Endocrine Abstracts

Objective: Exogenous estradiol increases cortisol binding globulin (CBG) and total cortisol (TC), and therefore it is debated if estradiol supplementation should be paused before evaluation of the adrenal axis. The aim was to evaluate how oral and transdermal estradiol influence TC in hypogonadal women with, or at risk of developing, adrenal insufficiency (AI)

Methods: This was a crossover study in 17 women with secondary hypogonadism who were tested without estradiol (baseline) and after 12 weeks on oral estradiol (2 mg) and transdermal estradiol (100 μg/day). At the end of the interventions, the following samples were measured: salivary cortisol, p-cortisol, s-CBG, and other pituitary hormones and binding proteins. Afterwards, a short 30 minute ACTH stimulation test was performed with a TC cut-off threshold for AI of 420 nmol/l.

Results: Estradiol levels were significantly higher on oral (0.45 (0.28-0.65) and transdermal estadiol (0.27 (0.09-0.44) compared to baseline (0.09 (0.09-0.09) nmol/l), P<0.005. Plasma SHBG was higher on oral vs. transdermal estradiol (92±36 vs 48±17 nmol/l, P<0.001). TC before ACTH stimulation was 124 (27-311) at baseline, 105 (15-262) on transdermal and 201 (26-315) nmol/l on oral estradiol, P= 0.015. TC after ACTH stimulation parallels that of baseline cortisol, but without any significant changes; baseline 309 (54-492), transdermal estradiol 304 (48-492) and oral estradiol 440 (74-600) nmol/l. Three participants crossed the TC cut-off threshold for AI between interventions: Patient 1: 401 at baseline vs. 442 on transdermal vs. 487 nmol/l on oral estradiol. Patient 2: 423 at baseline vs. 390 on transdermal vs. 490 nmol/l on oral estradiol. Patient 3: 395 on transdermal vs. 559 nmol/l on oral estadiol (the patient did not complete the no intervention period). Data on CBG and salivary cortisol are under preparation.

Conclusion: In opposite to oral estradiol transdermal estradiol did not influence the adrenal axis. In patients with overt AI TC was not influenced by oral estradiol. Thus, a diagnosis of severe AI can probably not be missed if ACTH test is performed in patients on oral estradiol. Three of 17 patients with borderline AI changed status from insufficient to sufficient when put on oral estradiol. Adrenal testes independent of CBG levels are warranted to secure reliable results during conditions with altered plasma CBG and to avoid inconvenient pause of gonadal substitution. Measurement of salivary cortisol or CBG might be away to move forward, and these data will soon be available in the present study.