Circadian Rhythm Disruption Presenting as Adrenal Insufficiency: Diagnostic Challenges and Clinical Implications

Abstract

We describe the case of a 24-year-old woman with persistently low early morning cortisol levels and an initial adrenocorticotropic hormone stimulation test demonstrating a preserved cortisol response, raising concern for possible secondary adrenal insufficiency. Pituitary imaging and laboratory evaluation revealed a nonfunctioning pituitary microincidentaloma. Subsequent testing demonstrated higher serum cortisol levels later in the day. Further history revealed a longstanding delayed sleep phase, and serial cortisol testing suggested a shifted diurnal rhythm. This case highlights the importance of interpreting cortisol results in the context of clinical presentation, behavioral patterns, and circadian timing and raises awareness of the emerging concept of circadian misalignment impacting endocrine evaluation.

Keywords

low morning cortisol - ACTH stimulation test - secondary adrenal insufficiency - pituitary microadenoma - circadian misalignment - HPA axis - hypothalamus pituitary axis

Introduction

Serum cortisol levels, particularly when measured early in the morning, remain the cornerstone in the screening for adrenal insufficiency. A low value, paired with a normal adrenocorticotropic hormone (ACTH) stimulation response, raises concern for central adrenal insufficiency and often prompts further pituitary evaluation.[1] However, cortisol secretion is inherently dynamic, influenced not only by pituitary signaling but also by circadian signals, stress exposure, and behavioral patterns such as sleep-wake cycles.[2]

We present a young woman with a biochemical profile initially concerning for central adrenal insufficiency, but ultimately reflective of a more complex interaction between physiology, sleep behavior, and diagnostic timing. The case underscores the importance of context and timing in hormonal interpretation and highlights how misalignment between sleep patterns and testing hours may result in apparent cortisol suppression despite preserved adrenal function.

Case Description

A 24-year-old Emirati woman presented with fatigue, low mood, and gradual weight gain. She denied symptoms of orthostatic hypotension, nausea, vomiting, or salt craving. She had no history of exogenous steroid use. Endocrine evaluations performed across multiple health care settings consistently revealed low morning cortisol levels. An ACTH stimulation test demonstrated a normal cortisol response, prompting an empirical diagnosis of secondary adrenal insufficiency and the initiation of hydrocortisone therapy. Pituitary magnetic resonance imaging (MRI) revealed a 4-mm microadenoma without evidence of optic chiasm compression or mass effect ([Fig. 1]).

Fig. 1 Illustration of the impact of circadian disruption on cortisol profile.

The patient was referred to our hospital for further assessment of the pituitary lesion. There was no personal history of pituitary disease, head trauma, or psychiatric disorders. Her physical examination was unremarkable, with normal vital signs and no cushingoid features, hyperpigmentation, or signs of pituitary dysfunction. She reported no changes in symptoms with either initiation or withdrawal of hydrocortisone. Hormonal evaluation, including thyroid-stimulating hormone, free thyroxine, ACTH, prolactin, and electrolytes, was within normal limits ([Table 1]), consistent with a nonfunctioning pituitary incidentaloma.

Table 1 Summary of baseline biochemical and endocrine investigations

Test	Baseline values	Reference range
Serum cortisol	64	64–536 nmol/L
ACTH	2.3	1.6–13.9 pmol/L
Prolactin	261	102–496 mIU/L
TSH	1.57	0.4–4.2 mIU/L
Free T4	12.2	12–22 pmol/L
Serum potassium	4.4	3.2–5.5 mmol/L

Abbreviations: ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; T4, thyroxine.

Further history revealed a longstanding pattern of delayed sleep onset (between 3 and 4 a.m.) and waking in the late afternoon. A repeat ACTH stimulation test performed at our facility, 3 weeks after discontinuing hydrocortisone, showed a baseline 8 a.m. cortisol of 46 nmol/L (reference 64–536 nmol/L), rising to 552 nmol/L at 60 minutes ([Table 2]); confirming an adequate adrenal response.

Table 2 Summary of serum cortisol before and ACTH stimulation before and after circadian alignment

Test description	Timing	Cortisol (nmol/L)	Reference range and interpretations
Before ACTH stimulation	8:00 a.m.	46	64–536 nmol/L
After ACTH stimulation cortisol	60 minutes post-ACTH	552	Adequate adrenal response (> 500 nmol/L at 60 min)
Repeat 8:00 a.m. cortisol after sleep plan	8:00 a.m.	283	Improved morning cortisol after circadian alignment

Abbreviation: ACTH, adrenocorticotropic hormone.

A structured plan was implemented to gradually normalize the patient's sleep-wake cycle over a 2-week period. This included progressive advancement of bedtime by 30 to 60 minutes every few days, limiting screen exposure at night, ensuring consistent wake times before 10 a.m., and promoting natural morning light exposure. The goal was to realign her circadian rhythm with the natural cortisol peak. After adhering to this schedule, a repeat 8 a.m. cortisol test was performed, revealing a level of 283 nmol/L, a significant improvement from the prior result of 46 nmol/L, suggesting that the previously low cortisol level was more likely due to a delayed sleep phase than true adrenal insufficiency.

Discussion

The initial working diagnosis of central adrenal insufficiency was based on persistently low morning cortisol levels, a normal ACTH level, and a normal cortisol response to ACTH stimulation. Although a 4-mm pituitary microadenoma was identified on imaging, it lacked features of mass effect, hormonal hypersecretion, or pituitary hormone deficiencies. As such, the tumor was deemed an incidental, nonfunctioning lesion. It is important to note that the imaging was performed and reported externally, and our interpretation was based on the available report as the original MRI scans were not accessible for independent review. Nevertheless, its presence introduced diagnostic uncertainty and acted as a red herring, diverting attention from functional causes and increasing the risk of overdiagnosis.

Repeat ACTH stimulation testing performed at our center confirmed a normal adrenal response, and the patient remained clinically stable without glucocorticoid therapy. Notably, cortisol levels measured later in the morning were significantly higher than those obtained at 8 a.m., suggesting a possible delay in the normal diurnal cortisol peak. Further history revealed a longstanding habit of delayed sleep onset and late waking, pointing toward circadian misalignment as a potential explanation for the initially low early morning cortisol levels ([Fig. 1]).

Cortisol secretion follows a circadian rhythm regulated by the suprachiasmatic nucleus, with peak levels typically occurring in the early morning and declining through the day.[2] [3] Disruption of this rhythm due to delayed sleep, shift work, or irregular light exposure can lead to misaligned cortisol timing and misleading early morning results.[4] Individuals with altered sleep-wake cycles, such as shift workers or those with psychiatric conditions, have been shown to exhibit blunted or delayed morning cortisol peaks.[5] [6]

Although rare, reverse or flattened cortisol rhythms have been reported in chronic fatigue syndrome, depression, and other circadian disorders.[5] [6] In such cases, cortisol peaks may occur later in the day ([Fig. 1]), leading to misinterpretation of adrenal insufficiency based on a single early morning value. Diagnostic reassessment in such patients should include a detailed sleep history, dynamic or serial cortisol testing, and consideration of chronotherapy or light-based interventions to realign circadian patterns.

This case reinforces the principle that cortisol results must be interpreted within the broader clinical and behavioral context. It also highlights the potential for overdiagnosis when incidental imaging findings, such as nonfunctioning pituitary microadenomas, are overvalued in the presence of borderline biochemical data.

Conclusion

This case underscores the importance of a contextual and holistic approach in evaluating adrenal function. While early testing and imaging raised concern for central adrenal insufficiency, a comprehensive history and follow-up revealed preserved hypothalamic-pituitary-adrenal axis integrity. It serves as a reminder that not all biochemical abnormalities reflect true pathology—sometimes, the axis is not broken, it is simply out of sync.

Conflict of Interest

None declared.

Authors' Contributions

S.A.: Conceptualization, data collection, manuscript writing, and submission.

B.A.: Clinical supervision, manuscript review, and editing.

Patient's Consent

The authors confirm that they have due consent from the patient on the basis of totally anonymous publication and that all efforts will be made to hide the identity of the patient.

Compliance with Ethical Principles

No prior ethical approval is required for single case reports and small case series.

• References

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• 2 Buckley TM, Schatzberg AF. On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. J Clin Endocrinol Metab 2005; 90 (05) 3106-3114
• 3 Arendt J. Melatonin and human rhythms. Chronobiol Int 2006; 23 (1-2): 21-37
• 4 Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 1996; 81 (07) 2468-2473
• 5 Cleare AJ. The neuroendocrinology of chronic fatigue syndrome. Endocr Rev 2003; 24 (02) 236-252
• 6 Kudielka BM, Buchtal J, Uhde A, Wüst S. Circadian cortisol profiles and psychological self-reports in shift workers with and without recent change in the shift rotation system. Biol Psychol 2007; 74 (01) 92-103

Publication History

Article published online:
10 October 2025