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Neuroendocrine Responses and the Social Gradient in Health

The development of disease can usefully be viewed in terms of information and energy transfer. This final section of the course considers how a person may receive, then perceive information about his or her psychosocial environment, and then translate this into a set of bodily responses that can be healthy or unhealthy. The first stages of information transmission involve the psychological and neural sciences of perception, consciousness, emotion and arousal. (Sensory information is received and processed both consciously and sub-unconsciously: we need not be aware of something for it to affect us). Conveying this information to elicit broader bodily responses involves three overlapping systems of cellular communication: the endocrine, the nervous and the immune systems.

The endocrine system may be distinguished by the diffuse nature of its signals, which spread throughout the body rather than going point to point, and by its capacity to regulate both gene expression and cellular metabolism. These give the system a key role in both regulating development and in the subsequent unfolding of an organism's life history. "Many of the key differences between closely related species – humans and chimpanzees, for instance – appear to the be consequences of differences in gene expression ... rather than in genetic complement per se" (see Ellison PT. Social relationships and reproductive ecology. Chapter 3 in: Ellison PT and Gray PB (eds). Endocrinology of social relationships. Cambridge Mass, Harvard U Press, 2009).

The signals of the endocrine system can be classified in several ways – by the type of hormone used, by the properties of the signalling molecules themselves, or by the pathways they follow. The types of hormones include steroid and peptide hormones (see below), while the pathways include the central nervous system (CNS) and the rest of the body (sometimes "soma"). This leads to a useful description by Ellison of four pathways:

Diagram showing circular flow of information from CNS through the endocrine system

The perspective represented in pathway (1) shows the brain as the controller. Typical routes from the CNS to the periphery is the HPA, which was discussed in the and this . The reverse information (2) flow runs via steroids and some peptide hormones, from blood to brain. Here the peripheral organs modulate the hypothalamic releasing hormones. Communication (3) among internal organs runs via circulating protein and peptide hormones. The information flow (4) within the CNS is via neurotransmitters, but these can also enter peripheral circulation from the adrenal medulla, where they function as hormones.


What are the major complexes involved in the stress response?

  1. The core structure is the limbic system. The amygdala receives sensory information, projects this to cerebral cortex (creating conscious perception of emotion), or can send it directly to the hypothalamus (therefore bypassing conscious perception). The hypothalamus is the central transducer of neural signals into endocrine signals. It releases hormones either to the pituitary or directly into the circulatory system. The pituitary plays a key role because pituitary hormones target a number of other glands. , and thence to the brain stem. This is governs arousal and basic functions of life, and is also where the locus coeruleus is located, which is part of the SAM axis. Note that the amygdala is also where a learned association between a stimulus and its rewarding properties is “stored.”   Link to more detail on the Limbic System.
    These neural signals are then transmitted throughout the body via two main endocrine channels:
  2. Hypothalamus-Pituitary Adrenal Axis (HPA)
  3. Sympathetico-Adrenal Medulla Axis (SAM).

Both of these systems send messages throughout the body via hormones circulating in the bloodstream. However, we no longer view the nervous and endocrine systems as separate; they are closely integrated (hence, 'neuroendocrine') and both respond to environmental stimuli and also monitor changes in the body's internal state. Hormones only carry information: they do not themselves cause changes in cells or organs. They do not act as enzymes or poisons: they simply carry information about the state of the organism. The receiving organ interprets this information and 'decides' how to react to it.

This diagram summarizes the main components, showing the hormones secreted on the right of the diagram. (Diagram taken from Wallen K, Hassett J. Neuroendocrine mechanisms underlying social relationships. Chapter 2 in: Ellison PT and Gray PB (eds.) Endocrinology of social relationships. Harvard University Press, Cambridge Mass, 2009.)

Diagram showing location of endocrine system organs in the body

Two broad groups of hormones are relevant: steroid and peptide hormones. These use similar mechanisms of hormone-specific receptors; they work both independently and in concert.

Steroid hormones are small molecules (18 to 21 carbons) arranged in rings. They are all derived from cholesterol, in the gonads or in the adrenal cortex. Enzymes convert cholesterol into a 21-carbon molecule, pregnenalone, and thence into different sub-families of steroids. (Enzymes are organic catalysts that accelerate a reaction, but are not themselves altered, and can be used again).

The differing chemical structure of the steroids determine where they bind and what effect they have. There are four families: progestins, estrogens and androgens (the three classic groups of sex steroids) and corticoids, which we met in the stress session. The corticoid family includes the gloucocorticoids and mineralocorticoids; they are produced by the enzyme 21-hydroxylase in the adrenal cortex.


Diagram of molecular structure of cortisol

Steroid levels are kept with a range by positive and negative feed-back loops, as shown by the arrows in the first diagram above. To increase levels, the hypothalamus secretes releasing hormones that act on the anterior pituitary which, in turn, secretes hormones that act on a particular endocrine gland. That gland responds by secreting the hormone that is required. For example, the hypothalamic-pituitary-gonadal (HPG) axis releases sex steroid hormones from gonads, while the HPA regulates the production of corticoid hormones from the adrenals. A negative feed-back then operates to turn off the secretion by way of yet another hormone from the target organ that feeds back via the circulatory system to suppress production of the trophic hormone from the anterior pituitary. Hence modulation of steroid secretion occurs at the level of the brain, or the anterior pituitary, or the gonads. This makes the whole system very sensitive to a range of stimuli, local or central.

Steroid hormones pass readily through cell walls, so can move around independently of the circulatory system. This is also convenient because we can measure their levels through saliva, urine or sweat. Because steroid hormones come to the body surface, they form the basis for pheromone communication between animals.

Peptide hormones (most importantly, oxytocin and vasopressin) are composed of strings of amino acids and are secreted from hypothalamic cells that end in the pituitary. They do not cross the blood-brain barrier. Oxytocin (OT) is most familiarly involved in parturition and suckling of the infant, but also plays a broader role in the formation of social bonds. Vasopressin (AVP) is mainly involved in blood pressure control and in other cardiovascular and kidney functions; but it, also has broader functions such as a role in attention, learning and memory (see the chapter by Wallen & Hassett).

Much of our understanding comes from animal research and it is not currently clear how well this applies to humans. However, one small study of humans is suggestive. It recorded OT and AVP levels in children who had experienced early neglect (having been raised in orphanages), comparing them to children form intact families. Early neglect was linked to reduced AVP levels, and contact with a mother raised OT levels to a lesser extent in the deprived children (Fries ABW et al. Proc Nat Acad Sci USA 2005; 102: 17237-40).

Variable yet Patterned Responses
For the purpose of understanding how social circumstances may generate physiological responses and thereby ultimately affect health, we distinguish two ways in which hormones act: organizational and activational. Organizational effects act early in life, during periods of developmental sensitivity, and more or less permanently alter the individual's potential to show a particular pattern of reactions. This is covered in more detail on the page on epigenetics. Activation responses are short-term and reversible, and include the familiar stress responses described by Selye. (Wallen K, Hassett J. Neuroendocrine mechanisms underlying social relationships. Chapter 2 in: Ellison PT and Gray PB (eds.) Endocrinology of social relationships. Harvard University Press, Cambridge Mass, 2009.) Our responses, both behavioural and somatic, are variable and yet patterned. Because the brain learns, context and prior experience offer important filters. This may work both ways: different exposures can produce the same response and, conversely, the same exposure can produce different responses at different times.

What is the evidence that social structure has an effect on physiological responses?

Primate studies

                    i.      Sapolsky, Alberts, & Altman (1997). Basal cortisol (stress hormone) levels were not associated with dominant status, but baboons of higher rank had greater cortisol suppression, suggests more effective glucocorticoid negative feedback

                    ii.      Shively, Laird, & Anton (1997). Subordinate monkeys have higher basal cortisol levels than dominant monkeys, post-manipulation dominants having greater suppression than post-manipulation subordinates, no differences between the change and no change groups, current social status and not change in social status is the salient component

Human adult studies

                      i.      LiVICORDIA  (Kristenson et al., 1998) Lithuanian men have higher resting (basal) cortisol levels then do Swedish men, the Lithuanian men also have a blunted cortisol response to experimental stressors (assumes greater stress exposure in Lithuanian men)

                      ii.      Daniels, et al. (1999), indigenous populations have higher glycosylated hemoglobin as compared to non-indigenous populations after taking into account diabetes and glucose intolerance (assumes social stress in indigenous populations)

                     iii.      Steptoe & Marmot present a review showing that in the few studies completed, cardiovascular reactivity is generally greater in lower SES individuals (confounding by stressor characteristics?)

Child studies

                     i.      Lupien, et al. (2000), lower SES children have higher salivary cortisol levels than higher SES children, as early as age 6, children’s cortisol also associated with mother’s depressive symptomatology.


How does chronic HPA activation lead to disease?

    1. may increase other risk factors (abdominal obesity, immune functioning, insulin resistance)
    2. may disrupt normal homeostatic processes resulting in abnormal physiological functioning