173 Gynecological Endocrinology, 2013; 29(2): 173–176 © 2013 Informa UK, Ltd. ISSN 0951-3590 print/ISSN 1473-0766 online DOI: 10.3109/09513590.2012.730568 Both estrogen and testosterone insufficiency has been associ- ated with reduced psychological well-being including fatigue. However, hormonal replacement studies on fatigue are rare. Therefore, we wanted to study the effect of testosterone and estrogen replacement therapy on cognitive fatigue and the relation between sex hormone levels and cognitive fatigue in oophorectomized women. Fifty women with surgically induced menopause (mean age: 54.0 ± 2.9 years) were randomly assigned to treatment with estradiol valerate in combination with testos- terone undecanoate or placebo for 24 weeks in a double-blind cross-over study. Neuropsychological tests and questionnaires were used to assess cognitive fatigue and psychological well- being. Cognitive fatigue was significantly associated to poor self-rated health and higher body mass index but not to general psychological well-being or sex hormone levels. Treatment with testosterone + estrogen had no significant effect on cogni- tive fatigue but the results indicated a curvilinear relation for hormonal levels. The estrogen/testosterone ratio was more related to functions rather than high or low hormone levels per se. We found that cognitive fatigue is frequent in oophorecto- mized women and negatively associated to self-perceived health and positively associated to BMI. A well-balanced ratio between estrogen and testosterone levels may be important for cognitive fatigue. Keywords: Fatigue, testosterone, estrogen, hormone therapy, psychological well-being, oophorectomy Introduction Fatigue is a major symptom in many medical and psychiatric disorders [1–3] and also androgen defciency have been associ- ated to fatigue [4–6]. Both testosterone and estrogens have been considered as potential neuroprotective hormones [7–9] but studies investigating associations between sex steroid levels and cognition have however shown inconclusive results [10–13]. In women testosterone levels are low compared to men and because testosterone can be aromatized to estradiol, relatively small diferences in testosterone levels could result in a diference in endogenous estradiol levels [14]. Terefore, the balance and ratio between estradiol and testosterone may be an important modulator in cognitive function in women [15]. Some studies indicate that the association between neuropsychological func- tions and sex steroid hormone levels might not be straightly dose dependent—rather a curvilinear model is more plausible for cognitive functions [16,17]. Although fatigue is commonly reported during testosterone and estrogen insufciency, few studies of this issue, in oophorec- tomized women, have been published. Fatigue has long been of interest for theory and research, but still its conceptualization and defnition is unclear [18,19]. Furthermore studies on fatigue mostly include self-report instruments although subjective ratings do not always corre- spond to the measurable aspects of fatigue [20]. Cognitive fatigue may result from an imbalance between the amount of mental efort required to perform a task and the internal resources of an individual [20]. Cognitive fatigue could there- fore refect a decreased performance during sustained mental efort [18]. Neuropsychological tests such as Digit Symbol test from Wechsler Adult Intelligence Scale (WAIS) and Symbol Digit Modalities Task have been used as objective measures to capture fatigue [21,22]. Te aim of this study was to investigate the presence of cogni- tive fatigue as measured with a neuropsychological test in oopho- rectomized women and its possible relation to self-perceived physical and psychological well-being. Furthermore, we wanted to explore the efects of testosterone treatment in combination with estrogen replacement therapy compared to estrogen treat- ment alone on cognitive fatigue. Methods Participants From the patient discharge register of Stockholm County, women who have undergone bilateral salpingo-oophorectomy for benign disease were invited. Fify consecutive women who fulflled the inclusion criteria at screening were recruited. At time of inclu- sion the mean age was 54.0 ± 2.9 years (range 45.7–60.2 years), mean BMI 25.7 ± 2.8 kg/m² and mean time since oophorectomy 4.6 ± 2.4 years. Six women (three from each group) discontinued the study. Tis study was part of a larger study including a broader neuropsychological test battery and other physiological measures [23,24]. Inclusion criteria Age between 45–60 years, BMI between 18–29 kg/m², blood pressure below 170/105 mm Hg, normal liver enzymes and a normal mammogram within the last 12 months. HORMONE THERAPY Effect of estrogen and testosterone replacement therapy on cognitive fatigue Marika Christina Möller 1,2 , Angelique Flöter Rådestad 3 , Bo von Schoultz 3 & Aniko Bartfai 1 1 Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Rehabilitation, Stockholm, Sweden, 2 Centre for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden, and 3 Karolinska Institutet, Department of Woman and Child Health, Division of Obstetrics and Gynecology, Stockholm, Sweden Correspondence: Marika Christina Möller, Department of Rehabilitation Medicine, Kullbergska Hospital, Box 110, 641 22 Stockholm, Sweden. Tel.: +46 150 56230; Fax: +46 150 19242. E-mail: marika.moller@dll.se Gynecol Endocrinol Downloaded from informahealthcare.com by Uppsala Universitetsbibliotek on 02/17/14 For personal use only.