Medical therapy versus adrenalectomy for metabolic outcomes in hypercortisolism

When a patient’s adrenal glands pump out too much cortisol without any signal from the pituitary, endocrinologists face a genuine clinical dilemma: should the culprit gland or glands be removed surgically, or should the hormone excess be quieted with drugs? A new retrospective study from Nancy University Regional Hospital in France suggests that the answer may matter more for a patient’s waistline and blood pressure than many clinicians assumed — and that for one common subtype of the disease, medication appears to outperform surgery when it comes to weight.

The study, led by Sophie Estienne and colleagues at Nancy University Hospital and the Université de Lorraine, followed 62 patients with confirmed endogenous ACTH-independent hypercortisolism, a condition in which the adrenal glands secrete cortisol autonomously rather than in response to adrenocorticotropic hormone. All patients were managed at a single center between January 2019 and January 2024. The researchers divided them into three groups: 42 patients who underwent adrenalectomy, the surgical removal of cortisol-producing adrenal tissue; 13 who received medical therapy with anticortisolic drugs; and 7 who were kept under observation without immediate intervention. Metabolic markers — body mass index, blood pressure, blood glucose and diabetes status, lipid profile, and liver parameters — were then tracked at baseline, six months, and twelve months.

ACTH-independent hypercortisolism encompasses a spectrum of adrenal disorders, from overt Cushing’s syndrome caused by a single adrenocortical adenoma to more indolent conditions such as mild autonomous cortisol secretion, or MACS, detected incidentally on imaging, and primary bilateral macronodular adrenocortical hyperplasia, known as PBMAH, in which both adrenal glands enlarge and secrete hormone autonomously. Prolonged cortisol excess is well established as a driver of morbidity: it promotes central obesity, hypertension, insulin resistance and type 2 diabetes, dyslipidemia, and fatty liver disease, and it ultimately raises cardiovascular mortality. Because of this burden, normalizing cortisol exposure — whether by removing the source surgically or suppressing it pharmacologically — is considered the most effective way to limit complications. Yet, as the French team notes, few studies have directly compared the metabolic consequences of the two strategies head-to-head.

The short-term results were broadly reassuring for both active treatments. At the six-month mark, patients in both the surgery and medication groups showed improvements in cortisol levels, weight, blood pressure, lipid profile, diabetes control, and liver parameters compared with their baseline values. In other words, whichever route clinicians chose to reduce cortisol burden, the downstream metabolic machinery began to respond. The metabolic syndrome that accompanies chronic hypercortisolism is, to a meaningful degree, reversible once the hormonal driver is controlled.

But one difference stood out — and it persisted. Weight loss, measured as change in body mass index, was significantly greater in the medication group. Over the first six months, medically treated patients lost an average of 1.61 kilograms per square meter of body surface, while surgically treated patients actually gained a slight average of 0.25 kilograms per square meter. That gap had not closed by twelve months, suggesting it reflects a genuine divergence in how the two treatment modalities affect body composition rather than a transient postoperative fluctuation. For all other measured metabolic parameters — blood pressure, glucose metabolism, lipids, and liver markers — the study found no significant difference between the surgery and medication arms.

The most striking findings emerged when the researchers broke the results down by the underlying cause of hypercortisolism. Among patients with PBMAH, those treated medically fared considerably better on several fronts than those who underwent surgery. Medically managed PBMAH patients saw their BMI fall by an average of 1.98 kilograms per square meter, compared with a gain of 0.68 in the operated group. Their blood pressure also improved dramatically: systolic pressure dropped by an average of 11.6 millimeters of mercury, versus an increase of 3 in the surgical group, while diastolic pressure fell by 4.5 millimeters of mercury against a rise of 5 in operated patients. For the other etiologies — such as unilateral adenomas treated by adrenalectomy — the researchers observed no significant differences between treatment strategies.

The authors’ conclusion is measured but clinically consequential: medical treatment appears more effective than surgery for improving weight in ACTH-independent hypercortisolism, particularly in patients with PBMAH, while the choice of treatment modality seems to have little impact on other short-term metabolic outcomes. The result makes physiological sense. PBMAH is a bilateral disease, so definitive surgical treatment typically involves bilateral adrenalectomy, leaving the patient in permanent adrenal insufficiency requiring lifelong glucocorticoid and mineralocorticoid replacement — a regimen that itself promotes weight gain and is notoriously difficult to titrate. Unilateral surgery in bilateral disease may also remove only part of the cortisol excess, and postoperative replacement steroid exposure can partially offset metabolic gains. Chronic medical therapy, by contrast, gradually titrates cortisol blockade while leaving the adrenal axis partially intact, potentially allowing a smoother return to eucortisolism without replacement-induced overshoot.

The study has limitations that the authors themselves acknowledge by design. It is retrospective, observational, and monocentric, with modest group sizes — particularly the 13 medically treated patients and 7 observed controls — and treatment allocation was not randomized. Patients selected for medical therapy often differ systematically from those sent to surgery: bilateral disease, older age, higher surgical risk, or patient preference may all have concentrated certain metabolic phenotypes in the medication arm. The relatively small observation group prevents firm conclusions about watchful waiting. The findings are also restricted to short- and medium-term follow-up of twelve months; whether the weight advantage of medical therapy translates into reduced cardiovascular events, improved bone mineral density, or better long-term survival remains untested.

Nevertheless, the work speaks to a rapidly evolving therapeutic landscape. For decades, adrenalectomy was essentially the only curative option for cortisol-producing adrenal disease, and the choice was binary: operate or watch. The emergence of effective steroidogenesis inhibitors and newer cortisol-modulating agents has changed that calculus, giving endocrinologists a genuine pharmacological alternative even for bilateral disease. This study is among the first to compare the two strategies specifically through a metabolic lens, rather than focusing solely on biochemical remission rates. Its message — that the goal of treatment should not merely be a normalized cortisol number but a demonstrably improved metabolic profile — adds a patient-centered dimension to treatment selection.

For the substantial population of patients with incidental adrenal findings and mild autonomous cortisol secretion, and for those with PBMAH facing the prospect of bilateral surgery, the results offer grounds for a more nuanced conversation. The evidence suggests that for patients whose primary threat is metabolic — obesity, hypertension, diabetes — medical cortisol control, where feasible, may deliver better weight and blood pressure outcomes than extirpative surgery, at least over the first year. Larger, prospective, and ideally randomized comparisons with longer follow-up will be needed to confirm whether these early metabolic signals endure, but the French data provide a compelling first head-to-head signal that, in the metabolic battle against excess cortisol, sometimes the better tool is a pill rather than a scalpel.