Significance of Exogenous Estradiol on Plasma Cortisol and Salivary Cortisol During Adrenocorticotropic Hormone Stimulation in Women With Pituitary Insufficiency

Objective Oral estrogens increase the levels of cortisol binding globulin (CBG) potentially affecting test results for adrenal insufficiency. The objective was to evaluate the influence of oral and transdermal estradiol on total plasma (p) and salivary cortisol in hypogonadal women with secondary adrenal insufficiency or at risk of developing adrenal insufficiency. Furthermore, to determine if estradiol treatment can lead to a change in the diagnosis of adrenal insufficiency based on a Synacthen‐test. Methods Crossover study. Intervention: 12 weeks oral estradiol (2 mg), 12 weeks transdermal estradiol (100 µg/day), and 12 weeks without estradiol. After each intervention plasma total cortisol (pTC), salivary cortisol and CBG were measured before and after a 250 ug Synacthen‐test (30 min) (normal response pTC > 420 nmol/L, overt adrenal insufficiency pTC < 250 nmol/L). Results Seventeen hypopituitary patients, mean age 42 ± 6 years were included. 30‐min pTC did not change significantly according to intervention (no estradiol 401 (interquartile range: 55–495), oral estradiol 440 (74–600), and transdermal estradiol 304 (48–492) nmol/L). Based on pTC no patients with overt adrenal insufficiency crossed the cut‐off for adrenal insufficiency between interventions whereas three patients with borderline adrenal insufficiency (pTC 390–559 nmol/L) crossed the cut‐off. CBG was higher on oral estradiol compared to no estradiol ( p < 0.001) and transdermal estradiol ( p = 0.017) whereas 30‐min salivary cortisol was lower on oral estradiol compared to no estradiol (6.6 (1.6–23.0) vs. 10.4 (3.6–25.5 nmol/L) p = 0.04) and transdermal estradiol ( p = 0.07). Conclusion In patients with overt adrenal insufficiency pTC was not influenced by estradiol supplementation. However, salivary cortisol decreased on oral estradiol concomitant with an increase in CBG levels. Our data may support the use of transdermal estradiol and the use of salivary cortisol when evaluating the adrenal axis.