Similarly, gender differences in the presentation, treatment, and outcomes of mental illness are often overlooked. The second part is devoted to the consideration of biological gender differences in the presentation of aspects of mental illnesses such as schizophrenia, bipolar disorder, depression and anorexia nervosa. Male and female rodents differ in their reactivity and adaptation to various stressors, and the authors show a link between this and differences in.
The final preclinical chapter provides an elegant review by Elizabeth Tunbridge and Paul Harrison of sex differences in the catechol-O-methyltransferase (COMT) gene. In summary, sex differences are observed in humans and animals in brain function and behavior and in the response to disease. The reactivation of the hypothalamic gonadotropin-releasing hormone (GnRH) secretion system (which can be stimulated by norepinephrine and glutamate and inhibited by GABA) results in the establishment of reproductive rhythms.
It is known that the sex steroids can be synthesized in the brain; for example, progesterone is synthesized by glial cells (Garcia-Segura and Melcangi2006). Aromatase is present at extragonadal sites including the breast (where its role and inhibition, using aromatase inhibitors or AIs, have been most extensively studied; for more details, see Furr 2006) and the brain where it appears to be concentrated in the preoptic area. ventro-medial hypothalamus and the bed nucleus striae terminalis (Balthazart et al.2003).
Oestrogen
In terms of clinical relevance, an example would be the expression of aromatase by astrocytes after injury (Garcia-Segura et al. 2003). Neurotransmitters such as dopamine and glutamate can inhibit aromatase activity, as can kainate and NMDA (Balthazart et al. 2003). They may also be involved in the etiology of diseases, including neurological disorders (Lonard et al. 2007).
The distribution of ERa and ERb has been extensively studied in different species (see O¨ sterlund and Hurd 2001; Weiser et al. 2008). ERa and ERb differ not only in brain distribution, but also in ligand binding capacity (Damdimopoulos et al. 2008) and roles (Bodo and Rissman 2006). One such receptor is called GPR30 and is a G-protein-coupled structure with 7 transmembrane domains (Lappano et al. 2010).
Most of the work on this receptor has been done in relation to breast cancer (for review, see Maggiolini and Picard2010), but GPR30 is expressed in the hypothalamic-pituitary axis, hippocampus and substantia nigra (Brailoiu et al. 2007). Estrogen can also rapidly induce nitric oxide synthase activity in cortical neurons, including the hippocampus (Mannella et al. 2009).
Progesterone
Findings from a study in female rats by Lubbers et al. 2010) indicate that SERMs may have the potential to selectively manipulate monoamines allowing some modulation of cognition and affective function. Estrogen has several other central properties, including (Amantea et al.2005): an antioxidant effect mainly due to direct free radical scavenging; anti-inflammatory action through suppression of interleukin-1 binding of COX-2 (for review and information on structure-activity relationships, see Prokal and Simpkins 2007). A small clinical trial involving patients with traumatic brain injuries showed that the use of progesterone was not harmful and may indeed have some beneficial effects (Wright et al.2007).
However, in animal studies it also has affinity for the glucocorticoid receptor, and antiglucocorticoid effects have been seen in animals. Not all progestogens have the same pharmacological profile (Hapgood et al. 2004), and these differences have implications for their use. MPA is the most potent of the three in terms of glucocorticoid activity and accordingly has the highest affinity for the glucocorticoid receptor, but this relationship is further complicated by the fact that the resulting effect appears to be dependent on glucocorticoid receptor density (Hapgood et al. .2004).
Unlike endogenous progesterone, both MPA and the 19-nortestosterone derivatives also have affinity for the androgen receptor (but MPA has less intrinsic activity), although this is reduced in the third-generation compounds such as desogestrel. In addition, natural progesterone and its metabolites allopregnanolone and pregnanolone have high affinity for GABAA receptors (Paul and Purdy 1992), and progesterone can reduce glutamic acid decarboxylase (GAD) and thus impair GABA synthesis (Wallis and Luttge 1980).
Androgen
L and S (LL>LS>SS) generate allele-dependent 5-HT activity with associated functional consequences (Lesch et al. 2008). However, the size of the lesion to the hippocampus (>75%) is still important for object recognition memory (Broadbent et al. 2004). Milner TA et al (2005) Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation.
Sfikakis A et al (1978) Implication of the estrous cycle on conditioned avoidance behavior in rats. Females also showed an increased number of DA transporters in the NA after repeated injections of intravenous nicotine (Harrod et al. 2004). Furthermore, uncontrollable shock induces higher serotonin levels in the frontal cortex of both sexes than controllable shock (Heinsbroek et al. 1991).
However, levels of adult neurogenesis in the hippocampus appear to correlate with helplessness behavior (Malberg and Duman 2003; Shors et al. 2007). Moreover, dopaminergic activity is increased in female rats, but not in males (Mitsushima et al.2006). On the other hand, serotonergic status in male rats was only moderately altered (Pitychoutis et al. 2009b).
In 4,014 Ashkenazi Jews (control subjects participating in a genetic association study of schizophrenia discussed below), Shifman et al. Many studies simply found an association that reached significance in one sex but not in the other (eg, Enoch et al. 2006). A meta-analysis of the panic disorder studies (Domschke et al. 2007) confirmed the presence of a gender difference in the association with COMT.
In summary, there are diverse data indicating substantial sex differences in central dopamine parameters (Cosgrove et al. 2007). Kaasinen V, Nogren K, Hietala J et al (2001) Sex differences in extrastriatal dopamine D2-like receptors in the human brain. Pohjalainen T, Rinne JO, Nogren K et al (1998) Sex differences in striatal dopamine D2 receptor binding characteristics in vivo.
Strous RD, Ritsner MS, Adler S et al (2009) Improvement in aggressive behavior and deterioration in quality of life after S-adenosyl-methionine (SAM-e) augmentation in schizophrenia. Young women in the luteal phase show a lower PPI compared to postmenopausal women (Bannbers et al.2010). However, it has been associated with a small increase in the risk of venous thromboembolism (Nelson et al.2009).
