The levonorgestrel-releasing intrauterine device potentiates stress reactivity.
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.
Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: j.aleknaviciute@erasmusmc.nl.
Jurate
J
Aleknaviciute
Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: j.h.m.tulen@erasmusmc.nl.
Joke H M
JHM
Tulen
Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: y.derijke@erasmusmc.nl.
Yolanda B
YB
De Rijke
Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: c.bouwkamp@erasmusmc.nl.
Christian G
CG
Bouwkamp
Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: m.vanderkroeg@erasmusmc.nl.
Mark
M
van der Kroeg
Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: m.timmermans.1@erasmusmc.nl.
Mirjam
M
Timmermans
Department of Internal Medicine, Division of Endocrinology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: v.wester@erasmusmc.nl.
Vincent L
VL
Wester
Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: v.bergink@erasmusmc.nl.
Veerle
V
Bergink
Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: w.hoogendijk@erasmusmc.nl.
Witte J G
WJG
Hoogendijk
Departments of Child and Adolescent Psychiatry and Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: h.tiemeier@erasmusmc.nl.
Henning
H
Tiemeier
Department of Internal Medicine, Division of Endocrinology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: e.vanrossum@erasmusmc.nl.
Elisabeth F C
EFC
van Rossum
Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: kooiman@cgkooiman.nl.
Cornelis G
CG
Kooiman
Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: s.kushner@erasmusmc.nl.
Steven A
SA
Kushner
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D003271:Contraceptive Agents, Female / Q000494:pharmacology; D003430:Cross-Sectional Studies; D004338:Drug Combinations; D004997:Ethinyl Estradiol; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007434:Intrauterine Devices; D016912:Levonorgestrel / Q000378:metabolism* / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects; D012463:Saliva; D055815:Young Adult
D003271:Contraceptive Agents, Female; D004338:Drug Combinations; C072593:ethinyl estradiol, levonorgestrel drug combination; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone
Adrenocorticotropic hormone; Affective disorders; Autonomic nervous system; Cortisol; Hypothalamus-Pituitary-Adrenal (HPA) axis; Levonorgestrel-releasing intrauterine device; Long-acting reversible contraception (LARC)