Sex differences in anxiety and depression clinical perspectives

“2% and lifetime rates are 2–3% (Kessler et al., 2005; Ruscio et al., 2010), with a similar prevalence internationally (Weissman et al.”

“The lifetime prevalence of social anxiety disorder is higher in women at 5.7–15.5% compared to 4.2–11.1% in men (Kessler et al., 1994; Grant et al., 2005), with the sex difference in prevalence emerging prior to puberty (Beesdo et al., 2009).”

“4% for women based on the National Comorbidity Survey (Kessler et al., 1995) Other studies also consistently”

“There is disagreement as to whether men or women have greater exposure to trauma (Robin et al., 1997; Breslau et al., 1999; CDC, 2010) and sex itself is relatively weak predictor of trauma exposure (Brewin et al., 2000).”

“, 2003), In general, under conditions of perceived threat, men are more likely to escape or cope by taking action, and women are more likely to express affiliative behavior and seek support from others (Taylor et al., 2000).”

“2% and lifetime rates are 2–3% (Kessler et al., 2005; Ruscio et al., 2010), with a similar prevalence internationally (Weissman et al.”

“The lifetime prevalence of bipolar I disorder in the National Comorbidty Survey Replication was 0.8% in men and 1.1% in women and the lifetime prevalence of bipolar II disorder is 0.9% in men and 1.3% in women (Merikangas et al., 2007).”

“In addition, the increased tendency to ruminate, a risk factor for major depression, emerges in girls by age 9, also prior to puberty (Nolen-Hoeksema and Girgus, 1994).”

“Women have twice the lifetime rates of depression and most anxiety disorders (Kessler et al., 1994, 1995; Weissman et al., 1994, 1996; Gater et al., 1998).”

“Of note, there did not seem to be a sex difference in response to non-sexual abuse or neglect, or non-military sexual assault in adulthood (Tolin and Foa, 2006).”

“The lifetime prevalence of social anxiety disorder is higher in women at 5.7–15.5% compared to 4.2–11.1% in men (Kessler et al., 1994; Grant et al., 2005), with the sex difference in prevalence emerging prior to puberty (Beesdo et al., 2009).”

“Sex differences in HPA axis regulation are much smaller and less consistent in humans than rodents (Kudielka and Kirschbaum, 2005; Panagiotakopoulos and Neigh, 2014) and most anxiety disorders do not show any consistent perturbation of the HPA axis.”

“In addition to higher rates of affective disorders that meet full diagnostic criteria, subclinical anxiety and depression symptoms are also more common in women (Nolen-Hoeksema et al., 1999; Hankin, 2009).”

“Sex differences in brain structure and function are abundant and fluctuate across development (Courchesne et al., 2000; Lampl and Jeanty, 2003; Patton et al., 2004; Lenroot et al., 2007; Raznahana et al., 2013; Ingalhalikar et al., 2014).”

“Sex-linked differences in social support are apparent well before puberty, as evident in the language in single-sex peer groups (Maltz and Borker, 1983; Maccoby, 1990).”

“However, these sex differences are also thought to result in women experiencing more sensitivity to rejection, criticism and separation, key features of depression and anxiety disorders (Cyranowski et al., 2000; Taylor et al., 2000; Zahn-Waxler et al., 2008, Martel, 2013).”

“Sex differences in brain structure and function are abundant and fluctuate across development (Courchesne et al., 2000; Lampl and Jeanty, 2003; Patton et al., 2004; Lenroot et al., 2007; Raznahana et al., 2013; Ingalhalikar et al., 2014).”

“, 2012) and similarly small subgroups of women experience perimenopausal or post-partum depression (Gaynes et al., 2005; Freeman et al., 2014).”

“find that PTSD is more common in women than men (Narrow et al., 2002; Tolin and Foa, 2006; Roberts et al., 2011).”

“Of women who have major depression postpartum, approximately one quarter have chronic depression, one third have depression that onset during pregnancy and only a little more than one third have actual postpartum onset of depression (Wisner et al., 2013).”

“In addition, recent animal studies suggest that maternal and paternal stress that occurs even prior to conception can have differential effects in male and female offspring on depression and anxiety related behaviors and stressresponse regulation (Dietz et al., 2011; Zaidan et al., 2013).”

“Sex differences in brain structure and function are abundant and fluctuate across development (Courchesne et al., 2000; Lampl and Jeanty, 2003; Patton et al., 2004; Lenroot et al., 2007; Raznahana et al., 2013; Ingalhalikar et al., 2014).”

“Longitudinal studies have identified Tanner Stage III, the start of ovarian cycling, when estrogen levels rise significantly, as the onset of increased rates of major depression in girls (Angold et al., 1998).”

“In this same study, only male placentas showed changes in expression of placental growth genes in response to the stress (Mueller and Bale, 2011).”

“…no history of postnatal depression and a comparison group with a history of postpartum depression suggests that with exposure to and withdrawal of pregnancy levels of estradiol and progesterone, there are subset of women who are particularly vulnerable to develop depression (Bloch et al., 2000).”

“…medical conditions associated with increased risk of depression including heart disease, obesity, type II diabetes, and teen pregnancy, setting in bold relief the impact of sex differences in early life exposures on long-term physical and mental health (Dube et al., 2005; Edwards et al., 2005).”

“Importantly, the risk for major depression appears to decline in the years postmenopause such that there are no longer sex differences in risks for major depression (Cohen et al., 2006; Freeman et al., 2014).”

“Adolescent girls experience more objective and subjective stressors than boys, and this sex difference in stress exposure, particularly interpersonal stress, has been shown to partially mediate the increased prevalence of depression in girls after puberty (Ge et al., 1994; Hankin et al., 2007).”

“2% of men in the United States (Gorey and Leslie, 1997) has been linked to both depression and anxiety disorders and to inflammatory illnesses during adolescence and adulthood (Felitti et al., 1998; Dube et al., 2009; DeBellis et al., 2011).”

“Adolescent girls experience more objective and subjective stressors than boys, and this sex difference in stress exposure, particularly interpersonal stress, has been shown to partially mediate the increased prevalence of depression in girls after puberty (Ge et al., 1994; Hankin et al., 2007).”

“find that PTSD is more common in women than men (Narrow et al., 2002; Tolin and Foa, 2006; Roberts et al., 2011).”

“In addition, blood levels of PACAP, a neuropeptide involved in coordinating the brain’s response to stress and a polymorphism in the gene that encodes PACAP’s receptor PAC1, are both associated with increased risk for PTSD in women, but not in men (Ressler et al., 2011).”

“In neuroimaging studies examining sex differences in responses to threatening social cues, such as angry facial expressions, women are consistently more sensitive to interpersonal threats and exhibit greater reactivity to social rejection when compared to men, and men were more reactive to achievement stress (Stroud e…”

“Experimental and treatment studies have shown that PMDD symptoms are relieved by elimination of ovulation (Schmidt et al., 1998).”

“In contrast to major depression which has an increased prevalence in girls beginning in mid-puberty, the increased risk of anxiety and anxiety disorders in girls begins in middle childhood (Lewinsohn et al., 1998).”

“It remains to be seen whether the sex differences in central CRH and noradrenergic regulation observed in rodents (Bangasser and Valentino, 2014) also are present in humans and to what degree they may contribute to increased rates of depression and anxiety disorders in women.”

“, 2013), organizational effects of gonadal steroid exposure during development, and activational effects of reproductive hormone exposure throughout the lifespan (Arnold, 2009; McCarthy et al., 2012).”

“In addition, two randomized clinical trials (Schmidt et al., 2000; Soares et al., 2001) indicate that typical hormone therapy doses of estradiol (50 or 100 lg/d) are significantly more effective than placebo in treating major depression with perimenopause onset, a finding that is lacking for major…”

“Several studies have noted better responses to serotonin reuptake inhibiting antidepressants (SSRIs) in women and better response to tricyclic antidepressants in men and older women (Kornstein et al., 2000; Khan et al., 2005), suggesting that inhibition of serotonin reuptake may mitigate the mood-destabilizing effects…”

“Understanding the biological and cultural underpinnings of sex differences in affective disorders is likely to be a useful window into mechanisms of illness in both men and women (Rutter et al., 2003).”

“In addition, elevated levels of maternal depression and cortisol during pregnancy (Buss et al., 2012; Sandman et al., 2013) and elevated milk cortisol levels during lactation (Grey et al., 2012) have been associated with more fearful and reactive behavior in female infants and children compared to…”

“, 2013), organizational effects of gonadal steroid exposure during development, and activational effects of reproductive hormone exposure throughout the lifespan (Arnold, 2009; McCarthy et al., 2012).”

“…Altemus et al. / Frontiers in Neuroendocrinology xxx (2014) xxx–xxx 5 depressive episodes and depression symptoms, than men with these disorders (Angst, 1978, Kessler et al., 1997).”

“The lifetime prevalence of social anxiety disorder is higher in women at 5.7–15.5% compared to 4.2–11.1% in men (Kessler et al., 1994; Grant et al., 2005), with the sex difference in prevalence emerging prior to puberty (Beesdo et al., 2009).”

“In addition, two randomized clinical trials (Schmidt et al., 2000; Soares et al., 2001) indicate that typical hormone therapy doses of estradiol (50 or 100 lg/d) are significantly more effective than placebo in treating major depression with perimenopause onset, a finding that is lacking for major…”

“, 1991; Condon, 1993) and may be distinct from genetic risk for anxiety and depression (Kendler et al., 1992).”

“Lifetime prevalence of specific phobia in adults have been reported as 6–12% in men Please cite this article in press as: Altemus, M., et al. Sex differences in anxiety a dx.doi.org/10.1016/j.yfrne.2014.05.004 and 12–27% in women (Kessler et al., 1994; Fredrikson et al., 1996; Stinson et al., 2007).”

“Similarly, fetal growth restriction and preterm birth are associated with more neurologic deficits in males than females (Halpern, 2007; Gur et al., 2012).”

“For example, adaptive behavioral differences in terms of childrearing seem to include, in females, superior social cognition and capacity for attunement with others, important for cognitive and social development of offspring (Halpern, 2007; Gur et al., 2012; Thompson and Voyer, 2014).”

“2% of men in the United States (Gorey and Leslie, 1997) has been linked to both depression and anxiety disorders and to inflammatory illnesses during adolescence and adulthood (Felitti et al.”

“…Altemus et al. / Frontiers in Neuroendocrinology xxx (2014) xxx–xxx 3 abuse is also strongly associated with experiencing multiple other forms of adverse childhood events (Dong et al., 2003).”

“There is disagreement as to whether men or women have greater exposure to trauma (Robin et al., 1997; Breslau et al., 1999; CDC, 2010) and sex itself is relatively weak predictor of trauma exposure (Brewin et al., 2000).”

“Moreover, sex differences in life experiences and cultural expectations in turn may alter gene expression and contribute to development of sex differences in brain and physiology throughout the lifespan (Curley et al., 2011; Springer et al., 2012).”

“004 childhood onset OCD are more likely to have comorbid tics, and attention deficit disorders (Leckman et al., 2010; Ruscio et al., 2010).”

“Women have twice the lifetime rates of depression and most anxiety disorders (Kessler et al., 1994, 1995; Weissman et al., 1994, 1996; Gater et al., 1998).”

“…and lactation suppress hypothalamic–pituitary adrenal axis and Please cite this article in press as: Altemus, M., et al. Sex differences in anxiety a dx.doi.org/10.1016/j.yfrne.2014.05.004 autonomic responses to stress (Matthews and Rodin, 1992; Altemus et al., 1995; Entringer et al., 2010).”

“Mood and anxiety disorders are highly comorbid and have shared symptoms and familial risk (Angold et al., 1999; Kotov et al., 2011; Kravitz et al., 2014), suggesting that some of the same mechanisms are likely contributing to increased female vulnerability across this group of disorders.”

“In the military, among troops deployed overseas, sexual assault is over 15 times more common in women, and military sexual assault has a greater likelihood to result in PTSD in women compared to men (Kimerling et al., 2010).”

“Retrospective reports of women who meet full diagnostic criteria for PMDD indicate high comorbidity between major depression, bipolar disorder, seasonal affective disorder and panic disorder among adult women who meet full diagnostic criteria for PMDD (Kim et al., 2011), but this indication of shared vulnerability for…”

“Women compared to men, however, are 10 times more likely experience sexual assault (Kessler et al., 1995) and sexual assault has been shown to be a major contributor to the sex difference in PTSD prevalence (Stein et al., 2000).”

“However, these sex differences are also thought to result in women experiencing more sensitivity to rejection, criticism and separation, key features of depression and anxiety disorders (Cyranowski et al., 2000; Taylor et al., 2000; Zahn-Waxler et al., 2008, Martel, 2013).”

“In addition, recent animal studies suggest that maternal and paternal stress that occurs even prior to conception can have differential effects in male and female offspring on depression and anxiety related behaviors and stressresponse regulation (Dietz et al., 2011; Zaidan et al., 2013).”

“Clinic-based studies suggest that childhood onset OCD may be a distinct subtype of OCD, more common in males, and with greater familial risk (Geller et al., 1998; Hemmings et al., 2004).”

“In addition, elevated levels of maternal depression and cortisol during pregnancy (Buss et al., 2012; Sandman et al., 2013) and elevated milk cortisol levels during lactation (Grey et al., 2012) have been associated with more fearful and reactive behavior in female infants and children compared to…”

“Alternatively, the greater efficacy of SSRIs in reproductive aged women may be due to SSRI induction of 3-alpha reductase (Uzunov et al., 1996; Pinna et al., 2009), the enzyme producing the anxiolytic metabolites allopregnanolone (3-alpha,5-alpha metabolite of progesterone) and the 3 alpha,…”

“Lifetime prevalence of specific phobia in adults have been reported as 6–12% in men Please cite this article in press as: Altemus, M., et al. Sex differences in anxiety a dx.doi.org/10.1016/j.yfrne.2014.05.004 and 12–27% in women (Kessler et al., 1994; Fredrikson et al., 1996; Stinson et al., 2007).”

“Sex differences in brain structure and function are abundant and fluctuate across development (Courchesne et al., 2000; Lampl and Jeanty, 2003; Patton et al., 2004; Lenroot et al., 2007; Raznahana et al., 2013; Ingalhalikar et al., 2014).”

“…Altemus et al. / Frontiers in Neuroendocrinology xxx (2014) xxx–xxx 5 depressive episodes and depression symptoms, than men with these disorders (Angst, 1978, Kessler et al., 1997).”

“Women with postpartum manic episodes often experience more disorganization, disturbed sensorium, bizarre behavior, and sense of persecution than seen in typical manic episodes (Brockington et al., 1981; Wisner et al., 1994).”

“, 2012) and similarly small subgroups of women experience perimenopausal or post-partum depression (Gaynes et al., 2005; Freeman et al., 2014).”

“Other studies support the observation that women are more likely to experience disturbances of sleep, appetite and energy during a depression (Silverstein, 1999), as well as more likely to experience ‘‘atypical’’ depression, with hypersomnia and weight gain (Young et al., 1990; Angst et al., 2002;…”

“Men are more likely to report comorbid alcohol and substance abuse (Marcus et al., 2008).”

“In neuroimaging studies examining sex differences in responses to threatening social cues, such as angry facial expressions, women are consistently more sensitive to interpersonal threats and exhibit greater reactivity to social rejection when compared to men, and men were more reactive to achievement stress (Stroud e…”

“Findings regarding the sex ratio of bloodinjection-injury phobia have been more mixed (LeBeau et al., 2010).”

“Among individuals with a chronic course of generalized anxiety, men are more likely to have co-morbid alcohol and substance abuse while women have higher rates of comorbid mood and anxiety disorders (Vesga-Lopez et al., 2008).”

“…reuptake inhibiting antidepressants (SSRIs) in women and better response to tricyclic antidepressants in men and older women (Kornstein et al., 2000; Khan et al., 2005), suggesting that inhibition of serotonin reuptake may mitigate the mood-destabilizing effects of changes in gonadal steroids.”

“Women do experience an age-independent decline in immediate and delayed verbal recall during the menopause transition suggesting that changes in reproductive function impact cognition in addition to mood in women (Epperson et al., 2013a,b).”

“…2000; Soares et al., 2001) indicate that typical hormone therapy doses of estradiol (50 or 100 lg/d) are significantly more effective than placebo in treating major depression with perimenopause onset, a finding that is lacking for major depression during the postmenopause (Morrison et al., 2004).”

“…to have a prior history of depression, and history of typical risk factors for Please cite this article in press as: Altemus, M., et al. Sex differences in anxiety a dx.doi.org/10.1016/j.yfrne.2014.05.004 depression including abuse and low social support (Stowe et al., 2005; Altemus et al., 2013).”

“The challenge is to discern which sex differences in brain are relevant to 86 87 88 89 physiology of affective disorders (DeVries and Sodersten, 2009).”

“…the observation that women are more likely to experience disturbances of sleep, appetite and energy during a depression (Silverstein, 1999), as well as more likely to experience ‘‘atypical’’ depression, with hypersomnia and weight gain (Young et al., 1990; Angst et al., 2002; Blanco et al., 2012).”

“Women with PMDD do not have abnormal levels of estrogen, progesterone, or other gonadal steroids across the cycle (Rubinow et al., 1988), but instead are more reactive to luteal phase progesterone in terms of both mood and physical symptoms (Schmidt et al.”

“, 2007) but not pre-adolescent (Costello et al., 2007; vanLieshout and Boylan, 2010) females.”

“However, a large adult population study demonstrated that risk of OCD in relatives was proportional to degree of familial relationship, there was no impact of the sex of the proband or relative (Mataix-Cols et al., 2013), suggesting that there is no sex difference in the heritability or familial risk for OCD.”

“Moreover, sex differences in life experiences and cultural expectations in turn may alter gene expression and contribute to development of sex differences in brain and physiology throughout the lifespan (Curley et al., 2011; Springer et al., 2012).”

“In addition to higher rates of affective disorders that meet full diagnostic criteria, subclinical anxiety and depression symptoms are also more common in women (Nolen-Hoeksema et al., 1999; Hankin, 2009).”

“OCD symptoms are unusually common in postpartum depression, occurring in up to 35% of women with postpartum onset depression (Wisner et al., 1999; Altemus et al., 2013).”

“Several studies have noted that female children and adults are less likely to have reduced hippocampal volume associated with trauma or PTSD (Debellis and Keshavan, 2003; Samplin et al., 2013) but this finding was not evident in a recent meta-analysis (Woon and Hedges, 2011).”

“…and lactation suppress hypothalamic–pituitary adrenal axis and Please cite this article in press as: Altemus, M., et al. Sex differences in anxiety a dx.doi.org/10.1016/j.yfrne.2014.05.004 autonomic responses to stress (Matthews and Rodin, 1992; Altemus et al., 1995; Entringer et al., 2010).”

“The findings are remarkably similar whether one assesses girls growing up in Asia, Africa, Canada or Slovakia or different areas of the United States (Ogebe et al., 2011; Steiner et al., 2011; Yang et al., 2012).”

“This difference in coping style persists into adulthood (Deacon et al., 2003), In general, under conditions of perceived threat, men are more likely to escape or cope by taking action, and women are more likely to express affiliative behavior and seek support from others (Taylor et al.”

“Prenatal stress is increases risk of these disorders (Mottagh et al., 2010; Schaafsma and Pfaff, 2014), suggesting that in utero, development of motor, attention and social communication systems are more vulnerable to stress in males than females.”

“(Hines, 2006)”

“, 2007; vanLieshout and Boylan, 2010), and adult (Rice et al., 2007) but not pre-adolescent (Costello et al.”

“Of all of the anxiety disorders, panic disorder is particularly responsive to benzodiazepine treatment (Offidani et al., 2013).”

“There is a remarkable increased risk of a mania and psychosis during the first few weeks postpartum, with an incidence of 0.1–0.2 (Stewart et al., 1991).”

“In addition, women who experience postpartum depression are at increased risk to develop bipolar disorder in long-term follow-up (Munk-Olsen et al., 2012).”

“Alternatively, the greater efficacy of SSRIs in reproductive aged women may be due to SSRI induction of 3-alpha reductase (Uzunov et al., 1996; Pinna et al., 2009), the enzyme producing the anxiolytic metabolites allopregnanolone (3-alpha,5-alpha metabolite of progesterone) and the 3 alpha,…”

“Those women who reported onset of OCD or worsening of their ongoing OCD symptoms in the perinatal period, were also more likely to indicate that their symptoms worsened premenstrually (Forray et al., 2010).”

“However, these sex differences are also thought to result in women experiencing more sensitivity to rejection, criticism and separation, key features of depression and anxiety disorders (Cyranowski et al., 2000; Taylor et al., 2000; Zahn-Waxler et al., 2008, Martel, 2013).”

“Address: Box 244, 1300 York Avenue, New York, NY 10065, United States.”

“(Sheikh et al., 2002).”

“Childhood sexual abuse has been linked to dysregulation of biological stress response systems and alterations in brain development, which may mediate the association with affective disorders (DeBellis et al., 2011).”

“There is disagreement as to whether men or women have greater exposure to trauma (Robin et al., 1997; Breslau et al., 1999; CDC, 2010) and sex itself is relatively weak predictor of trauma exposure (Brewin et al., 2000).”

“Among army personnel deployed to combat settings, risk of PTSD was attenuated by supportive personal relationships in women but not men (Maguen et al., 2012).”

“Sex differences in HPA axis regulation are much smaller and less consistent in humans than rodents (Kudielka and Kirschbaum, 2005; Panagiotakopoulos and Neigh, 2014) and most anxiety disorders do not show any consistent perturbation of the HPA axis.”

“Several studies have noted that female children and adults are less likely to have reduced hippocampal volume associated with trauma or PTSD (Debellis and Keshavan, 2003; Samplin et al., 2013) but this finding was not evident in a recent meta-analysis (Woon and Hedges, 2011).”

“, 2013) and elevated milk cortisol levels during lactation (Grey et al., 2012) have been associated with more fearful and reactive behavior in female infants and children compared to male offspring.”

“Although women make more suicide attempts, men are more likely to make a lethal attempt (Rudmin et al., 2003).”

“Lower amniotic fluid testosterone levels at mid gestation (weeks 13–20) was associated with a negative response bias and less response to rewarding stimuli during a functional magnetic resonance imaging (fMRI) task among boys studied between 8 and 11 years of age (Lombardo et al., 2012).”

“Also, men with OCD have more social phobia and are less like to marry (Torresan et al., 2012).”

“As negative response bias to affective tasks is a common finding in individuals with major depression (Jaworska et al., 2014); the Please cite this article in press as: Altemus, M., et al. Sex differences in anxiety a dx.doi.org/10.1016/j.yfrne.2014.05.004 relatively greater levels of androgen…”

“Prenatal stress is increases risk of these disorders (Mottagh et al., 2010; Schaafsma and Pfaff, 2014), suggesting that in utero, development of motor, attention and social communication systems are more vulnerable to stress in males than females.”

“…the observation that women are more likely to experience disturbances of sleep, appetite and energy during a depression (Silverstein, 1999), as well as more likely to experience ‘‘atypical’’ depression, with hypersomnia and weight gain (Young et al., 1990; Angst et al., 2002; Blanco et al., 2012).”

“Women with postpartum manic episodes often experience more disorganization, disturbed sensorium, bizarre behavior, and sense of persecution than seen in typical manic episodes (Brockington et al., 1981; Wisner et al., 1994).”

“Although environmental influences, particularly cultural gender stereotypes, contribute to sex differences in human behavior and risk for psychiatric disorders, it is difficult to disentangle to what degree sex-specific cultural stereotypes are based on biologically determined sex-specific traits (Carter, 2011).”

“Testosterone levels peak in the fetal serum between weeks 12 and 18 of pregnancy (Finegan et al., 1989).”

“Two recent meta-analyses found that when controlling for type of trauma, women do seem to be more likely than men to develop PTSD in response to a number of stressors including combat (Crum-Cianflone and Jacoson, 2014), refugee status, accidents, witnessing death and illness/injury (Freedman et al., 2002; Tolin and Fo…”

“On the other hand, twin studies in adults suggest there are also specific genetic factors contributing to specific phobia, generalized anxiety disorder and panic disorder (Kendler et al., 1992).”

“Biologically-determined sex differences can arise from effects of sex chromosome genes (Arnold et al., 2012; Lee and Harley, 2012; Raznahan et al., 2013; Seney et al., 2013), organizational effects of gonadal steroid exposure during development, and activational effects of reproductive hormone…”

“Clinic-based studies suggest that childhood onset OCD may be a distinct subtype of OCD, more common in males, and with greater familial risk (Geller et al., 1998; Hemmings et al., 2004).”

“There is preliminary evidence from retrospective twin and family studies that risk for PMDD is heritable (Wilson et al., 1991; Condon, 1993) and may be distinct from genetic risk for anxiety and depression (Kendler et al.”

“Loss of this inhibition once the child is born causes a peak in testosterone in boys and a peak in estrogens in girls (Quigley, 2002).”

“At birth the testosterone levels of the male fetus are ten times higher than those of females (DeZegher et al., 1992).”

“Finally, a few experimental studies have demonstrated increased vulnerability to intrusive negative memories, when traumatic material is presented in the early luteal phase of the menstrual cycle compared to the follicular or late luteal phase (Soni et al., 2013).”

“There has been relatively little study of the effect of the menstrual cycle on bipolar symptoms, but preliminary evidence suggests that women with bipolar disorder have increased rates of premenstrual dysphoric disorder and approximately 50% of women with bipolar disorder report mood changes tied to their menstrual cy…”

“…internalizing symptoms and negative emotionality in boys (Martin et al., 1999; deBruijn et al., 2009), while maternal stress in later trimesters has been linked to increased risk of internalizing symptoms in girls during childhood (deBruijn et al., 2009) and adolescence (vandenBergh et al., 2008).”

“In a female rodent model, using mice transfected with the human Vall66Met BDNF polymorphism, only animals homozygous for the human depression risk allele, which reduces BDNF availability, showed fluctuation in anxiety behaviors across the estrus cycle (Bath et al., 2012).”

“Sex differences in brain structure and function are abundant and fluctuate across development (Courchesne et al., 2000; Lampl and Jeanty, 2003; Patton et al., 2004; Lenroot et al., 2007; Raznahana et al., 2013; Ingalhalikar et al., 2014).”

“…and lactation suppress hypothalamic–pituitary adrenal axis and Please cite this article in press as: Altemus, M., et al. Sex differences in anxiety a dx.doi.org/10.1016/j.yfrne.2014.05.004 autonomic responses to stress (Matthews and Rodin, 1992; Altemus et al., 1995; Entringer et al., 2010).”

“In addition, recent animal studies suggest that maternal and paternal stress that occurs even prior to conception can have differential effects in male and female offspring on depression and anxiety related behaviors and stressresponse regulation (Dietz et al., 2011; Zaidan et al., 2013).”

“…that when controlling for type of trauma, women do seem to be more likely than men to develop PTSD in response to a number of stressors including combat (Crum-Cianflone and Jacoson, 2014), refugee status, accidents, witnessing death and illness/injury (Freedman et al., 2002; Tolin and Foa, 2006).”

“Childbirth also seems to be a trigger for a hypomanic episodes, which can occur in 10–20% of women and in the early postpartum period (Heron et al., 2009).”

“Sex differences in brain structure and function are abundant and fluctuate across development (Courchesne et al., 2000; Lampl and Jeanty, 2003; Patton et al., 2004; Lenroot et al., 2007; Raznahana et al., 2013; Ingalhalikar et al., 2014).”

“The vast majority of these episodes are a first episode or recurrence of bipolar I disorder (MunkOlsen et al., 2012; Sharma and Pope, 2012).”

“OCD symptoms are unusually common in postpartum depression, occurring in up to 35% of women with postpartum onset depression (Wisner et al., 1999; Altemus et al., 2013).”

“Prevalence rates of bipolar II in adolescents was higher at 3–4% in recent studies, likely because some of these individuals will convert to bipolar I or other diagnoses over time (Merikangas and Lamers, 2012).”

“…may be due to SSRI induction of 3-alpha reductase (Uzunov et al., 1996; Pinna et al., 2009), the enzyme producing the anxiolytic metabolites allopregnanolone (3-alpha,5-alpha metabolite of progesterone) and the 3 alpha, metabolites of androstanedione and dihydrotestosterone (Porcu et al., 2009).”

“…sex differences can arise from effects of sex chromosome genes (Arnold et al., 2012; Lee and Harley, 2012; Raznahan et al., 2013; Seney et al., 2013), organizational effects of gonadal steroid exposure during development, and activational effects of reproductive hormone exposure…”

“%) with clinically significant distress, particularly during future pregnancies (Forray et al., 2009).”

“Women with social anxiety often experience symptom exacerbation premenstrually (vanVeen et al., 2009), but little is known about the course of social anxiety during pregnancy or perimenopause.”

“, 2013) but this finding was not evident in a recent meta-analysis (Woon and Hedges, 2011).”

“Support for the notion that prenatal androgen exposure plays a role in the sex differential in risk for these conditions comes from the observation that girls with tic disorders have more gender dysphoria, masculine play preferences, and masculine performance style on spatial tasks (Alexander and Peterson, 2004), simi…”

“Mood and anxiety disorders are highly comorbid and have shared symptoms and familial risk (Angold et al., 1999; Kotov et al., 2011; Kravitz et al., 2014), suggesting that some of the same mechanisms are likely contributing to increased female vulnerability across this group of disorders.”

“Biologically-determined sex differences can arise from effects of sex chromosome genes (Arnold et al., 2012; Lee and Harley, 2012; Raznahan et al., 2013; Seney et al., 2013), organizational effects of gonadal steroid exposure during development, and activational effects of reproductive hormone…”

“Many studies have found that females of all ages have greater anxiety sensitivity than males (Deacon et al., 2003; Bernstein et al., 2006).”

“, 2007) but not pre-adolescent (Costello et al., 2007; vanLieshout and Boylan, 2010) females.”

“Biologically-determined sex differences can arise from effects of sex chromosome genes (Arnold et al., 2012; Lee and Harley, 2012; Raznahan et al., 2013; Seney et al., 2013), organizational effects of gonadal steroid exposure during development, and activational effects of reproductive hormone…”

“There is preliminary evidence from retrospective twin and family studies that risk for PMDD is heritable (Wilson et al., 1991; Condon, 1993) and may be distinct from genetic risk for anxiety and depression (Kendler et al.”

“Address: Box 244, 1300 York Avenue, New York, NY 10065, United States.”

“Premenstrual exacerbation of depression has been linked in several studies to shorter time to relapse (Haley et al., 2013).”

“Retrospective reports of women who meet full diagnostic criteria for PMDD indicate high comorbidity between major depression, bipolar disorder, seasonal affective disorder and panic disorder among adult women who meet full diagnostic criteria for PMDD (Kim et al., 2011), but this indication of shared vulnerability for…”

“However, there is evidence that on self-report scales, women report more carbohydrate cravings, more weight gain, and more hours of sleep per night in the winter (Lucht and Kasper, 1999).”

“…the observation that women are more likely to experience disturbances of sleep, appetite and energy during a depression (Silverstein, 1999), as well as more likely to experience ‘‘atypical’’ depression, with hypersomnia and weight gain (Young et al., 1990; Angst et al., 2002; Blanco et al., 2012).”

“Other studies have found that in middle childhood boys develop more avoidant coping and girls more often demonstrate preoccupied and anxious coping in personal relationships (Carter, 2011; Gluck et al., 2014).”

“…here are broadly consistent with previous studies in finding higher rates of both anxiety disorders and MDD among women (Parker & Brotchie, 2010; Altemus et al. 2014) and the previously married (Scott et al. 2010; Leach et al. 2013) along with less consistent inverse associations with age (de…”

“Our results complement and expand the findings of recent reviews that address this topic by focusing only on biological factors,(21,74) those that consider gender-sex differences but only in a specific anxiety disorder,(74,75) or those that do not clearly distinguish between gender and sex differences.(23) A novel con…”