol/L
Potassium	2.4 mmol/L	3.6–4.8 mmol/L
Calcium	7.2 mg/dL (1.80 mmol/L)	8.5–10.5 mg/dL (2.12–2.62 mmol/L)
Fasting plasma glucose	122 mg/dL (6.8 mmol/L)	73–109 mg/dL (4.0–6.0 mmol/L)
HbA1c	6.2% (44.0 mmol/mol)	4.6–6.2% (26.7–44.2 mmol/mol)
ACTH	< 1.5 pg/mL (< 0.3 pmol/L)	7–63 pg/mL (1.6–13.9 pmol/L)
Cortisol	26.79 µg/dL (738.7 nmol/L)	7.1–19.6 µg/dL (195.1–540.7 nmol/L)
DHEA-S	21 µg/dL (0.57 µmol/L)
Plasma renin activity	2.6 ng/mL/h
Aldosterone	< 4.0 pg/mL (< 11.1 pmol/L)
AVP	1.2 pg/mL (1.1 pmol/L)
S-Osm	283 mOsm/L
U-Osm	274 mOsm/L
Urinary free cortisol	1500 µg/day (413.9 nmol/day)	< 80.3 µg/day (< 221.5 nmol/day)
Night-time cortisol (11 pm)	31.64 µg/dL (872.9 nmol/L)	Not specified
Cortisol after 1 mg DST	30.14 µg/dL (831.6 nmol/L)	Not specified

Abbreviations: AST aspartate aminotransferase, ALT alanine aminotransferase, T-Bil total bilirubin, HbA1c glycated hemoglobin A1c, ACTH adrenocorticotropin, DHEA-S dehydroepiandrosterone-sulfate, LH luteinizing hormone, FSH follicle-stimulating hormone, TSH thyrotropin, FT₃ Free triiodothyronine, FT₄ Free thyroxine, GH growth hormone, IGF- 1 insulin-like growth factor- 1, AVP arginine vasopressin, S-Osm serum osmolarity, U-Osm urine osmolarity, DST dexamethasone suppression test

After her transfer, the patient’s blood pressure and blood glucose levels improved with antihypertensive therapy and basal-bolus insulin therapy, respectively. However, polyuria persisted at 4–6 L/day despite potassium supplementation. T1-weighted magnetic resonance imaging revealed a high signal in the posterior pituitary lobe, with no enlargement beyond the physiological swelling typically seen during pregnancy (Fig. 1A) [10]. Considering the risk of reduced circulating plasma volume, fluid replacement therapy was initiated, and oral desmopressin acetate (DDAVP) was administered at 27 weeks and 1 day of gestation to manage fluid balance. At 27 weeks and 2 days, the patient developed fever and pyuria. Computed tomography (CT) revealed bilateral renal enlargement, leading to a diagnosis of pyelonephritis, for which antibiotic therapy was initiated. Escherichia coli was isolated from two separate blood culture specimens and a urine culture sample. CT also revealed a 26 mm × 26 mm mass on the left adrenal gland with a density of 28 Hounsfield Units (HU), suggesting adrenal CS (Fig. 1B). Considering the risk of severe infection due to hypercortisolism, metyrapone therapy (500 mg) was initiated, which rapidly improved the symptoms of hypercortisolism (Fig. 2).

Fig. 1.

Imaging findings during pregnancy. A Pituitary MRI performed at 27 weeks and 1 day of gestation: high signal in the posterior lobe is preserved on T1-weighted MRI, and the pituitary gland is not enlarged beyond the physiological swelling during pregnancy. B Abdominal CT performed at 27 weeks and 2 days of gestation: the CT scan shows bilateral renal enlargement and reveals a 26 mm × 26 mm mass with a density of 28 Hounsfield Units (HU) in the left adrenal gland (arrowhead)

Fig. 2.

Clinical course of the patient. A Changes in serum and urine cortisol: cortisol decreased in response to metyrapone use. B Changes in blood pressure and serum potassium: blood pressure and serum potassium were managed with antihypertensive and potassium medications. C Changes in fluid balance (urine volume and in) and body weight: treatment was administered to avoid negative balance due to intravenous infusion and DDAVP. Stool: 250 mL and insensible loss: 600 mL (lungs and skin) were used as outbalances, other than urine volume, when calculating fluid volume. The maximum daily doses of medications, as listed at the top of each figure, are as follows: methyrapone, 500 mg; nifedipine, 80 mg; nicardipine, 60 mg; methyldopa, 750 mg; potassium chloride, 80 mEq; potassium gluconate, 7.5 mg; DDAVP, 240 mg. Abbreviations: U-cortisol, urinary free cortisol; S-cortisol, serum cortisol; sBP, systolic blood pressure; dBP, diastolic blood pressure; DDAVP, desmopressin acetate

However, the patient progressed to preeclampsia without apparent liver dysfunction at 28 weeks of gestation. At 29 weeks, fetal dysfunction was confirmed, necessitating delivery via cesarean section. The infant weighed 1197 g (–1.1 SD), measured 37 cm in length (–1.0 SD), and had a head circumference of 27.0 cm (–0.1 SD), confirming a very low birth weight. The Apgar scores were 4 and 8 at 1 and 5 min, respectively. No morphological abnormalities were observed. The neonate required ventilator management for neonatal asphyxia, which was implemented in the NICU unit. The neonate was weaned off the ventilator 9 h after birth. Placental pathology revealed several infarcted nests of up to 2 cm in length within the split-placental plane. In the fetal membrane, there were signs of necrosis and neutrophil infiltration. Fibrinoid necrosis was also observed in some decidual vessels (Fig. 3). The pathological findings of the placenta were consistent with HDP.

Fig. 3.

Pathological findings of the placenta from the patient. A The figure shows a placenta that is small for gestational age, measuring 15 cm × 11 cm. B Hematoxylin and eosin (HE)-stained image depicting deciduitis of decidual vessels. Within the fetal membrane, necrosis and neutrophil infiltration, indicative of deciduitis, were observed. Additionally, fibrinoid necrosis were observed in some decidual vessels

DDAVP was discontinued on the day of surgery; urine output decreased to < 3L/day and polyuria disappeared 6 days after surgery. A hypertonic saline infusion test was performed 4 days postpartum, which had not been performed during pregnancy owing to concerns regarding its potential impact on hemodynamics. AVP response was within the normal range (Fig. 4) [11]. Postpartum evaluation of nighttime cortisol, UFC levels and a midnight-to-morning serum TSH ratio of 0.19 (< 1) were also consistent with a diagnosis of CS [12]. The patient underwent left adrenalectomy 4 months after discharge. Histological examination of the mass in the left adrenal gland revealed that the lesion was composed of polygonal cells with pale eosinophilic granular cytoplasm arranged in a nested growth pattern. Additionally, certain regions exhibited a foamy cytoplasm (Fig. 5). The criteria assessed in the Weiss Scoring System confirmed a score of 0, indicating that the tumor is not suspected to be malignant. After adrenalectomy, the changes in blood pressure, hypokalemia, blood glucose levels, and central obesity due to CS improved.

Fig. 4.

Relation between plasma arginine vasopressin (AVP) concentrations and serum sodium levels before and during the infusion of 5% hypertonic saline 4 days after delivery. The normal range of plasma AVP levels was based on data measured using a Yamasa AVP kit (Yamasa Shoyu Corporation, Choshi, Japan). The results of the hypertonic saline infusion test were negative for central diabetes insipidus (CDI)

Fig. 5.

Pathological findings of left adrenal tumors resected from the patient. A Macroscopically, a solid, well-demarcated mass with a brown-to-yellow appearance can be observed (arrowhead), exerting compressive effects on the adjacent adrenal gland. B Histologically, the lesion is composed of polygonal cells with pale eosinophilic granular cytoplasm, arranged in a nested growth pattern. Additionally, some regions contains cells with a foamy cytoplasm

Discussion

CS during pregnancy is a rare and challenging condition, with < 250 reported cases [13]. Management options include conservative treatment for milder cases, surgery during the second trimester, or medications such as metyrapone or cabergoline. Therefore, a multidisciplinary approach is recommended for optimal care [13].

DI in pregnancy is also a rare condition with various etiologies, affecting up to 1 in 30,000 pregnancies [14]. It can result from decreased AVP secretion (central DI or AVP-D), renal tubule resistance to AVP (nephrogenic DI or AVP-R), or increased AVP breakdown by placental vasopressinase (Gestational diabetes insipidus, GDI) [8]. GDI is an uncommon pregnancy complication that is believed to result from elevated levels of vasopressinase, an enzyme produced by the placenta that breaks down AVP.

Moreover, pregnancy-induced changes in osmoregulation, such as lowered basal plasma osmolality and osmolar thirst threshold, may exacerbate pre-existing DI or trigger its onset during pregnancy [15]. Management of DI during pregnancy typically involves DDAVP, which is a AVP analog resistant to vasopressinase degradation [14, 16]. In cases of pituitary apoplexy during pregnancy, postoperative DI should be treated with DDAVP rather than AVP owing to its placental vasopressinase activity [16]. Early diagnosis and appropriate treatment are crucial to reducing maternal and fetal morbidity risks associated with DI in pregnancy [14].

GDI is often associated with increased vasopressinase activity due to hepatic dysfunction, such as HELLP syndrome or acute fatty liver, which impairs vasopressinase degradation, leading to excessive AVP clearance and resulting in DI [17]. GDI involves elevated placental AVP production. Vasopressinase, produced by trophoblasts starting in the 7 th week of pregnancy, increases up to 1,000 folds as the trophoblast mass grows from the 7 th to the 40 th week. It peaks during the third trimester and typically decreases to undetectable levels at 5–6 weeks postpartum [17]. The amount of vasopressinase correlates with the placental volume [18]. However, our case showed neither increased placental weight nor obvious liver damage on blood tests, unlike typical cases of GDI, where excessive placental vasopressinase production or maternal liver dysfunction impairs AVP activity. This suggests that alternative mechanisms may have contributed to the development of DI in the present case.

In this case, hypokalemia could have been exacerbated by pregnancy-induced elevated cortisol levels, leading to increased urinary output. Prolonged hypokalemia can cause a type of nephrogenic DI (AVP-R), in which the kidneys fail to respond appropriately to AVP, resulting in increased urine output [19]. When potassium levels are restored to normal, polyuria resolves promptly [20]. In this case, urine output was slightly reduced after correction for hypokalemia; therefore, hypokalemia may have contributed, in part, to the excessive urine output. However, as polyuria persisted after potassium correction and resolved the day after fetal delivery, the primary cause of polyuria may have been a mechanism other than hypokalemia-induced polyuria.

First, pregnancy is associated with increased levels of cortisol-binding globulin (CBG), leading to higher total cortisol levels. In CS, this hormonal surge can worsen hypercortisolism symptoms such as hypertension, diabetes, and immunosuppression. Elevated cortisol levels in pregnant women with CS may contribute to inducing resistance to AVP in the renal tubules [21]. Corticosteroids interfere with AVP binding to its receptors, reducing its antidiuretic effect. This resistance may have been further exacerbated by the physiological demands of pregnancy, which increase the water turnover and osmoregulatory stress. Additionally, glucocorticoids exert a direct inhibitory effect on the hypothalamus, resulting in the suppression of AVP secretion from magnocellular neurosecretory cells [22]. This tonic inhibition serves as a regulatory mechanism for AVP release, highlighting the complex interplay between glucocorticoids and neuroendocrine functions in fluid homeostasis.

Second, increased renal clearance of AVP during pregnancy, potentially amplified by the hemodynamic changes associated with CS, may have contributed to transient polyuria. Enhanced glomerular filtration rates and renal blood flow during pregnancy influence AVP metabolism and clearance [6], and these effects may be more pronounced in patients with CS owing to cortisol-induced vascular changes.

Prostaglandin-mediated mechanisms might also play a role. Prostaglandin levels are elevated in some biological fluids during pregnancy and parturition [23]. Elevated prostaglandin levels, as observed during pregnancy, can antagonize AVP activity, further complicating water reabsorption in the renal tubules [24]. These interactions could impact the overall effectiveness of AVP in regulating water reabsorption. Pregnancy is also characterized by elevated levels of progesterone, in addition to corticosteroids and prostaglandins, which can interfere with the action of AVP [25].

In summary, the mechanisms for DI during pregnancy in our patient with CS are multifactorial.

This case report has some limitations. Vasopressinase expression was not examined in the placenta. While an increased activity of vasopressinase, an insulin-regulated aminopeptidase in the syncytiotrophoblasts of the placental tissue, cannot be ruled out, this appears unlikely owing to the low placental volume, which could be associated with vasopressinase overproduction [18]. Additionally, the influence of stress-induced oxytocin cannot be excluded. Stress-induced oxytocin, which has uterine contracting effects, can stimulate the production of oxytocinase in the placenta as a protective mechanism against preterm labor. As oxytocinase and vasopressinase are structurally identical, this process may degrade circulating AVP, leading to DI, a condition associated with preterm delivery [18]. Moreover, copeptin, a stable surrogate for AVP, was not measured in this case owing to a lack of availability of the diagnostic test. Copeptin offers advantages in differentiating central DI (AVP-D), nephrogenic DI (AVP-R), and primary polydipsia. In non-pregnant individuals, copeptin-based tests demonstrate high diagnostic accuracy [26]. However, more research is needed to establish its clinical utility and standardize its use in pregnant women with suspected DI.

This case report presents a rare instance of the concurrent occurrence of CS and DI during pregnancy, emphasizing the distinctive challenges involved in both diagnosis and clinical management. Unlike typical presentations, the absence of high placental volume or hepatic dysfunction directs attention to other possible pathophysiological interactions.

While both CS and DI in pregnancy have been described individually, their concurrent presentation has not been previously reported. This case provides novel insights into the potential interplay between hypercortisolism and AVP resistance, expanding our understanding of mechanisms of polyuria in CS. Furthermore, the case underscores the clinical complexity of diagnosing and managing coexisting rare endocrine disorders during pregnancy, necessitating a multidisciplinary approach. The unique pathophysiology observed in this patient suggests that hypercortisolism may contribute to transient AVP resistance, warranting further investigation in this regard.

Conclusions

The diagnosis of CS or DI during pregnancy is uncommon; however, early identification of both conditions is crucial, as they significantly affect maternal and fetal morbidity and prognosis. Unlike typical cases with GDI, polyuria in individuals with CS can be attributed to hypercortisolism-induced AVP resistance and increased renal clearance. Polyuria resolved postpartum, highlighting the unique pathophysiology of DI and CS during pregnancy.

Abbreviations

CS

Cushing’s syndrome

DI

Diabetes insipidus

AVP

Arginine vasopressin

AVP-D

Arginine Vasopressin Deficiency

AVP-R

Arginine Vasopressin Resistance

HDP

Hypertensive disorders of pregnancy

DST

Dexamethasone suppression test

GDM

Gestational diabetes mellitus

DDAVP

1-Deamino-8-D-arginine vasopressin

HU

Hounsfield Units

UFC

Urinary free cortisol

GDI

Gestational diabetes insipidus

CBG

Cortisol-binding globulin

Authors’ contributions

SH, SO, OT, and TN treated the patient, and SH drafted the manuscript. NS, YH, CK and HI participated in the data analysis and interpretation. TT revised the manuscript accordingly. All authors have read and approved the final manuscript.

Funding

Not applicable.

Data availability

All the data generated and/or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent form is available for review by the journal editor.

Competing interests

The authors declare no competing interests.