474_Sox Storolds, Response to Stress and Susceptibility to Depression Sex Steroids, Response to Stress and Susceptibility to Depression MV Seeman and LE Ross University of Toronto, Toronto, Ontario, Canada (© 2007 Elsevier inc. All rights reserved, This article Is revision of the previous edition artcle by MV Seeman, volume, pp 429-434, (© 2000, Elevier ine Introduction Gender Differences in Depression and Stress Syndromes Sex Steroids Stress Conclusion Glossary Circadian shythms Estrous cycles Genomic effects Growth hormone Hypothalamic. pituitary- ‘adrenal axis Hypothalamic. pituitary- ‘gonadal axis Hypothalamic. pituitary thyroid axis Melatonin Neurotrans- Posttraumatic syndrome “Twenty-four-hour sleep-wake cycles. Cyclic sexual receptivity in female animals that is accompanied by specific hormonal periodicity and that lays the groundwork for impregnation, Direct effects on DNA in cell nucle A polypeptide hormone secreted by the lmterior lobe of the pituitary gland that promotes tissue and skeletal growth and influences the metabolism of proteins, carbohydrates, and lipids. "The hormonal circuit from the hypothal- amus to the anterior pituitary gland to the adrenal gland and back to the hypothalamus "The hormonal circuit from the hypothal: amus to the anterior pituitary gland to the ovaries or testes and back to the hypothalamus "The hormonal circuit from the hypothal- amus to the anterior pituitary gland to the thyroid gland and back to the hypothalamus. A hormone that is secreted by the pineal gland and that regulates the onset and timing of sleep. Chemical messengers that cross. the ‘gap between neurons to either excite or inhibit the neighboring neuron, A. set of psychiatric sympeoms that develop as a reaction to a traumatic Prolactin A hormone secreted by the anterior pitui- tary gland whose function, among others, is to stimulate the growth of milk-secret- jing lands in the breast in preparation for, ‘or maintenance of, lactation, Peychophysio- Disorders such as chronic fatigue syn- logical drome, iritable bowel syndrome, and disorders fibromyalgia, which are’ stress-related body symproms Introduction From a physiological point of view, both depression and anxiety are the product of complex alterations of the hypothalamic-pituitary-thyroid axis, of prolac- tin, growth hormone, and melatonin irregularity, of sleep, activity, appetite, and temperature disturbance, of hypothalamic-pituitary-gonadal axis and hypo: thalamic-pituitary-adrenal axis deregulation, and of multiple neurotransmitter disequilibrium. Given the gender ratio of the prevalence of depression and anx- iety and the generally accepted role that stressful life events and powerful emotions play in che precipita- tion of mood disorders, this article focuses on the effects of ovarian hormones on the body's response Gender Differences in Depression and Stress Syndromes ‘Women are more susceptible than men to all forms of depression. Even in bipolar affective (manic- depressive) illness, in which the gender prevalence is equal, the frequency of depressive episodes is higher in women. Chronic, subthreshold depression (dys thymia) and episodic major depressive disorder are at least twice as common in women as they are in ‘men. These sex differences have been replicated in all major door-to-door epidemiological surveys and in treatment-seeking population samples from around the world, with the exception of reports from coun- tries where women are known to have reduced access to medical services. Strikingly, this sex ratio does not emerge until adolescence, when gonadal hormones are activated. Before puberty, depressive episodes are as frequent in boys as they are in giels. Anxiety may be a symptom of a depressive episode ‘rit may constitute the major component of a varietySex Steroids, Response to Stress and Susceptibility to Depression 475, of anxiety syndromes such as posttraumatic stress disorder (PTSD), phobia, panic disordes, agorapho- bia, obsessive-compulsive disorder, and generalized anxiety. With the exception of obsessive-compulsive disorder, in which the gender ratio is equal, adult ‘women are more susceptible than men to all the pre- ceding Diagnostic and Statistical Manual of Mental Disorders (DSM)-defined syndromes. As in depres- sion, the sex differences in most forms of anxiety emerge only after adolescence. ‘The aftermath of stressful life events may be expe- rienced in the psychological realm, as in PTSD, or primarily in the somatic realm, as in the various psy- chophysiological disorders. Both forms are more pre- valent in women, When exposed to a major trauma, approximately twice as many women as men develop PTSD, and women make up about 85% of PTSD sufferers whose symptoms last for over 1 year after exposure. After the World Trade Center attack, gen- der differences in PTSD could be explained by differ- ences in marital status (more common among women living alone without a permanent relationship) and education (more common among women with rela- tively little education and low income), but signifi- cantly more women experienced major depression and significantly more men were diagnosed with a substance abuse disorder. These differences persisted after adjustment for demographic variables. Both depression and anxiety are more severe and ‘more frequent during the premenstrual, postpartum, and menopausal periods of women’s lives. An exam- ple of experimentally elicited menstrual phase vulner- ability is the Van Goozen et al. report of a study involving 58 healthy women. Deliberately arranged anger provocation evoked most emotionality in those women who were premenstrual at the time of the experiment. Bloch et al. used an analogous design to investigate susceptibility to depression in response t0 exogenous estrogen and progesterone among women with a history of postpartum depression. Five of eight women with 2 history of postpartum depression, and none of the control women, with no psychiatric history, developed significant mood symptoms during, hypogonadism induced via administration of a gonadotropin releasing-hormone agonist. In summary, depressive and anxious states, as well as stress-provoked somatic conditions, are two 0 three times as common in women as in men, but there is no consistent sex difference in their preva lence prior to puberty. In women, symptom severity and frequency are associated with times in the repro- ductive cycle when the circulating level of ovarian hormones (estrogens and progestins) are falling, Sex Steroids Male-Female Differences Gender differences in illness prevalence can result from a combination of inborn, learned, and socially imposed factors, but what distinguishes the sexes during fetal development are sex-specific hormones that exert powerful effects on the fetal brain and contribute to its sexual differentiation. While the hormonal milieu does not differ appreciably for boys and girls between birth and puberty, their brains are sexually differentiated from early gestation. The dramatic hormonal changes at puberty, superimposed ‘on a dozen or more years of differential sex role experience, exert a profound effect on the adolescent brain. In addition to median levels of sex steroids, what also differs after puberty (and this may turn ‘out to be the crucial difference) is that only women undergo menstrual cycles. Both sexes are subject to pulsatile changes in hormone level and circadian fluctuations, but the monthly repetitive hormonal cycles interrupted by pregnancy are unique to women. Ir is not until very old age, when the testes stop producing testosterone, that the hormonal environ- ment of the male brain and that of the female brain ‘once again approach the par that existed prior to puberty. Even then, receptor densities for the various hormone agonists and their site specificity remain gender distinct. ‘These biological differences may play out in the context of differential exposure to social andlor psy- chological stress. It has been proposed that women may experience a greater frequency of stressful life events than men. Alternatively, women may be more likely than men to interpret life events as stressful However, a recent twin study by Kendler et al revealed that men and women were equally likely to experience an episode of major depression associated with a major life event, although the categories of significant events differed between the sexes (i.e. interpersonal events were more relevant to women; work problems were more relevant to men). In summary, although exposure to the impact of different experiences modulates the internal cascade ‘of neurochemical events in which sex hormones play such a crucial part, neuroendocrine differences and their sex-specific rhythms are arguably central to male-female differences in the vulnerability to de- pression and anxiety. Hormones determine how the male and female brain processes the experience to which it is exposed, in particular, how it differen- tially responds to stressful experience and powerful416_Sox Storolds, Response to Stress and Susceptibility to Depression Sex Steroids and Neurotransmitter Systems Sex steroids operate through genomic effects on neurotransmitter receptor protein or through direct membrane effects on the electrical firing rate of neurotransmitter-seereting cells. The genomic effect is relatively slow (minutes to hours); the membrane effect is rapid (microseconds to minutes). Ieis well recognized that the serotonergic system is important in the maintenance of mood. The effective- ness of selective serotonin reuptake inhibitors (SSRIs) in the treatment of both depression and anxiety has, highlighted the serotonin system. Estrogens exert mul- tiple effects on serotonin function, many of which are site specific. In the amygdala, a key brain structure involved in the mediation of environmental stress, estrogens increase serotonin turnover. Estrogens in- crease the density of serotonin S-hydroxytryptamine 2A (SHT2A) receptors in rat cerebral cortex and rnucleus accumbens. They decrease SHTIA mRNA. in the medial amygdala, piriform cortex, and peri thinal cortex, suggesting a possible pathway through which mood and memory are modulated. Through- out the brain, estrogens increase the rate of degrada- tion of monoamine oxidase, which, in turn, leads to increased brain availability of both serotonin and catecholamines. The interaction between estrogen and the serotonin system may have clinical implica tions: there is recent evidence that SSRIs are effective in reducing vasomotor symptoms associated with estrogen decline during menopause, and estrogen therapies may hold promise in management of hormone-dependent psychiatric conditions, including postpartum depression. Finally, there is some evi- dence that concurrent estrogen therapy may augment or accelerate response to SSRIs in women Estrogen-responsive and_progesterone-responsive neurons use the inhibitory -aminobutysic acid (GABA) as a transmitter, producing an anxiolytic affect. Estrogen also induces choline aceryltransferase and potentiates excitatory amino acids such as glu tamate and aspartate. The estrogen effect on the dopaminergic system is complex and phasic, causing alterations in pre- and postsynaptic dopamine recep- tors and differential distribution of the isoforms of the dopamine D2 receptor messenger RNA. More specific to stress and depression, estrogens block both the synthesis and the depletion of catecholamines, including norepinephrine. Norepinephrine plays a ‘major role in the autonomic stress response. Estro- gens work via endogenous opiate peptides to exert an activating influence on the autonomic sympathet- ic response to stress, which results in vasoconstric~ tion, quickened heartbeat, and sweating, common symptoms of anxiety. In summary, ovarian hormones exert multiple complex effects on neurotransmitter systems under” stood t0 be involved in depression and anxiety syndromes, Effects on Membrane Stability Because of their mainly activational influences, estrogens are proconvulsants in susceptible indivi duals, decreasing seizure threshold and increasing the magnitude of seizure activity. In experimental animals, this appears 10 be a direct consequence of depolarization of cellular membranes. Progesterone, oon the other hand, raises the seizure threshold, an effect opposite to that of estrogen and probably re- sponsible for catamenial or premenstrual epilepsy, ‘when progesterone levels deop. Seizure activity (8 electric shock treatment) has been known for a very long time to ameliorate depressive mood, In summary, the net effect of progesterone is to re- duce anxiety but to deepen depression. The opposite is true for estrogen: levels of circulating esteo- gens correlate with increased alertness in animals, reduced distractibility, and shorter reaction times. ‘The two hormones maintain a balance or homeosta- sis that, when disturbed, can tip a vulnerable person in the dizection of mental states that are diagnosed as depression or anxiety. Other Variables Estrogens increase blood flow to the brain and within the brain, which speeds metabolism and increases the general efficiency of neural networks and increases the effectiveness of drug delivery. Estrogens stimulate glucose transport and metabolism, promoting the ability of neuronal networks to perform their work. Neuronal responsiveness to steroid stimulation results from both genetic and membrane effects at multiply distributed sites involving large neural cir- cuitry. Network effects may differ depending on the particular configuration of a specific circuit. Hor- ‘monal effects on neural network properties appear to be state dependent. In other words, effects may differ widely depending on the light-dark eyele, the sleep cycle, the activity cycle, the glucose level, the noise level, the presence or absence of an animal of the opposite sex, the general stress level, and the specific type of stressor. Genomic Effects ‘Among the many genes suspected to come under the influence of estrogens are those responsible for neuronal development, migration, growth, and sur- vival, for dendritic spine formation and density, and ‘for antioxidant activity, synaptic plasticity,