Abstract
Women are relatively protected against schizophrenia. The illness has a similar rate in women and men, but it starts later in women and is less severe. It is tempting to attribute this to the neuroprotective effect of estrogen, but the story is not straightforward and contains many unknowns. Women begin their schizophrenia trajectory later in development compared with men and this probably accounts for their relatively superior prognosis. Estrogen agonists are potential therapeutic agents but need to be proven safe, and the timing of administration may be crucial. This article examines what is known about estrogen and the development of schizophrenia.
Keywords
Schizophrenia (see
This suggests that gonadal hormones may play a role and, if this proves true, it could lead to new therapeutic possibilities.
Course of schizophrenia in women
While the symptoms of schizophrenia are approximately the same in women and men, there are some clinical observations regarding the experience of schizophrenia in women that suggest a protective effect of estrogen.
Even prior to the era of today's antipsychotics, which all act as dopamine antagonists and therefore inhibit estrogen production by elevating prolactin levels (not all antipsychotics inhibit prolactin since some do not occupy the dopamine D2 receptor for long), there were reports of hypoestrogenism in women with schizophrenia [7–9].
Whereas early puberty positively correlates with mental health problems [10], paradoxically, the earlier that puberty (first menstrual period) occurs in women with first-episode schizophrenia, the later their first psychotic symptoms occur [11]. This effect holds in an animal model of schizophrenia [12] but two separate research groups have not been able to replicate the results in their clinical samples [13,14].
For both schizophrenia and affective psychosis, the modal age of first onset (or, at least, for first diagnosis) is considerably older in women than it is in men and, in women, modal onset occurs within the perimenopause [15].
In women with schizophrenia, symptoms (especially thought disturbance) have been found to be exacerbated premenstrually [16], although several studies have found that the exacerbated symptoms are more likely to be affective symptoms than psychotic symptoms [17–19].
In women with schizophrenia, symptoms abate during pregnancy but are markedly aggravated postpartum [20,21].
Whereas schizophrenia symptoms tend to diminish in severity over time in men, this is not the case in women, in whom symptoms are often increased after the age of 40 years [22,23].
A small percentage of first-time schizophrenia begins after the age of 40 years. This is rare in men but not as rare in women [24,25].
In general, women require lower maintenance doses of antipsychotics than men, but this is no longer true after menopause [25–27].
Male/female differences in neuropsychiatric disease such as those that exist in schizophrenia are attributed either to brain structural dimorphism [28,29], the epigenetic influence of steroid hormones on gene expression [30,31] or the various extragenomic effects of estrogens on neurocellular pathways [32].
Schizophrenia symptoms in American Psyciatric Association Diagnostical Manual.
Delusions (misinterpretations of everyday phenomena)
Hallucinations (perceptual abnormalities)
Disorganized speech
Disorganized behavior
Lack of ambition, energy, interest in others or motivation
Estrogens affect neuron growth and differentiation and protect against injury, in this way perhaps accounting for differences between males and females in many of the neurodevelopmental illnesses [33–37]. The actions of estrogen in the CNS are summarized in Box 2.
Although male and female cells presumably differ to some extent from the time of conception due to the differential effects of genes situated on X and Y chromosomes, most sex differences in brain function and subsequent psychiatric disease are attributable not to this basic dimorphism but, rather, to the CNS effects of gonadal secretions [38,39]. Problems that have roots in fetal life or early childhood, when the brain has been exposed only to the CNS organizational effects of gonadal hormones, are generally more pervasive in males [40–42].
Neurodevelopmental disorders
The developing fetus shows a sex-specific (and, as yet undetermined, genetic) vulnerability to a variety of environmental insults that may increase the risk of schizophrenia. Infection, malnutrition, anoxia or chemical insult during pregnancy can all interfere with normal fetal brain development and thus impair the formation of connecting brain circuits. Several studies have detected a weak correlation between infection of various kinds in pregnancy and schizophrenia in offspring [43]. The puzzle is why it takes at least two decades (from fetal life to schizophrenia onset) before a putative prenatal insult expresses itself as illness. Given that redundancy abounds in neural circuits, it is presumed that symptoms emerge only after normal postpubertal neuronal pruning has taken place and exposed brain networks, imperfectly formed, to the increased cognitive demands of adolescence or to a second ‘hit’ (e.g., infection, toxicity or trauma) [44]. That second hit could be the normal hormonal perturbations of puberty [45,46].
Actions of estrogens in the CNS.
Modulate blood-brain barrier
Selectively increase cerebral blood flow
Increase neuronal supply of glucose and oxygen
Increase myelination
Improve connectivity and circuitry
Regulate calcium and other electrolyte channels
Decrease seizure threshold
Stimulate growth of synapses and dendrites
Modulate most neurotransmitters
Modulate signal transduction intracellularly
Protect against oxidative, amyloid and glutaminergic stress
Protect against corticoid stress
Decrease apoptosis
Specific neurodevelopmental disorders
The various neurodevelopmental disorders appear to be related to one another. Children with attention-deficit/hyperactivity disorder (ADHD) and pervasive developmental disorders (PDDs) often display symptoms of comorbid psychotic disorders. Approximately 30% of patients with ADHD show signs of comorbid PDDs, and vice versa. Results from a longitudinal birth cohort suggest that 5–8% of children with PDDs and/or ADHD develop a psychotic disorder [47,48]. Epidemiological studies of PDD report a male:female ratio of 3–6:1 [49–51]. ADHD is up to nine-times more prevalent in males than females during childhood [52–54].
Other developmental disorders, such as transitory tics, are present in up to 18% of all children, boys being affected three- to four-times more commonly than girls [55]. Chief among the tic disorders is Tourette's Syndrome, for which a role for gonadal hormones has been postulated [56]. Stuttering begins early in life and often resolves spontaneously. It affects 15% of children in the age range 4–6 years. When there is no family history, stuttering is largely a male disorder, with males outnumbering females by a ratio of 3–5:1 [57].
Schizophrenia as a neurodevelopmental disorder
As stated previously, the current understanding of schizophrenia as a neurodevelopmental disorder is that hypoxic, ischemic, viral or other stress during critical periods of fetal development changes the cytoarchitecture of a genetically vulnerable brain. The effect of such changes is not always evident in childhood but manifests during adolescence when further brain changes take place and cognitive demands increase [58].
Estrogen effects in experimental animals
Working through at least two nuclear receptors (α and β), estrogen signaling activates or represses gene expression via DNA methylation and inhibition of histone acetylation [35]. The acetylation of histones unravels the chromatin structure, allowing gene transcription to proceed. Conversely, deacetylation of histones tightens up chromatin conformation and inhibits transcription [59]. Many genes expressed in the brain are influenced by estrogen. Estrogen also works through neuronal membrane receptors that activate a nongenomic intracellular signaling pathway. Estrogen interacts with growth factors in neurodevelopment and is involved in a nonreceptor antioxidant free-radical scavenging cell cascade that protects against neuronal death [33].
The fetal brain is highly responsive to the neurotrophic effects of estradiol. Beginning in the sixth week of gestation, the male testis produces testosterone, which easily crosses the blood–brain barrier and is, in part, converted to estradiol through the action of aromatase, an enzyme that is well expressed in numerous sites of the mammalian fetal brain [60]. The amount of aromatase and, hence, of estradiol depends on the age of the organism [61]. Via estradiol, testicular hormones organize brain structures and functions into a ‘male’ pattern. During this time, female fetal brains are not exposed to ovarian estrogen to the same degree due to a variety of species-specific mechanisms that protect the fetus from maternal hormones. In primates, these are mainly placental secretions.
Due to its earlier exposure to estrogens, the male brain ought to be advantaged during fetal development. Brain estrogens in early life increase neuronal communication by promoting nerve-cell migration, differentiation and connectivity [62]. Pertinent to neurodevelomental disorders, age strongly influences the effect of estrogen on the promotion of connectivity [63]; the younger the animal, the greater the influence [64]. Among the many neurotrophic genes influenced by estrogens are those responsible for neuronal growth and survival, and for dendritic spine formation and density. In addition, estrogen protects neurons during development through suppression of postischemic inflammation and attenuation of apoptosis.
Paradoxically, it is girls who suffer fewer neurodevelopmental disorders, even though their brains are exposed to relatively less estrogen in fetal life. The reasons for this remain obscure: brain protection against circulating estrogen differs in primates and rats, the brain distribution of estrogen receptors differs in the two sexes, and aromatase levels converting androgens to estradiol vary over the course of fetal life. There is still much to be learned regarding the effects of gonadal steroids on human development.
Brain aromatase activity (converting androgens to estrogens in the brain) rises after puberty, as a result of which brain estradiol concentrations are roughly similar in boys and girls (approximately 3–4 pg/ml), but this does not happen until 3 years postpuberty [65]. This 3-year gap during which girls have a higher level of estrogens in the brain than boys may be relevant to the gender gap in the onset of schizophrenia symptoms. Estrogens also delay synaptic pruning and specifically ‘protect’ dopamine pathways, which are implicated in the pathogenesis of schizophrenia [66,67].
Other protective effects of estrogen
Estrogens also protect the brain against toxicity, infection, inflammation and hypoxia. They reduce inflammation, modulate levels of anti-apoptopic proteins, improve cerebral blood flow and buffer the effects of excitotoxicity [68,69]. In response to hypoxia or injury, estrogen helps neuronal regeneration and this effect may be mediated via astroglia. Gonadal steroids induce the expression of glial fibrillary acidic protein, which leads to the growth and neuron sheathing capacity of astrocytic processes. Astrocytes may be key to increases in synaptic connectivity and synaptic plasticity induced by estrogen. They may also secrete neuroactive regulatory substances [70–73].
Estrogen treatment
Several groups have tried adjunctive estrogen therapy in women suffering from psychosis. Although several have reported positive results, a recent Cochrane Review concluded that adjunctive estrogen with or without progesterone does not appear to offer convincing advantages over placebo in women with psychosis [74]. The difficulty is that gonadal hormones are not safe over long periods of time and that, to test the hypothesis, it would be wiser to try using selective estrogen receptor modulators (SERMS), especially those that enter the brain and act as estrogen-receptor agonists in relevant brain tissue cells.
Conclusion
The scientific understanding of the effects of estrogen on neuropsychiatric illness is continuously evolving, the hope being that such effects can eventually shed light on the etiology and pathophysiology of many mental disorders [75,76]. Although there has been much work with experimental animals, effects in lower animals do not always apply to humans. In neurodevelopmental disorders, boys are affected more frequently or, as in schizophrenia, illness starts earlier in males, and yet it is the male brain that is relatively more exposed to the beneficial effects of fetal estrogens. Our knowledge, while expanding, currently cannot account for the gender effects seen in schizophrenia. Estrogens exert powerful, reproducible influence on the brain function of experimental animals but the direction of effects in humans is unpredictable.
Future perspective
It has long been suspected that gonadal hormones play a part in the development of schizophrenia but, thus far, it is not clear how they do so. During the next decade, new insights into fetal brain development and the changes that take place in the brain during adolescence immediately prior to the first overt signs of schizophrenia will substantially expand this field, as will the development of new SERMs that exert their effects on specific neural cells.
Executuve summary
Women become ill with schizophrenia later than men.
Early puberty in women delays the onset of schizophrenia.
Schizophrenia symptoms are exacerbated premenstrually, postpartum and at menopause, when estrogen levels are low.
Incidence of schizophrenia in later life is more prevalent in women than in men, although late-life incidence is under 2%.
Women with schizophrenia show lower estrogen levels than control women.
Estrogens exert actions on the fetal brain in a number of ways considered to be neuroprotective.
Adjunctive estrogen therapy has, thus far, not been shown to be useful for women with schizophrenia.
In the future, it is hoped that there will be a role for selective estrogen receptor modulators.