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ESTROGEN AND DEPRESSION



Although estrogen (and testosterone) affect the tissues of the reproductive system, they also affect other tissues including the brain. The receptors for sex steroids are more abundant in certain parts of the brain including the hypothalamus, amygdala, and hippocampus. In females, secretion of estrogen seems to begin after birth and is maintained at a low level throughout childhood. With the onset of puberty, the secretion of estrogen generally increases and undergoes monthly fluctuations. Since the regions of the brain include those which control emotions and drives, it is not surprising that the secretion of steroid hormones are implicated in both normal fluctuations in mood and in mood disorders (affective disorders). (Ramirez, 2003; Steiner, 2003).Affective disorders are the most common mental disorders and women are afflicted at twice the rate as men (with an 8% lifetime risk as opposed to 4% in males). Low concentrations estrogen have been associated with PMS, postnatal depression, and postmenopausal depression and estrogen can be used to treat the latter two. Estrogen decreases are associated with panic, obsessive-compulsive disorder, anxiety, and postmenopausal depression (Sickel from Steiner, 2000) About 75% women experience some form of PMS and 3-8% of these women suffer from the more serious emotional and behavioral symptoms of PMDD (premenstrual dysphoric disorder) (Steiner, 2003; Osterlund, 2001). PMDD affects 5% of women in reproductive years (Shors, 2003). The late luteal phase and the early menstrual phase represent the periods in which most hospital admissions for psychiatric illness occur (Sickel from Steiner, 2000).

An estimated 10% of women experience postpartum depression (Brizendine, 2006). After birth, estrogen levels drop 400 to 1000 times in 48 hours. Estrogen can be used to treat post-partum depression. . Postpartum depression more likely in women who are unmarried, experience an unplanned pregnancy, a problem pregnancy, or have less emotional support during their pregnancy (Sickel from Steiner, 2000).


A number of studies show that estrogen can relieve depression. Reduction of serotonin (or the tryptophan it is derived from) increases irritability and the severity of PMS. Estrogen increases serotonin synthesis, uptake and receptor number, and functions as an antidepressant . Evidence suggests that estrogen decreases the expression of 5-HT1A serotonin receptors and increases the expression of 5-HT2A receptors (Steiner, 2003; Osterlund, 2001; Genazzani, 2002). Estrogen affects synthesis of serotonin through TH (tryptophan hydrozxylase) and can increase serotonin receptors in areas of the brain known to affect mood (Shors, 2003). Given that estrogen can both increase body fat and fight depression, there actually may have been some observational evidence which gave rise to past sterotypes linking body size and disposition (Oinonen, 2001). Gonadal hormones change the transcription rates of serotonin receptors which affects predisposition to anxiety and depression (Dunn from Steiner, 2000).

GABA is essential for the developing brain where its receptors can cause depolarization by allowing chloride efflux and can interact with voltage regulated calcium channels. (As a result, GABA is an excitatory neurotransmitter in the developing brain and gradually is converted to an inhibitory neurotransmitter in the mature brain.) GABA influences patterns of neuronal cell death and synapse formation. Estrogen enhances the excitatory effects of GABA in brain development, which is the first mechanism for gender differentiation of the brain to be discovered. Alterations of GABA circuits can alter maternal and sexual behavior and change some sexually dimorphic regions of the brain (McCarthy, 2002).


Estrogen is an antioxidant and it offers protection from oxidative stress. The brain is particularly sensitive to oxidative stress., (Behl, 2001). In general, estrogen seems to offer some protection from schizophrenia. Schizophrenia symptoms are milder in women and onset occurs about 4 years later in women than men. Estrogen also seems to decrease susceptibility to Alzheimer's disease (Osterlund, 2001). Higher levels of estrogen are correlated with lower incidence and later onset of Alzheimers disease. Alzheimers risk increases after menopause when estrogen levels drop and more women than men suffer from age-related Alzheimers (Behl, 2001). Estrogen treatment decreases the risk of dementia, perhaps by stopping NMDA-induced neuronal death (Sickel from Steiner, 2000). Estrogen lowers risk of stroke (Behl, 2001).

Estrogen in mice affects learning (Shors, 2003) and cell proliferation in the adult mouse hippocampus is increased by estrogen (Behl, 2001). Estrogen improves some cognitive functions, such as memory, which is not surprising given that it increases ACh formation in neurons, such as ACh neurons which project to the hippocampus (Genazzani, 2002). In mice, astrocytes produce aromatase in lesioned areas of the brain (Behl, 2001).

Men who were exposed to DES as fetuses have an increased frequency of depression (Sickel from Steiner, 2000).


A woman's performance on motor and spatial tasks varies over the course of the menstrual cycle (Hampson, 1988) and the loss of gonadal hormones at menopause affects mood, libido, and some aspects of cognition. The mood and emotional changes also seem to involve changes in the serotoin, noradrenaline, dopamine, and opiate pathways. (Genazzani, 2002). After menopause, the rate of depression in females approaches that seen in men (Shors, 2003). A polymorphism in the estrogen receptor alpha is associated with variation in some of the characteristics of menopause such as vaginal dryness and hot flashes (Malacara, 2004).


PROGESTERONE
Progesterone can cause depression and increases monoamine oxidase activity (which breaks down serotonin) (Steiner, 2003). Progesterone opposes estrogen's effects in the brain and can alter mood, increasing the risk of depression (Genazzani, 2002). Progesterone mediates changes in the ventromedial hypothalamus which affects female behavior in mice (Krebs, 2000). Decreases in progesterone increases the risk of seizure, PMS symptoms, and anxiety (Dunn from Steiner, 2000).


ADRENAL HORMONES
Individuals suffering from depression have higher levels of adrenal hormones and corticotrophin releasing factor (CRF). Male and female mice react to stressful stimuli with different hormones (Shors, 2003).