The paper is a brief review of the relationship among age-of-onset in major psychoses (schizophrenia, bipolar disorder and recurrent unipolar major depression), proband sex, genes and estrogens. Beyond the well-known differences in age-of-onset between females and males in schizophrenia and recurrent unipolar major depression, the paper reports new findings concerning the bipolar disorder. Until recently it was unanimously stated that no gender differences in age-of-onset exist in bipolar disorder. In 2005 we reported for the first time in the literature that the age- of-onset varies in bipolar females according to the type of familial loading, while bipolar males are not affected

by such a variation [Grigoroiu-Serbanescu et al., Am. J. Medical Genetics (Neuropsychiatric Genetics), 2005, 133B]. Although the oldest hypothesis trying to explain gender differences in major psychoses was based on the interaction between estrogens and neurotransmitter systems (Haefner, 1989), recent genetic studies showed that this does not entirely hold true. The last two years revealed the existence of sex specific genes (Zubenko et al., 2003) and of genes determining the age-of-onset in affective disorders independent of the genes underlying the disease susceptibility (Faraone et al., 2004).

Key words: gender differences; age-of-onset; psychosis.

The hypothesis of gender differences in major psychoses as regards clinical picture, age of onset, epidemiology, morbid risk to relatives and treatment response has a long and confuse history. We limit our presentation to the age of onset of major psychoses: schizophrenia, bipolar (manic-depressive) disorder and recurrent unipolar major depression.

The oldest and most consistent observation is related to the gender differences in age of onset of schizophrenia with females showing a later onset than males (Loranger et al. 1984, Haefner et al., 1989; Faraone et al. 1994) in studies where age at interview was also controlled for. Two groups (DeLisi et al, 1994; Albus and Maier, 1995) showed that this effect appears in sporadic cases but it is not detectable in patients with familial schizophrenia.

In bipolar disorder, epidemiologic and family studies consistently reported equal age at onset (AO) in females and males (Loranger and Levine 1978; Gershon et al., 1982; Smeraldi et al., 1993; Johnson et al., 2000). Therefore, little attention has been paid to gender differences in AO in the literature of bipolar disorder ( Leibenluft, 1996; Moorhead et al., 2003). Angst (1966) reported a younger AO in bipolar females than in bipolar males in a small sample of patients (N=38) consecutively admitted at the Zurich hospital who were not selected according to the familial loading.

McMahon et al. (1994) also reported a younger AO in women than in males with major affective disorders (bipolar and unipolar depressive probands) with at least two affected relatives. The authors treated together bipolar and unipolar cases and probands and relatives in their analysis of the age-of-onset by sex. Therefore no inference can be done with respect to differences between bipolar females and males from independent families. No comparison with sporadic cases or by type of familial loading were undertaken in the above mentioned studies. Our study (Grigoroiu-Serbanescu et al.., 2005) was the first one that systematically examined types of familial loading [no familial loading (sporadic), recurrent unipolar major depression only, bipolar/ schizoaffective disorder loading], proband gender and age-of-onset in a sample of unrelated bipolar I probands (N=264) recruited independent of psychiatric family history from consecutive hospital admissions with the objective of analyzing in detail the relationships among the three variables and under the hypothesis that family history and gender might act as age-of- onset modifiers both per se and in their interaction. In our sample the probands with familial loading were unilineally affected with major psychoses. Bilineal cases were excluded since bilineality may reduce the age of onset (McMahon et al., 1994).

In accordance with the literature, no difference in age"of-onset was observed between females and males in our sample of bipolar I probands. Cox regression, however, showed a strong influence of family history-type on age-of-onset (P = 0.006). This was due to a significant variation in age-of-onset according to the type of family history in females (P = 0.002) but not in males (P = 0.64). Sporadic female bipolar patients had a later age-of-onset than females with either a family history of bipolar and/or schizoaffective disorder (P = 0.001) or a family history of recurrent unipolar major depression only (P = 0.04). Sporadic bipolar females had a later age-of-onset than sporadic bipolar males (P = 0.03). No sex difference was observed for age-of-onset in the group with family history of recurrent unipolar depression. In the group with a family history of bipolar and/or schizoaffective disorder, females had an earlier age-of-onset than males (P = 0.01). The findings on the Romanian sample were replicated in a German sample of 217 bipolar I probands recruited under similar conditions at the psychiatric clinic of Bonn University by prof. M. Rietschel and W. Maier (Grigoroiu- Serbanescu et al., 2005).

In the recurrent unipolar major depression, the mean age-of-onset seems to be globally older in females than in males (Baron et al., 1983; Johnson et al., 2000) although the prevalence of the disorder begins to be higher in women than in men in adolescence. Both mentioned studies had small samples (N < 100) and no distinction by type of psychiatric family history was made when computing the gender mean age-of-onset. the only major psychosis. It is interesting that although in the European and the American culture the frequency of the affected females outnumbers the frequency of the affected males with unipolar major depression (female/male ratio equals 2:1 across different life periods beginning in adolescence) (Kessler, 2003), in the Jewish population as well as in Asian countries the sex ratio for the frequency of the unipolar major depression is 1:1 (Seeman, 1997). But the unipolar major depression " melancholic type equally affects both sexes also in the Western culture (Gershon et al., 1982; Weissman et al., 1984; Bebbington et al., 1988).

Based on the gender differences observed in the age-of-onset of schizophrenia, Haefner et al. (1989; 1991) advanced the hypothesis that this difference is due to the estrogen effect (particularly estrradiol interacting with the neurotransmitter activity). But no clear evidence favoring a hormonal contribution was provided yet. Recent psychobiological studies found no significant correlation between the average estrogen level and psychiatric symptoms in schizophrenic women, although there was a significant positive correlation with cognitive functions (memory, perceptual-motor speed) (Seeman, 1997;. Hoff et al., 2002).

Studies on genes encoding the estrogen receptors alpha and beta that mediate the estrogen influence on neurotransmitters did not find any associations between the genotypes of these receptors and age-of-onset, psychiatric symptoms, and outcome in schizophrenic patients (Ouyang et al., 2001).
As regards the bipolar disorder, a series of genetic studies failed to reveal an association between the estrogen receptors alpha and beta genes and the vulnerability for bipolar disorder or puerperal psychosis (Jones et al., 2000; Kealy et al., 2001; Middle et al., 2003). Kumar et al. (2003) demonstrated that estrogen administration to bipolar women after childbirth does not prevent the postpartum relapse.

In the unipolar major depression, Epperson et al. (1999) summarized the results of several pharmacological studies and reached the conclusion that there is no demonstrated superiority of the treatment with estrogens over placebo in women with major depression. These results show that a pure hormonal explanation of gender differences in age-of-onset of major psychoses would be rather difficult.

The finding that sporadic women have a later age- of-onset than sporadic males both in schizophrenia and bipolar disorder, while females with familial affective load have a younger age-of-onset than males at least in bipolar disorder (no data are available for the other psychoses) makes us to hypothesize that females might have a protective factor which does not act if familial loading is present.

The nature of this factor (or factors) can only be speculated at the current state of knowledge. Contributions of hormonal factors (estrogens, particularly estrradiol interacting with the neurotransmitter activity) (Haefner et al. 1991), gender differences in the activity of different neurotransmitter systems and in their interaction (Halbreich and Lumley, 1993), genetic (genomic and non-genomic) (Zubenko et al., 2003) or environmental effects are equally possible to be involved.

Another explanation might reside in the involvement of sex-specific genes, as it was recently shown for the early-onset (< 25 years) recurrent unipolar depression; Zubenko et al., (2003) have detected several loci that show significant linkage only in unipolar depressive females and not in males and suggest that sex specificity of susceptibility loci may be rather the rule than the exception in major depression.

Faraone et al. (2003) revealed another genetic specificity for affective disorders when showing that the age-of-onset of mania in bipolar disorder is regulated by specific loci which are not among those commonly reported by linkage studies to be associated with the risk of bipolar illness. Therefore an independence of the genes determining the age-of-onset from the genes creating the illness predisposition may be inferred. Probably the activity of these genes is differently influenced by different familial loadings.


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