Perspective: Sex Matters: Gonadal Steroids and the Brain

Abstract

Sex matters to every cell of the body and thus gonadal steroids have the capability of affecting numerous behaviors and neurotransmitters. Several reports in this issue highlight the importance of gonadal steroids: estradiol and progesterone modulate the serotonin transporter in rodents changes in D2 receptors across the menstrual cycle in female cynomolgus monkeys testosterone influences amygdala reactivity in women and temporary suppression of gonadal steroids influences sexual in both men and women. This body of work challenges all of neuropsychopharmacology to consider the importance of sex and gonadal steroids in future studies. Neuropsychopharmacology (2009) 34, 537-538; doi:10.1038/npp.2008 Sex matters to every cell of the body (Wizemann and Pardue, 2001). Despite this conclusion by the IOM, the area of sex and gonadal hormones is frequently ignored in the field of neuropsychopharmacology and other basic biomedical fields. This is to a large extent because of the difficulty of parsing the roles of chromosomal sex, gonadal sex, and gonadal steroid hormones (Becker et al, 2005). Nevertheless, these are factors that are increasingly important to address, as evidenced by the articles in this issue of Neuropsychopharmacology. In this issue of Neuropsychopharmacology the importance of sex/gender differences in the brain as well as the effects of steroid hormones on brain function are examined from the perspective of psychiatric disorders, the neurological basis of sexual behavior and neurotransmitter receptor/ transporter function.Depression is more common in women, and women appear to respond better to SSRIs than men (Kornstein et al, 2000;Young et al, 2008). In addition, SSRIs are an excellent treatment for premenstrual dysphoria disorder. Thus, the report by Benmansour et al (2008) demonstrating a sex specific effect of estradiol and progesterone on function of the serotonin transporter is quite important. However, the effect is the opposite of what would be predicted from the clinical literature, further underscoring the complexity of understanding the interactions between ovarian hormones and serotonin systems. Perhaps these findings help us to better understand the vulnerability to mood disorders at times when estradiol and progesterone are high, such as the luteal phase of the menstrual cycle. Of note is the fact that these changes in response to estradiol and progesterone were not observed in hippocampi of male rats, underscoring the importance of sexual differentiation of the brain on the effects of gonadal steroids.Studying nonhuman primates with PET imaging of D2 receptors, Czoty et al (2008) found that [18F]FCP binding sites showed a greater availability in the caudate and putamen during the luteal phase, suggesting more unoccupied receptors during this menstrual cycle phase. Although the changes might be due to increased numbers of receptors, the use of a ligand displaceable by endogenous DA suggests the alternative possibility that higher receptor availability reflects decreased DA release during...

Sex Differences in Ethanol Reward Seeking Under Conflict in Mice

“…Our findings here do not differentiate between an increase in sensitivity to shock, an increase in fear learning, or reduction in willingness to seek EtOH under conflict in CIE‐exposed female mice, which are important questions for further study. Our current findings did not consider estrous cycle effects on behavior, but this important question will be of interest in future studies as estrous stage and ovarian hormone signaling contribute to EtOH reward, learning, and EtOH‐seeking behavior (Becker et al., ; Bertholomey and Torregrossa, ; Bertholomey et al., ; Hilderbrand and Lasek, ; Young and Becker, ).…”

Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”): The Influence of Gender and Genetics (CYP2D6, COMT, 5-HTT)

“…The negative subjective effects observed in women could be due to a higher predisposition to suffer from psychological/mood disorders than men [49], [15]. MDMA may act as a trigger for such symptoms by the depletion of the limited 5-HT reserves in women.…”

Manipulation of GABAergic steroids: Sex differences in the effects on alcohol drinking- and withdrawal-related behaviors

“…Certainly, the importance of sex and the impact of gonadal steroids on brain function and behavior are being increasingly recognized (e.g., Young & Becker, 2009). Given the sex differences in human disease, it is desirable to consider sex differences in preclinical models.…”