Schizophrenia: Reproductive Hormones and the Brain

OBJECTIVE: Onset of schizophrenia occurs during the reproductive period in more than 80% of those affected. The author reviews neuroendocrine and physiologic events that occur in the basal forebrain at the initiation of and throughout the reproductive period and proposes their possible relationship to the onset of schizophrenia. METHOD: The neuroendocrine changes that occur in specific areas of the anterior basal forebrain during the reproductive period are reviewed and analyzed in relation to reported anatomic, molecular, and biochemical pathologies of schizophrenia. RESULTS: The reproductive period is associated with development of regular pulsatile release in the brain and bloodstream of gonadotropic releasing hormones from the hypothalamus, luteinizing and follicle stimulating hormones from the pituitary, and gonadal hormones from the ovaries and testes. In addition to being concentrated in the hypothalamus, brain receptors for gonadotropic and gonadal hormones are concentrated in specific subcortical forebrain nuclei of the limbic system that project to the thalamus and to cortical and subcortical structures that subserve perception, cognition, and behavior. CONCLUSIONS: There is a flood of estrogen and testosterone to the brain and body during puberty and throughout the reproductive period. To avoid hyperexcitability and seizures, the surge of these excitatory hormones must be counterbalanced by appropriate inhibitory factors. Excessive focal inhibition may be induced by increased release of or increased receptors for one or more inhibitory transmitters, e.g., dopamine, serotonin, and γ-aminobutyric acid in the anterior basal forebrain. Further investigation of the physiology and pathology of this brain region, where abnormal electrical activity was recorded from individuals with schizophrenia many years ago and where dopamine D₂ and dopamine D₃ receptors targeted by the most effective antipsychotic agents are maximally expressed, could lead to greater understanding of the critical pathophysiology for development of schizophrenia.