Hypertensive disorders affect approximately 5–10% of pregnancies and are a leading cause of maternal, foetal, and neonatal morbidity and mortality [1]. The vast majority of these cases are caused by primary hypertension, with a prevalence of 1.52%. Although secondary hypertension accounts for only 0.24% of cases [2], it is associated with a significantly increased risk of adverse outcomes for both mothers and foetuses. The possibility of secondary hypertension should be considered, especially when it is accompanied by hypokalaemia. Primary aldosteronism is the most common cause of secondary hypertension, and aldosterone/cortisol co-secreting tumours represent a special subtype of PA, accounting for 5.31–21% of PA cases [3]. These tumours are characterized by the abnormal secretion of both aldosterone and cortisol. Research on the incidence and prevalence of PA and Cushing’s syndrome (CS) during pregnancy is extremely limited, and the literature consists of single case reports and studies involving a small number of patients. Currently, there are no reports of pregnancy complicated by aldosterone/cortisol co-secreting tumours.

Normal pregnancy is often characterized by elevated cortisol levels. According to the latest consensus [4], the course of normal pregnancy is referred to as nontumorous hypercortisolism (formerly known as pseudo-Cushing’s syndrome). During this period, owing to the stimulation of the pituitary and placenta by corticotropin-releasing hormone (CRH), the synthesis and secretion of ACTH increase, promoting adrenal hypertrophy and increased cortisol production [5]. In turn, high cortisol levels stimulate the placenta to synthesize and release more CRH, creating a positive feedback loop that maintains elevated cortisol levels [6]. This makes it extremely challenging to confirm the presence of CS through laboratory tests during pregnancy. In normal pregnant women, the false-positive rate of the low-dose dexamethasone suppression test (DST) is as high as 80% [7]. Although elevated midnight plasma and salivary cortisol levels are potential diagnostic markers, their diagnostic thresholds have yet to be established during pregnancy [8]. Moreover, overlapping clinical features between CS pregnancies and normal pregnancies, such as weight gain, abdominal striae, and peripheral edema, often lead to delayed diagnosis in practice. Currently, there is no consensus on the treatment of such patients. In this case, after antihypertensive and potassium supplementation treatments proved ineffective, the obstetrician opted for a caesarean section after adequate preoperative preparation. Fifty days postpartum, the persistence of hypertension and hypokalaemia suggested the presence of a pathological condition unrelated to pregnancy. At that time, abdominal CT revealed bilateral adrenal adenomas, and elevated cortisol levels with suppressed ACTH helped confirm the diagnosis of ACTH-independent Cushing’s syndrome.

Due to the limitations in diagnostic capabilities at the local hospital, the surgeon chose to remove the larger right adrenal tumor without fully characterizing the functional status of the bilateral adrenal adenomas, a decision that aligns with some current treatment recommendations [9]. Postoperative pathological examination and subsequent signs of overt adrenal insufficiency provided indirect evidence that the removed tumor was a hyperfunctioning cortisol-secreting adenoma. However, the patient’s persistent hypertension after surgery suggested the presence of additional unrecognized pathologies, whereas her continuous hypokalaemia and the remaining adrenal adenoma suggested a diagnosis of primary aldosteronism. Although the ARR was negative during the first screening, this may have been due to the overall upregulation of the RAAS during pregnancy. Oestrogen produced by the placenta increases the hepatic synthesis of angiotensinogen [10], whereas renal oestrogen stimulation and extrarenal synthesis in the ovaries and maternal decidua lead to a significant increase in the plasma renin concentration and activity [11]. Increased renin activity promotes elevated angiotensin II levels, which in turn stimulates aldosterone production in the zona glomerulosa. After delivery, the sharp decline in progesterone and estrogen levels following placental expulsion leads to a decrease in the ARR. The relatively high and proportionate increase in renin activity may further reduce the ARR, potentially increasing the likelihood of false-negative results. Furthermore, abnormal increases in cortisol levels can also elevate angiotensinogen levels [12], and the use of nifedipine can make test results unreliable. After adjusting the medication, we reinitiated the diagnostic process for primary aldosteronism; during this time, the patient exhibited a significant decrease in renin and an elevated ARR, and both captopril and saline infusion tests confirmed autonomous aldosterone secretion, establishing a diagnosis of primary hyperaldosteronism.

Differentiating the subtype of primary aldosteronism and the secretory function of adrenal lesions is crucial for managing primary aldosteronism. Given our patient’s youth and autonomous cortisol hypersecretion, genetic disorders such as familial hyperaldosteronism or hereditary Cushing’s syndrome had to be considered, but whole-exome sequencing of peripheral blood did not reveal any significant pathogenic gene defects. We then focused on determining the subtype of primary aldosteronism. Although adrenal venous sampling (AVS) is universally regarded as the “gold” standard for distinguishing between unilateral and bilateral secretion in primary aldosteronism patients, its interpretation becomes challenging in patients with concomitant high cortisol secretion. In this case, although the factor causing autonomous cortisol secretion was surgically removed, postoperative adrenal insufficiency and glucocorticoid replacement therapy could still interfere with the serum cortisol concentrations in the inferior vena cava and adrenal veins. Additionally, AVS is an invasive procedure and the patient had undergone two invasive abdominal surgeries in a short period, namely, a caesarean section and right adrenal tumor resection, which significantly increased the risk of AVS failure and complications. Thus, AVS was deemed unsuitable for this case.

Recent studies have verified that 68Ga-Pentixafor PET/CT imaging, which targets the CXCR4 receptor, demonstrates substantial concordance with AVS in differentiating the subtypes of primary aldosteronism [12]. For nodules larger than 1 cm in PA patients, when the SUVmax is greater than 7.3, the specificity of CXCR4 imaging for identifying APA is 100% [13]. Therefore, we opted for CXCR4 PET/CT imaging to ascertain the functional status of the adrenal lesion. The results revealed that the left adrenal adenoma had a maximum SUV of 8.75, which was significantly greater than that of the surrounding adrenal tissue (a maximum SUV of 2.7 and an average SUV of 2.34), confirming that the adenoma was an aldosteronoma. The patient was thus diagnosed as having a rare case of A/CPA with a right adenoma secreting cortisol and a left adenoma secreting aldosterone. However, notably, individual studies have reported increased uptake of CXCR4-targeted 68 Ga-PentixaFor in cortisol-producing adrenal adenomas. Therefore, this technique needs to be combined with hormone assays and functional tests to more accurately differentiate functional adrenal adenomas[14].

For the treatment of unilateral aldosteronoma, both national and international guidelines recommend complete adrenal resection, but there is currently no consensus on the surgical approach for A/CPA. The average incidence of postoperative adrenal insufficiency in Cushing’s syndrome patients is as high as 99.7% [15], and avoiding permanent adrenal insufficiency is a crucial factor in determining the surgical approach. Since the patient had already undergone resection of the right adrenal cortical adenoma and experienced adrenal insufficiency, further resection of the left adrenal gland would have significantly increased the risk of permanent adrenal insufficiency. Given that CT and CXCR4 imaging revealed no abnormal changes beyond the tumors, we opted to remove the left adrenal tumor while preserving the remaining adrenal tissue. The surgery was scheduled nine months after the first operation, as ACTH stimulation tests indicated nearly normal adrenal function. This treatment approach proved effective over a one-year follow-up. After the operation, the patient’s hypertension and hypokalaemia were completely relieved. However, adrenal insufficiency appeared as predicted, for which we administered glucocorticoid and mineralocorticoid replacement therapy, later adjusting the dosage on the basis of follow-up findings and finally discontinuing the treatment after nine months. Biochemical tests and ACTH stimulation tests confirmed normal adrenal cortical function, and the patient felt well, validating our treatment approach. Thus, the choice of surgical approach for patients with bilateral adrenal adenomas that secrete aldosterone and cortisol independently should be made while considering the specific location and secretion status of the adrenal tumors, as well as the patients’ individual circumstances.

Given the absence of germline mutations in the peripheral blood, we performed immunohistochemical and genetic analyses of the bilateral tumors. In the left adrenal adenoma, a classical somatic missense mutation in KCNJ5, c.503(exon2)T > G (p.L168R), was detected, and immunohistochemistry revealed predominant expression of CYP11B2, indicating that it was the source of autonomous aldosterone production. Research has confirmed that the p.L168R mutation of the KCNJ gene leads to depolarization of the ZG cell membrane, allowing an influx of extracellular calcium ions, which activates aldosterone synthesis and secretion [16]. On the right side, the adenoma harbored a PRKACA c.617(exon7)T > G (p.L206R) mutation with immunohistochemistry confirming strong CYP11B1 expression. This p.L206R mutation activates PKA independently of cAMP, disrupting normal cortisol regulation and leading to autonomous glucocorticoid secretion and Cushing’s syndrome development [17]. However, whether pregnancy is a potential predisposing factor for the simultaneous occurrence of two adenomas independently secreting different hormones in a single patient, or if this case is merely the result of coincidence, requires further investigation with a larger sample size.