ORIGINAL ARTICLE Mild dementia is associated with increased adrenal secretion of cortisol and precursor sex steroids in women Per Johansson* , †, Jan-Ove Johansson†, Fernand Labrie‡, Niklas Mattsson§, Oskar Hansson–, Kaj Blennow§, Henrik Zetterberg§, Anders Wallin§, Claes Ohlsson† and Johan Svensson† , ** *Department of Neuropsychiatry, Skaraborg Hospital, Falko ¨ping, Sweden, †Department of Internal Medicine, Sahlgrenska University Hospital/Go ¨teborg, University of Gothenburg, Gothenburg, Sweden, ‡Research Center in Molecular Endocrinology, Oncology, and Human Genomics, Laval University and Laval University Hospital Research Center and Laval University (CRCHUL), Quebec City, Canada, §Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Mo ¨lndal, Sweden, –Clinical Memory Research Unit, Department of Clinical Sciences, Malmo ¨ University Hospital, Lund University, Malmo ¨, Sweden and **Department of Endocrinology, Skaraborg Hospital, Sko ¨vde, Sweden Summary Context Sex steroid levels decrease with increasing age, but little is known whether this is of importance for the age-related decline in cognitive function. Design and patients A cross-sectional study of 50 (26 men) consecutive patients under primary evaluation of cognitive impair- ment (D group) and 18 (9 men) matched healthy controls (C group). Measurements Sex steroid and precursor levels were determined in serum and, when measurable, in cerebrospinal fluid (CSF) using gas chromatography/mass spectroscopy (GC-MS) or liquid chro- matography/mass spectroscopy (LC-MS). Sex hormone binding globulin (SHBG) and cortisol concentrations were measured using conventional assays. Results Patients in the D group had higher 24-h urine cortisol levels and increased serum levels of dehydroepiandrosterone (DHEA) and its sulphate ester dihydroepiandrosterone sulphate (DHEAS), androsterone (ADT), and oestrone (E1) and its sulphate ester E1S, compared with the controls. When men and women were analysed separately, increased serum concentrations of E1 and E1S were observed in both D men and D women, whereas increased levels of other sex steroids and cortisol were seen only in D women. Conclusions In both D men and women, serum E1 and E1S levels were increased, whereas other changes were gender specific and only seen in D women. Further studies are needed to determine whether these changes are a cause of, or merely a consequence of, cognitive impairment in elderly subjects. (Received 16 November 2010; returned for revision 12 December 2010; finally revised 12 April 2011; accepted 15 April 2011) Introduction Serum testosterone (T) concentration decreases slowly with increasing age in men, whereas in women, estradiol (E2) secretion dramatically stops at menopause. 1 In both genders, dehydroepi- androsterone (DHEA) and its sulphate ester dihydroepiandroster- one sulphate (DHEAS) gradually decrease with ageing. 1 These changes may be of importance for the decline in cognitive function observed with increasing age because in healthy subjects, inverse associations have been observed between circulating sex steroid levels and cognitive function. 2,3 However, the hypothesis that the decline in sex steroid levels with ageing is of importance for the age-associated decrease in cognitive function was challenged by the results of the Women’s Health Initiative Memory Study, which demonstrated that oestrogen-based replacement therapy induced a small increase in the risk of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). 4 In patients with AD or other forms of dementia, there is at pres- ent no clear consensus regarding circulating levels of sex steroids as previous studies have shown conflicting results. 3,5,6 In the brain, increased production of DHEA has been observed in patients with AD that correlates with increased levels of DHEA in the cerebrospi- nal fluid (CSF). 7 However, the regulation of DHEA metabolism in the central nervous system is complex as increased DHEA values in CSF of patients with AD or vascular dementia (VAD) were accompanied by a reduced CSF level of DHEAS and unchanged levels of the metabolites 7a-hydroxy-DHEA, 7b-hydroxy-DHEA and 16a-hydroxy-DHEA. 8 In addition to the direct secretion of sex steroids by the gonads, the adrenal glands secrete precursors of sex steroids. 9 In postmeno- pausal women, the adrenal glands are the major source of Correspondence: Johan Svensson, Department of Internal Medicine, Gro ¨na Stra ˚ket 8, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden. Tel.: +46 31 7411712; Fax: +46 31 821524; E-mail: johan.svensson@medic.gu.se Clinical Endocrinology (2011) 75, 301–308 doi: 10.1111/j.1365-2265.2011.04082.x Ó 2011 Blackwell Publishing Ltd 301