Connshing syndrome: complexity of cortisol co-secretion in primary aldosteronism

Abstract

Summary

Connshing syndrome, a distinct subtype of primary aldosteronism (PA), is characterized by the co-secretion of aldosterone and cortisol from an adrenal adenoma. This condition complicates diagnosis and treatment, as cortisol co-secretion can interfere with adrenal vein sampling (AVS), the gold standard for determining lateralization in PA. We present a case of a 57-year-old woman with resistant hypertension and an adenoma in the left adrenal gland, diagnosed with PA. During the investigation, cortisol co-secretion was identified. AVS results were confounded by this co-secretion, complicating the interpretation of lateralization. Despite this, a presumptive diagnosis of unilateral aldosteronism was made, leading to the decision for adrenalectomy. Postoperative analysis confirmed the resolution of PA and normalization of aldosterone and cortisol levels. This case emphasizes the diagnostic challenges posed by cortisol co-secretion, which can distort AVS results and complicate treatment decisions. Further research is necessary to improve diagnostic accuracy and develop tailored management strategies for patients with Connshing syndrome.

Learning points

• As the number of adrenal incidentalomas identified through imaging increases, more cases of Connshing syndrome are likely to be uncovered during biochemical evaluation.

• The co-secretion of aldosterone and cortisol from adrenal adenomas can interfere with diagnostic tests such as AVS, leading to misinterpretation of lateralization and complicating treatment decisions.

• It is important to explore alternative markers to cortisol, such as plasma metanephrines, to improve AVS accuracy and guide management decisions in patients with Connshing syndrome.

Background

Connshing syndrome, a rare entity within the spectrum of adrenal disorders, is characterized by the co-secretion of aldosterone and cortisol from a unilateral adrenal adenoma or, less commonly, bilateral adrenal hyperplasia (1, 2). It represents a distinct subtype of primary aldosteronism (PA) with autonomous cortisol secretion, estimated to occur in 10–20% of PA cases (3, 4, 5). However, its prevalence is likely underestimated due to diagnostic challenges, particularly regarding the tests used to identify cortisol overproduction (1).

Connshing syndrome often manifests with subtler or ‘subclinical’ hypercortisolism, currently referred to as ‘mild autonomous cortisol secretion’ (MACS) (1, 2). However, cortisol co-secretion can have significant clinical implications. The coexistence of cortisol and aldosterone can exacerbate hypertension (2) and increase the risk of spontaneous hypokalemia compared to isolated aldosterone or cortisol excess (1, 2).

Adrenal vein sampling (AVS) is considered the gold standard for determining whether PA is unilateral or bilateral (3). However, in Connshing syndrome, the co-secretion of cortisol can complicate the interpretation of AVS results, as elevated cortisol levels may distort the aldosterone-to-cortisol ratio used to assess lateralization (4, 5). This raises concerns regarding the use of cortisol measurements in AVS for these patients, as the reliability of this approach in the context of cortisol co-secretion remains uncertain. Furthermore, there are currently no specific recommendations for the use of AVS or other diagnostic approaches in these cases, due to the lack of robust evidence in the literature. Few cases have been reported that characterize the clinical features and diagnostic approaches in these patients.

With the increasing use of tests to assess hypercortisolism, as recommended by guidelines advocating for the dexamethasone suppression test in all adrenal incidentalomas (6), it is likely that more cases of Connshing syndrome will be identified. Therefore, it is crucial to deepen our understanding of its pathophysiology and establish the best diagnostic and therapeutic approaches to optimize clinical management in these patients.

Case presentation

A 57-year-old woman was referred to the endocrinology consultation in April 2024 due to an adenoma in the left adrenal gland, identified during the investigation of hypertension. She had a 15-year history of resistant hypertension, managed with azilsartan 40 mg, bisoprolol 5 mg, lercanidipine 20 mg, and spironolactone 25 mg. Her medical history included a prior episode of spontaneous hypokalemia (2.5 mEq/L, normal range (NR): > 3.5), requiring intravenous potassium chloride treatment in the emergency setting. Initial workup revealed a 22 mm lesion in the left adrenal gland on abdominal CT angiography, consistent with an adenoma, confirmed by abdominal magnetic resonance imaging. Laboratory tests showed renin of 4.8 µUI/mL (NR: 4.2–45.6), aldosterone of 58 ng/dL (NR: 2.8–37.6), and an aldosterone-to-renin ratio of 12 (NR: < 3.7). Both renin and aldosterone samples were collected in the seated position in the morning. The overnight 1 mg dexamethasone suppression test yielded 4.1 μg/dL (NR: < 1.8), confirmed on repeat testing, with a morning ACTH level of 15.8 ng/L (NR: < 46). These findings suggested a diagnosis of primary adrenal hypercortisolism.

Investigation

Based on PA, AVS with ACTH stimulation was performed. Spironolactone was suspended for 4 weeks, and azilsartan dose was increased to 80 mg once daily, in accordance with the patient’s longstanding, difficult-to-control hypertension, with persistently elevated home blood pressure readings despite ongoing therapy. Potassium supplementation was introduced at 750 mg once daily. After 15 days, follow-up electrolyte testing showed hypokalemia with a potassium level of 3.3 mEq/L (NR: > 3.5). Consequently, potassium supplementation was increased to 750 mg twice daily. The patient’s systolic blood pressure readings at home ranged between 140 and 160 mmHg.

AVS results demonstrated a selectivity index >10 and a lateralization index of 1.76. Aldosterone levels were >2,000 ng/dL on the left (after multiple dilutions) and 830 ng/dL on the right, with corresponding cortisol levels of 1,219 μg/dL (left) and 896 μg/dL (right) (Table 1). Although formal lateralization criteria were not met, due to unquantifiable aldosterone levels (being extremely high) in the left adrenal gland and confirmed cortisol co-secretion, a confounding factor in AVS interpretation, a presumptive diagnosis of unilateral aldosteronism was made. The patient was scheduled for adrenalectomy. While awaiting surgery, spironolactone 50 mg once daily, azilsartan 80 mg once daily, bisoprolol 5 mg once daily and lercanidipine 20 mg once daily were prescribed, achieving blood pressure readings of 125–130 mmHg systolic and 85–90 mmHg diastolic. No further episodes of hypokalemia occurred during this period.

Table 1.

Results from adrenal venous sampling.

	Peripheral	Left adrenal vein	Right adrenal vein
Cortisol (μg/dL)	27.4	1,219	896
Aldosterone (ng/dL)	93.2	>2,000	830
Aldosterone/cortisol ratio	3.4	1.64	0.93

Treatment

The patient underwent laparoscopic left adrenalectomy in November 2024 with steroid replacement to avoid adrenal insufficiency. The surgery was uneventful. On the first postoperative day, laboratory tests revealed an aldosterone level of <0.8 ng/dL (NR: 2.8–37.6). After surgery, the patient’s hypertension improved significantly, requiring reduced antihypertensive therapy. Laboratory evaluation after corticosteroid suspension documented a cortisol level of 7 μg/dL (NR: 6.2–19.4). She was discharged on hydrocortisone 10 mg in the morning and 5 mg in the evening and bisoprolol 5 mg in the morning. Postoperative steroid replacement included only hydrocortisone, as there was no clinical evidence of hypoaldosteronism.

Outcome and follow-up

Biochemical analyses after surgery (collected in the seated position in the morning) confirmed normalization of aldosterone levels (4.5 ng/dL, NR: 2.8–37.6), with normal renin (11.7 µUI/mL, NR: 4.2–45.6) and an aldosterone-to-renin ratio of 0.4, consistent with resolution of PA. Histological analysis confirmed the diagnosis of adrenal adenoma. Three months later, the patient maintained good blood pressure control after discontinuation of bisoprolol 5 mg daily and had no recurrence of hypokalemia. She underwent a Synacthen test, which did not document adrenal insufficiency, leading to the suspension of hydrocortisone.

Discussion

This case highlights the diagnostic challenges of Connshing syndrome. In patients with PA, AVS is used to determine if aldosterone hypersecretion is unilateral or bilateral (3). However, cortisol co-secretion can compromise AVS accuracy (4, 5). Elevated cortisol levels may interfere with the interpretation of the aldosterone-to-cortisol ratio, potentially masking true aldosterone secretion in the ipsilateral adrenal gland and leading to a false bilateral diagnosis (4, 5), although current evidence is insufficient to quantify this effect. These challenges can lead to delays in treating patients appropriately.

In cases with large unilateral lesions and significant hormone excess, bypassing AVS and proceeding directly to surgery could be a potential strategy. However, this remains controversial, as AVS provides definitive confirmation of lateralization, minimizing the risk of unnecessary adrenalectomy, since MACS is not, per se, a criterion for surgery (7). Despite its limitations, AVS remains central to therapeutic decision-making for confirming lateralization.

Alternatives to cortisol evaluation for assessing the selectivity and lateralization indexes in patients undergoing AVS have been proposed and explored in previous studies, such as plasma metanephrines, chromogranin A, or dopamine (8, 9, 10), which were not measured in our case. Among these, plasma metanephrines appear to be the most promising (9, 10), due to their short half-life, almost exclusive adrenal production (over 90%), and constant excretion, which is independent of systemic stress responses (9, 10). These biomarkers may play a key role in improving the diagnostic accuracy of AVS, particularly in patients with Connshing syndrome, by reducing the incidence of inconclusive or misleading results. Nonetheless, further research is warranted to confirm their clinical applicability. In our case, aldosterone levels were markedly elevated – exceeding the assay’s upper detection limit even after dilution – which already posed a limitation to the interpretation of the AVS. However, in patients with measurable aldosterone concentrations, the availability of reliable alternative markers becomes even more relevant to improve diagnostic precision and avoid misclassification.

Guidelines for the management of PA, such as those from the Endocrine Society (3), do not explicitly account for the diagnostic challenges introduced by cortisol co-secretion, and there is no clear recommendation on the need to proceed with AVS or on whether to proceed directly to surgery in the presence of co-secretion. Therefore, it is essential that future research focuses on refining diagnostic methods, including the consideration and validation of new markers for use in AVS, as well as developing personalized management strategies that account for the complexities introduced by cortisol co-secretion. Such an approach would ensure that patients receive the most appropriate and effective treatment based on accurate diagnostic information.

Our case illustrates how cortisol co-secretion can complicate the diagnostic pathway in patients with PA, reinforcing the need for further research to accurately quantify the impact of cortisol interference on AVS interpretation. Moreover, there is a clear need to validate alternative biomarkers for use in AVS and to develop specific therapeutic algorithms tailored to these patients.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.

Funding

This study did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent for publication of the clinical details and clinical images was obtained from the patient.

Author contribution statement

DFS provided clinical care. PF analyzed the data and wrote the main manuscript text. All authors provided clinical feedback in interpreting the results, contributed critically to subsequent revisions, and approved the final version of the manuscript.