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Hormones are an important bridge between the CNS and various effector organs and they regulate key metabolic processes. Changes in hormone levels are important for many psychological disorders, for example those associated with the menstrual cycle, and some of the key hormonal regulation systems feature prominently in current theories of affective and stress related disorders. Hormones and their receptors have also recently become a target for drug development in biological psychiatry. This chapter describes the central role of the hypothalamus in providing the release factors for pituitary hormones and the three main systems arising from it, the hypothalamic-pituitary-adrenal (HPA) axis, the hypothalamic-pituitary-thyroid (HPT) axis and the hypothalamic-pituitary-gonadal (HPG) axis. It then focuses on the role of the HPA axis in mediating the stress response and that of the HPG axis for the impact of sex hormones on mental health.
3.1 Hormones aid communication between cells
Like neurotransmitters, hormones communicate between cells, but not just between neurons. Hormones can act on the cell that neighbours the secreting cell (paracrine), on the secreting cell itself (autocrine), or they are secreted into blood and act on cells that are further afield (endocrine). Peptides (chains formed from up to 100 amino acids), amino acid derivatives and steroids are the commonest forms of hormones. They are synthesised in endocrine glands such as the pituitary, thyroid, adrenal or gonadal glands, or by endocrine cells that are interspersed in the various tissues. In their target organs the hormones bind with extracellular or intracellular (cytosolic or nuclear) receptors and regulate the metabolism of the target cell.
3.2 The hypothalamic-pituitary system regulates basic functions of the life cycle
The hypothalamic-pituitary system is the main neuroendocrine system. It regulates basic functions of the life cycle - growth, procreation and survival. The hypothalamus is the main link between the neural and endocrine systems. Its secretory cells are activated by NTs and release hormones, some of which, the so-called release factors, stimulate the pituitary to release other hormones into the blood. Both the hypothalamic release-promoting or -inhibiting factors and the pituitary hormones are peptides (with the exception of dopamine) (Table 3.1). The other main neuro-endocrine system is the sympathetic-adrenal-medullary (SAM) pathway, which controls the release of adrenaline and noradrenaline.
The pituitary and peripheral hormones control the secretion of the hypothalamic release factors, and thus their own release through feedback loops. Although all the hypothalamic-pituitary-peripheral gland systems are of immense importance for physical and mental wellbeing, those most directly related to mental disorders and their treatment are the tuberoinfundibular dopamine-prolactin system and the HPA axis, which will therefore be described here in more detail.
3.3 The tuberoinfundibular dopamine pathway regulates lactation
Dopamine is synthesised in the arcuate and periventricular nuclei of the mediobasal hypothalamus (the "tuberal region" from tuber (Latin) = lump) and released into the system of portal veins that connect the hypothalamus with the anterior pituitary through the pituitary stalk (also called infundibulum (Latin) = funnel). Because the anterior pituitary is outside the blood-brain barrier dopamine can exert direct effects on the prolactin producing pituitary cells, which are called lactotrophs. Lactotrophs have a high baseline activity, which may explain why hypothalamic inhibiting factors (mainly dopamine) are generally more important than the factors that stimulate prolactine release (thyrotropine releasing hormone, TRH and vasoactive intestinal peptide, VIP). Lactotrophs comprise up to half the cell population of the anterior pituitary, and some are more responsive to the inhibitory effects of dopamine, whereas others are more responsive to the stimulating effects of TRH. Unlike in the HPA axis, there is no hormone produced by the target gland (like cortisol) to regulate the hypothalamic release (or in this case: inhibiting) factor. Hypothalamic dopamine secretion is thus under the direct control of prolactin, a mechanism termed "short-loop feedback"(Fitzgerald and Dinan, 2008). The dopaminergic neurons of the arcuate and periventricular nuclei possess prolactin receptors, and increasing prolactin concentrations enhance their activity, and vice versa, producing a negative feedback loop (increasing prolactin production leading to enhanced release of the inhibiting factor). The mechanism through which prolactin stimulate dopaminergic activity in the hypothalamus seems to be activation and induction (stimulation of the gene expression) of tyrosine hydroxylase, which is the rate limiting enzyme for dopamine synthesis (see Chapter 2). Prolactin secreted from the pituitary travels through the blood stream to the choroid plexus where it enters the CSF and diffuses to the hypothalamus - amongst other parts of the brain, where it is almost ubiquitous. Its enhancing effects on tyrosine hydroxylase seem confined to the dopamine producing hypothalamic nuclei.
The tuberoinfundibular pathway is of great importance for clinical psychiatry because of the antidopaminergic effects of antipsychotic agents. The dopamine effects on the lactotroph are mediated through D2 receptors, which are blocked by all typical antipsychotics. The resulting disinhibition of prolactin production leads to side effects that can include growth of breasts and even milk secretion in men, impotence in men and infertility in women, and persistent milk secretion, lack of libido and vaginal soreness in women. Of the atypical antipsychotics, some (risperidone, sulpiride and aminosulpiride) frequently lead to increased prolactin levels, whereas others (e.g., olanzapine, quetiapine) show this problem much less. One explanation may be that the blood brain barrier is less permeable for the former class, necessitating higher levels of the antipsychotic agent in the circulation (and thus in the anterior pituitary) in order to obtain a given central dopamine receptor occupancy (and antipsychotic effect). However, even those antipsychotics that do not lead to lasting increases in prolactin levels and the associated side effects produce a marked transient increase. The transient nature of this initial prolactin increase may be explained by the fast dissociation from the D2 receptor that is a pharmacokinetic property of some of the atypical antipsychotics. Furthermore, prolactin is also under the control of the serotonergic system. Stimulation of 5-HT2 receptors promotes prolactin release, and this effect is utilised by the fenfluramine test that assesses the viability of the serotonin system through its ability to increase prolactin levels.
3.4 The HPA axis regulates metabolism and the stress response
The paraventricular nucleus (PVN) of the hypothalamus secretes corticotrophin releasing factor (CRF) and vasopression (also called arginin vasopressin, AVP or antidiuretic hormone, ADH) into the infundibular portal veins. The adrenocorticotrophic hormone (ACTH)-secreting cells of the anterior pituitary, called corticotrophs, express receptors for CRF and AVP, which act synergistically to stimulate the release of ACTH. ACTH is secreted into the circulation and stimulates the adrenal cortex to release glucocorticoids, a class of steroid hormones (Table 3.2). Glucocorticoids increase blood glucose levels, counteracting the effects of insulin. They also contribute to the regulation of water and electrolyte homoeostasis, increase blood pressure and can suppress immune responses. Several effects on the CNS have been postulated, for example in the formation of new memories, but also damage to the hippocampus after longer periods of upregulation. The best documented psychiatric effect is probably the acute psychosis that can arise from high levels of glucocorticoids owing to overproduction (e.g. from overstimulation of the adrenal glands by an ACTH-secreting tumour of the anterior pituitary, Cushing's disease) or medical use (e.g., as immunosuppressant in autoimmune disease). The effects of glucocorticoids on the brain can be mediated through the Glucocorticoid (GR) or the Mineralocorticoid Receptor (MR). The affinity of glucocorticoids for the MR, which is mainly expressed in the pituitary, hippocampus and amygdala, is actually much higher than that for the GR. The MR is thus probably saturated most of the time, whereas the GR, which is more widely expressed in the brain and in peripheral tissue, is mainly activated during times of peak concentration in the early morning or during stress. GR binding of cortisol in the hypothalamus, anterior pituitary and adrenal cortex lead to downregulation of the HPA axis (Fig. 3.1), constituting a negative feedback loop(Thomson and Craighead, 2008).
The synthesis and secretion of CRF and AVP increase after exposure to stressful stimuli, for example encounter with a predator or immobilisation. The HPA axis has thus been implicated in the "fight or flight" response, a common response pattern to threat that was first described by the American physiologist Walter Bradford Cannon (1971-1945) in 1915. Stress and in particular dysfunctional coping with and adaptation to stress play a key role in psychological models of anxiety and depression, and it was therefore natural to probe changes in the HPA axis in these disorders. Normally, blood cortisol levels show a clear diurnal pattern with a peak in the morning and a second, smaller peak in the evening. Studies in patients with depression found a less pronounced circadian cortisol rhythm and reduced suppression of CRF and ACTH secretion in response to glucocorticoids. This is typically tested with the dexamethasone suppression test (DST). Dexamethasone (DEX) is a synthetic steroid that has glucocorticoid function and suppresses CRF and AVP release from the PVN. Reduced suppression of cortisol levels after intake of dexamethasone thus indicates insufficient negative feedback, which may result in a chronic upregulation of the HPA axis. The elevated urinary cortisol levels found in some patient studies would support such a link. However, the dexamethasone suppression test is abnormal only in about 50% of patients, and HPA axis dysregulation can therefore explain only some aspects of the biology of depression. It may be associated with psychotic and melancholic depression more than with other forms, but has been reported in anxiety disorders like posttraumatic stress disorder (PTSD) and panic disorder as well. A recent extension of the DST, the DEX/CRF challenge test, may be more sensitive. In healthy individuals, prior administration of DEX suppresses the increased ACTH and cortisol release that is normally observed after intravenous application of CRF. This effect was reversed in patients with depression, who showed an increase of ACTH and cortisol at the same DEX dose, and only showed the suppression after administration of a higher dose. However, even the DEX/CRF is not consistently altered in patients with depression. Additional evidence for a role of the HPA axis in depression comes from the effects of several antidepressant drugs that upregulate central GRs, which should theoretically lead to reduced peripheral cortisol production. Research developing modulators of the HPA axis, for example CRF and AVP receptor antagonists, into a potential treatment for depression is currently very active but has yet to produce tangible results.
The HPA axis interacts with neurotransmitter systems at various levels. Serotonergic projections to the hypothalamus increase CRF release, and glucocorticoids can modulate both 5-HT receptor expression and sensitivity(Porter et al., 2004). This link provides another possible avenue for exploring the relationship between cortisol levels and depression.
BOX 3-1: What is stress?
The term "stress" is used in a variety of ways. We talk about stress at work or in a relationship, or stressful periods of our lives. In laboratory settings, stress can be induced in animals by cold or heat, bright light, painful stimuli such as electroshocks or immobilisation. Imminent danger to our lives or those of our loved ones produces stress, and even the past experience of threatening situations can result in ongoing stress, as in "post-traumatic stress disorder". What these scenarios have in common is that they consist in perceived or real threats to the homoestasis, the balance of bodily functions, and ultimately to survival. Although "stress" is sometimes used to denote maladaptive responses to environmental changes, its psychological (e.g. heightened arousal) and physiological (e.g. increased heartbeat) components can serve important purposes, for example the flight from a predator. It thus makes sense to follow the endocrinologist Hans Selye (1907-1982) and distinguish adaptive "eustress" from maladaptive "distress", which results from insufficient coping with challenging life situations and can lead to avoidance behaviour and anxiety. It is the latter type of psychological stress that has been mostly implicated in the genesis of mental disorders.
A stressor thus cannot be defined by its intrinsic properties but only by the response it evokes in the organism concerned. One person might find a five minute journey in an underground train extremely stressful, whereas this is a perfectly routine undertaking for the majority of the population. The biological cascade that defines the stress response and has the goal of returning the body to homoestasis relies on three main neuroendocrinological systems. In addition to the HPA axis, these are the noradrenergic brainstem pathways and the neuropeptide system (particularly Î±-melanocyte stimulating
hormone and Î²-endorphin)(Chrousos, 2009).
The stress response involves many important changes in the CNS and peripheral organs that can subserve a fight or flight response. The psychological effects of heightened arousal, vigilance, aggression and memory probably arise from the activation of positive feedback loops involving the central nucleus of the amygdala by CRF, by stimulation of the ascending reticular activating system through heightened noradrenergic tone and by activation of the mesolimbic and mesocortical dopamine systems. At the same time the growth hormone, thyroid and reproductive axes arising from the hypothalamus and pituitary are inhibited at various levels. Important effects of the cortisol and catecholamine release on peripheral organs include increasing blood pressure and heart rate and increased blood glucose levels.
As with all homoeostatic processes, the stress response can be described as an inverted U-shape function (Fig. 3.2). For example, both too little and too much fear can be bad for an animal's survival. An insufficient stress response may lead to lack of vigilance for dangers in the environment, whereas an exaggerated response could exhaust the resources of the body prematurely and lead to long term damage to the CNS (as hypothesised for the hippocampus in PTSD) and peripheral organs.
--- Fig. 3.2 ---
Modulations of the stress response are a part of coping styles. More aggressive animals will show a more proactive response style to potential threats and tend to activate the stress response at lower environmental thresholds, whereas less aggressive animals with a more avoidant response style will show a fight or flight response only when absolutely necessary. The proactive coping style is commonly associated with higher sympathetic tone, whereas the avoidant or reactive coping style has been associated with higher reactivity of the HPA axis. However, these endocrine changes may also depend on the outcome of the coping behaviour. Different coping styles are adaptive for different types of environment. Proactive responses will work better in stable environments where actions and their consequences are highly predictable, whereas the more cautious and avoidant approach seems more appropriate for new or rapidly changing environments(Koolhaas, 2008). Coping styles seem to remain stable over relatively long periods, though, ranging from months in rodents to years in domestic animals, and may be fixed personality characteristics in humans from a relatively early time in development.
The stress response seems to have evolved for the important function of protecting an organism and restoring homoeostasis in the short term. However, chronic overactivity, or lack of feedback suppression, of the stress pathways can lead to physiological and psychological changes that result in obesity and type 2 diabetes mellitus, hypertension and cardiac ischaemina, autoimmune disorders and allergies, anxiety and depression, insomnia and fatigue, and possibly even to addiction (through the overstimulation of the reward system)(Chrousos, 2009). Many of the disorders on the list of the top ten of common diseases in Western societies thus have a potential link with stress, although the important contribution from unhealthy nutrition and lifestyle and genetic vulnerability factors must not be neglected.
3.5 The neuroendocrine and immune systems interact
Mutual links between psychological wellbeing and immune function have long been postulated. The first observations of the influence of emotions on the immune system and on the conditioning of immune responses go back to the early decades of the 20th century, but systematic research only took off in its last quarter. Because of its considerable potential clinical relevance, the interface between psychoendocrinology and immunology has since received a great deal of attention. There is even a dedicated journal with the title "Brain, Behaviour and Immunity", which was started in 1987.
Several lines of evidence suggest influences of psychological processes on the immune system. Similar to other physiological processes such as the famous salivation of Pavlov's dog (see Chapter 1), immune responses can be conditioned(Ader and Cohen, 1993). For example, the immunomodulatory effect of cyclophosphamide, an immunosuppressant, could be elicited by a sugar-flavoured drink in a classical conditioning paradigm. Modulation of immune responses through sensory imagery or specific hypnotic suggestions has also been claimed(Zachariae, 2009). Emotions may influence inflammatory responses as well.
However, the best established link is probably that between stress and the immune system. The white blood cells or leukocytes, which are crucial to the cellular immune response, are upregulated after acute glucocorticoid administration. Glucocorticoids and catecholamines also suppress the release of several cytokines (messenger molecules between the different types of immune cells) that are proinflammatory (promote immune responses), tumor necrosis factor (TNF), and Interleukin (Il)1, Il6, Il8 and Il12. The relationship between hormones and cytokines is bidirectional. One example of the effects of hormones on cytokines is that increased growth hormone release from lymphocytes can lead to higher production of interferon-gamma-alpha. One influence in the other direction is the effect of IL6 and TNF-alpha, which are both produced in the human adrenal gland, on the local regulation of glucocorticoid secretion. Furthermore, cytokines can suppress the expression of the GR.
The effect of chronic stress on the immune system is harder to evaluate than that of acute stress, in particular in humans, where a considerable number of confounding effects such as lifestyle, nutrition and general health play a role. Coping styles may lead to different patterns of immune response. Proactive coping style has been shown to facilitate the experimental induction of the autoimmune disease EAE (experimental
allergic encephalomyelitis) in experimental animals, perhaps because of its association with higher noradrenalin and proinflammatory cytokine levels. However, mice with proactive coping style also showed slower growth of experimentally induced tumours, which could be a beneficial effect of the enhanced immune response. Reliable data in humans on the clinical association between personality factors and emotional reactivity and tumours or autoimmune disorders are difficult to obtain for the reasons mentioned above. Although there are thus clear biological links between the homoeostatic systems of the brain and the immune system and psycho-immunological interaction therefore entirely possible, the clinical relevance of such mutual influences is still awaiting confirmation.
3.6 Sex hormones have an impact on mental health
Many mental disorders have uneven gender distributions. Depression, for example, is about twice as common in women, whereas the pattern is reverse for mania or alcohol addiction, and autism is even four times more common in boys than girls. Although psychosocial factors may explain some of these differences, genetic (e.g., relation to y-chromosome) and hormonal factors have been implicated as well. In females, at least three distinct syndromes point to a link with sex hormones and their fluctuations. These are postpartum depression (PPD), premenstrual syndrome (PMS) or premenstrual depressive disorder (PMDD) and menopausal depression.
About 10% of women suffer from a depressive episode after childbirth, which can have all the features of melancholic depression, including somatic symptoms like sleep disturbance or loss of appetite, inability to enjoy anything and feelings of guilt (see chapter 11). Although again psychosocial factors may play a role, most researchers implicate the sudden drop in the concentrations of oestrogens and progesterone after the birth of the child. However, it is not entirely clear how such oestrogen or progesterone "withdrawal" could bring about psychological changes. Perhaps downregulation of the gonadal steroid receptors during pregnancy plays a role. PPD is normally treated with psychotherapy and/or classical antidepressants, although some studies with hormone replacement, which is still in the experimental phase, are under way. Depression can also occur during pregnancy, again in about 10% of cases, which shows that high concentrations of gonadal steroids are not automatically a protection against depression. The biological mechanisms behind this antenatal depression are unknown and may involve the overactivity of the HPA axis during pregnancy(Kammerer et al., 2006). However, we must not forget the life changing effect particularly of the first pregnancy, which can induce considerable anxiety and ensuing depression in its own right.
Oestrogen withdrawal has also been adduced to explain menopausal depression. Women in the late menopause, when the organism has to adjust to the declining levels of gonadal steroids, show a peak in the incidence of depression. Although this association between the transition to menopause and depression (as well as anxiety) has been well documented(Harsh et al., 2009), it is not clear whether this is confined to a single episode, or whether the hormonal change triggers a new, recurrent depressive illness. Hormone replacement improves not only the physical symptoms of menopause, for example the hot flushes, but also the depression and anxiety. This "antidepressant" effect of oestradiol might be mediated through monoamine systems, but the reported effects on serotonin transporters and receptors are inconsistent. Oestradiol may also act directly on brain cells through the Î±- or Î²-oestrogen receptors, which are expressed in the limbic system, amongst other brain regions. Finally, oestradiol may enhance concentrations of brain-derived neurotrophic factor (BDNF) and contribute to dendrite formation in the hippocampus. BDNF is a crucial activator of neural growth and survival and its deficient function has been implicated in both affective and psychotic disorders. Through its effects on BDNF, oestradiol may counteract the effects of chronic overstimulation of the HPA axis, which has been implicated in hippocampal damage. However, we must not forget that the "female" gonadal hormones are not the only ones to decrease in menopause. Their precursor 5-Dehydroepiandrosterone (5-DHEA), which is also the prohormone for testosterone and acts directly on androgen receptors, is also reduced by about 50%, and thus reduced androgen activity may play a role in female mental disorders as well.
Symptoms of dysphoria, anxiety, tension, lability, irritability, apathy, changes in appetite and sleep, which can amount to a full-blown depressive syndrome, make up PMS or PMDD. "Premenstrual" is not a particularly precise temporal term and can essentially denote the whole second half of the menstrual cycle. The precise hormonal correlates are therefore impossible to ascertain, particularly has hormone levels do not differ between women with and without PMS. The rising or falling phases of progesterone and oestrogens as well as alterations in the progesterone metabolite allopregnanolone have all been implicated. An hormonal origin is further suggested by the frequent observation that PMS becomes worse or even arises first after the birth of the first child. Because allopregnanolone interacts with the GABA-A receptor, which may have reduced sensitivity in PMS, benzodiazepines, which are GABA-A agonists, have been tried with some success. PMS is also helped by selective serotonin reuptake inhibitors (SSRI) and worsened by tryptophan depletion(Cunningham et al., 2009), which again points to a role for the serotonin system in the interaction between sex hormones and mental health.
3.7 Learning points
Horomes, like NTs, convey signals between neurons, but their action is not confined to the nervous system. Some neuropeptides with effects both inside and outside the nervous system can be conceptualised both as NTs and as hormones. Most classical hormonal pathways start in the hypothalamus, where their release or inhibition factors are secreted to the pituitary. This hypothalamic control of pituitary hormone release provides and important link between the nervous and endocrine systems. The pituitary hormones and the hormones they stimulate in effector organs regulate important functions of the life cycle, such as growth (growth hormone, TSH/thyroid hormones), stress responses (ACTH/ cortisol), sexual functions (LH/FSH and gonadal steroids) and metabolism (ACTH/ cortisol, TSH/thyroid hormones), to name only a few. Hormonal function and dysfunction is the topic of a separate medical subspecialty, endocrinology, but its impact on mental health is considerable and neuroendocrinology thus of great importance to psychiatrists and clinical psychologists as well. The hypothalamic-pituitary-adrenal axis in particular, which regulates cortisol release, has been implicated in stress-related disorders including PTSD and depression, and the affective disorders associated with the menstrual cycle and pregnancy point to a role of gonadal steroids as well. Finally, interactions between the hormonal and immune systems are important in determining the multifaceted relations between mental and physical health.
3.8 Revision and discussion questions
What are the main neuroendocrine systems that start in the hypothalamus?
Discuss the relationship between hormones and mental health
What distinguishes adaptive from maladaptive stress responses?
3.9 Further reading: (Brown, 1994)
Table 3.1: The release factors and hormones of the hypothalamic-pituitary systems
Hypothalamic release factor
Pituitary hormone (upregulated unless stated otherwise)
Target organ and function of pituitary hormone
Corticotrophin Releasing Factor (CRF), Vasopressin (AVP)
Adrenocorticotrophic hormone (ACTH)
Adrenal cortex (zona fasciculata): Cortisol production
TSH Releasing Hormone (TRH)
Thyroid-stimulating hormone (TSH); Prolactin
Thyroid gland: Production of the thyroid hormones T3 and T4
Luteinising Hormone Releasing Hormone (LHRH)
Luteinising Hormone (LH)
Follicle-stimulating hormone (FSH)
LH: Leydig cells of testicles: Production of testosterone;
FSH: Sertoli cells of testicles: Spermatogenesis
LH/FSH: Ovary - regulation of menstrual cycle
Growth Hormone Releasing Hormone (GRH)
Growth hormone/ Somatotropin (STH)
Liver - Production of insulin like growth factors (IGF); Cartilage - Stimulates division of chondrocytes
STH and TSH (downregulation)
Mammary glands - Lactation; Brain - reduction of dopamine release from hypothalamus (short feedback loop), otherwise unknown
Table 3.2: Steroid hormones
Main production organ
Glucocorticoid receptor (intracellular): forms complex with Glucocorticoids
Gluconeogenesis, anti-inflammatory, immune suppression
Cortisol (human), Corticosterone (rodents)
Mineralocorticoid receptor (MR) (intracellular): forms complex with Gluco- or Mineralocorticoids
Sodium retention, potassium secretion
Testicles (Leydig cells)
Androgen receptor (intracellular)
Male secondary sex characteristics; Anabolic
Oestrogen receptor (intracellular); GPR30 (G Protein-coupled Receptor 30)
Female secondary sex characteristics; Regulation of menstrual cycle
Oestrone [E1], Oestradiol [oestradiol-17 beta, E2], Oestriol [E3])
Progesterone receptor (intracellular); MR (high affinity blockade)
Regulation of pregnancy
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BROWN, R. E. 1994. An introduction to neuroendocrinology, Cambridge University Press.
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Fig. 3.1: The HPA axis mediates physiological responses to changes in the environment.
Fig. 3.2: The inverted U-shape model of the stress response.