Effects of sex, menstrual cycle phase, and endogenous hormones on cognition in schizophrenia

Abstract

Background

In women with schizophrenia, cognition has been shown to be enhanced following administration of hormone therapy or oxytocin. We examined how natural hormonal changes across the menstrual cycle influence cognition in women with schizophrenia. We hypothesized that female patients would perform worse on “female-dominant” tasks (verbal memory/fluency) and better on “male-dominant” tasks (visuospatial) during the early follicular phase (low estradiol and progesterone) compared to midluteal phase (high estradiol and progesterone) in relation to estradiol but not progesterone.

Methods

Fifty-four women (23 with schizophrenia) completed cognitive assessments and provided blood for sex steroid assays and oxytocin at early follicular (days 2–4) and midluteal (days 20–22) phases. Men were included to verify the expected pattern of sex differences on cognitive tests.

Results

Expected sex differences were observed on “female-dominant” and “male-dominant” tasks (p < 0.001), but the magnitude of those differences did not differ between patients and controls (p = 0.44). Cognitive performance did not change across the menstrual cycle on “female-dominant” or “male-dominant” tasks in either group. Estradiol and progesterone levels were unrelated to cognitive performance. Oxytocin levels did not change across the menstrual cycle but were positively related to performance on “female-dominant” tasks in female patients only (p < 0.05).

Conclusions

Sex differences in cognitive function are preserved in schizophrenia. Oxytocin levels do not change across the cycle, but relate to enhanced performance on female dominant tests in women. Physiological levels of oxytocin may thus have a more powerful benefit in some cognitive domains than estrogens in schizophrenia.

Introduction

Intervention studies demonstrate a beneficial effect of short-term hormone therapy on clinical symptoms and cognitive performance in premenopausal women with schizophrenia (Kulkarni et al., 1996, Kulkarni et al., 2002, Kulkarni et al., 2008, Akhondzadeh et al., 2003, Louza et al., 2004, Ko et al., 2006a, Bergemann et al., 2008, Ghafari et al., 2013, Huerta-Ramos et al., 2014, Kulkarni et al., 2014). Hormone therapy was found to specifically enhance verbal memory and fluency in premenopausal women with schizophrenia (Ko et al., 2006a) suggesting that these cognitive abilities might also be influenced by endogenous hormone levels. Physiological levels of estradiol and progesterone are higher during the midluteal phase of the menstrual cycle compared to the early follicular phase and have been shown in some studies to influence cognitive abilities in healthy women (Hampson, 1990a, Hampson, 1990b, Maki et al., 2002, Hampson et al., 2014). Little is known about how these variations in endogenous levels of sex hormones might influence cognition in women with schizophrenia. Oxytocin may also have beneficial effects on cognition in schizophrenia (Feifel et al., 2012, Frost et al., 2014). Whether endogenous levels of oxytocin are related to cognitive performance in women with schizophrenia and whether there are cycle-related variations in these relationships is unknown. Examining these relationships in schizophrenia is important because there is an overlap in the cognitive abilities that are impaired in schizophrenia, that improve with hormone therapy in healthy women (Hogervorst and Bandelow, 2010) and in schizophrenia (Ko et al., 2006a, Bergemann et al., 2008, Huerta-Ramos et al., 2014), and that favor women over men (e.g., verbal memory) (Kramer et al., 1988).

In this study, we examined sex differences in cognition in patients with schizophrenia and controls, and then evaluated whether cognitive performance varies across the menstrual cycle in women with and without schizophrenia in relation to levels of estradiol, progesterone, and oxytocin. The primary outcomes were “male” and “female” dominant cognitive domains that show reliable advantages in one sex compared to the other (Rubin et al., 2008). Women show an advantage in verbal memory, verbal fluency, visual scanning, and fine motor skills whereas men show an advantage in visuospatial abilities (Kramer et al., 1988, Kramer et al., 1997, Mann et al., 1990, Snow and Weinstock, 1990, Schmidt et al., 2000, McCurry et al., 2001, Weiss et al., 2003, Weiss et al., 2006, Halari et al., 2005). Based on previous studies, we hypothesized that both patients and controls would show the expected sex differences in these cognitive domains and that the magnitude of those sex differences would be preserved in schizophrenia. We also hypothesized that female patients and controls would show enhancements in “female-dominant” abilities during the midluteal compared to follicular phase, but the opposite pattern on “male-dominant” abilities. Based on evidence in healthy women, we expected those changes to relate to estradiol but not progesterone. Lastly, in exploratory analyses, we examined the relationship between cognitive performance and endogenous levels of oxytocin predicting that higher levels of endogenous oxytocin would be positively associated with cognitive abilities more generally.