May 1, 2018

Beyond Brain Damage

Endocrine effects of traumatic brain injury
A fascinating review article describes in detail the many downstream effects of endocrine damage caused by traumatic brain injury, effects that manifest themselves in symptoms that may not be recognized as a consequence of brain trauma.


This paper is part of NMJ's 2018 Cognition and Mental Health Special Issue. Download the full issue here.


Traumatic brain injury (TBI) incidence and survivorship is on the rise, leading to an increase in people suffering from post-TBI complications and post-concussion syndrome. Regardless of severity, the injury event can also damage endocrine tissue in the brain, causing downstream endocrine dysregulation in nearly half of all TBI cases. Recognition and management of the endocrine sequelae provides a possible pathway to alleviate post-TBI symptoms.


According to the Centers for Disease Control and Prevention (CDC), traumatic brain injury (TBI) is a major cause of death and disability, contributing to about 30% of all injury deaths in the United States. Due to improved acute management and emergency care, survivorship of TBI events has increased, resulting in more people suffering post-TBI complications. Those who survive a TBI can have effects that last anywhere from a few days to the rest of their lifetimes. The realm of natural medicine has many tools to offer, but even natural medicine may be approaching TBI too narrowly. For instance, could previous TBI be contributing to seemingly unrelated health issues?

The missing link may be the endocrine system of the brain, the body’s central hormone control center. Among TBI survivors, 30% to 50% have one or more endocrinopathies.1,2 Studies suggest 35% to 40% of TBI survivors have some degree of hypopituitarism, which is associated with serious morbidity and an estimated 20% reduction in life expectancy.3,4 Injury to the endocrine systems of the brain can occur both during, and as a result of, the TBI. A TBI of any severity compromises the integrity of the blood-brain barrier and induces localized neuroinflammation. Endocrine areas potentially involved include the thalamus, hypothalamus, pituitary gland, and pineal gland.

Many post-TBI endocrinopathies have a delayed onset of up to 6 to 12 months following the TBI, so they often aren't intuitively tied back to the brain injury.

Endocrine system injury comprises at least 2 known mechanisms: direct mechanical injury and chemical injury from chronic neuroinflammation. In mechanical injury, the forces affecting the brain tissue may also affect the endocrine glands as follows. Nestled in the bony structures at the base of the skull in the sella turcica, or saddle, the hypothalamus and pituitary may sustain a blunt trauma by being pulled by the neighboring brain tissue and thrust into the bony prominences which normally hold the gland safely in place. A similar blunt trauma may occur to the other endocrine areas of the brain, causing a cascade of inflammation that affects neighboring tissue. That neuroinflammation can cause downstream neurotransmitter and hormone dysregulation, as well as persistent ketosis of the brain tissues.5 The resulting post-TBI endocrinopathies not only create a confusing clinical picture, but significantly delay treatment progress and negatively impact overall outcomes.

There is little correlation between the severity of the TBI and the degree of endocrine impairment. A mild TBI may induce significant endocrinopathies, while a patient with moderate-to-severe TBI requiring hospitalization may walk away from the event with little or no endocrine complications. Chronic traumatic encephalopathy (CTE) is not even linked to concussion or TBI, but to repetitive subconcussive contacts to the head. Even so, endocrinopathies could be contributing to the progressive degeneration of the brain in this condition.6 It is important for the clinician to remember that no 2 brain injuries are alike. As aptly stated on the Brain Injury Association of North Carolina website, “if you’ve seen one brain injury, you’ve seen one brain injury.”7

The determinants of post-TBI endocrinopathies are still being identified, but similar to metrics for general TBI outcomes, the total number of TBIs and “recency” are sure to be important for the endocrine glands of the brain as well. For instance, repetitive head injury syndrome (RHIS) describes the phenomenon of significant delays in treatment progress with each subsequent TBI. In addition, a well-known phenomenon called second impact syndrome (SIS) occurs when a person sustains a repeat TBI before adequate healing of the first. It’s hard to fathom, but once a person sustains a brain injury, their risk of future TBIs increases exponentially. There’s a 3 times greater risk of getting a second TBI after the initial TBI, and 7 to 9 times greater risk of a third TBI after a second.8 The cause for this is yet to be uncovered.

One potential determinant that plays a role in overall outcome is thyroid function. Low thyroid function at the time of injury is shown to contribute to poorer outcomes following a TBI.9 Therefore, immediate thyroid assessment and treatment is warranted. In addition, neuroinflammatory specialists theorize that brain tissue docosahexaenoic acid (DHA)10 and glutathione levels may be related due to their use in TBI treatment, though their roles as determinants of outcome have yet to be studied.

To date, the generally accepted later stage symptoms of TBI, such as fatigue, headache, chronic muscle pain, and sleep issues are symptomatically managed conventionally with medications. Treatments such as cognitive behavioral therapy are offered for other common later stage symptoms, such as balance issues, difficulty activating and allocating working memory, and personality changes. Furthermore, we find additional statistics such as greater incidence of chronic infections,11 greater incidence of all-cause morbidity, and earlier onset of dementia.12 To what extent could this suffering be due to unrecognized endocrinopathies?

Table 1. Endocrine Systems of the Brain and Their Functions

Endocrine GlandHormone/PeptidePrimary Target TissuesAction

Cerebral cortex

Cranial nerve sensory feedback

(except olfactory)Hippocampus


Information hub

Process and relay sensory information


Regulation of sleep/alertness

Relay sensory and motor signals

Pain perception

HypothalamusReleasing hormones: GHRH, TRH, CRH, GnRH, HCRT, MC4

Hypothalamus (self)

Anterior pituitary


Central endocrine regulation

Autoimmune hypophysitis antibody

 Orexin (hypocretin)


Midbrain/descending pain tract

Feedback to pituitary




Chronic inflammatory pain modulcation

Appetite/feeding behavior

Thermogenic brown fat activation

Energy homeostasis

Addiction/reward processes

Anterior pituitaryGHMost tissues

Growth and thermoregulation

Tiessue repair

Bone density

Muscle mass and strangeth

Central adiposity and insulin sensitivity

Appropriate cardiovascular repair

Central and peripheral neuronal repair

 TSHThyroidMetabolic regulation

Liver: glucose regulation


Immune regulation



Immune cells (T-cells)

Skin pigmentation







Secondary sex characteristics


Bone and soft tissue maintenance

Cardiovascular protection


Mammary glands


Immune system

Oligodendrocyte precursors

Kidneys and adrenals






CNS myelination

Hematopoiesis and angiogenesis role

 Beta-endorphinOpioid receptorsRegulate central pain sensitivity
Posterior pituitaryADHKidneys

Water resorption




Mammary glands

Labor induction



Vaginal tissue integrity



Anterior pituitary


Pigment cells

Sex organs

Circadian rhythm

Sleep cycle

Skin Pigmentation

Seasonal reproductive behaviors


Primary respiratory mechanism

Body proprioceptors

Basal respiratory rhythm

Basal CSF pulse

ECM ebb and flow

Abbreviations: GHRH, growth hormone–releasing hormone; TRH, thyrotropin-releasing hormone; CRH, corticotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; HCRT, hypocretin; MC4, melanocortin 4; GH, growth hormone; TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropic hormone; α-MSH, alpha-melanocyte–stimulating hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; ADH, antidiuretic hormone; ANS, autonomic nervous system; CNS, central nervous system; CSF, cerebrospinal fluid; ECM, extracellular matrix.

© Dr. Jill Crista

Post-TBI endocrinopathies are well-understood in the literature, but have yet to be translated into clinical trials, leaving clinicians without guidelines for testing and treatment. In clinical practice, the difficulty recognizing them can be due to many factors. Lack of awareness is chief among them, but so are their delayed onset and difficulty with laboratory assessment. Many post-TBI endocrinopathies have a delayed onset of up to 6 to 12 months following the TBI, so they often aren't intuitively tied back to the brain injury. Therefore, evaluations for post-TBI endocrinopathies are recommended for symptomatic patients with TBI of any severity,13 done at regular intervals for up to 2 years. Regarding laboratory values, practitioners must understand that dysregulation may not present as frank deficiency or excess. The hormone may not be able to respond when demanded or sufficiently communicate with its targets, making it dysfunctional. Laboratory clarification of the picture can be aided with more expanded panels and the use of 24-hour urine assessments.

The term dysregulation regarding post-TBI endocrinopathies is used purposefully. Befitting the complicated interconnectedness of the endocrine system, each hormone follows its own reactionary path after TBI, and can be dictated by reactions to injury from related endocrine systems. With no association to location or severity of the TBI, a particular hormone may increase, decrease, increase then decrease, or display any number of wave patterns and with no concrete timeline. One notable finding is that the more delayed the onset of the endocrinopathy, the poorer the prognosis for spontaneous recovery of the source gland. Without supportive treatment there is little hope of full restoration of the affected endocrine gland. As it relates to clinical practice, a review of downstream endocrinopathies will be examined, beginning with the hypothalamus.


The hypothalamus essentially has 3 key roles. It secretes releasing hormones targeting the pituitary gland, produces the wakefulness hormone orexin (also named hypocretin), and plays a role in central pain/analgesia. In TBI, both the physical trauma and neuroinflammation damage the hypothalamus, and in some cases may spark an autoimmune reaction against the gland, called hypophysitis.14 TBI can disrupt both the formation of, and the responsiveness to, hypothalamic releasing hormones, creating symptoms categorized as hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Persistent inflammation, or astrocytosis, of the cortico-hypothalamic-pituitary axis causes persistence of TBI symptoms and delayed healing progress.


Regarding the direct hypothalamic hormone orexin, TBI reduces production of this wakefulness hormone and is correlated with up to 30% of new onset narcoleptic symptoms.15 Narcolepsy, commonly thought of as a sleep disorder, is actually a wakefulness disorder. Lack of discernment between day and night presents clinically similar to insomnia. Therefore, a daytime sleep study is warranted in any case of insomnia, hypersomnia, or nonrestful sleep following a TBI.

Orexin also preserves thermogenic brown fat stores and regulates feeding and reward-seeking. Weight gain, body mass composition changes, and sarcopenic fat can be seen in the post-TBI patient who has sustained hypothalamic injury. In the case of comorbid pituitary endocrinopathies, low growth hormone may compound the reduction of the thermogenic brown fat by increasing leptin, which inhibits orexin formation at the cellular level.

The hypothalamus’s role in central pain management cannot be overstated, especially in the era of an opioid crisis. Utilizing orexin, the hypothalamus modulates chronic inflammatory pain globally from the lateral hypothalamus.16 Pondering those suffering with post-TBI chronic pain, might they be managed better with natural medicine interventions than by sedating and addicting medications? Intermittent fasting, preventing glucose surges, and essential amino acid supplementation appear to be possible interventions to stimulate orexin neurons, though human trials are needed.17


Injury to the pituitary, resulting in hypopituitarism, is the most prevalent endocrinopathy following a TBI, with both the anterior and posterior gland affected.18 Studies show that all pituitary hormones are affected, but are commonly missed clinically. The individual reactions of all downstream pituitary hormones must be understood to better manage the TBI patient.

Growth Hormone

Growth hormone (GH) deficiency is the most common pituitary endocrinopathy after TBI, and in some cases it may be the only endocrinopathy that develops.19 Despite the statistics, adult TBI patients may not be assessed for GH deficiency due to the common misperception that GH is no longer important past puberty. Growth hormone deficiency in the pediatric TBI patient does indeed stunt growth and development, but also causes the same risks as adult GH deficiency. The symptoms of adult GH deficiency are vast but can be summarized as lack of tissue integrity, growth, and repair; persistent inflammation in the brain; and insulin resistance.20

Tissue integrity symptoms from lack of GH include soft-tissue complaints, endothelial cardiovascular risks, prolapses, and decreased muscle mass and bone density. Growth hormone’s action on insulin accounts for weight gain, cognitive changes, energy depletion, insulin resistance, and central adiposity.21 Growth hormone deficiency also alters lipoprotein metabolism and elevates fibrinogen.22 On laboratory evaluation, it is common for GH deficiency to present with increased fibrinogen and an increased low-density lipoprotein (LDL) that is resistant to treatment. Evaluation of insulin-like growth factor (IGF)-1 may be used as a reflection of GH deficiency unless the patient has concomitant liver disease, as this hormone is formed in the liver.23 In a rat study, injected flavonoids from ginkgo were capable of stimulating growth hormone release from the anterior pituitary.24 Translational study is needed to establish an effective oral dose.

Thyroid-Stimulating Hormone

Secondary hypothyroidism can present after TBI with a reduction in pituitary production of thyroid-stimulating hormone (TSH). The resulting secondary hypothyroidism can complicate clinical management of the post-TBI hypothyroid patient, since the standard practice is to only monitor TSH on lab assessment. This practice is not sufficient for secondary hypothyroidism. Full thyroid panels, tracking both free and total T4 (thyroxine) and T3 (triiodothyronine), are necessary to intricately control hypothyroid symptoms in a post-TBI patient.

Adrenocorticotropic Hormone

The adrenals are true to form following a TBI. In reaction to the stress and injury, adrenocorticotropic hormone (ACTH) increases temporarily in an attempt to continue to manage the cognitive and endocrine load, as well as reduce inflammation.25 This can present as an almost heroic or stoic reaction by the patient, masking other endocrinopathies for up to 1 year. A possible survival mechanism so as not to be culled from the herd, it is quite common to hear the overcompensation statement, “I’m fine!” from the TBI patient. As time passes, and this singular heroic effort on the part of the adrenals can no longer be sustained, post-TBI survivors exhibit adrenal insufficiency.

Alpha-Melanocyte–Stimulating Hormone

A more recently understood pituitary hormone, alpha-melanocyte–stimulating hormone (α-MSH), is a neuropeptide with immunomodulatory properties, which may also offer neuroprotection. It acts as a suppressor of proinflammatory cytokine production and induces interleukin (IL)-10 expression, which is one of the most important mediators of the anti-inflammatory effect of α-MSH.26 Alpha-melanocyte-stimulating hormone controls hypothalamic production of melatonin and endorphins. Deficiency creates chronic nonrestful sleep and chronic increased perception of pain. A single administration of α-MSH offers a promising neuroprotective property by modulating inflammation and preventing apoptosis after TBI. However, the potential therapeutic value of α-MSH is limited by its short half-life and melanotropic effects.27


Both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are reduced as the body prioritizes fight or flight over procreation.28 The resultant andropause/menopause risks need to be mitigated. There are many schools of thought regarding evaluation and treatment of gonadotropin deficiencies, but because of lipid storage of these hormones, practitioners must be aware that these deficiencies may be the last to present clinically. All other protective benefits of balanced sex hormones aside, as they relate to TBI, management is recommended for the neuroprotective benefits.


Even though hypopituitarism is associated with suppression of all downstream hormones, the issue with prolactin is excess, or hyperprolactinemia. Prolactin rises due to inhibition of transport of prolactin inhibitory factor down the pituitary stalk into the gland. Prolactin plays a role in homeostasis as a mediator of the immuno-neuroendocrine network, osmoregulation, and angiogenesis.29 Increased prolactin also counteracts dopamine and reduces gonadotropin releasing hormone (GnRH). Excess prolactin symptoms include sexual and female cycle changes, headaches, and neurological symptoms, particularly visual field defects. There are recent promising rat studies on Schisandra chinensis and its ability to modulate prolactin.30

Antidiuretic Hormone

Both increases and decreases in antidiuretic hormone (ADH) are seen post-TBI. The immediate response is an increase, causing a temporary syndrome of inappropriate secretion of antidiuretic hormone (SIADH), including symptoms of headache and increased blood pressure. This soon shifts into deficiency of ADH as the pituitary reduces production and secretion, correlated with an increased incidence of later onset diabetes insipidus in TBI patients.31,32 This results in increased thirst, increased urinary volume, and urinary frequency. Traumatic brain injury patients with unrecognized diabetes insipidus left untreated are at risk for severe dehydration, chronic electrolyte imbalances, and neuropathies.


Known best as the bonding hormone, oxytocin plays a role in determining a sense of safety, sexual function, and stress management. Much more than a female-only lactation hormone, oxytocin is a neuromodulator and modulates pain perception in both genders.33 It alters the synapses toward empathy and prosocial behavior, and is intricately woven with the HPA axis and dopamine. It’s involved in weight management by suppressing food intake. Oxytocin deficiency can lead to leptin resistance.


Pineal gland damage causes a reduction in melatonin, a potent brain antioxidant known best as the sleep hormone.34 Imagine a post-TBI survivor who sustained damage to both the hypothalamus and pineal gland—making neither the wakefulness hormone nor the sleep hormone—with no distinction between day and night. In some cases, enforcing a circadian cycle with wakefulness measures improves sleep.

Vitamin D

This vitamin could easily be renamed hormone D and is included herein as such. As it relates to TBI outcomes, vitamin D plays a key role assisting overall endocrine balance and endocrine intercommunication. In its immune modulation role, vitamin D reduces the risk of further morbidity, such as bone loss and cardiovascular disease. In an observational study of post-TBI patients, participants with optimum vitamin D levels reported an increase in overall quality of life.35 Therefore maintaining adequate vitamin D levels post-TBI is recommended.


Nearly half of all TBI patients may suffer from at least one endocrinopathy following the injury event, with hypopituitarism being chief among them. All endocrine systems of the brain may be affected, including the thalamus, the hypothalamus, and the pituitary and pineal glands. Unrecognized post-TBI endocrinopathies significantly delay treatment progress, negatively impact overall outcomes, and are associated with serious morbidity and reduced life expectancy. Endocrinopathy symptoms may not be recognized as post-TBI sequelae due to their breadth and typical delay in onset.

Because no 2 brain injuries are alike, defining the severity of the TBI does not help the clinician determine the extent of endocrine dysregulation. It is time to explore broader standard-of-care options for TBI. Other than a practitioner’s chief role of TBI risk reduction education, evaluation and management of the TBI patient should be guided by an understanding of the mechanisms of injury and the strong possibility of a resultant endocrinopathy. Even though research related to post-TBI endocrinopathies is robust, clinical trials are not. Clinicians therefore have to assess for endocrinopathies and manage this aspect of the TBI patient with little guidance. A path to clinical management has yet to be designed, and so at this point it must be forged in clinical practice, one TBI patient at a time.

Categorized Under


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