MANY STUDIES HAVE indicated the vulnerability to the pathological process of male schizophrenia patients relative to female patients. Female schizophrenia patients have lower antipsychotic dosage, and a less malignant course of illness than male patients. In addition, several studies have reported that schizophrenia has a later onset in female patients, with the first peak of onset in female patients occurring at age 25–29 years, in contrast to the peak of onset in male patients at age 20–24 years. In addition, a second smaller peak of onset occurs in women after age 44 years, around perimenopause and menopause.[4, 5] Based on these findings, it had been hypothesized that estrogen exerts a protective effect against the pathological process in schizophrenia.
Studies regarding gender differences of brain morphology in schizophrenia had demonstrated more vulnerability in male patients than female patients. Magnetic resonance imaging (MRI) and postmortem studies have reported a tendency of greater abnormalities in male patients, and male patients had larger lateral ventricle and smaller medial temporal volume, that is, hippocampus and amygdala, superior temporal gyrus,[7-9] and frontal and temporal lobe volumes than normal controls. Although these findings related to gender differences cannot be explained only by the degree of estrogen level, it could be hypothesized that the effect of estrogen partly reduces brain morphological changes in schizophrenia.
To our knowledge the relationship between estrogen and brain morphology in schizophrenia has not been reported in previous studies, although in postmenopausal female subjects without schizophrenia, several studies have reported the effect of estrogen therapy on brain atrophy.[11-13]
If female patients are under hormonal protection that can reduce the particular brain morphological changes of this disease, it could be suggested that premenopausal patients are under similar protection relative to postmenopausal patients. This would explain why only female patients have a second peak of onset in the paramenopausal phase.
In this study, we examined the influences of menopause on brain morphological changes of schizophrenia patients by classifying them into two subgroups, postmenopausal and premenopausal, using MRI. Although there is no previous study that investigated the effect of menopause on brain morphology of schizophrenia, studying gray matter (GM) volume by voxel-based morphometry (VBM) has helped detect the localized effects of clinical characteristics, such as symptoms, duration of illness, and antipsychotic treatment, and we considered VBM suitable for this investigation. We also examined whether the volumetric changes of postmenopausal patients were related to years elapsed after menopause.
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As a first step, we examined regional GM changes in female schizophrenia patients in relation to healthy female subjects by conducting VBM. The regions with remarkable GM volume reduction in patients were the insula, superior temporal gyrus, anterior cingulate, parahippocampal gyrus, and thalamus. The changes were predominantly found on the left side.
A meta-analysis reviewing 31 studies of VBM for GM volume in schizophrenia showed that patients had reduced GM density relative to control subjects in the bilateral insula, anterior cingulate, left postcentral gyrus, left parahippocampal gyrus, left middle frontal gyrus, and thalamus. Another meta-analysis reviewed 15 studies of VBM for GM and WM volume in schizophrenia, reporting that the areas significantly reduced in schizophrenia patients in >50% of the studies were the bilateral superior temporal gyrus, left medial frontal gyrus, left inferior frontal gyrus, and left parahippocampal gyrus.
These two meta-analyses identified the morphology trait of schizophrenia using VBM. Generally, the present findings regarding patients versus controls are consistent with those of these meta-analyses in terms of locations and laterality.
We then examined the GM volume difference between postmenopausal patients and premenopausal patients. Direct comparison between the patient groups indicated morphological change in the left middle frontal gyrus. In addition, a significant correlation between brain morphology and interval after menopause was found in the right superior frontal gyrus. These regions are not identical, but both are located in the prefrontal area.
Volume reduction in the prefrontal area in schizophrenia patients has been observed in past studies, and morphological change in the prefrontal area has been indicated in relation to negative symptoms and cognitive impairment. Additionally, a study regarding the relationship between illness duration and brain volume indicated that the right middle frontal cortex is particularly vulnerable to the long-term effect of schizophrenia. According to these reports, the present results may indicate that postmenopausal patients are at a more advanced stage of progression.
A study on gender differences of brain morphology in schizophrenia reported that GM reductions in prefrontal areas were found predominantly in male patients. It may be assumed that the duration of the low estrogen condition played a role in the morphological change in this area.
In the studies on menopause age of healthy subjects, the estimated median age at last menstruation period lies between 50 and 52 years.[31-33] A cross-sectional study concerning natural menopause of Japanese women reported that the median age of menopause was 50.54 years.
The age of menopause of the postmenopausal patients in the present study, 41.8 ± 9.0 years, seemed considerably earlier than that of the healthy subjects. A major reason for this might be an antipsychotic medication-induced side-effect. Because of the very early age at menopause, the postmenopausal patient group in this study may not be a representative sample. This is a limitation of the study.
A study concerning the effect of antipsychotic-induced hyperprolactinemia in schizophrenia patients on antipsychotic medication showed that there was a significant inverse relationship between the prolactin levels in female patients and estradiol levels, and when female patients with hyperprolactinemia were compared to those with a normal range of prolactin, only estradiol levels were significantly different between the two groups with regard to measured hormone levels (estradiol, testosterone, progesterone, luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone).
According to that study, it could be assumed that the young patients in the postmenopausal group with probable hyperprolactinemia had low estrogen levels in the present study. The gradual decline of ovarian estrogen production begins in the years prior to menopause, although a dramatic decline in plasma estrogen level occurs at the final menstrual cycle. Research concerning gender differences and age of onset in schizophrenia has shown a second peak of onset in female patients in the age range 45–54 years, and it was hypothesized that the vulnerability threshold for schizophrenia is raised in women until menopause due to the effect of estrogen. Therefore, a gradual loss of the protective role of estrogen against brain morphological change may also begin prior to menopause.
In healthy subjects, according to studies investigating the effect of estrogen on brain morphology in postmenopausal women, some reported adverse effects of hormone therapy associated with greater atrophy in the hippocampal region or in the putamen, while several others demonstrated that estrogen therapy slows age-related GM loss in frontal cortices,[11, 13] temporal, parietal, and occipital cortices, cerebellum,[11, 13] and the hippocampal region,[11, 12] findings partially in agreement with the present ones. Therefore, it is suggested that the effect of menopause on brain structural changes in schizophrenia patients could be attributable to the loss of the protective effect of estrogen against the pathophysiology of schizophrenia.
A limitation of the present study is that blood concentrations of sex hormones were not measured. Therefore, the present results do not represent the effects of sex hormones but rather the effects of menopause. In addition, because neither hormone levels nor menstrual state were checked in the healthy controls, the main purpose the patients versus controls analysis was to demonstrate that the overall tendency of the present patients would reflect the previous studies concerning the brain morphology of schizophrenia.
In conclusion, volumetric comparisons showed differential morphological alterations due to female hormonal change in schizophrenia. Postmenopausal patients had more GM volume reduction than premenopausal patients at the left middle frontal gyrus. In addition, there was significant correlation between brain morphology and interval after menopause in the right superior frontal gyrus. These results support the hypothesis of the protective role of estrogen against schizophrenia.