What is the HPA (Hypothalamic-Pituitary-Adrenal) axis in a pregnant woman with PUPPP (Pruritic Urticarial Papules and Plaques of Pregnancy)?

What is the HPA Axis?

The HPA (Hypothalamic-Pituitary-Adrenal) axis is a neuroendocrine system that mediates the body's stress response through a hormonal cascade: the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to secrete adrenocorticotropin hormone (ACTH), which then triggers the adrenal glands to produce cortisol. 1

Core Anatomical Components and Hormonal Cascade

The HPA axis operates through three distinct anatomical levels that communicate via hormonal signals:

• The hypothalamus initiates the cascade by releasing CRH (also called corticotropin-releasing factor), which travels to the anterior pituitary gland 2, 1
• The pituitary gland amplifies the signal by secreting ACTH into the bloodstream in response to CRH stimulation 1
• The adrenal cortex responds to ACTH by producing and releasing cortisol, the primary glucocorticoid hormone essential for maintaining physiological homeostasis 1

Primary Physiological Functions

The HPA axis serves as the body's principal stress response system:

• Stress response coordination: The axis functions as the final common pathway for responding to emotional and physical stressors, with activation intensity proportional to stressor severity 1
• Homeostatic regulation: The system maintains physiological balance in response to both internal and external stimuli 1, 3
• Immune system integration: The HPA axis coordinates with the immune system, regulating release of cortisol, pro-inflammatory cytokines, and other glucocorticoids 1

Feedback Control Mechanisms

The system employs sophisticated negative feedback loops to prevent excessive activation:

• Cortisol feedback: Circulating cortisol inhibits further CRH release from the hypothalamus and ACTH secretion from the pituitary, creating a self-limiting regulatory circuit 2, 4
• Receptor-mediated control: This feedback occurs through mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) located in the brain and pituitary 4
• Multiple feedback speeds: Rapid nongenomic effects occur within minutes, while slower genomic effects involve gene repression over hours 4

Circadian and Ultradian Rhythms

Normal HPA axis function follows predictable temporal patterns:

• Diurnal rhythm: Cortisol levels peak in the morning and decline throughout the day to reach their lowest point in the evening 2, 5
• Ultradian pulsatility: Underlying the daily rhythm are approximately hourly cortisol pulses that directly affect gene transcription 5
• Dynamic variability: These secretory patterns are highly dynamic and change substantially during illness 5

Clinical Significance and Pathophysiology

In Chronic Stress

• Persistent activation: Chronic stress leads to sustained HPA axis activation, resulting in insulin resistance, reduced hippocampal volume, and decreased neurogenesis 1, 6
• Neuroinflammation: Elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) contribute to depression and anxiety disorders 6
• Metabolic dysregulation: Chronic activation causes metabolic remodeling with disturbed energy production and lipotoxicity 6

In Psychiatric and Inflammatory Disorders

• Depression association: Altered HPA axis activity represents one of the most commonly observed neuroendocrine abnormalities in depressive disorders 1
• Cytokine interactions: Upregulated inflammatory signaling leads to HPA axis dysfunction, with blunted cortisol responses associated with cancer-related fatigue 2
• Circadian disruption: HPA dysfunction contributes to disrupted activity/rest rhythms and sleep disturbances 2

In Pregnancy and Postpartum

• Predictive value: Altered cortisol responses during pregnancy may predict subsequent postpartum depression 7
• Impaired sensitivity: Women with postpartum depression may demonstrate absent cortisol awakening responses, indicating HPA axis dysfunction 7

Clinical Assessment Considerations

When evaluating HPA axis function:

• Dynamic testing: Static cortisol measurements are insufficient for most cases; dynamic tests that simulate major stress responses are required for diagnosing secondary adrenal insufficiency 3, 5
• Screening tools: The 1 mg dexamethasone suppression test screens for autonomous cortisol secretion 1
• Context matters: Frank adrenal insufficiency with obvious manifestations requires only basal cortisol measurement, but subtle cases need more sophisticated evaluation 3

Common Pitfalls

• Ignoring pulsatility: Previously used static assessment tools fail to capture the dynamic, pulsatile nature of cortisol secretion 5
• Overlooking feedback bypass: Some physiological stressors may partially bypass hypothalamic feedback sites, while others may override negative feedback entirely 4
• Misinterpreting variability: Individual variability in HPA axis responses is substantial and influenced by multiple factors including inflammatory state, circadian timing, and stress intensity 2, 5