Adrenal Cortisol in Pregnancy, Children, Older Adults on Steroids, and Athletes

Why Cortisol Physiology Cannot Be Read the Same Way in Every Population

Standard cortisol reference ranges were built almost entirely on non-pregnant, non-pediatric, non-athlete adults who were not taking exogenous glucocorticoids. Applying those ranges to a 28-week pregnant woman or a collegiate cross-country runner produces false positives and false negatives at rates that affect real clinical decisions. Each of the four populations below has a distinct HPA axis state, and each requires a different interpretive framework.

The hypothalamic-pituitary-adrenal (HPA) axis works as follows: the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH), which then drives the adrenal cortex to synthesize and release cortisol. Cortisol feeds back at both the hypothalamus and pituitary to suppress further CRH and ACTH release. Disrupting any point in this axis, whether through pregnancy, exogenous steroids, or chronic physiologic stress, changes the interpretive meaning of a serum cortisol result. A comprehensive overview of HPA axis physiology is available from the National Institute of Diabetes and Digestive and Kidney Diseases.

Cortisol in Pregnancy: A Dramatic but Purposeful Rise

During pregnancy, measured total serum cortisol rises two- to threefold by the late second and third trimesters, primarily because estrogen stimulates the liver to produce more corticosteroid-binding globulin (CBG). Free, biologically active cortisol rises by a smaller amount, roughly 20-40% above the pre-pregnancy baseline, and this rise is physiologically intentional. It supports fetal lung maturation, metabolic adaptation, and immune tolerance of the semi-allogenic fetus.

What Normal Looks Like in Each Trimester

In the first trimester, total cortisol remains close to baseline. By 30 weeks, values commonly reach 40-60 mcg/dL on immunoassay, a range that would suggest Cushing syndrome in a non-pregnant adult. A 2014 study published in the Journal of Clinical Endocrinology and Metabolism measured late-pregnancy free cortisol at 1.5-2.5x non-pregnant values and noted that urinary free cortisol also increases across gestation, complicating screening for Cushing syndrome. Read the study at PubMed.

Diagnosing adrenal insufficiency in pregnancy is therefore difficult. The standard 250-mcg cosyntropin stimulation test remains the preferred diagnostic tool, but peak cortisol thresholds may need to be adjusted upward. A peak below 18 mcg/dL at 30-60 minutes post-cosyntropin is still considered inadequate by most guidelines, though some experts suggest a threshold of 22-25 mcg/dL in the third trimester. ACOG guidelines on adrenal disorders in pregnancy are available here.

Antenatal Corticosteroids: The Most Evidence-Supported Intervention

When preterm birth is anticipated between 24 and 34 weeks of gestation, ACOG and the Society for Maternal-Fetal Medicine recommend a single course of betamethasone 12 mg IM every 24 hours for two doses. This protocol, unchanged in its core design from the original Liggins and Howie 1972 trial, reduces the incidence of respiratory distress syndrome, intraventricular hemorrhage, and neonatal death. A 2017 Cochrane review of 30 trials (N>7,000 infants) confirmed a 34% relative risk reduction in respiratory distress syndrome with antenatal corticosteroids. Access the Cochrane review here.

Betamethasone crosses the placenta efficiently because it is not inactivated by placental 11-beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2), unlike cortisol. That same enzyme protects the fetus from excess maternal cortisol under normal conditions. Administering betamethasone therefore bypasses a key fetal protection mechanism, which is why rescue or repeat courses require individualized risk-benefit assessment.

Adrenal Insufficiency During Labor and Delivery

Women with known primary adrenal insufficiency (Addison disease) or secondary adrenal insufficiency need stress-dose glucocorticoids during labor, a physiologically demanding event comparable to major surgery. A widely cited protocol is hydrocortisone 25 mg IV at the onset of active labor, followed by 100 mg IV every 8 hours during labor and delivery, then a rapid taper over 24-48 hours postpartum if the patient is clinically stable. NIH guidance on adrenal insufficiency management is available at.

Failing to provide stress-dose coverage during delivery can precipitate adrenal crisis, which presents with hypotension, vomiting, and confusion and carries maternal mortality risk if untreated.

Cortisol in Children: Age-Specific Reference Ranges Matter

Pediatric cortisol values are not simply smaller versions of adult values. Neonates display a transient surge in the first 24 hours of life, and cortisol secretion then follows a maturation curve that does not fully resemble adult diurnal rhythm until mid-childhood. Using adult reference ranges in children younger than 6 years may miss early-morning hypocortisolism.

The Neonatal and Infant Window

Cortisol in the first 48 hours of life typically peaks above 15 mcg/dL in term infants, then declines. By 4-6 weeks, AM cortisol values of 5-15 mcg/dL are common. Premature infants show blunted responses; a 2015 study in Pediatrics found that infants born before 28 weeks have adrenocortical immaturity with reduced basal and stimulated cortisol output, placing them at higher risk for relative adrenal insufficiency of prematurity (RAIP). Access that study at PubMed.

Hydrocortisone supplementation for RAIP remains controversial. The PREMILOC trial (N=255) tested low-dose hydrocortisone (1 mg/kg/day for 7 days) in extremely preterm infants and found improved survival without bronchopulmonary dysplasia, but the benefit was modest and did not meet all secondary endpoints. PREMILOC is indexed at PubMed.

Congenital Adrenal Hyperplasia in Childhood

The most common cause of adrenal cortisol deficiency in children is congenital adrenal hyperplasia (CAH), with 21-hydroxylase deficiency accounting for approximately 95% of cases. Classic salt-wasting CAH presents in the first weeks of life with vomiting, poor feeding, hyponatremia, and hyperkalemia. Treatment is hydrocortisone 10-15 mg/m² per day in three divided doses, a regimen that replaces cortisol while suppressing excess ACTH-driven androgen production. The Endocrine Society's 2018 CAH guidelines specify that doses above 17 mg/m²/day in children risk growth suppression. Read the full guideline at endocrine.org.

Stress dosing in children with CAH or adrenal insufficiency requires weight-based calculation. The standard approach is three times the maintenance hydrocortisone dose during febrile illness above 38.5°C, and hydrocortisone 1-2 mg/kg IV for adrenal crisis or surgical stress. Every family with a child on cortisol replacement should carry an emergency hydrocortisone injection kit.

Diagnosing HPA Dysfunction in Pediatric Patients

The low-dose (1-mcg) cosyntropin stimulation test is considered more sensitive than the standard 250-mcg test for detecting partial adrenal insufficiency in children, though neither test is perfectly sensitive for central (hypothalamic or pituitary) causes. An insulin tolerance test (ITT), which is considered the gold standard for central adrenal reserve, carries hypoglycemia risk and requires close monitoring; it should not be performed in children with seizure disorders or cardiac disease. A pediatric endocrinology reference for these protocols is available at NCBI.

Older Adults on Long-Term Steroids: HPA Suppression Is Underdiagnosed

Prolonged glucocorticoid therapy suppresses the HPA axis through sustained negative feedback at the hypothalamus and pituitary, reducing ACTH secretion and causing adrenocortical atrophy. The degree and reversibility of suppression depend on dose, duration, time of day of dosing, and the specific glucocorticoid used.

Threshold Doses and Suppression Risk

Not all steroid exposure carries equal suppression risk. Prednisone at doses below 5 mg/day for any duration is unlikely to cause clinically significant HPA suppression. Doses of 7.5 mg/day or more taken for 3 weeks or longer carry a meaningful risk of suppression. Doses above 20 mg/day for more than 30 days nearly always suppress the axis. These thresholds are summarized in a 2020 review in the Annals of Internal Medicine.

A nuance relevant to older adults: cortisol clearance declines with age. A 65-year-old patient on 10 mg prednisone/day has higher net glucocorticoid exposure than a 30-year-old on the same dose. This means suppression may occur at lower doses and persist longer in older populations.

How to Taper and Test

No single taper protocol applies to every patient. A pragmatic approach for a patient on prednisone 20 mg/day for 6 months is to reduce by 2.5 mg every 2-4 weeks until reaching 5 mg/day, then by 1 mg every 4 weeks. Once the patient is at physiologic replacement range (roughly 5 mg prednisone or 15-20 mg hydrocortisone equivalent per day), an 8 AM serum cortisol drawn 24 hours after the last dose can screen for HPA recovery. A value above 18 mcg/dL generally indicates adequate HPA recovery. A value below 3 mcg/dL indicates persistent suppression. Values between 3 and 18 mcg/dL warrant formal cosyntropin stimulation testing. The Endocrine Society's adrenal insufficiency guideline addresses steroid-induced suppression specifically.

The HealthRX clinical team uses a three-tier triage model for steroid-tapered patients presenting for outpatient follow-up: (1) patients on physiologic or sub-physiologic replacement who have an AM cortisol above 18 mcg/dL are cleared for full taper; (2) patients with AM cortisol 10-18 mcg/dL undergo a 250-mcg cosyntropin test before taper continues; (3) patients with AM cortisol below 10 mcg/dL are maintained on a physiologic hydrocortisone dose and retested at 8 weeks. This model is intended for clinician use and does not replace individualized clinical judgment.

Adrenal Crisis Risk in Older Adults During Intercurrent Illness

Older adults on long-term steroids who develop infection, undergo surgery, or experience physical trauma face adrenal crisis risk even if they are still on a glucocorticoid, because their adrenocortical reserve cannot mount the 3- to 10-fold cortisol surge that acute stress normally demands. The presenting signs in older adults (fatigue, confusion, hypotension) overlap extensively with sepsis, dehydration, and polypharmacy effects, leading to missed diagnoses.

The Endocrine Society's 2016 adrenal insufficiency guideline states: "All patients with adrenal insufficiency should carry a steroid emergency card and be educated about sick-day rules." For major surgery, the guideline recommends hydrocortisone 50-100 mg IV at induction, followed by 50 mg every 6-8 hours for 24 hours, then return to baseline dosing if the patient is clinically stable. Read the 2016 guideline at endocrine.org.

A 2013 population-based study using the UK Clinical Practice Research Datalink (N=70,638 patients on oral glucocorticoids) found that adrenal crisis occurred at a rate of 8.3 per 100 patient-years among those on long-term therapy, a rate three times higher than in age-matched controls. This study is indexed at PubMed.

Athletes with HPA Dysfunction: Overtraining Meets the Adrenal Axis

High-volume, high-intensity training without adequate recovery can blunt the HPA axis response over time, producing a state that resembles central adrenal insufficiency on biochemical testing, even without structural pituitary or adrenal pathology. This is sometimes labeled functional HPA suppression or, within the broader syndrome, overtraining syndrome (OTS).

What the Data Actually Show

Morning cortisol below 10 mcg/dL has been documented in elite endurance athletes during periods of excessive training load. A 2019 review in the British Journal of Sports Medicine described HPA axis changes in OTS: basal cortisol was reduced, ACTH responses to corticotropin-releasing hormone (CRH) challenge were blunted, and the normal AM cortisol-to-DHEA-S ratio was shifted, suggesting chronic hyperstimulation followed by downregulation. Access this review at PubMed.

Acute exercise, by contrast, does the opposite. A single bout of high-intensity exercise lasting more than 30 minutes raises cortisol transiently, peaking 20-30 minutes after the session ends. This acute rise is beneficial. The pathological state emerges when cumulative training stress exceeds recovery capacity over weeks to months, preventing the HPA axis from restoring its baseline reactivity.

Distinguishing OTS from Primary or Secondary Adrenal Insufficiency

The cosyntropin stimulation test is key. Athletes with functional HPA suppression secondary to OTS typically show an adequate peak cortisol response (above 18 mcg/dL) to exogenous ACTH stimulation, because the adrenal gland itself is structurally intact. Athletes with true primary adrenal insufficiency show a flat response. Athletes with secondary adrenal insufficiency (pituitary origin) may show a suboptimal peak response to the 250-mcg test and a clearly blunted response to the more sensitive 1-mcg test.

Relative Energy Deficiency in Sport (RED-S), formerly called the Female Athlete Triad, is a related condition in which chronic caloric restriction suppresses the hypothalamic GnRH pulse generator and simultaneously blunts the HPA axis. The International Olympic Committee's 2023 consensus statement on RED-S identifies HPA axis disruption as one of the physiologic consequences of energy deficit in athletes of all sexes. Read the IOC consensus statement at the British Journal of Sports Medicine.

Management in Athletes

The intervention that most reliably restores HPA axis function in overtrained athletes is reduction or cessation of high-intensity training for 6-12 weeks, combined with caloric adequacy. No pharmaceutical intervention specifically addresses OTS-related HPA blunting. Sleep optimization (targeting 8-9 hours per night) and structured periodization with planned deload weeks of roughly 40-50% training volume reduction may prevent the syndrome from developing.

Screening with an 8 AM serum cortisol during a preseason or off-season baseline check allows clinicians to identify athletes whose values fall below 10 mcg/dL before clinical symptoms appear. Repeating the test after a 2-week deload provides a simple before-and-after comparison. An increase of 3 mcg/dL or more after deload supports a functional rather than structural diagnosis. A relevant review of cortisol in sport is available at PubMed.

Athletes using anabolic steroids present a separate but related scenario. Exogenous testosterone and anabolic-androgenic steroids (AAS) suppress gonadotropins but do not directly suppress the HPA axis in the same way glucocorticoids do. However, AAS use can alter cortisol-binding globulin levels and modulate glucocorticoid receptor sensitivity, making cortisol interpretation less straightforward. Any athlete presenting with morning fatigue, salt craving, and low blood pressure while using or recently stopping AAS deserves adrenal evaluation.

Interpreting Cortisol Lab Results Across All Four Populations

A single serum cortisol value is rarely diagnostic in isolation. Collection timing, assay methodology, and clinical context all shift interpretation. The following principles apply across all four populations covered in this article.

First, always collect AM samples. The diurnal cortisol peak occurs between 7 AM and 9 AM. Samples drawn after noon have significantly lower cortisol and produce false positives for adrenal insufficiency. Second, note the assay type. Immunoassays overestimate cortisol in some conditions (cross-reactivity with cortisone or synthetic steroids) and underestimate it in others. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the reference standard for accurate measurement. Third, assess concurrent medications. Any exogenous glucocorticoid, including inhaled corticosteroids at high doses, can suppress the axis and artificially lower AM cortisol. A 2021 meta-analysis at PubMed found that inhaled corticosteroids at doses equivalent to fluticasone above 500 mcg/day produced measurable HPA suppression in 13% of adult patients.

The Endocrine Society's 2016 clinical practice guideline on adrenal insufficiency notes that "the diagnosis of adrenal insufficiency should not be made or excluded by any single test result alone, but in combination with clinical findings." This principle applies with particular force to pregnant women, children, and athletes, where physiologic shifts routinely produce values outside normal adult reference ranges without indicating disease.