**5.3.3 Sex difference and a protective effect of estrogen in schizophrenia**

The hypothesis predicts that endogenous antioxidants exhibit a protective effect against schizophrenia, and may give a plausible explanation for sex difference of the disease.

A consistent and specific finding for schizophrenia is that the age at onset is significantly lower in males than in females (Jablensky, 1995; Kulkarni & Fink, 2000); schizophrenia starts earlier on average in males and reaches its peak between 15 and 25 years of age, whereas in females it occurs almost between 20 and 30 years of age and shows a less steep curve after that age. It also appears that women are vulnerable to relapses or first episode of schizophrenia in the perimenoposal period (the second peak of onset for females) (Kulkarni & Fink, 2000), when estrogen production diminishes. A close association between premenstrual or menstruation phase and exacerbation of the illness in females has been well documented (Kulkarni & Fink, 2000). In addition, less negative symptoms, less brain morphological changes, and better response to neuroleptic medication are relatively consistent finding in female patients with schizophrenia (Jablensky, 1995; Goldstein & Lewine, 2000).

These observations lead to the concept that estrogen protects predisposed females (Kulkarni & Fink, 2000), which seems to accord with the hypothesis; estrogen has been shown to have antioxidant activity due to its intrinsic antioxidant structure that lies in the phenolic moiety of the steroidal compound (Behl, 2002), to increase antioxidant enzyme activities (Strehlow et al., 2003; Pajović et al., 2003), and to have neuroprotective effect against oxidative stress (Behl, 2002; Brann et al., 2007). Furthermore, mitochondrion has estrogen binding sites (Monje & Boland, 2001; Chen et al., 2004) and estrogen increases mitochondrial efficiency and reduces intracellular oxidative stress (Stirone et al, 2005).
