The levonorgestrel-releasing intrauterine device potentiates stress reactivity

Psychoneuroendocrinology. 2017 Jun:80:39-45. doi: 10.1016/j.psyneuen.2017.02.025. Epub 2017 Feb 28.


Background: The levonorgestrel-releasing intrauterine device (LNG-IUD) is currently recommended as a first-line contraceptive with an exclusively local intrauterine influence. However, recent clinical trials have identified side effects of LNG-IUD that appear to be systemically mediated, including depressed mood and emotional lability.

Methods: We performed two experimental studies and a cross-sectional study. For each study, women were included from three groups: LNG-IUD (0.02mg/24h), oral ethinylestradiol/levonorgestrel (0.03mg/0.15mg; EE30/LNG) and natural cycling (NC). Study 1-Salivary cortisol was measured at baseline and at defined intervals following the Trier Social Stress Test (TSST). Heart rate was monitored continuously throughout the TSST. Study 2-Salivary cortisol and serum total cortisol were evaluated relative to low-dose (1μg) adrenocorticotropic hormone (ACTH) administration. Study 3-Hair cortisol was measured as a naturalistic index of long-term cortisol exposure.

Results: Women using LNG-IUD had an exaggerated salivary cortisol response to the TSST (24.95±13.45 nmol/L, 95% CI 17.49-32.40), compared to EE30/LNG (3.27±2.83 nmol/L, 95% CI 1.71-4.84) and NC (10.85±11.03nmol/L, 95% CI 6.30-15.40) (P<0.0001). Heart rate was significantly potentiated during the TSST in women using LNG-IUD (P=0.047). In response to ACTH challenge, women using LNG-IUD and EE30/LNG had a blunted salivary cortisol response, compared to NC (P<0.0001). Women using LNG-IUD had significantly elevated levels of hair cortisol compared to EE30/LNG or NC (P<0.0001).

Conclusions: Our findings suggest that LNG-IUD contraception induces a centrally-mediated sensitization of both autonomic and hypothalamic-pituitary-adrenal (HPA) axis responsivity. LNG-IUD sensitization of HPA axis responsivity was observed acutely under standardized laboratory conditions, as well as chronically under naturalistic conditions.

Keywords: Adrenocorticotropic hormone; Affective disorders; Autonomic nervous system; Cortisol; Hypothalamus-Pituitary-Adrenal (HPA) axis; Levonorgestrel-releasing intrauterine device; Long-acting reversible contraception (LARC).

MeSH terms

  • Adrenocorticotropic Hormone / metabolism
  • Adult
  • Contraceptive Agents, Female / pharmacology
  • Cross-Sectional Studies
  • Drug Combinations
  • Ethinyl Estradiol
  • Female
  • Humans
  • Hydrocortisone / analysis
  • Hydrocortisone / blood
  • Hypothalamo-Hypophyseal System / drug effects
  • Intrauterine Devices
  • Levonorgestrel / metabolism*
  • Levonorgestrel / pharmacology*
  • Pituitary-Adrenal System / drug effects
  • Saliva
  • Young Adult


  • Contraceptive Agents, Female
  • Drug Combinations
  • ethinyl estradiol, levonorgestrel drug combination
  • Ethinyl Estradiol
  • Levonorgestrel
  • Adrenocorticotropic Hormone
  • Hydrocortisone