Effects of sex, menstrual cycle phase, and endogenous hormones on cognition 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.
Section snippets
Participants
Participants included 50 patients (23 women) and 58 controls (31 women). Participants were 18 to 40 years of age and spoke English as their first language. Diagnosis of schizophrenia or schizoaffective disorder depressed type was confirmed with a Structured Clinical Interview for DSM (SCID). All women were regularly menstruating (28 ± 5 days) and were not taking any oral contraceptives. Exclusion criteria for all participants were: history of head trauma or other neurological disorder; history of
Results
Patients and controls did not significantly differ on parental education or ethnicity; however, patients (M = 30.9, SD = 6.2) were three years older than controls (M = 27.7, SD = 6.3) (p < 0.05) (Table 1).
Discussion
In the present study, we sought to examine hormonal correlates of cognitive function in schizophrenia by comparing performance of male and female patients and controls after grouping tests according to their typical sex difference. We sought to determine whether those sex differences are preserved in schizophrenia, change across the menstrual cycle in schizophrenia, and related to physiological levels of sex hormones and oxytocin. Consistent with findings from healthy individuals (Halpern, 1986
Conclusions
In sum, the present study demonstrates that individuals with schizophrenia show expected sex differences in cognitive performance but this performance is unrelated to sex steroid hormone levels across the menstrual cycle. Our findings add to a growing literature showing that cognitive changes across the menstrual cycle are often difficult to detect and might not be as reliable as the changes in clinical symptoms and social cognition in schizophrenia (Rubin et al., 2010, Rubin et al., 2011).
Role of funding source
The funding agencies had no role in the design and conduct of the study collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Contributors
Drs. Rubin and Maki conceived the idea and methodology for the study. Dr. Carter developed the methodology to explore oxytocin and served as an advisor and resource on this project for understanding oxytocin. Dr. Sweeney served as an advisor on this project and provided his expertise in schizophrenia. Drs. Pournajafi-Nazarloo and Drogos ran the oxytocin assays and helped interpret the data. Dr. Sweeney provided his expertise in schizophrenia, and all authors were involved in data interpretation
Conflict of interest
Dr. Sweeney is a consultant to Pfizer, BMS, Takeda, and Lilly and had a research grant from Janssen. Dr. Maki received honoraria from the American Nutraceutical Association and research support from the Soy Health Research Program. Dr. Rubin declares that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal
Acknowledgments
This publication was made possible by Grant Number F31MH082480 from the National Institute of Mental Health, Grant Number K12HD055892 from the National Institute of Child Health and Human Development (NICHD), and the National Institutes of Health Office of Research on Women's Health (ORWH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development or the National Institutes of
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2021, Journal of Psychiatric ResearchCitation Excerpt :Our blood drawing procedures did not take the menstrual cycle into consideration, which could have affected the OT concentrations of subjects to some extent, since OT secretion might be influenced by the diurnal rhythm and the menstrual cycle [Engel et al., 2019; Ogawa, 1980]. However, despite this evidence regarding the fluctuation of OT secretion, the two studies that measured OT concentrations in patients with schizophrenia with consideration for the menstrual cycle reported that there was no significant difference in the values between the follicular phase and the midluteal phase [Rubin et al., 2010; 2015]. A study with a strict design concerning the timing of blood drawing is strongly warranted.
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2021, Hormones and BehaviorCitation Excerpt :We were unable to examine menstrual cycle dynamics, hormonal contraceptive use, or endogenous hormone levels in this study. Other studies have found an association between cognitive performance and estrogen levels (e.g. Ko et al., 2006) as well as serum oxytocin levels (Rubin et al., 2015) among women with schizophrenia. Thus, the impact of endogenous-exogenous oxytocin interactions in women clearly requires further investigation.
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2019, Journal of Psychiatric ResearchMenstrual cycle-related fluctuations in oxytocin concentrations: A systematic review and meta-analysis
2019, Frontiers in NeuroendocrinologyCitation Excerpt :We used reference days to mark these phases. Day 4 was used as reference day for the follicular phase since the risk of bias caused by an early ovulation is low and the early follicular phase is frequently used as a reference point in the literature (Altemus et al., 2001; Rubin et al., 2015). Day 14 was used as a reference day for ovulation since it is considered as the average day of ovulation (Hoffbauer, 2005).
Peripheral oxytocin and vasopressin modulates regional brain activity differently in men and women with schizophrenia
2018, Schizophrenia ResearchCitation Excerpt :Among female patients, we found lower levels of AVP but not OT. This hormone profile is consistent with many (Rubin et al., 2014; Rubin et al., 2010; Rubin et al., 2015; Rubin et al., 2018), but not all (Rubin et al., 2018), of our previous studies. Furthermore, among female patients, there were some hormone-brain physiology associations that suggested a loss of hormonal modulation such as the association of AVP and ALFF in frontal cortex (superior frontal gyri), while other findings suggested increased hormonal modulation such as the association of OT and ALFF in frontal (superior frontal/middle frontal gyri) and cerebellar cortices even though OT levels were not themselves abnormal.