Endocrine System
Multiple mechanisms exist to control the magnitude of inflammation. As we have seen, the magnitude of inflammation has a direct bearing on nociception. The hypothalamic-pituitary-adrenal axis (HPA), the sympatho-adrenal axes, nociceptive neurons, and the sympatho-neural system are all contributing factors. The autonomic nervous system regulates physiological systems by integrating afferent inputs from internal and external environments with the neuronal system, endocrine system, and cell modulated responses.
The HPA is involved in nociception and serves as an intermediary between the neuro and endocrine and immune systems. These systems normally communicate to maintain physiologic homeostasis. There has been a relative history of skepticism surrounding the relevance of this system to the pain experience; but the current literature suggests a mechanistic pathway of communication.5 Various immune cells, including lymphocytes and monocytes, have receptors for corticosteroids, insulin, prolactin, growth hormone, somatostatins, estrogens, testosterone, leptin, ghrelin, opioids, corticosteroids, neuropeptide Y, and vasoactive intestinal polypeptide. Neuronal cells and endocrine organs express receptors for immune-derived cytokines and growth factors. There is a true bi-directional communication between these systems.
Pain has profound effects on the HPA system. Pain activates the hypothalamus to release corticotropin-releasing hormone (CRH), gonadal-releasing hormone (GRH), and thyroid-releasing hormone (TRH). These activate the pituitary and then end organs to release hormones that ultimately play a role in pain control—cortisol, pregnenolone, DHEA, testosterone, progesterone, estrogen, triiodothyronine (T,), and thyroxine (T4).61 If pain levels become severe enough, these levels may be seen to elevate.62 63 Over time, with sustained severe pain, the HPA may not be able to provide sufficient hormone levels, and serum levels may drop.63-65 Hypercortisolemia may result in calcium resorption (osteoporosis, joint degeneration, tooth decay, nephrolithiasis, vertebral compression fractures), hypertension, hyperlipidemia, obesity, and mental deterioration.61 Hypocortisolism produces weight loss, muscle wasting, mental apathy, hypotension, brown pigmentation on the skin, or even sudden death.61
The hypothalamic-pituitary-gonadal axis (HPG) plays a role in nociception. These initial observations occurred by noting variations in several painful conditions in relation to the menstrual cycle. Temporomandibular joint dysfunction, fibromyalgia syndrome, irritable bowel syndrome (IBS), interstitial cystitis (IC), and migraine can show cyclical variations.66 These findings suggest that rapidly falling estrogen plays a role in pain. Stabilizing hormone levels (with oral contraceptives) or abolishing hormone levels with GnRH antagonists or menopause can improve IBS and IC but worsen migraine (unless an additional low-dose estrogen is given).67 Pregnancy analgesia can also improve pain conditions such as migraine and pelvic pain.68 Androgens also play a role in pain. Rheumatoid arthritis patients have lower androgen levels than sex-based controls and improve with exogenous androgen administration.69 Interestingly in a 2007 study on transgender patients, one out of three of male to female transitions developed chronic pain, and those who did not develop chronic pain appeared to develop increased sensitivity to pain. On the other hand, one out of every two female to male transition patients who had chronic pain before transition appeared to improve with the administration of androgens.70 Testosterone and progesterone function as analgesics in the brain. Testosterone modulates endogenous opioids in the brain and modulates dorsal horn response to neuropathic pain. Progesterone mediates spinal cord hypersensitivity after nerve root damage. Estrogen increases p-opioid receptor availability in the brain and modulates dorsal horn response to pain. Estrogen alters T- and В-cell proliferation and phenotype as well as changing the cytokine and immunoglobulin balance. Progesterone has an anti-inflammatory impact on the immune system. Testosterone decreases cellular immune response.67
Pituitary hormones impact nociception. Growth hormone (GH) production and the resulting insulin-like growth factor-1 (IGF-1) production mediate immune cell proliferation or the survival of immune cells such as T-lymphocytes and inhibit the dexamethasone-induced inhibition of T-cell proliferation.71 Prolactin sustains antibody response and cell-mediated immunity.72 The immune system also influences the endocrine system. Inflammatory cytokines have also been shown to result in hormone resistance—such as insulin, glucocorticoids, GH, and IGF-1.5
Stress has a large impact on the nociceptive system. Stress activates the HPA and the sympathetic nervous system. On one hand, the HPA can create stress-induced analgesia. Hormonal or neural signals of injury can lead to the activation of the hypothalamic periventricular nucleus which induces the release of pro-opiomelanocortin (POMC). POMC is cleaved into various peptides including beta-endorphin which binds to p-opioid receptors to dampen neuronal excitability by inhibiting voltage-gated Ca2+ channels and/or opening K+ channels in the periphery, DRG, PAG, and RVM.4 On the other hand, chronic stress or fear can activate the HPA and sympathetic nervous system, creating multiple downstream effects. The activation of the HPA axis results in an increased production of glucocorticoids.
