CHAPTER 4

Psychoneuroendocrinology

Roxanne Keynejad, M.A., M.B.B.S., M.R.C.P.

Ania Korszun, Ph.D., M.D., F.R.C.Psych.

Carmine M. Pariante, Ph.D., M.D., F.R.C.Psych.

The associations between hormonal changes and psychiatric disorders have long been recognized, but only in recent decades have the underlying mechanisms begun to be understood. A renewed interest in the associations linking stressful early life events, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, inflammatory processes, and potential vulnerability to depression, psychosis, and posttraumatic stress disorder (PTSD) has prompted a resurgence of research in this field. Although the association between reproductive hormone changes and psychiatric disorders has been less well studied, there is likewise a growing clinical recognition of the burden of postpartum psychopathology and a new impetus for research progress in this area. A full account of how each endocrine system influences neurobehavioral function is beyond the scope of a single chapter; we focus here on summarizing the most firmly established findings from classic literature in the field, and on providing an overview of some recent promising research findings.

Hypothalamic-Pituitary-Adrenal Axis

The HPA axis produces a primary response to stressors to ensure adaptation to environmental change and to maintain homeostasis (Figure 4–1). In response to a threat, which may be physical (such as starvation) or psychological (such as perceived danger or a stressful life event), an increase in synthesis of corticotropin-releasing hormone (CRH) occurs in the hypothalamus. CRH stimulates secretion of pituitary adrenocorticotropic hormone (ACTH), which in turn triggers production of glucocorticoids by the adrenal cortex in a feedforward cascade. Cortisol is the main glucocorticoid, and its secretion is tightly controlled by the negative-feedback effects of glucocorticoids at both pituitary and brain sites, such as the hippocampus and hypothalamus (Pariante and Lightman 2008). These effects include rapid inhibition of the stress response, preventing oversecretion of glucocorticoids (Keller-Wood and Dallman 1984) via regulation of messenger ribonucleic acid (mRNA) and subsequent protein stores of the ACTH precursor pro-opiomelanocortin (Roberts et al. 1979) and CRH in the central nucleus of the amygdala (Makino et al. 1994).

FIGURE 4–1. Schematic diagram of the hypothalamic-pituitary-adrenal (HPA) axis.

See Plate 14 to view this figure in color.

In response to a threat, the hypothalamus synthesizes corticotropin-releasing hormone (CRH), which stimulates pituitary secretion of adrenocorticotropic hormone (ACTH), triggering adrenal glucocorticoid production in a feedforward cascade.

The HPA axis regulates peripheral body functions, including metabolism and immune response, as well as brain function. For example, glucocorticoids have well-established effects on carbohydrate metabolism, modulating pancreatic insulin release and hepatic and nonhepatic responses to insulin. Glucocorticoids have a wide range of enhancing and suppressive actions on both innate and adaptive immune responses, including upregulation of phagocytosis by neutrophils and macrophages; suppression of cytokine release by type 1 T helper (Th1) cells; and selective enhancement of type 2 T helper (Th2) cells (Franchimont 2004). Centrally, glucocorticoids regulate neuronal survival, neurogenesis, the acquisition of new memories, and the emotional appraisal of events, as well as the sizes of complex anatomical structures such as the hippocampus (Herbert et al. 2006).

Stressful stimuli activate all levels of the HPA axis, causing increases in CRH, ACTH, and cortisol secretion. However, these increases are superimposed on an intrinsic circadian pattern of HPA activity driven by the suprachiasmatic nucleus. HPA axis hormone secretion is pulsatile in nature, with the trough of integrated secretion occurring in the evening and early nighttime and the peak of secretion occurring just before awakening; active secretion continues throughout the morning and early afternoon. Under normal conditions, the pulsatile secretion of glucocorticoids causes continuous mineralocorticoid receptor (MR) activation and phasic and short-acting glucocorticoid receptor (GR) activation after each endogenous pulse (Conway-Campbell et al. 2007). The synergy of MR and GR activation is key to mediating glucocorticoid feedback inhibition. The pulsatile or “ultradian” pattern of HPA axis hormone secretion is essential for optimal transcription as well as for maintenance of neuroendocrine and behavioral responsiveness to stress. Recent research suggests that chronic (e.g., obstructive sleep apnea) and acute disease states (e.g., cardiac surgery) are associated with disruptions of the dynamic changes in adrenocortical steroid-producing cells that are required to maintain the normal ultradian pattern (Spiga and Lightman 2015).

The HPA Axis in Depression, Psychosis, and Posttraumatic Stress Disorder

Depression

Major depressive disorder (MDD) is widely considered to represent a maladaptive, exaggerated response to stress, and although it is associated with abnormalities in multiple endocrine systems, the HPA axis seems to be the most significant of these systems, with overactivity being a well-established phenomenon in depression. Studies have demonstrated cortisol hypersecretion in a proportion of people with depression, as evidenced by elevated 24-hour urinary free cortisol (UFC) and plasma and cerebrospinal fluid (CSF) cortisol concentrations (Carroll et al. 1976; Rubinow et al. 1984).

The role of hypothalamic CRH secretion in triggering the HPA axis response led to the CRH hypothesis of depression (Nemeroff 1996), which proposed that HPA hyperactivity in depression is attributable to CRH overexpression. This hypothesis is supported by evidence of elevated CRH levels in the lumbar CSF of depressed patients compared with nondepressed controls (Banki et al. 1992) as well as postmortem evidence of elevated CRH levels in the cisternal CSF of people who died by suicide (Arató et al. 1989). The presence of elevated CSF CRH further suggests hypersecretion of CRH by sources outside the hypothalamus, such as the amygdala, which is noted to be overactive in depression (Drevets 2003). Studies in rodents have found that HPA axis hyperactivity can be stimulated by chronic overexpression of CRH by the central amygdala (Flandreau et al. 2012).

In addition, HPA axis hyperactivity is thought to result from impaired negative feedback, mediated by changes in the binding of endogenous glucocorticoids to MR and GR (see Figure 4–1). The MR has a high affinity for endogenous corticosteroids, whereas the GR has a high affinity for dexamethasone and a lower affinity for endogenous corticosteroids. This profile supports a potentially more important role for the GR in regulating responses to stress in disorders associated with high levels of endogenous glucocorticoids, such as depression. Indeed, impaired GR-mediated negative feedback by glucocorticoids in MDD is suggested by studies reporting nonsuppression of cortisol secretion on the dexamethasone suppression test and other studies demonstrating a lack of ACTH inhibition in response to CRH following dexamethasone pretreatment (i.e., the combined dexamethasone/CRH test) (Pariante and Lightman 2008).

This hypothesis is supported by evidence that impaired HPA axis feedback inhibition by glucocorticoids resolves after successful antidepressant treatment. Furthermore, persistently impaired HPA axis negative feedback is associated with a high risk of early relapse and poor outcomes following discharge (Zobel et al. 2001). This inhibition of GR-mediated negative feedback could be due to reduced expression of the GR, as evidenced by both postmortem studies of human brains (Webster and Carlstedt-Duke 2002) and studies of the peripheral blood of depressed patients (Cattaneo et al. 2013; Nikkheslat et al. 2015). Experimental models of GR resistance have shown that activation of the P38 mitogen-activated protein kinase pathway by proinflammatory cytokines can reduce GR function (Miller and Raison 2006), a result that yields a potential explanation for the association of depression with inflammation, HPA axis hyperactivity, and glucocorticoid resistance.

In addition to considerable evidence supporting the role played by the GR in HPA axis regulation, there has been increasing interest in the effects of the MR, which is found at high concentrations in limbic brain regions and has a high affinity for cortisol and corticosterone in rats. Dexamethasone binds only to GR, meaning that both the dexamethasone suppression test and the combined dexamethasone/CRH test assess only GR function. Spironolactone (the precursor of the MR antagonist canrenoate) activates the HPA axis through blockade of MR-mediated negative feedback by endogenous glucocorticoids. A 2003 study found elevated cortisol secretion in response to spironolactone challenge in depressed patients compared with nondepressed controls (Young et al. 2003), suggesting increased MR activity in depression, whereas a more recent study found the opposite, perhaps because patients were treated with antidepressants and benzodiazepines (Juruena et al. 2009). Prednisolone is a synthetic glucocorticoid that, unlike dexamethasone, binds to the GR and the MR with similar affinity. Juruena et al. (2009) found normal cortisol secretion in response to administration of prednisolone (which affects both GR and MR) in depressed patients but impaired cortisol secretion in response to dexamethasone (which affects GR only). It is notable that nonsuppression in response to prednisolone (but not to dexamethasone) predicted lack of treatment response to antidepressants (Juruena et al. 2009).

Some studies suggest that HPA axis hyperactivity does not occur uniformly in all patients with depression at all times. For example, Posener et al. (2000) demonstrated different patterns of HPA axis abnormality in patients with psychotic and nonpsychotic depression. In this study, patients with nonpsychotic depression showed significantly lower 24-hour cortisol levels compared with controls but no difference in ACTH levels, whereas patients with psychotic depression showed significantly higher 24-hour mean ACTH levels compared with controls but no difference in cortisol levels (Posener et al. 2000).

The evidence described here highlights the role of the adrenal gland in HPA axis hyperactivity in depression. The process-oriented model proposed by Parker et al. (2003) postulated that in acute depression, excess cortisol results from hypersecretion of both hypothalamic CRH and pituitary ACTH, whereas in chronic depression, elevated cortisol levels are maintained by increased adrenal sensitivity to ACTH and negative feedback by glucocorticoids despite lower ACTH levels (Parker et al. 2003). Quantification of hormone-level variability through use of the approximate entropy statistic (ApEN) yielded significantly increased cortisol ApEN and significantly reduced ACTH ApEN in men with MDD compared with control participants (Posener et al. 2004), a finding that suggests abnormal cortisol regulation and highlights the role of adrenal gland pathology in depression. This finding is in keeping with findings of previous studies demonstrating adrenocortical hypertrophy in people with depression compared with healthy controls (Nemeroff et al. 1992) as well as resolution of the hypertrophy following effective antidepressant treatment (Rubin et al. 1995). A recent study that used magnetic resonance imaging to investigate the association of depression with cardiovascular disease found elevations in adrenal gland volumes that correlated with increased intra-abdominal and pericardial volumes of adipose tissue (Kahl et al. 2015).

Of note, studies investigating early stressful life events suggest that HPA axis hyperactivity may be a premorbid risk factor for depression rather than a consequence or an epiphenomenon of depression. Neonatal rodents and nonhuman primates separated from their mothers for extended periods show HPA axis hyperactivity and CRH-containing circuit overactivation that persist into adulthood (Sánchez et al. 2001). In humans, marked HPA axis hyperactivity in adulthood has been demonstrated in women with a history of childhood physical and sexual abuse. In a study using laboratory tests of standardized psychosocial stress (e.g., the Trier Social Stress Test), participants with a history of childhood abuse exhibited elevated ACTH secretion and elevated heart rates compared with participants without such a history, with the most elevated responses and markedly high cortisol levels observed in participants with a history of childhood abuse who were currently depressed (Heim and Nemeroff 2002). Another study, using the dexamethasone/CRH test, reported persistent HPA axis overactivation in men with a history of early life trauma (Heim et al. 2008). These findings suggest that the association between HPA axis hyperactivity and depression may indicate a persistent neurobiological predisposition to depression associated with early life stressors. Inconsistencies in the literature regarding HPA axis hyperactivity in depression may be explained by failure to control for exposure to childhood stressful life events. However, although these findings could explain the comorbidity between early life stressors and adult depression, they do not imply inevitability or irreversibility. Indeed, a key finding of mood disorder research has been that polymorphisms in stress-related genes can modify susceptibility to depression after stressful life events. Modification of susceptibility to depression has been shown for the genes encoding the 5-HT transporter (Caspi et al. 2003), CRH (Bradley et al. 2008), and the GR-bound protein FKBP5 (Zannas et al. 2016).

Complementary studies from immunology have demonstrated clinically significant inflammation in adulthood in healthy participants with a history of early life trauma, as evidenced by elevated levels of C-reactive protein (CRP; a peripheral inflammatory marker and an acute phase protein) and interleukin (IL) 6 during the Trier Social Stress Test (Danese et al. 2007; Pace et al. 2006). Elevated levels of IL-6, IL-1β, tumor necrosis factor α (TNF-α), and CRP have also been reported in patients with depression (Raison et al. 2006). Similarly to HPA axis feedback impairment, CRP elevation normalizes following antidepressant treatment (O’Brien et al. 2006). One unifying hypothesis to explain these findings is that in patients with depression or a history of childhood trauma, glucocorticoid resistance (ineffective action of glucocorticoid hormones on target tissues, as seen in HPA axis hyperactivity) triggers immune activation (Danese et al. 2008).

Psychosis

HPA axis abnormalities likewise have been demonstrated in patients with psychosis. Studying patients who are experiencing their first psychotic episode has been considered the preferred approach to avoid confounding by illness and treatment duration. A recent systematic review (Borges et al. 2013) reported evidence of HPA axis hyperactivity in first-episode psychosis, with higher baseline cortisol levels and blunted cortisol awakening responses in patients compared with control participants. Studies of patients at ultrahigh risk of developing psychosis have reported associations between higher cortisol levels and prodromal and psychotic symptoms (Corcoran et al. 2012; Mittal and Walker 2011), and pituitary gland enlargement at baseline has been shown to predict future psychotic illness (Garner et al. 2005). The association of HPA axis abnormalities with psychosis-like symptoms has also been found in patients with schizotypal personality disorder (Mittal et al. 2007) and in healthy participants scoring high on measures of schizotypal traits (Hori et al. 2011). Elevated ACTH responses to stress (Brunelin et al. 2008) and raised cortisol at baseline and following stress (Collip et al. 2011) have been demonstrated in healthy relatives of patients with psychosis. Pituitary gland enlargement also has been reported in first-degree relatives of people with schizophrenia compared with healthy controls (Mondelli et al. 2008). Borges et al. (2013) suggested that these studies point to the presence of a familial, potentially genetic, vulnerability to HPA axis hyperactivity in individuals who develop schizophrenia. It is noteworthy that studies in two independent samples have identified enlarged pituitary gland volumes—one study in the context of psychotic depression, psychotic mania, and schizophrenia (Pariante et al. 2004) and the other study in the context of the pre-psychosis prodromal phase (Garner et al. 2005). A possible mechanism for the pituitary gland enlargement seen in these studies may be ineffective negative feedback by circulating glucocorticoid hormones, leading to proliferation and expansion of the pituitary cells that produce ACTH.

Posttraumatic Stress Disorder

Although there is evidence that HPA axis abnormalities are present in PTSD, methodological difficulties initially made some of the literature challenging to interpret, with evidence of both increased and decreased HPA axis activity based on comorbidity with depression, type of trauma, and other sociodemographic features of the sample. For example, in a study of combat veterans with a diagnosis of PTSD, both low cortisol and enhanced cortisol suppression in response to dexamethasone were reported, irrespective of comorbid MDD (Yehuda 2002). However, that sample included only male combat veterans, whereas in community samples, women are more likely to experience PTSD (Frans et al. 2005; Kessler et al. 1995). Furthermore, studies of PTSD in veteran populations are subject to significant confounding with current and past alcohol and substance use disorders. Additional evidence of elevated CSF CRH levels and blunted ACTH responses to CRH suggests that pituitary CRH receptors are downregulated in PTSD (Bremner et al. 1997). A study using serial CSF sampling over a period of 6 hours demonstrated elevated CRH despite normal free urinary cortisol in war veterans diagnosed with PTSD compared with veterans without PTSD and healthy controls (Baker et al. 1999). PTSD studies generally report comorbid depression in participants, and depression studies often fail to measure and report trauma histories. As a result, documented depression confounds much of literature on the HPA axis in PTSD, and undocumented trauma and abuse may confound some of the literature on the HPA axis in depression.

These problems were avoided by Heim et al. (2001) in their studies on childhood abuse and MDD, which examined multiple HPA axis challenges in the same participants. The authors found an effect of early abuse (with comorbid PTSD in 11 of 13 participants) and MDD on stress reactivity, documenting both increased ACTH and increased cortisol response to the stressor in depressed patients with a history of childhood abuse compared with either healthy controls or depressed patients without a history of childhood abuse. In this same cohort, patients with MDD showed a blunted response to CRH challenge irrespective of the presence or absence of an abuse history, whereas patients with a history of childhood abuse who were not depressed showed a heightened response to CRH challenge. Thus, childhood abuse produced an increased pituitary response with adaptive adrenal compensation, a change compatible with low or normal basal cortisol levels. Furthermore, lower cortisol levels and greater CRH suppression in the low-dose dexamethasone suppression test were found in women with a history of abuse who developed depression but not in those without depression (Newport et al. 2004), irrespective of PTSD features.

A meta-analysis of 37 studies of basal cortisol levels in adults with current PTSD compared with adults without psychiatric disorders (Meewisse et al. 2007) examined data from 828 patients and 800 control participants. Although the authors found no significant differences in basal cortisol between the two groups, significantly lower serum cortisol was observed in studies that included only female participants, in studies that investigated physical or sexual abuse, and in studies that used afternoon cortisol sampling. A second meta-analysis of 47 studies comparing patients with PTSD, patients with PTSD and comorbid MDD, and control subjects with and without trauma exposure (Morris et al. 2012) found that cortisol levels were lower for the PTSD and the PTSD + MDD groups than for the no-trauma control group (which did not differ significantly from the trauma-exposed control group). Cortisol levels in response to dexamethasone suppression testing were lower in the PTSD group, the PTSD + MDD group, and the trauma-exposed control group relative to the no-trauma control group, with effect sizes moderated by age, time since traumatic event, and age at traumatic experience. The authors proposed that whereas lower daily cortisol may represent a marker of PTSD, increased HPA axis response to dexamethasone suppression testing may represent a marker of trauma exposure more generally.

Studies demonstrating increased GR binding and function in patients with PTSD have given rise to the suggestion that hypocortisolism may result from hypersensitivity of negative feedback inhibition (Yehuda 2006). Indeed, prospective studies have found evidence that the presence of hypocortisolism prior to traumatic experiences may predict vulnerability to PTSD (Yehuda et al. 1998), prompting the hypothesis that low baseline cortisol could represent a risk factor for abnormal stress response (Sherin and Nemeroff 2011). Furthermore, some studies report that PTSD can be averted by hydrocortisone treatment following trauma (de Quervain 2008), while others suggest that treatment aimed at replicating the normal cortisol secretion pattern is effective (Aerni et al. 2004). A possible explanation for hypocortisolism in PTSD is that cortisol may interfere with traumatic memory retrieval (de Quervain and Margraf 2008). A recent intriguing study of intergenerational transmission of susceptibility to PTSD reported differential effects of paternal and maternal PTSD on the offspring of Holocaust survivors (Yehuda et al. 2014). Offspring with paternal PTSD but no maternal PTSD showed higher methylation of the exon 1_F promoter of the glucocorticoid receptor (GR-1_F) gene (NR3C1), whereas offspring with both maternal and paternal PTSD showed lower methylation.

Hypothalamic-Pituitary-Thyroid Axis

Despite the well-recognized importance of the hypothalamic-pituitary-thyroid (HPT) axis in clinical psychiatry, it has been far less researched in recent times than the HPA axis. In this important hormonal system, hypothalamic secretion of thyrotropin-releasing hormone (TRH) stimulates the anterior pituitary gland to release thyroid-stimulating hormone (TSH). TSH in turn stimulates thyroid secretion of triiodothyronine (T₃) and thyroxine (T₄), which exert negative feedback on the pituitary gland and hypothalamus. There is a well-known association between hypothyroidism and mood disorders, including depression and rapid-cycling bipolar disorder, and between hyperthyroidism and symptoms of anxiety and dysphoria (Hendrick et al. 1998). Studies of depressed patients have found evidence of changes in the TSH response to TRH, higher levels of antithyroid antibodies, and elevated concentrations of TRH in the CSF (Musselman and Nemeroff 1996). However, despite these promising findings, a double-blind randomized, placebo-controlled trial of T₃ augmentation of sertraline treatment in patients with MDD found no added benefit from combining T₃ with sertraline (Garlow et al. 2012).

Studies examining the relationship between HPT axis abnormalities and PTSD have been limited, but there is some evidence of thyroid abnormalities in combat veterans. Elevated T₃ and T₄ were reported in Vietnam veterans diagnosed with PTSD (Prange 1999), whereas in World War II veterans with more chronic PTSD diagnoses, T₃ was elevated but T₄ levels were normal (Wang and Mason 1999).

Growth Hormone and the Hypothalamic-Pituitary-Somatotrophic Axis

Like the role of the HPT, the role of the hormonal system regulating growth hormone (GH, or somatotropin)—the hypothalamic-pituitary-somatotrophic axis—in mental health has been understudied. GH is synthesized by the anterior pituitary gland and is used in research predominantly as a marker of the integrity of the noradrenergic system following challenge. GH-releasing hormone (GHRH) and somatostatin regulate GH secretion through stimulation and inhibition, respectively, and are themselves regulated by a number of neurotransmitters, including acetylcholine, dopamine, γ-aminobutyric acid (GABA), norepinephrine, and serotonin. GH and insulin-like growth factors exert negative feedback to inhibit GH secretion. Studies of clonidine-induced GH release have documented a blunted GH response in depression that is thought to result from HPA axis changes (Dinan 1998). Reduced serum levels of GH have been observed in patients with schizophrenia, and reduced pituitary levels of GH have been found postmortem in people with chronic schizophrenia (Guest et al. 2011). A recent study reported a higher insulin:GH ratio in patients with schizophrenia, their siblings with a mood disorder diagnosis, and their unaffected siblings compared with healthy control participants (van Beveren et al. 2014).

Prolactin

Prolactin is secreted by the anterior pituitary gland in 14 pulses over 24 hours in a circadian pattern consisting of increased pulsation at the time of sleep onset, with the peak level occurring halfway through the sleep period and the trough level occurring on awakening. Prolactin trough levels are higher during the luteal phase of the menstrual cycle. Dopamine acts at anterior pituitary D₂ receptors to inhibit prolactin secretion, whereas serotonin exerts a stimulatory effect. Studies using serotonin-challenge agents to examine basal prolactin in patients with depression have yielded mixed findings, likely attributable to issues such as methodological difficulties, the complexity of the serotonin system, and the multifactorial nature of depression itself (Nicholas et al. 1998). A study in antipsychotic-naïve adults identified hyperprolactinemia (which is frequently attributed to iatrogenic causes) in more than 30% of individuals diagnosed as being at risk for psychosis (n=43) and more than 20% of those experiencing a first psychotic episode (n=26) (Aston et al. 2010).

Hypothalamic-Pituitary-Gonadal Axis

In contrast to the HPT and HPS axes, the hypothalamic-pituitary-gonadal (HPG) axis has been far more widely investigated in relation to mental health. Secretion of the principal gonadal steroids, estrogen and progesterone, is governed by cyclic changes in ovarian follicular and corpus luteum development over the course of the menstrual cycle. Critical to the proper functioning and timing of the monthly hormonal cycle is the pulsatile secretion of gonadotropin-releasing hormone (GnRH). GnRH secretion from the hypothalamus drives the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from pituitary gonadotropes.

The pulsatile secretion of GnRH is driven by a pulse generator in the arcuate nucleus of the hypothalamus. This pulsatile pattern is critical for the control of serum LH, FSH, and ovulation. LH secretory pulses in the peripheral circulation are used as the marker of GnRH secretory pulses. In humans, the follicular phase of the menstrual cycle is characterized by LH pulses of relatively constant amplitude every 1–2 hours (Reame et al. 1984).

It has been established that an increased incidence of depression in women (Weissman and Klerman 1977) extends from adolescence until menopause (Kessler et al. 1993), suggesting a potential role for ovarian steroids in the etiology of depressive disorders. This hypothesis is supported by evidence that in women with a history of depression, times of rapidly changing gonadal steroid concentrations, such as those occurring premenstrually or postpartum, constitute periods of particular vulnerability to depressive symptoms. Several studies have shown that a history of depression increases the risk of both postpartum “blues” and postpartum MDD (O’Hara 1986; O’Hara et al. 1991) and that premenstrual hormonal changes may affect mood (Halbreich et al. 1984). Other studies found a relationship between elevated estrogen and testosterone levels and the rising incidence of depression in girls during adolescence (Angold et al. 1999).

Premenstrual syndrome (PMS) is one of the best-studied depressive disorders in terms of the effects of ovarian steroids on mood. Studies of follicular, mid-luteal, and late-luteal phases of the menstrual cycle found no significant differences between healthy controls and women diagnosed with PMS (Reame et al. 1984). The hypothesis that PMS symptoms are related to delayed effects of progesterone on mood prompted several studies of RU486, a progesterone antagonist. Schmidt et al. (1991) found no reduction in mood symptoms following RU486 creation of an artificial follicular phase during the second half of the menstrual cycle. Furthermore, human chorionic gonadotropin did not reduce mood symptoms; progesterone blockade caused early menses without preventing depression. A subsequent 6-month randomized double-blind, placebo-controlled crossover study also showed no benefit of RU486 on depressive symptoms (Chan et al. 1994). Rubinow and Schmidt (1989) proposed that PMS is a cyclical mood disorder “entrained” to the menstrual cycle, rather than a disorder caused by changes in ovarian steroids.

Because of the documented increased incidence of depression at critical hormonal transition phases (e.g., postpartum, perimenopause), much speculation has focused on estrogen’s role as a precipitant. Two epidemiological cohort studies (Cohen et al. 2006; Freeman et al. 2006) also identified an increased incidence of depressive symptoms and MDD during the menopausal transition. Both high and low estrogen levels were associated with depression (Freeman et al. 2004, 2006), suggesting that estrogen levels may drive depression, and women who showed rapid changes in estrogen (from high to low levels and vice versa) tended to develop depressive symptoms during the perimenopause transition. Schmidt and Rubinow (2009) proposed that in some women, menopausal changes in estrogen secretion may trigger CNS effects that predispose to depression. These authors pointed to evidence that perimenopausal depressive episodes tend to occur during the late menopausal transition (Steinberg et al. 2008), a phase of estradiol withdrawal (Santoro et al. 1996). Furthermore, double-blind, placebo-controlled trials of estradiol therapy in perimenopausal women diagnosed with depression have shown significant improvement in symptoms after 3 weeks of treatment (Schmidt et al. 2000; Soares et al. 2001). Finally, a randomized double-blind, placebo-controlled trial of the effect of estradiol withdrawal on mood in women with a history of perimenopausal depression documented a recurrence of depressive symptoms during blinded hormone withdrawal (Schmidt et al. 2015).

Another time of increased vulnerability to depression in women is pregnancy and the postpartum period. Although it is known that this period coincides with a sudden drop in progesterone and estradiol levels, there is limited evidence on how this drop relates to depression onset. A recent systematic review of risk factors for antenatal and postnatal depression identified a wide range of biological, psychological, and social factors in both high- and low-income countries (Howard et al. 2014). Studies of both animals and humans provide evidence of a subtype of depression associated with 1) sensitivity to reproductive hormone changes; 2) higher rates of depression premenstrually, postnatally, and perimenopausally (Craig 2013; Schiller et al. 2015); and 3) a personal or family history of postnatal depression (Cooper and Murray 1995; Forty et al. 2006). Although some studies have reported elevated CRH (Yim et al. 2009), glucocorticoid, and CRH receptor polymorphisms (Engineer et al. 2013) and raised leptin levels (Skalkidou et al. 2009) as risk factors during pregnancy, the relative paucity of literature addressing this clinically significant area underscores the need for replication studies and further research.

In their review of perinatal bipolar disorder, affective psychosis, and schizophrenia, Jones et al. (2014) concluded that most of the evidence supporting a role for hormones in these disorders has been circumstantial (Bloch et al. 2003). The reviewers suggested that rather than indicating abnormal hormone levels, postpartum psychotic disorders may indicate abnormal responses to normal perinatal hormone changes (Bloch et al. 2000). Furthermore, Jones et al. (2014) pointed to evidence of a dysregulated immune–neuroendocrine set point in postpartum psychosis, including monocyte and macrophage overactivity (Bergink et al. 2013; Weigelt et al. 2013), a finding that requires further investigation.

Effects of the Hypothalamic-Pituitary-Adrenal Axis on the Hypothalamic-Pituitary-Gonadal Axis

Stress has long been known to inhibit the HPG axis, and there is a well-established association between infertility and high population density. Shortly after the isolation and sequencing of the CRH gene, it was demonstrated in rats that CRH inhibited LH secretion (Rivier and Vale 1984) and GnRH secretion (Petraglia et al. 1987), and further primate studies showed inhibition of LH secretion by injection of CRH (Olster and Ferin 1987).

Studies in ewes found that LH secretory amplitude was inhibited by stress, that the effects of stress were reversed by metyrapone inhibition of cortisol synthesis, and that infusion of stress levels of cortisol could produce inhibition of LH pulse amplitude but not frequency (Breen et al. 2004; Debus et al. 2002). These data suggest that cortisol, in addition to central CRH, may play a role in LH disruption.

Human studies have linked HPG axis abnormalities to HPA axis activation in anorexia nervosa, exercise-induced amenorrhea, and hypothalamic amenorrhea. In all three syndromes, hypercortisolemia has been observed, indicating overactivity of the HPA axis (Berga et al. 1989; Casanueva et al. 1987; Hohtari et al. 1988; Loucks et al. 1989; Suh et al. 1988; Villanueva et al. 1986). In all three conditions, exogenous CRH challenge elicits diminished ACTH or cortisol responses, suggesting that high baseline cortisol exerts negative feedback on hormonal effects of CRH (Berger et al. 1983; Biller et al. 1990; Gold et al. 1986; Hohtari et al. 1991). In anorexia nervosa, the hormonal abnormalities in the HPA and HPG axes are secondary to the weight loss. Weight restriction and low body weight are also observed in exercise-induced amenorrhea, and low body weight has been reported in hypothalamic amenorrhea. Even relatively mild degrees of weight loss in normal-weight or obese patients can lead to disturbances in both of these axes, as manifested by resistance to dexamethasone and by disturbances in menstrual cycle regularity or amenorrhea (Berger et al. 1983; Edelstein et al. 1983; Pirke et al. 1985). In anorexia nervosa, LH secretory patterns may revert to prepubertal levels of low nonpulsatile secretion or to a pubertal pattern of entrainment of LH secretion to the sleep cycle. Studies by Reame et al. (1985) in women with hypothalamic amenorrhea demonstrated that LH secretion during the follicular phase was slowed to the rate normally observed during the luteal phase.

Conclusion

In this chapter, we have sought to provide an overview of the established findings and the most promising developments in the dynamic field of psychoneuroendocrinology. Following a resurgence of research in this area, the interrelationships among early stressful life events, HPA axis dysregulation, altered immune function, vulnerability to psychiatric disorders, and inadequate response to treatment have become increasingly well characterized, although many findings remain correlational in nature. The growing clinical recognition of the burden of postpartum psychopathology and the associations between reproductive hormone changes and psychiatric disorders has provided further impetus for academic progress in this area. Stressful life events are strongly associated with depression, psychosis, and PTSD, but the relative contributions of genetic, developmental, and environmental factors to an individual’s vulnerability have yet to be fully understood.

References

Aerni A, Traber R, Hock C, et al: Low-dose cortisol for symptoms of posttraumatic stress disorder. Am J Psychiatry 161(8): 1488–1490, 2004 15285979

Angold A, Costello EJ, Erkanli A, Worthman CM: Pubertal changes in hormone levels and depression in girls. Psychol Med 29(5):1043–1053, 1999 10576297

Arató M, Bánki CM, Bissette G, Nemeroff CB: Elevated CSF CRF in suicide victims. Biol Psychiatry 25(3):355–359, 1989 2536563

Aston J, Rechsteiner E, Bull N, et al: Hyperprolactinaemia in early psychosis—not only due to antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry 34(7): 1342–1344, 2010 20188136

Baker DG, West SA, Nicholson WE, et al: Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. Am J Psychiatry 156(4): 585–588, 1999 10200738

Banki CM, Karmacsi L, Bissette G, Nemeroff CB: Cerebrospinal fluid neuropeptides in mood disorder and dementia. J Affect Disord 25(1):39–45, 1992 1352520

Berga SL, Mortola JF, Girton L, et al: Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 68(2):301–308, 1989 2493024

Berger M, Pirke KM, Doerr P, et al: Influence of weight loss on the dexamethasone suppression test. Arch Gen Psychiatry 40(5):585–586, 1983 6838337

Bergink V, Burgerhout KM, Weigelt K, et al: Immune system dysregulation in first-onset postpartum psychosis. Biol Psychiatry 73(10):1000–1007, 2013 23270599

Biller BM, Federoff HJ, Koenig JI, Klibanski A: Abnormal cortisol secretion and responses to corticotropin-releasing hormone in women with hypothalamic amenorrhea. J Clin Endocrinol Metab 70(2):311–317, 1990 2153693

Bloch M, Schmidt PJ, Danaceau M, et al: Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry 157(6):924–930, 2000 10831472

Bloch M, Daly RC, Rubinow DR: Endocrine factors in the etiology of postpartum depression. Compr Psychiatry 44(3):234–246, 2003 12764712

Borges S, Gayer-Anderson C, Mondelli V: A systematic review of the activity of the hypothalamic-pituitary-adrenal axis in first episode psychosis. Psychoneuroendocrinology 38(5):603–611, 2013 23369532

Bradley RG, Binder EB, Epstein MP, et al: Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry 65(2):190–200, 2008 18250257

Breen KM, Stackpole CA, Clarke IJ, et al: Does the type II glucocorticoid receptor mediate cortisol-induced suppression in pituitary responsiveness to gonadotropin-releasing hormone? Endocrinology 145(6):2739–2746, 2004 15033919

Bremner JD, Licinio J, Darnell A, et al: Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 154(5):624–629, 1997 9137116

Brunelin J, d’Amato T, van Os J, et al: Effects of acute metabolic stress on the dopaminergic and pituitary-adrenal axis activity in patients with schizophrenia, their unaffected siblings and controls. Schizophr Res 100:206–211, 2008 18155448

Carroll BJ, Curtis GC, Mendels J: Cerebrospinal fluid and plasma free cortisol concentrations in depression. Psychol Med 6(2):235–244, 1976 1005564

Casanueva FF, Borras CG, Burguera B, et al: Steroids and neuroendocrine function in anorexia nervosa. J Steroid Biochem 27(1–3):635–640, 1987 3121928

Caspi A, Sugden K, Moffitt TE, et al: Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301(5631):386–389, 2003 12869766

Cattaneo A, Gennarelli M, Uher R, et al: Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology 38(3):377–385, 2013 22990943

Chan AF, Mortola JF, Wood SH, Yen SS: Persistence of premenstrual syndrome during low-dose administration of the progesterone antagonist RU 486. Obstet Gynecol 84(6):1001–1005, 1994 7970453

Cohen LS, Soares CN, Vitonis AF, et al: Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry 63(4):385–390, 2006 16585467

Collip D, Nicolson NA, Lardinois M, et al; G.R.O.U.P: Daily cortisol, stress reactivity and psychotic experiences in individuals at above average genetic risk for psychosis. Psychol Med 41(11):2305–2315, 2011 21733219

Conway-Campbell BL, McKenna MA, Wiles CC, et al: Proteasome-dependent down-regulation of activated nuclear hippocampal glucocorticoid receptors determines dynamic responses to corticosterone. Endocrinology 148(11):5470–5477, 2007 17690167

Cooper PJ, Murray L: Course and recurrence of postnatal depression. Evidence for the specificity of the diagnostic concept. Br J Psychiatry 166(2):191–195, 1995 7728362

Corcoran CM, Smith C, McLaughlin D, et al: HPA axis function and symptoms in adolescents at clinical high risk for schizophrenia. Schizophr Res 135(1–3):170–174, 2012 22226904

Craig MC: Should psychiatrists be prescribing oestrogen therapy to their female patients? Br J Psychiatry 202(1):9–13, 2013 23284147

Danese A, Pariante CM, Caspi A, et al: Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A 104(4):1319–1324, 2007 17229839

Danese A, Moffitt TE, Pariante CM, et al: Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry 65(4): 409–415, 2008 18391129

de Quervain DJ: Glucocorticoid-induced reduction of traumatic memories: implications for the treatment of PTSD. Prog Brain Res 167:239–247, 2008 18037019

de Quervain DJ, Margraf J: Glucocorticoids for the treatment of post-traumatic stress disorder and phobias: a novel therapeutic approach. Eur J Pharmacol 583(2–3):365–371, 2008 18275950

Debus N, Breen KM, Barrell GK, et al: Does cortisol mediate endotoxin-induced inhibition of pulsatile luteinizing hormone and gonadotropin-releasing hormone secretion? Endocrinology 143(10): 3748–3758, 2002 12239084

Dinan TG: Psychoneuroendocrinology of depression. Growth hormone. Psychiatr Clin North Am 21(2):325–339, 1998 9670229

Drevets WC: Neuroimaging abnormalities in the amygdala in mood disorders. Ann N Y Acad Sci 985:420–444, 2003 12724175

Edelstein CK, Roy-Byrne P, Fawzy FI, Dornfeld L: Effects of weight loss on the dexamethasone suppression test. Am J Psychiatry 140(3):338–341, 1983 6829806

Engineer N, Darwin L, Nishigandh D, et al: Association of glucocorticoid and type 1 corticotropin-releasing hormone receptors gene variants and risk for depression during pregnancy and post-partum. J Psychiatr Res 47(9):1166–1173, 2013 23726670

Flandreau EI, Ressler KJ, Owens MJ, Nemeroff CB: Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus. Psychoneuroendocrinology 37(1):27–38, 2012 21616602

Forty L, Jones L, Macgregor S, et al: Familiality of postpartum depression in unipolar disorder: results of a family study. Am J Psychiatry 163(9):1549–1553, 2006 16946179

Franchimont D: Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies. Ann N Y Acad Sci 1024:124–137, 2004 15265777

Frans O, Rimmö PA, Aberg L, Fredrikson M: Trauma exposure and post-traumatic stress disorder in the general population. Acta Psychiatr Scand 111(4):291–299, 2005 15740465

Freeman EW, Sammel MD, Liu L, et al: Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry 61(1):62–70, 2004 14706945

Freeman EW, Sammel MD, Lin H, Nelson DB: Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry 63(4):375–382, 2006 16585466

Garlow SJ, Dunlop BW, Ninan PT, Nemeroff CB: The combination of triiodothyronine (T3) and sertraline is not superior to sertraline monotherapy in the treatment of major depressive disorder. J Psychiatr Res 46(11):1406–1413, 2012 22964160

Garner B, Pariante CM, Wood SJ, et al: Pituitary volume predicts future transition to psychosis in individuals at ultra-high risk of developing psychosis. Biol Psychiatry 58(5):417–423, 2005 16026767

Gold PW, Loriaux DL, Roy A, et al: Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. Pathophysiologic and diagnostic implications. N Engl J Med 314(21):1329–1335, 1986 3010108

Guest PC, Schwarz E, Krishnamurthy D, et al: Altered levels of circulating insulin and other neuroendocrine hormones associated with the onset of schizophrenia. Psychoneuroendocrinology 36(7):1092–1096, 2011 21251762

Halbreich U, Vital-Herne J, Goldstein S, Zander K: Sex differences in biological factors putatively related to depression. J Affect Disord 7(3–4):223–233, 1984 6151956

Heim C, Nemeroff CB: Neurobiology of early life stress: clinical studies. Semin Clin Neuropsychiatry 7(2):147–159, 2002 11953939

Heim C, Newport DJ, Bonsall R, et al: Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry 158(4):575–581, 2001 11282691

Heim C, Mletzko T, Purselle D, et al: The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biol Psychiatry 63(4):398–405, 2008 17825799

Hendrick V, Altshuler L, Whybrow P: Psychoneuroendocrinology of mood disorders. The hypothalamic-pituitary-thyroid axis. Psychiatr Clin North Am 21(2):277–292, 1998 9670226

Herbert J, Goodyer IM, Grossman AB, et al: Do corticosteroids damage the brain? J Neuroendocrinol 18(6):393–411, 2006 16684130

Hohtari H, Elovainio R, Salminen K, Laatikainen T: Plasma corticotropin-releasing hormone, corticotropin, and endorphins at rest and during exercise in eumenorrheic and amenorrheic athletes. Fertil Steril 50(2):233–238, 1988 2840309

Hohtari H, Salminen-Lappalainen K, Laatikainen T: Response of plasma endorphins, corticotropin, cortisol, and luteinizing hormone in the corticotropin-releasing hormone stimulation test in eumenorrheic and amenorrheic athletes. Fertil Steril 55(2):276–280, 1991 1846825

Hori H, Teraishi T, Ozeki Y, et al: Schizotypal personality in healthy adults is related to blunted cortisol responses to the combined dexamethasone/corticotropin-releasing hormone test. Neuropsychobiology 63(4):232–241, 2011 21494051

Howard LM, Molyneaux E, Dennis C-L, et al: Non-psychotic mental disorders in the perinatal period. Lancet 384(9956):1775–1788, 2014 25455248

Jones I, Chandra PS, Dazzan P, Howard LM: Bipolar disorder, affective psychosis, and schizophrenia in pregnancy and the post-partum period. Lancet 384(9956):1789–1799, 2014 25455249

Juruena MF, Pariante CM, Papadopoulos AS, et al: Prednisolone suppression test in depression: prospective study of the role of HPA axis dysfunction in treatment resistance. Br J Psychiatry 194(4):342–349, 2009 19336786

Kahl KG, Schweiger U, Pars K, et al: Adrenal gland volume, intra-abdominal and pericardial adipose tissue in major depressive disorder. Psychoneuroendocrinology 58:1–8, 2015 25935636

Keller-Wood ME, Dallman MF: Corticosteroid inhibition of ACTH secretion. Endocr Rev 5(1):1–24, 1984 6323158

Kessler RC, McGonagle KA, Swartz M, et al: Sex and depression in the National Comorbidity Survey, I: lifetime prevalence, chronicity and recurrence. J Affect Disord 29(2–3):85–96, 1993 8300981

Kessler RC, Sonnega A, Bromet E, et al: Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 52(12):1048–1060, 1995 7492257

Loucks AB, Mortola JF, Girton L, Yen SS: Alterations in the hypothalamic-pituitary-ovarian and the hypothalamic-pituitary-adrenal axes in athletic women. J Clin Endocrinol Metab 68(2):402–411, 1989 2537332

Makino S, Gold PW, Schulkin J: Effects of corticosterone on CRH mRNA and content in the bed nucleus of the stria terminalis; comparison with the effects in the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus. Brain Res 657(1–2):141–149, 1994 7820612

Meewisse M-L, Reitsma JB, de Vries G-J, et al: Cortisol and post-traumatic stress disorder in adults: systematic review and meta-analysis. Br J Psychiatry 191:387–392, 2007 17978317

Miller AH, Raison CL: Cytokines, p38 MAP kinase and the pathophysiology of depression. Neuropsychopharmacology 31(10):2089–2090, 2006 16980982

Mittal VA, Walker EF: Minor physical anomalies and vulnerability in prodromal youth. Schizophr Res 129(2–3):116–121, 2011 21429715

Mittal VA, Dhruv S, Tessner KD, et al: The relations among putative biorisk markers in schizotypal adolescents: minor physical anomalies, movement abnormalities, and salivary cortisol. Biol Psychiatry 61(10):1179–1186, 2007 17188254

Mondelli V, Dazzan P, Gabilondo A, et al: Pituitary volume in unaffected relatives of patients with schizophrenia and bipolar disorder. Psychoneuroendocrinology 33(7):1004–1012, 2008 18640787

Morris MC, Compas BE, Garber J: Relations among posttraumatic stress disorder, comorbid major depression, and HPA function: a systematic review and meta-analysis. Clin Psychol Rev 32(4):301–315, 2012 22459791

Musselman DL, Nemeroff CB: Depression and endocrine disorders: focus on the thyroid and adrenal system. Br J Psychiatry Suppl 30(30):123–128, 1996 8864158

Nemeroff CB: The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. Mol Psychiatry 1(4):336–342, 1996 9118360

Nemeroff CB, Krishnan KR, Reed D, et al: Adrenal gland enlargement in major depression. A computed tomographic study. Arch Gen Psychiatry 49(5):384–387, 1992 1586274

Newport DJ, Heim C, Bonsall R, et al: Pituitary-adrenal responses to standard and low-dose dexamethasone suppression tests in adult survivors of child abuse. Biol Psychiatry 55(1):10–20, 2004 14706420

Nicholas L, Dawkins K, Golden RN: Psychoneuroendocrinology of depression. Prolactin. Psychiatr Clin North Am 21(2): 341–358, 1998 9670230

Nikkheslat N, Zunszain PA, Horowitz MA, et al: Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression. Brain Behav Immun 48:8–18, 2015 25683698

O’Brien SM, Scott LV, Dinan TG: Antidepressant therapy and C-reactive protein levels. Br J Psychiatry 188:449–452, 2006 16648531

O’Hara MW: Social support, life events, and depression during pregnancy and the puerperium. Arch Gen Psychiatry 43(6): 569–573, 1986 3707289

O’Hara MW, Schlechte JA, Lewis DA, Wright EJ: Prospective study of postpartum blues. Biologic and psychosocial factors. Arch Gen Psychiatry 48(9):801–806, 1991 1929770

Olster DH, Ferin M: Corticotropin-releasing hormone inhibits gonadotropin secretion in the ovariectomized rhesus monkey. J Clin Endocrinol Metab 65(2):262–267, 1987 3110201

Pace TW, Mletzko TC, Alagbe O, et al: Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry 163(9):1630–1633, 2006 16946190

Pariante CM, Lightman SL: The HPA axis in major depression: classical theories and new developments. Trends Neurosci 31(9):464–468, 2008 18675469

Pariante CM, Vassilopoulou K, Velakoulis D, et al: Pituitary volume in psychosis. Br J Psychiatry 185:5–10, 2004 15231549

Parker KJ, Schatzberg AF, Lyons DM: Neuroendocrine aspects of hypercortisolism in major depression. Horm Behav 43(1):60–66, 2003 12614635

Petraglia F, Sutton S, Vale W, Plotsky P: Corticotropin-releasing factor decreases plasma luteinizing hormone levels in female rats by inhibiting gonadotropin-releasing hormone release into hypophysial-portal circulation. Endocrinology 120(3):1083–1088, 1987 3542513

Pirke KM, Schweiger U, Lemmel W, et al: The influence of dieting on the menstrual cycle of healthy young women. J Clin Endocrinol Metab 60(6):1174–1179, 1985 3923022

Posener JA, DeBattista C, Williams GH, et al: 24-Hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major depression. Arch Gen Psychiatry 57(8):755–760, 2000 10920463

Posener JA, Charles DeBattista, Veldhuis JD, et al: Process irregularity of cortisol and adrenocorticotropin secretion in men with major depressive disorder. Psychoneuroendocrinology 29(9):1129–1137, 2004 15219636

Prange AJ Jr: Thyroid axis sustaining hypothesis of posttraumatic stress disorder. Psychosom Med 61(2):139–140, 1999 10204963

Raison CL, Capuron L, Miller AH: Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 27(1):24–31, 2006 16316783

Reame N, Sauder SE, Kelch RP, Marshall JC: Pulsatile gonadotropin secretion during the human menstrual cycle: evidence for altered frequency of gonadotropin-releasing hormone secretion. J Clin Endocrinol Metab 59(2):328–337, 1984 6429184

Reame NE, Sauder SE, Case GD, et al: Pulsatile gonadotropin secretion in women with hypothalamic amenorrhea: evidence that reduced frequency of gonadotropin-releasing hormone secretion is the mechanism of persistent anovulation. J Clin Endocrinol Metab 61(5):851–858, 1985 3900122

Rivier C, Vale W: Influence of corticotropin-releasing factor on reproductive functions in the rat. Endocrinology 114(3): 914–921, 1984 6321146

Roberts JL, Budarf ML, Baxter JD, Herbert E: Selective reduction of proadrenocorticotropin/endorphin proteins and messenger ribonucleic acid activity in mouse pituitary tumor cells by glucocorticoids. Biochemistry 18(22):4907–4915, 1979 228704

Rubin RT, Phillips JJ, Sadow TF, McCracken JT: Adrenal gland volume in major depression. Increase during the depressive episode and decrease with successful treatment. Arch Gen Psychiatry 52(3): 213–218, 1995 7872849

Rubinow DR, Schmidt PJ: Models for the development and expression of symptoms in premenstrual syndrome. Psychiatr Clin North Am 12(1):53–68, 1989 2652113

Rubinow DR, Post RM, Savard R, Gold PW: Cortisol hypersecretion and cognitive impairment in depression. Arch Gen Psychiatry 41(3):279–283, 1984 6703846

Sánchez MM, Ladd CO, Plotsky PM: Early adverse experience as a developmental risk factor for later psychopathology: evidence from rodent and primate models. Dev Psychopathol 13(3):419–449, 2001 11523842

Santoro N, Brown JR, Adel T, Skurnick JH: Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab 81(4):1495–1501, 1996 8636357

Schiller CE, Meltzer-Brody S, Rubinow DR: The role of reproductive hormones in postpartum depression. CNS Spectr 20(1):48–59, 2015 25263255

Schmidt PJ, Rubinow DR: Sex hormones and mood in the perimenopause. Ann N Y Acad Sci 1179:70–85, 2009 19906233

Schmidt PJ, Nieman LK, Grover GN, et al: Lack of effect of induced menses on symptoms in women with premenstrual syndrome. N Engl J Med 324(17):1174–1179, 1991 2011161

Schmidt PJ, Nieman L, Danaceau MA, et al: Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 183(2):414–420, 2000 10942479

Schmidt PJ, Ben Dor R, Martinez PE, et al: Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry 72(7):714–726, 2015 26018333

Sherin JE, Nemeroff CB: Post-traumatic stress disorder: the neurobiological impact of psychological trauma. Dialogues Clin Neurosci 13(3):263–278, 2011 22034143

Skalkidou A, Sylvén SM, Papadopoulos FC, et al: Risk of postpartum depression in association with serum leptin and interleukin-6 levels at delivery: a nested case-control study within the UPPSAT cohort. Psychoneuroendocrinology 34(9):1329–1337, 2009 19427131

Soares CN, Almeida OP, Joffe H, Cohen LS: Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 58(6):529–534, 2001 11386980

Spiga F, Lightman SL: Dynamics of adrenal glucocorticoid steroidogenesis in health and disease. Mol Cell Endocrinol 408: 227–234, 2015 25662280

Steinberg EM, Rubinow DR, Bartko JJ, et al: A cross-sectional evaluation of perimenopausal depression. J Clin Psychiatry 69(6):973–980, 2008 18505304

Suh BY, Liu JH, Berga SL, et al: Hypercortisolism in patients with functional hypothalamic-amenorrhea. J Clin Endocrinol Metab 66(4):733–739, 1988 3346352

van Beveren NJ, Schwarz E, Noll R, et al: Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia. Transl Psychiatry 4:e430, 2014 25158005

Villanueva AL, Schlosser C, Hopper B, et al: Increased cortisol production in women runners. J Clin Endocrinol Metab 63(1): 133–136, 1986 3011836

Wang S, Mason J: Elevations of serum T3 levels and their association with symptoms in World War II veterans with combat-related posttraumatic stress disorder: replication of findings in Vietnam combat veterans. Psychosom Med 61(2):131–138, 1999 10204962

Webster JI, Carlstedt-Duke J: Involvement of multidrug resistance proteins (MDR) in the modulation of glucocorticoid response. J Steroid Biochem Mol Biol 82(4–5):277–288, 2002 12589934

Weigelt K, Bergink V, Burgerhout KM, et al: Down-regulation of inflammation-protective microRNAs 146a and 212 in monocytes of patients with postpartum psychosis. Brain Behav Immun 29:147–155, 2013 23295264

Weissman MM, Klerman GL: Sex differences and the epidemiology of depression. Arch Gen Psychiatry 34(1):98–111, 1977 319772

Yehuda R: Current status of cortisol findings in post-traumatic stress disorder. Psychiatr Clin North Am 25(2):341–368, vii, 2002 12136504

Yehuda R: Advances in understanding neuroendocrine alterations in PTSD and their therapeutic implications. Ann N Y Acad Sci 1071:137–166, 2006 16891568

Yehuda R, McFarlane AC, Shalev AY: Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Biol Psychiatry 44(12): 1305–1313, 1998 9861473

Yehuda R, Daskalakis NP, Lehrner A, et al: Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry 171(8):872–880, 2014 24832930

Yim IS, Glynn LM, Dunkel-Schetter C, et al: Risk of postpartum depressive symptoms with elevated corticotropin-releasing hormone in human pregnancy. Arch Gen Psychiatry 66(2):162–169, 2009 19188538

Young EA, Lopez JF, Murphy-Weinberg V, et al: Mineralocorticoid receptor function in major depression. Arch Gen Psychiatry 60(1):24–28, 2003 12511169

Zannas AS, Wiechmann T, Gassen NC, Binder EB: Gene-stress-epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology 41(1):261–274, 2016 26250598

Zobel AW, Nickel T, Sonntag A, et al: Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression. a prospective study. J Psychiatr Res 35(2): 83–94, 2001 11377437