New reference intervals for cortisol, cortisol binding globulin and free cortisol index in women using ethinyl estradiol

Abstract

Healthy women using contraceptives containing a low dose of an estrogen may have a higher serum concentration of cortisol (s-cortisol) and cortisol binding globulin (s-CBG) than the commonly used upper reference limits. There are no published reference intervals for s-cortisol, s-CBG, serum free cortisol index (s-FCI) or cortisol in saliva (sa-cortisol) for these women. The aim was to establish the above-mentioned reference intervals and document the differences in s-cortisol and s-CBG in one group of women using and another group not using ethinyl estradiol (EE). In this cross-sectional study, the reference limits presented were given as the 2.5 and 97.5 percentiles of the distribution of reference values in a population of 277 healthy volunteer women, aged 18–45 years. 157 women were not using any type of estrogen, while 120 women were using contraceptives containing a daily dose of 15–35 μg of EE. Serum and salivary cortisol, and serum CBG were measured using standard laboratory methods. S-FCI was calculated as s-cortisol/s-CBG. The reference intervals for s-cortisol in samples collected at 0800–1030 am in women using and not using EE contraception were: 284–994 nmol/L and 159–569 nmol/L respectively, and for s-CBG: 847–3366 nmol/L and 860–1940 nmol/L, respectively. For s-FCI and sa-cortisol, no clinically significant differences were found. Sa-cortisol may be the preferred measurand for evaluation of possible hypercortisolism in women using estrogens, since cortisol in saliva is not influenced by estrogen. If assessing morning s-cortisol and s-CBG in women using EE, we recommend using separate – and not the commonly used – reference intervals.

Keywords:

• Cortisol
• corticosteroid binding globulin
• reference values
• agents
• estrogen contraceptive
• ethinyl estradiol
• assay
• chemiluminescence

Acknowledgement

We would like to thank the department of Immunology and Transfusion Medicine at St. Olavs Hospital, Trondheim University Hospital, for their cooperation when collecting the material needed for the study. Thanks to the women who donated blood, saliva and a few minutes of their time to this study, and to Dr. Johan Bjerner at Fürst Medical laboratory for his assistance in making the figure.

Disclosure statement

The authors alone are responsible for the content and writing of the article.