The influence of the route of oestrogen administration on serum levels of cortisol-binding globulin and total cortisol

Clin Endocrinol (Oxf). 2007 May;66(5):632-5. doi: 10.1111/j.1365-2265.2007.02784.x.


Objectives: Oral oestrogen preparations increase total cortisol concentration by increasing circulating cortisol-binding globulin (CBG) levels. Transdermal oestrogen treatments are being used increasingly in clinical practice. These topical preparations may have less of an effect on CBG and hence on total serum cortisol levels by reducing hepatic oestrogen exposure. The purpose of this study was to compare the effects of oral and topical oestrogen treatments on CBG, total serum cortisol and salivary cortisol levels.

Design and patients: This was a single-centre, cross-sectional study of 37 women aged 33 +/- 6 years (mean +/- SD). Fourteen women were using oral oestrogen therapy, eight were using transdermal therapy and 15 were oestrogen-naïve control subjects.

Measurements: Following a screening visit, the subjects attended the endocrine investigation unit following an overnight fast. Blood and salivary samples were taken from 0830 to 0930 h between days 10 and 18 of the menstrual cycle (where appropriate).

Results: Total serum cortisol concentrations were 67% higher in those receiving oral oestrogen when compared to control subjects (660.9 +/- 89.9 vs. 395.4 +/- 53.2 nmol/l, P < 0.001). Values in those receiving transdermal oestrogen (334.7 +/- 72.0 nmol/l) were no different from the control group. CBG levels were higher in those on oral oestrogen therapy (110.9 +/- 19.6 mg/l, P < 0.001) when compared with either those on transdermal oestrogen (51.0 +/- 5.4 mg/l) or the control population (49.0 +/- 11.8 mg/l). Similar salivary cortisol concentrations were recorded in the three groups (controls 13.8 +/- 2.6 nmol/l, oral oestrogen 15.5 +/- 2.6 nmol/l, transdermal oestrogen 15.7 +/- 3.9 nmol/l).

Conclusions: Oral oestrogen-containing preparations increase total cortisol levels by increasing circulating CBG concentration. These effects were not seen in patients using transdermal oestrogen replacement. Although further studies are indicated, it is probably unnecessary to routinely discontinue transdermal oestrogen replacement when performing an assessment of the hypothalamic-pituitary-adrenal (HPA) axis or evaluating adequacy of hydrocortisone replacement.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Cutaneous
  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Carrier Proteins / blood*
  • Case-Control Studies
  • Cross-Sectional Studies
  • Estrogen Replacement Therapy / methods*
  • Estrogens / administration & dosage*
  • Female
  • Humans
  • Hydrocortisone / analysis
  • Hydrocortisone / blood*
  • Middle Aged
  • Postmenopause*
  • Saliva / chemistry


  • Carrier Proteins
  • Estrogens
  • cortisol binding globulin
  • Hydrocortisone