CNS Spectrums (2012), 17, 214–220. & Cambridge University Press 2012 doi:10.1017/S1092852912000685 ORIGINAL RESEARCH Gender effect on the relationship between stress hormones and panic-agoraphobic spectrum dimensions in healthy subjects Liliana Dell’Osso, 1 Donatella Marazziti, 1 Eleonora Da Pozzo, 2 Ciro Conversano, 1 Stefano Baroni, 1 Gabriele Massimetti, 1 Claudia Martini, 2 and Claudia Carmassi 1 * 1 Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Pisa, Italy 2 Dipartimento di Farmacia, University of Pisa, Pisa, Italy Introduction. Alterations of the hypothalamic-pituitary-adrenal (HPA) axis and of its peripheral indices have been reported in both normal and pathological anxiety with controversial findings. The aim of the present study was to investigate the possible correlations between serum cortisol and dehydroepiandrosterone- sulfate (DHEA-S) levels and DHEA-S/cortisol ratio, and panic-agoraphobic spectrum dimensions in a sample of healthy subjects. Methods. Forty-two healthy subjects of both sexes, with no current or lifetime psychiatric disorders, were assessed by means of the Structured Clinical Interview for DSM-IV (SCID-I/P) and the so-called Panic Agoraphobic Spectrum-Self Report lifetime version (PAS-SR). Results. Significant, negative correlations were found between cortisol levels and the total score of the separation sensitivity, panic-like symptoms, and medication/substance sensitivity PAS-SR domains. The PAS-SR total and the panic-like symptoms domain scores were positively related to the DHEAS/cortisol ratio. When the sample was divided in women and men, these correlations were present in women only. Discussion. These findings, while indicating the presence of significant relationships between panic- agoraphobic traits and some indices of HPA axis functioning in healthy women, would suggest this as one of the factors explaining the greater vulnerability of women to cross the line between normal and pathological anxiety. Conclusions. Further studies are needed to explore gender differences in the relationships between HPA axis alterations and the panic-agoraphobic spectrum dimensions. Received 10 July 2012; Accepted 24 August 2012 Key words: Anxiety, cortisol, dehydroepiandrosterone-sulfate, spectrum, subthreshold symptoms. Introduction A link between anxiety and dysfunctions of the hypothalamic-pituitary-adrenal (HPA) axis has been widely reported in both normal and pathological anxiety. Some data would indicate that healthy subjects with high levels of trait anxiety or neuroticism might be characterized by low basal cortisol concentra- tions, 1–5 or by a blunted cortisol increase under stress conditions. 6–11 Interestingly, after a psychological stress, but not at baseline, highly anxious women had lower cortisol levels than men. 12–14 Recently, a gender-specific association between the gene promoter polymorphism of the serotonin transporter and the cortisol awakening response, which is a reliable marker of basal cortisol secretion, was described in a sample of healthy women. 15 Disturbances of the HPA axis, as reflected by peripheral cortisol levels, have been reported in panic disorder (PD); however, the ensuing findings are controversial. In fact, elevated or normal basal plasma or salivary cortisol concentrations were observed in PD patients, as compared with healthy subjects. 16–26 More recently, a review of four studies carried out in PD patients reported enhanced overnight cortisol levels that correlated with sleep disruption. 27 In the same patients, the Adrenocorticotropic hormone (ACTH) secretion triggered by a challenge drug (doxapram) was more exaggerated than in resting conditions, and panic symptoms could be elicited without HPA axis activa- tion. Further, PD male patients, but not women, showed higher levels of dehydroepiandrosterone (DHEA) than *Address for correspondence: Claudia Carmassi, MD, PhD, Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Via Roma 67, 56127 - Pisa, Italy. (Email: ccarmassi@gmail.com)