Can cortisol levels be elevated during pregnancy, particularly in females with a history of conditions such as Cushing's syndrome or adrenal insufficiency?

Cortisol Elevation in Pregnancy

Yes, cortisol levels are physiologically elevated throughout pregnancy, reaching values that would be considered pathological in non-pregnant individuals, with total cortisol increasing approximately 3-fold and free cortisol rising 1.6-fold by the third trimester. 1, 2

Normal Physiological Changes

Pregnancy induces dramatic alterations in the hypothalamic-pituitary-adrenal (HPA) axis that result in cortisol levels comparable to those seen in Cushing's syndrome in non-pregnant patients. 1

Magnitude of Cortisol Elevation

• Total plasma cortisol increases progressively throughout pregnancy, peaking in the third trimester at approximately 3-fold higher than non-pregnant baseline levels 2
• Free (unbound) cortisol increases 1.6-fold by the third trimester, demonstrating true HPA axis upregulation beyond just protein binding changes 2
• 24-hour urinary free cortisol (UFC) shows a mean 3-fold elevation during the third trimester compared to non-pregnant controls 2
• Salivary cortisol levels are elevated during pregnancy, with noon and evening levels more than twice as high as the non-pregnant state 3

Preservation of Circadian Rhythm

Despite the hypercortisolism, the normal diurnal cortisol pattern is preserved throughout all trimesters of pregnancy. 3, 4

• The cortisol awakening response remains intact during pregnancy, with a relative increase of approximately 40% from awakening levels 3
• Circadian rhythm is maintained in the first, second, and third trimesters, with characteristic morning peaks and evening nadirs 4

Mechanisms of Elevation

The increase in cortisol during pregnancy reflects resetting of HPA axis sensitivity rather than simply elevated corticosteroid-binding globulin (CBG) or displacement by progesterone. 5

• Placental synthesis and release of biologically active CRH and ACTH contribute to elevated ACTH levels 1
• Pituitary desensitization to cortisol feedback occurs, allowing higher cortisol levels to be maintained 1
• CBG levels increase 2.6-fold during pregnancy, but this alone does not account for the rise in free cortisol 2
• The elevation is not due to progesterone displacement of cortisol from CBG, as no relationship exists between salivary cortisol and progesterone levels 5

Clinical Implications for Specific Conditions

Congenital Adrenal Hyperplasia (CAH)

Pregnant women with CAH require increased hydrocortisone dosing in the third trimester, typically by 2.5-10 mg/day, due to estrogen-stimulated increases in CBG and total cortisol. 6

• Dose adjustments should be based on clinical symptoms and overall patient health 6
• Fludrocortisone may need to be increased in later pregnancy due to progesterone's anti-mineralocorticoid effect 6
• During labor, administer 100 mg hydrocortisone IV or IM, repeated every 6 hours if necessary 6

Cushing's Syndrome in Pregnancy

Cushing's syndrome during pregnancy is uncommon but carries significant fetal morbidity and mortality risk, with diagnosis complicated by overlapping features with normal pregnancy. 1

• The proportion of patients with primary adrenal causes of Cushing's syndrome is increased in pregnancy 1
• CRH stimulation testing and inferior petrosal sinus sampling can identify Cushing's disease 1
• Surgery is safe in the second trimester; medical therapy may be used otherwise 1
• Clinical signs requiring investigation include rapid weight gain, moon facies, purple striae, proximal muscle weakness, and hypertension 7

Adrenal Insufficiency in Pregnancy

Women with known adrenal insufficiency require higher maintenance doses in late pregnancy, with serum total and free cortisol normally increased 20-40% during gestation. 8

• A higher cortisol target of 1.5 × upper limit of normal (ULN) should be used when treating pregnant women with adrenal insufficiency 8
• During delivery, administer 100 mg hydrocortisone at onset of active labor, followed by continuous infusion of 200 mg/24h or 50 mg IM every 6 hours 8
• Rapid tapering over 1-3 days to regular replacement dose is appropriate after uncomplicated delivery 8

Important Caveats

No glucocorticoid supplementation is needed for physiologic cortisol elevation at delivery in healthy pregnant women. 7

• Stress-dose steroids should only be considered if the patient has been on exogenous glucocorticoids >5 mg prednisolone daily for >3 weeks 7
• Pregnant women with glucocorticoid exposure should be screened for gestational diabetes mellitus, as elevated cortisol increases GDM risk 7
• Blood pressure monitoring throughout pregnancy is essential, as elevated cortisol may contribute to hypertension 7

Postpartum Considerations

Cortisol levels fall slowly postpartum over several days, making it unlikely that the increase during pregnancy is solely due to elevated CRH levels. 5

• Women with more pronounced cortisol responses to acute stressors during pregnancy (13-31 weeks) show greater postpartum depression symptoms 2-27 days following delivery 8
• Accelerated CRH trajectories and higher CRH levels in mid-to-late pregnancy may predict postpartum depression symptoms during the first few postpartum months 8