Restoring Cortisol Rhythm May Be Key to Recovery After Cushing Syndrome

Highlights

Even after biochemical control of Cushing syndrome, many patients continue to experience anxiety, depression, impaired quality of life, and metabolic comorbidity.

In this cross-sectional study of 90 treated, biochemically controlled patients, normal late-night salivary cortisol was associated with better mood and better patient-reported quality of life than abnormal late-night salivary cortisol or long-term glucocorticoid replacement.

Among patients with surgically remitted Cushing disease, nearly one in five still had abnormal late-night salivary cortisol, suggesting a distinct post-remission phenotype that may merit closer follow-up.

The findings support the concept that circadian cortisol normalization, not simply biochemical remission, may be an important therapeutic and prognostic target in Cushing syndrome survivorship.

Clinical Background

Cushing syndrome is characterized by chronic exposure to excess glucocorticoids, either endogenous or exogenous, and is associated with substantial morbidity affecting mood, cognition, cardiovascular risk, metabolism, bone health, and overall quality of life. Although treatment can achieve biochemical remission or control, clinical recovery is often incomplete and slow. Many patients report persistent fatigue, emotional distress, sleep disruption, and reduced social functioning long after cortisol excess has been treated.

This disconnect between laboratory normalization and lived experience is increasingly recognized as one of the central challenges in Cushing syndrome care. Traditional follow-up focuses on confirming remission using standard hormonal measures, but these tests may not capture whether the physiologic circadian pattern of cortisol secretion has truly recovered. In healthy individuals, cortisol follows a robust diurnal rhythm, peaking in the early morning and reaching its nadir late at night. Loss of this rhythm is a hallmark of active Cushing syndrome and may have downstream effects on sleep, mood regulation, energy balance, and metabolic homeostasis.

The study by Theodorou and colleagues addresses an important and clinically relevant question: in patients already considered biochemically controlled, does restoration of circadian cortisol rhythm, measured by late-night salivary cortisol (LNSC), correlate with better psychological and quality-of-life outcomes? This is not just a biomarker question. It speaks to whether endocrine recovery should be judged by more than average hormone levels and whether persistent circadian dysregulation could explain why some patients feel unwell despite “successful” treatment.

Study Design and Population

This was a cross-sectional study conducted at a tertiary-care center. The investigators enrolled 90 treated patients with biochemically controlled Cushing syndrome, including 84 with Cushing disease and 6 with adrenal Cushing syndrome. Patients were stratified into three groups: Group A, normal late-night salivary cortisol; Group B, abnormal late-night salivary cortisol; and Group C, patients on long-term glucocorticoid replacement.

The primary patient-centered outcomes were assessed using validated instruments: the Hospital Anxiety and Depression Scale (HADS) for mood symptoms, the CushingQoL questionnaire for disease-specific quality of life, and the Nottingham Health Profile (NHP) for broader health-related quality-of-life domains. This is an important methodological strength, because the study did not rely on a single global measure but instead captured several dimensions of recovery relevant to daily functioning.

The main analytical objective was to determine whether normalization of circadian cortisol rhythm, as reflected by normal LNSC, was associated with more favorable psychological and quality-of-life outcomes among patients considered biochemically controlled. The investigators also explored metabolic associations and performed multivariable analyses to adjust for potential confounding factors. Notably, some analyses excluded Group C, which is appropriate given that chronic glucocorticoid replacement introduces a distinct physiologic and clinical context.

Key Findings

The central finding was consistent and clinically intuitive: patients with normalized LNSC had better psychological well-being and better quality of life than those with abnormal LNSC or those requiring long-term glucocorticoid replacement. The magnitude of the differences was meaningful, not merely statistical.

For mood, Group A had lower HADS-Anxiety scores than Group B, with a median of 4 versus 7 (p=0.006). Depressive symptoms showed an even clearer gradient: Group A had lower HADS-Depression scores than Group B and Group C, with medians of 2.5 versus 6 versus 9, respectively (p=0.006 for A vs B; p<0.001 for A vs C). These results suggest that restoration of circadian cortisol rhythm may be associated with less emotional distress, and that long-term glucocorticoid replacement may represent the least favorable phenotype with respect to depressive symptoms.

Quality-of-life outcomes followed the same pattern. On the CushingQoL questionnaire, Group A performed better than Group C in both psychosocial and physical domains, with medians of 67.5 versus 39.5 for psychosocial health (p<0.001) and 63.9 versus 44.3 for physical health (p=0.005). These are clinically important differences because they reflect how patients feel and function in everyday life, beyond biochemical endpoints.

The Nottingham Health Profile provided additional granularity. Compared with Group B, Group A had better Emotional Reaction scores (0 vs 24; p=0.002). Compared with Group C, Group A had better Energy Level (0 vs 63; p=0.001) and Sleep (13 vs 56; p<0.001). These domains are especially relevant in Cushing syndrome, where fatigue, sleep disturbance, and emotional lability are common lingering complaints after treatment. The pattern across multiple instruments supports the robustness of the association rather than suggesting a single questionnaire artifact.

In multivariable analyses excluding the long-term replacement group, normalization of LNSC remained consistently associated with better outcomes across all HADS domains, as well as with the psychosocial domain of CushingQoL and several NHP domains, including Emotional Reaction, Social Isolation, Physical Abilities, and Home Relationships. This is important because it suggests that the relationship between circadian cortisol normalization and patient-reported recovery persists even after accounting for other measured factors. While the abstract does not provide full regression coefficients or confidence intervals, the repeated associations across outcomes imply a biologically coherent signal.

The metabolic findings also deserve attention. Group B had the highest diabetes rate, indicating that persistent circadian cortisol abnormality may be linked not only to mood and quality of life but also to adverse metabolic status. Although the cross-sectional design cannot establish causality, this association aligns with known glucocorticoid effects on insulin resistance and glucose metabolism. It also reinforces the possibility that circadian dysregulation may represent a residual disease burden even when conventional biochemical criteria suggest control.

One of the most notable observations was that among patients with surgically remitted Cushing disease, 18.6% had abnormal LNSC. The investigators describe this as a previously unrecognized clinical phenotype. Clinically, this matters because surgery is often considered the definitive treatment, yet a substantial minority may not regain a normal nocturnal cortisol nadir. Whether this reflects incomplete axis recovery, altered hypothalamic-pituitary-adrenal regulation, residual disease biology, or other endocrine adaptations remains unclear. Nevertheless, it signals that a subset of “remitted” patients may still carry physiologic abnormalities relevant to symptoms and long-term outcomes.

Expert Commentary

This study adds to a growing body of evidence that endocrine remission is not the same as full recovery. For clinicians managing Cushing syndrome, it is increasingly insufficient to ask only whether cortisol has normalized in a general sense; it may also be necessary to ask whether the normal circadian pattern has returned. Late-night salivary cortisol is attractive in this setting because it is noninvasive, reflects the physiologic nocturnal nadir, and is already familiar as a diagnostic tool in active Cushing syndrome.

The biological plausibility is strong. Cortisol rhythms influence sleep architecture, arousal, energy regulation, and affective processing. Persistent loss of the nocturnal nadir, even in the absence of overt hypercortisolism, could plausibly contribute to ongoing symptoms. In addition, prolonged exposure to excess glucocorticoids may produce durable changes in central nervous system signaling, inflammatory pathways, metabolic circuitry, and health behaviors. Thus, psychological recovery may lag behind biochemical control, and circadian restoration may be one marker of more complete physiologic normalization.

At the same time, the study has important limitations. Its cross-sectional design prevents causal inference. It cannot determine whether abnormal LNSC causes worse mood and QoL, whether sicker patients are more likely to have abnormal LNSC, or whether both are downstream of another unmeasured factor such as sleep disruption, residual hypothalamic-pituitary-adrenal axis dysfunction, concurrent medications, or illness severity before treatment. The sample size was modest, especially for the adrenal Cushing subgroup and for the long-term glucocorticoid replacement group. The study was conducted at a single tertiary center, which may limit generalizability.

There are also unanswered methodological questions. The abstract does not specify how many LNSC measurements were used, whether assay variability was considered, or how comorbid psychiatric disease and psychotropic medication use were handled. These factors can influence both LNSC interpretation and patient-reported outcomes. In addition, the directionality of the observed association could be influenced by sleep patterns: poor sleep can affect both cortisol rhythm and questionnaire responses, making sleep both a potential mediator and confounder.

Despite these limitations, the study is clinically valuable because it shifts attention toward patient-centered endpoints. Patients with treated Cushing syndrome often care most about whether they can sleep, think clearly, feel emotionally stable, and regain energy—not just whether a lab value has normalized. The findings argue that these outcomes may improve more fully when the circadian cortisol rhythm is restored.

Clinical Implications

For practice, the study suggests several actionable points. First, clinicians caring for patients after treatment for Cushing syndrome should recognize that biochemical control does not guarantee symptom resolution. Persistent fatigue, mood symptoms, and sleep disturbance deserve active assessment rather than reassurance alone.

Second, late-night salivary cortisol may have value beyond diagnosis. In selected treated patients, it could help identify residual circadian abnormality that may be relevant to prognosis and follow-up intensity. This is especially noteworthy in surgically remitted Cushing disease, where abnormal LNSC was not rare.

Third, long-term glucocorticoid replacement should remain a careful balancing act. Although replacement is necessary for adrenal insufficiency, patients receiving chronic replacement in this cohort had less favorable mood and quality-of-life outcomes than those with normal LNSC. This does not imply that replacement should be avoided when clinically indicated, but it does reinforce the importance of using the lowest effective dose, educating patients about adrenal recovery, and monitoring for over-replacement or persistent symptoms.

Finally, the work raises the possibility that circadian restoration could become a therapeutic target. Whether this can be achieved through surgical completeness, medical therapy, optimized replacement regimens, sleep-focused interventions, or other strategies remains to be tested prospectively.

Conclusion

In treated, biochemically controlled Cushing syndrome, normalization of late-night salivary cortisol was associated with better mood, better quality of life, and more favorable metabolic status. The results suggest that recovery from Cushing syndrome may depend not only on lowering cortisol levels, but also on restoring the normal circadian rhythm of cortisol secretion.

Although the study is cross-sectional and cannot prove causality, it identifies an important and potentially actionable concept for clinical care: nocturnal cortisol normalization may be a meaningful marker of deeper physiologic recovery. Future longitudinal studies should determine whether improving circadian cortisol patterns leads to better psychological and metabolic outcomes, and whether LNSC can serve as a practical biomarker for patient-centered remission.

Funding and ClinicalTrials.gov

Funding and ClinicalTrials.gov registration were not stated in the provided abstract.

References

1. Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing’s syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540.

2. Feelders RA, Newell-Price J, Pivonello R, Nieman LK, Hofland LJ, Lacroix A. Advances in the diagnosis and treatment of Cushing’s syndrome. Lancet Diabetes Endocrinol. 2019;7(4):300-312.

3. Lindsay JR, Nansel T, Baid S, Gumowski J, Nieman LK. Long-term impaired health-related quality of life in patients with Cushing’s syndrome despite biochemical remission. J Clin Endocrinol Metab. 2006;91(2):471-476.

4. Vilar L, Naves LA, Azevedo M, et al. Effect of cure of Cushing’s syndrome on quality of life. Eur J Endocrinol. 2007;156(2):119-126.

5. Dekkers OM, Biermasz NR, Pereira AM, et al. Mortality in patients treated for Cushing’s disease is increased, compared with patients with nonfunctioning pituitary macroadenomas. J Clin Endocrinol Metab. 2007;92(3):976-981.

6. Theodorou A, Tan EC, Reiner AS, Sazo M, Cohen MA, Lin AL, Tabar V, Geer EB. Impact of Cortisol Circadian Rhythm on Psychological Well-Being in Treated Cushing Syndrome: A Cross-Sectional Study. J Clin Endocrinol Metab. 2026. PMID: 42290613.