Proposed algorithm for patient follow-up
As demonstrated, there is a lack of standardized post-surgical monitoring of patients with CD. To address this gap in clinical practice, we propose an evidence- and empirically-based algorithm to facilitate early detection and treatment of recurrence (Fig. 1). As determined by post-surgical early morning (8–10 a.m.) serum cortisol levels measured 2–3 days post-surgery, patients may be categorized as being in immediate remission (cortisol <2 µg/dL) [40, 41], potentially persistent (cortisol 2–5 µg/dL), or persistent (i.e., surgical failures; cortisol >5 µg/dL). Different courses of action are suggested for each of the three outcomes. As there is a scarcity of timing guidelines in the literature, proposed timing of evaluations is based on our own experiences.
Fig. 1 Proposed algorithm for the post-operative monitoring of patients with CD. Evaluation strategies are determined by a patient’s immediate post-surgical status as determined by early morning serum cortisol levels. Asterisk repeat surgery practice varies by center. Longer follow-up could be considered in patients with subnormal levels of post-operative cortisol as they may either experience delayed remission and/or may not necessarily experience recurrence. Re-intervention can be considered if cortisol levels begin to rise or if symptoms of the disease return. Dagger UFC upper limit of normal (ULN) as determined by specific assay used. Double dagger medical therapy: pasireotide (somatostatin analog), cabergoline (dopamine receptor agonists), mifepristone (glucocorticoid receptor antagonist), steroidogenesis inhibitors (ketoconazole, mitotane, etomidate, metyrapone)
The biochemical measure we recommend for monitoring cortisol levels is early morning serum cortisol. This is based on the following: (a) as discussed, this is the test most commonly utilized to evaluate surgical success and employing the same method ensures consistency over time, thereby providing traceable changes, and (b) it is our opinion that this is a convenient test as the patient needs only to visit the clinic to have blood drawn. Alternatively, urinary free cortisol (UFC) measurements, the most commonly used test for diagnosis of hypercortisolism, can also be used. Although assessments such as ACTH levels, CRH stimulation test, dexamethasone suppression test, and desmopressin stimulation test may be used, they are less convenient: ACTH degrades quickly and sample collection needs to be handled with great care; CRH and desmopressin stimulation tests require intravenous administration, and the dexamethasone suppression test requires the patient to take a dose of the glucocorticoid late at night and return to the clinic the next morning to have their blood drawn [42]. Although late-night salivary cortisol is useful for the screening and diagnosis of patients with CD [43], it has not been extensively studied in post-surgical patients and is therefore not currently recommended over morning serum cortisol [5].
Certain post-surgical treatment strategies apply to every patient with CD, regardless of surgical outcome. It is common for patients to experience psychiatric and physical consequences of the disease and should receive therapeutic care. The most common psychiatric manifestation of CD is depression, but anxiety, mania, and psychosis also occur [44]. Reduction of glucocorticoid action improves the system, but patients may experience significant ‘steroid withdrawal’ symptoms following remission despite adequate glucocorticoid replacement [45]. Some patients may have persistently reduced quality of life and impaired cognitive function despite long-term cure [44].
Occurrence of myopathy in patients with CD is also common and is most likely due to reduced muscle fiber conduction and decreased levels of circulating muscle proteins [46]. Osteoporosis is also a common feature of prolonged hypercortisolism [20] that leads to increased risk of bone fractures. Duration of physical and psychological therapy will depend on individual patient needs and could potentially lead to improvement in overall quality of life.

Immediate remission cases
Immediate remission is, by definition, a condition of acute post-operative hypocortisolism. Accordingly, patients whose post-operative serum levels are <2 µg/dL will require glucocorticoid therapy. These patients should be monitored regularly to evaluate recovery of adrenal function and exogenous glucocorticoid dose should be tapered appropriately.
We propose that early morning serum cortisol levels of patients in immediate remission be monitored at semiannual intervals for 3 years. This recommendation is based on the finding that the highest rates of recurrence are observed within approximately 5 years following TSS [27]. If no elevation is observed within 3 years, monitoring frequency can be tapered to an annual basis. However, patients should be strongly encouraged to return for testing sooner if symptoms of CD begin to reappear at any point.

Potentially persistent cases
Patients with post-operative serum cortisol levels between 2 and 5 µg/dL require much closer monitoring. These individuals are at increased risk for subclinical CD that is challenging to diagnose. We recommend that the first test be performed at 3 weeks following surgery to evaluate changes in cortisol levels (i.e., identify cases of delayed remission). If serum cortisol level declines to <2 µg/dL, the patient can be considered in remission. If serum cortisol remains elevated or if there is a mild increase in UFC values, the patient could potentially be afflicted with subclinical CD.
Careful consideration of any accompanying clinical symptoms will determine the course of action. If symptoms worsen over time, the first surgery was probably not curative and a second surgery, pituitary irradiation (radiotherapy or radiosurgery, depending on availability and the center’s practice), or medical therapy may be considered, as appropriate. If a mild elevation in serum cortisol or UFC is accompanied by either no changes or by slight improvements in clinical symptoms, the patient should be further monitored every 2–3 months. If serum cortisol levels then decrease to <2 µg/dL, the patient can be considered to be in remission. If not, treatment options, such as a second surgery, pituitary irradiation, or medical therapy may be considered if appropriate, especially if other symptoms of CD begin to reappear.

Persistent cases
Surgery is not always curative and some patients will remain hypercortisolemic following TSS. For patients with post-operative serum cortisol >5 µg/dL, immediate repeat surgery, pituitary irradiation, or medical therapy are possible further treatment options [43, 47]. Bilateral adrenalectomy (BLA) can be an alternative in some cases, although there is a risk of the patient developing Nelson’s syndrome; BLA also necessitates lifelong glucocorticoid and mineralocorticoid replacement therapy.