Natural and synthetic sex hormones: Effects on higher-order cognitive function and prepulse inhibition

Abstract

Little is known about the effects of the commonly-used oral contraceptive pill (OC) on cognition. This study compared matched healthy women across the menstrual cycle (early-follicular ‘Low E/P’, mid-luteal ‘High E/P’), women using the combined OC, and men. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess immediate and delayed memory, visuospatial ability, language and attention. Assessment of prepulse inhibition (PPI) included 21 pulse-alone trials (115 dB) and 42 prepulse-pulse trials (74, 78, 86 dB). The OC and High E/P groups outperformed men on the total RBANS score, an overall measure of cognition. For the immediate memory/learning and attention domains, the OC group outperformed men; for the delayed memory domain, the OC and High E/P groups outperformed men. In conclusion, high levels of natural or synthetic sex hormones had a positive effect on higher-order cognition but had little effect on baseline PPI.

Introduction

Estrogens and progestins are groups of sex steroid hormones predominantly found in women, but are also found in smaller concentrations in men. During the menstrual cycle, there are two peaks of estrogen secretion, one just before ovulation and a smaller peak during the mid-luteal phase. Progesterone levels remain low during the follicular phase and there is one peak in its secretion during the mid-luteal phase (Ganong, 1979, Ross and Vande Wiele, 1974). Synthetic estrogens and progestins are used in preparations such as the commonly-used combined oral contraceptive pill (OC). Among young Australian women the OC is the most popular contraceptive method, with 76% of women having ever used it and 45% of 20–24 year olds currently using it (Yusuf and Siedlecky, 2007).

Sex hormones have a number of non-reproductive effects; of interest here are their effects on cognitive function. Women have been found to perform better on verbal and memory tests and poorer on spatial ability tests during the high estrogen/progesterone phase of the menstrual cycle (Hampson, 1990, Maki et al., 2002, Rosenberg and Park, 2002, Sherwin, 2012). A number of studies have examined the effects of hormone replacement therapy on cognition in post-menopausal women (LeBlanc et al., 2001, Maki and Sundermann, 2009, Zec and Trivedi, 2002). Overall, it is suggested that estrogen has a small positive effect on cognition, particularly verbal memory (Joffe et al., 2006, Sherwin, 2012, Zec and Trivedi, 2002), however the positive effect may depend on the cognitive domain (Bayer and Hausmann, 2009), type of estrogen (Maki and Sundermann, 2009) and the time period when the estrogen was administered (Craig and Murphy, 2010, Maki, 2006, Sherwin, 2012). Less is known about the effect of estrogen administration in healthy, pre-menopausal women or of the effect of the OC on cognition. OC users showed enhanced verbal memory during the active pill phase compared to the inactive pill phase, while naturally cycling women showed no change across the menstrual cycle (Mordecai et al., 2008). Other studies showed that OC use improved spatial attention (Cicinelli et al., 2011) but had no effect on recognition memory (Wharton et al., 2008). On the other hand, mental rotation task performance is dependent on the type of progestin used in the OC (Griksiene and Ruksenas, 2011), whereby highly androgenic OCs improved performance (Wharton et al., 2008). The present study measured various domains of cognitive function, including memory, attention, language and visuospatial ability, in OC users and non-users.

Prepulse inhibition (PPI) is a measure of sensorimotor gating or information processing. It is proposed to reflect a normal protective mechanism in the brain that filters irrelevant sensory, motor or cognitive information, thus allowing for coherent thought (Braff and Geyer, 1990). Deficits in gating incoming information may result in information overload and misinterpretation of stimuli (Braff et al., 2001). There is an extensive literature describing how PPI is disrupted in schizophrenia (Braff et al., 2001), and other illnesses including bipolar disorder (Gogos et al., 2009), suggesting that PPI deficits are the result of abnormalities within a specific brain circuit rather than a specific psychopathology (Swerdlow et al., 2001).

A limited number of studies have recently examined PPI in sex hormone affected states, such as during the menstrual cycle, pregnancy and premenstrual dysphoric disorder (Kask et al., 2008a, Kask et al., 2008b, Kumari et al., 2010). For example, women have the greatest PPI during the early follicular (low estrogen/progesterone) phase of the menstrual cycle (Jovanovic et al., 2004, Kumari et al., 2010, Swerdlow et al., 1997). Kask et al. (2008a) found that women had lower PPI during late pregnancy, a time of high circulating levels of estrogen and progesterone, compared to the postpartum period when these hormone levels decline (Kask et al., 2008a). Further, lower levels of PPI were found in cycling women compared with post-menopausal women (Bannbers et al., 2010), where menopause is a time of dramatic decline of sex hormone levels. These studies suggest that sex steroid hormones, such as estrogen, play a role in modulating PPI, whereby high levels of estrogen may reduce PPI. We previously showed that estrogen treatment reversed drug-induced disruptions of PPI in healthy women and in female rats (Gogos et al., 2006, Gogos et al., 2010b, Gogos and Van den Buuse, 2004), and suggested that the dopaminergic system is involved in mediating the effects of estrogen on PPI (Chavez et al., 2010, Gogos et al., 2010b). Little is known about the effects of the OC on PPI. One study found that women with adverse mood-related side-effects from the OC had lower levels of PPI, compared to women with no adverse effects of the OC (Borgstrom et al., 2008). This study did not, however, statistically compare PPI in OC users with naturally cycling women or with men; this will be examined in the present study.

Although millions of women worldwide either currently or have previously used OCs (Burkman et al., 2011), surprisingly little is known about their effects on the brain. This study aimed to examine the effects of natural and synthetic sex hormones on cognitive function, particularly higher-order cognition and PPI. Healthy, pre-menopausal women who were either currently using the OC or were naturally cycling (follicular or mid-luteal phase), and healthy men, were tested.