Sex-specific association between the 5-HTT gene-linked polymorphic region and basal cortisol secretion

Stefan Wüst, Robert Kumsta, Jens Treutlein, Josef Frank, Sonja Entringer, Thomas G. Schulze, Marcella Rietschel

Research output: Contribution to journalArticlepeer-review

82 Scopus citations


Objective: A key regulator of serotonergic neurotransmission is the serotonin transporter (5-HTT) and a common 5HTT gene promoter polymorphism, termed 5HTTLPR, is associated with phenotypes related to anxiety and depression. Furthermore, the serotonergic system influences hypothalamus-pituitary-adrenal (HPA) axis activity, which, in turn, is related to psychiatric diseases. Methods: To explore the association between the 5-HTTLPR and HPA axis regulation we performed a detailed endophenotyping in 216 healthy subjects (all 126 females used oral contraceptives). Results: While ACTH and cortisol responses to an established psychosocial stress paradigm (Trier Social Stress Test) were not found to be related to the 5-HTTLPR, we observed a significant and sex-specific association with the cortisol awakening response, which is a reliable marker of basal cortisol secretion, and with ACTH levels after dexamethasone administration. The supplementary inclusion of a 5-HTT A/G polymorphism (rs25531) in the analyses did not substantially modify our results. Conclusion: These findings support the view that the 5-HTTLPR is associated with a major neuroendocrine stress system. It could be speculated that the sex-specific nature of this association contributes to the distinct gender differences in the vulnerability for depression.

Original languageEnglish (US)
Pages (from-to)972-982
Number of pages11
Issue number7
StatePublished - Aug 2009
Externally publishedYes


  • 5-HTTLPR
  • Cortisol awakening response
  • Dexamethasone suppression test
  • Gender differences
  • Trier Social Stress Test

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Psychiatry and Mental health
  • Biological Psychiatry
  • Endocrine and Autonomic Systems


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