Endocrinology of Traumatic Brain Injury

TREATMENT STRATEGIES FOR TRAUMATIC BRAIN INJURIES

“He’s my cousin,” George said.  “I told his old lady I’d take care of him. He got kicked in the head by a horse when he was a kid.  He’s awright.  Just ain’t bright.  But he’ll do anything you tell him.” ¹

TRAUMATIC BRAIN INJURY (TBI) DEFINED

In simpler times, this classic line from John Steinbeck’s, Of Mice and Men, depicting a head trauma and any subsequent bizarre behaviors was thought of as a quirk of nature, nothing to see here.  With improved diagnosis and treatment modalities, the notion that “It’s God’s will” or “It is what it is,” gave way to the recognition that the over 1.7 million head injuries per year resulting in 52,000 deaths, 275,000 hospitalizations, and 1.365 million ER visits,² is a modern-day medical epidemic.

The bad news—the number of reported head injuries and emergency visits has skyrocketed since 2007, and the number of hospitalizations has remained unchanged.  Upwards of ten million Americans suffer from the consequence of undiagnosed traumatic brain injury.³  The good news—better recognition of the effects of TBI has led to a dramatic drop in deaths.

Traumatic brain injuryis an induced structural injury, with or without intracranial lesions or physiologic disruption of brain function,caused by an external force.  Additionally, there needs to be a new onset or worsening of consciousness level, amnesia of the event immediately before or after the injury, and an altered mental state at the time of the injury.  Symptoms include confusion, disorientation, slow thinking, and an altered mental state; neurologic deficits including weakness, loss of balance, change in vision, praxis, paresis/plegia, sensory deprivation, and aphasia that may or may not be transient.

Symptoms of Traumatic Brain Injuries

Traumatic brain injuries disrupt normal hormonal homeostasis, leading to peripheral hormone insufficiencies and comorbid affective disorders.  Traumatic brain injuries also alter behavior related to employment, maintaining social relationships and social roles, all of which are a primary factor leading to long-term disability.  Traumatic brain injuries lead to psychiatric issues including depression, suicide ideation, anxiety, agitation, anger, paranoia, sexual dysfunction, and drug-and-alcohol abuse, all of which are common sequelae in TBI survivors.⁴

THE HORMONE CONNECTION TO TBI

TBI vs. Hypothalamic Failure vs. Panhypopituitarism

• Symptoms of hypothalamic failure include fatigue, temperature dysregulation, weight gain, insatiable appetite, sugar cravings, sleep disturbances, pain, especially in trigger points, mood and libido disorders.
• Symptoms of panhypopituitarism are fatigue, lethargy, depression with or without panic, difficulty concentrating, memory Impairment, decreased libido, sexual dysfunction, insomnia, faulty judgment, emotional outbursts, and new onset or worsening substance abuse.
• Long-term signs and symptoms of TBI sequelae match hypopituitarism and overlap those of hypothalamic dysfunction.

The Six Primary Hormones

1. Testosterone
2. Estrogen
3. Progesterone
4. Growth Hormone
5. Thyroid Hormone
6. Cortisol

The Three Secondary Hormones

1. DHEA
2. Pregnenolone
3. Prolactin

Supplements: My Magnificent Seven

1. Omega-3s (EPA/DHA)
2. MCT Oil
3. Vitamin D3
4. Probiotics/Prebiotics
5. Glutathione
6. L Threonine
7. Branch Chain Amino Acids

THE SIX PRIMARY HORMONES

Testosterone

• Testosterone acts as an antidepressant and anti-anxiety agent, improves mental clarity, strength, energy, mood, motivation, a sense of well-being, muscle tone, sexual energy, and sexual desire. Androgen receptors, present throughout the brain, positively impact cognitive function and exhibit ongoing effects in the mature brain.⁸
• Testosterone attenuates inflammatory cytokines, increasing IL-10, an inhibitor of pro-inflammatory cytokines IFN-gamma, IL3, TNF alpha, and GM-CSF; protects against mitochondrial dysfunction; controls neuronal excitability, and improves seizure control. ⁹ Testosterone alleviates pain, particularly in the lower back and knees, and moderates anorexia nervosa.
• Testosterone deficiency results in depression, fatigue, and suicide ideation. Testosterone levels are inversely proportional to depressive symptoms.  Free testosterone levels in the lowest quartile presage the highest incidences of depression.

Estrogen

• Estrogen maintains cerebral blood flow, glucose, oxygen, lactic acid production, modulates pain, prevents apoptosis (cell death), and inhibits the progression of neurologic deterioration and neuronal loss in the central nervous system. Estrogen lowers the risk of PTSD after trauma and aids in recovering from a stroke or TBI. ¹⁰
• Elevated estrogen levels result from increases in aromatase activity, the testosterone metabolizing enzyme. Estrogen excess is a byproduct of obesity, alcohol excess, environmental estrogens, estrogen-containing foods, zinc deficiency, liver dysfunction, supraphysiologic testosterone therapy, calcium deficiency, and diabetes.  An excess of estrogen leads to headaches, insomnia, bloating, mood swings, anxiety, depression, panic attacks, fibrocystic breast disease, breast tenderness, vaginal spotting, uterine fibroids, endometriosis, ovarian cysts, and gallstones.
• Symptoms of estrogen deficiency include hot flashes, night sweats, brain fog, an increase in belly fat, generalized pain, PTSD, and depression.

Progesterone

• Progesterone dominates the second half of the female menstrual cycle. It cleans up estrogens messes, the equivalent of a behind-the-scenes political operative.  Progesterone relieves estrogen-dominant headaches; breast, uterine and ovarian cysts; moodiness, abdominal cramps, andProgesterone is calming, regulates fluid balance, increases blood sugar, and improves thyroid function and mineral balance.  It relieves menopausal symptoms and decreases the risk of endometrial cancer, fibrocystic breast disease, osteoporosis, and heart disease.

◆  Progesterone improves mood and sleep, acts as a neutral diuretic, maintains estrogen-induced arterial dilation, and reduces estrogenic stimulation of the breasts.  Progesterone, allo-progesterone, and DHEA protect neurons from oxidative stress, aidsin neuroregeneration, and myelin regeneration; reduce the inflammatory cytokines, interleukins IL-1B, and TNF alpha.  The result is anti-anxiety, antidepressant, anti-aggressive, anti-inflammatory, anti-stress, and anti-convulsant behavior.

Growth Hormone

• Growth hormone preserves memory, improves concentration and mental clarity. Untreated GH deficiency results in rapid weight gain, anxiety, depression, poor cognition, loss of memory, obsessive-compulsive activity, brain fog, dark moods, paranoia, and outlandish, destructive, and criminal behavior. ¹¹
• Growth hormone (GH) deficiency is the first and most common hormone deficiency post-traumatic brain injury. Acutely, three months post-injury, 20% of TBI victims exhibit growth hormone deficiency.   Untreated, rates increase to 35-40% of survivors one-year post incident.^12-14

Thyroid

• Thyroid hormones act as the body’s gas pedal, providing fuel for every organ in the body. It is a Goldilocks hormone; we need “not too much, nor too little.”
• The thyroid influences the neurotransmitters dopamine, serotonin, glutamine and GABA, acting as a fine-tuning mechanism in the functioning of neural networks, tempering psychotic ideation. ¹⁵The thyroid manages the patient’s energy and mental clarity.
• Ninety-eight percent of patients with thyroid issues are hypothyroid. Thyroid deficits lead to fatigue, depression, poor cognition, and psychosis.Signs and symptoms include dry skin, dry hair, nails that crack and break easily, constipation, an inability to lose weight, cold intolerance, constantall day fatigue, and thinning of the outer third of the eyebrow.

Cortisol

• Cortisol regulates electrolyte balance, blood sugar cravings, the immune response, and the effects of stress. In an ideal world, tensions arise, pass quickly, and the adrenal glands resume business as usual.  In the real world, stress A begets stress B, which generates stress C, ad infinitum.  The adrenals flood the body with cortisol,resulting in a syndrome marked by an intermittent, peculiar “burnout” type of fatigue.(Fatigue attributed to hypothyroidism is steady in nature.)
• Cortisol levels and symptom severity are due to the augmenting effects of cortisol on dopamine activity. High cortisol levels lead to elevated dopamine levels, which in turn, decrease prolactin production, resulting in treatment-resistant anxiety and depression.¹⁶
• Patients with cortisol excess crave salt and foods high in sodium, often become hypoglycemic under stress, experience increased PMS, perimenopausal, and menopausal symptoms. Depression and fatigue are common, and the ability to handle stressful situations diminishes.  The patient complains of muscle weakness, histamine-like allergic reactions, lightheadedness when rising from lying down or sitting, diminished libido and apathy.

THE THREE SECONDARY HORMONES

Dehydroepiandrosterone (DHEA)

• Dehydroepiandrosterone acts as an antidepressant and mood regulator; builds energy and confidence, and improves one’s sense of wellbeing. It decreases visceral and subcutaneous fat; reduces serum low-density lipoprotein and triglyceride levels; improves bone density, insulin resistance, insulin sensitivity, myelin sheath production, the immune system, and allergy symptoms; raises growth hormone levels in the evening; promotes wound healing; lessens fatigue, and alleviates dry eye syndromes.^17-18
• Low levels of DHEA manifest as dry hair, skin, and eyes; flabby muscles, especially in the abdomen; scant hair under the arms and pubic area; atrophic tissue in the pubic area; noise intolerance; and deficient libido.
• Symptoms of DHEA excess mimic those of excess testosterone: fatigue, anger, deepening of the voice, insomnia, mood changes, weight gain, excess facial hair, acne, sugar cravings, restless sleep, and irritability.
• Patients with cortisol excess crave salt and foods high in sodium, often become hypoglycemic under stress, experience increased PMS, perimenopausal, and menopausal symptoms. Depression and fatigue are common, and the ability to handle stressful situations diminishes.  The patient complains of muscle weakness, histamine-like allergic reactions, lightheadedness when rising from lying down or sitting, and apathy.
• High DHEA-S concentrations are protective;low DHEA-S levels, due to stress and aging, lead to cognitive decline.

 Pregnenolone

• Pregnenolone blocks the effects of cortisol and is a GABA-A receptor antagonist. It stimulates excitation and inhibition of the nervous system, increases stress resistance,and acts as an anti-inflammatory agent by decreasing sensitivity to pain following peripheral nerve injury.
• Pregnenolone sulfate regulates neurotransmission in the hippocampus, the site of memory and learning. ¹⁹ It improves both physical and mental energy, myelination, synaptic transmission; and stimulates NMDA receptors.Pregnenolone repairs nerve damage; blocks the production of acid-forming compounds; and enhances alertness, learning, and sleep.
• Pregnenolone deficiency results in a 100-fold drop in inhibiting presynaptic GABAergic synaptic mechanisms versus GABA-A receptors. Neurotransmission is reduced, manifesting as anxiety, panic attacks, agitation, aggression, insomnia, and social phobias.  Peripheral manifestations of lack of pregnenolone include arthritis, insomnia, poor focus, memory loss, fatigue, depression and an inability to handle stress.
• Pregnenolone excess results in anger, anxiety, drowsiness, muscle aches,fluid retention, headaches, palpitations, irritability, and insomnia. ²⁰

 Prolactin

• Prolactin, produced in the anterior pituitary gland, is the hormone responsible for promoting milk production, along with over 300 other functions in the human body. Prolactin stimulates breast development, inhibits gonadotropin-releasing hormone (GnRH) synthesis, inhibits ovulation in females, spermatogenesis in males, and increases dopamine secretion.
• Prolactin deficiency manifests as edginess, agitation, aggressiveness, anxiousness, fidgetiness, panic attacks, restlessness, and “treatment resistant” depression.Effects in men are impotence, loss of libido, and hypospermatogenesis.
• Elevated prolactin levels negatively affect testosterone, progesterone and sex hormone binding globulin (SHBG).Significant effects of hyperprolactinemia in women are amenorrhea, cessation of normal cyclic ovarian function, loss of libido, occasional hirsutism, and increased long-term risk of osteoporosis. Breast cancer, ovarian cancer, chronic renal failure, hypopituitarism, autism, schizophrenia, restless leg syndrome, insomnia, polycystic ovary syndrome, herpes, epilepsy, surgery, and stressful conditions are the result of hormonal failure.

SYMPTOM QUIZ FOR THE SIX PRIMARY HORMONES⁽²¹⁾

 1. Testosterone

Add up your overall score ____________.Women: 5 or less: satisfactory level;between 6 and 10: possible testosterone deficiency; 11 or more: probable testosterone deficiency.   Men: 10 or less: satisfactory level; between 11 and 20: possible testosterone deficiency; 21 or more: probable testosterone deficiency.

2. Estrogen

Add up your overall score ____________. 10 or less: satisfactory level; between 11 and 20: possible estrogen deficiency; 21 or greater: probable estrogen deficiency

3. Progesterone

Add up your overall score ____________.Post-menopausalwomen without hormone replacement therapy: 4 or less: satisfactory level; between 5 and 8: possible progesterone deficiency; 9 or more: probable progesterone deficiency.  Menstrual women and women taking hormone replacement therapy: 10 or less: satisfactory level;between 11 and 20: possible progesterone deficiency; 21 or more: probable progesterone deficiency.

 4. Growth Hormone

Add up your overall score ____________.10 or less:satisfactory level;between 11 and 20:possible growth hormone deficiency; 21 or greater:probable growth hormone deficiency

5. Thyroid

Add up your overall score ____________. 10 or less: satisfactory level; between 11 and 20:possible thyroid deficiency; 21 or more: probable thyroid deficiency.

6. Cortisol

 Add up your overall score: ________. 10 or less: satisfactory level;between 11 and 20: possible cortisol deficiency.;21 or greater:probable cortisol deficiency

 SYMPTOM QUIZ FOR THE THREE SECONDARY HORMONES

1. DHEA

Add up your overall score:____________.  10 or less: satisfactory level; between 11 and 20:possible DHEA deficiency; 21 or greater: probable DHEA deficiency

2. Pregnenolone

Add up your overall score:____________. 10 or less: satisfactory level; between 11 and 20: possible pregnenolone deficiency; 21 or greater:probable pregnenolone deficiency

2. Prolactin

Add up and about your overall score ____________: 10 or less: satisfactory level; between 11 and 20: possible prolactin deficiency; 21 or greater:probable prolactin deficiency

DOSAGE SUMMARY SCHEDULE

The Six Primary Hormones

Testosterone

• Males
  1. Transdermal cream: 1-20%, ½ to 1 gm daily to the inner thigh or inner arm
  2. Intramuscular (injections): 40-100 mg IM weekly or split dose twice weekly
  3. Pellets: 500-1400 mg/Rx. (Lasts 4-6 mo.)
  4. Under 40 or to preserve fertility:
     1. Clomiphene citrate: 25-50 mg 2-5 times weekly.
     2. HCG: 3000 IU subcutaneously weekly x 2; then 1000 IU twice weekly. Change off every third month to avoid antibodies

• Females
  1. Transdermal: 5-20 mg/gram, ½ to 1 gram daily to inner thigh or inner arm
  2. Intramuscular: 5-20 Mg every 7 to 14 days
  3. Pellets: 80-150 mg/Rx
• Notes

1. Elevated estrogen levels in men result from aromatase activity.
   1. Zinc citrate (30-90 mg/d)
   2. Quercetin (250 -500 mg/d)
   3. Glycyrrhiza – licorice
   4. Grape seed extracts composed mainly of proanthocyanins
   5. Resveratrol
   6. DIM (1-3 gm/d p.o.}
   7. Chrysin (250 mg bid p.o., topical 50 mg/d)
   8. Progesterone Cream 2-5%, caps 10-15 mg/d
   9. Myomin
   10. Berberine
   11. Vitamin K
   12. Anastrozole (0.5-1.0 mg 1-3x/wk.)
2. Transdermal preparations for women often contain multiple hormones. See chart after progesterone dose discussion for combination estrogen/progesterone/testosterone transdermal formulas.
3. Testosterone excess remedy
   1. Saw Palmetto:240-260 mg. twice daily
   2. Metformin: 250-1000 mg/d
   3. Spironolactone:100 mg 1-2x/d
   4. Spearmint tea

4. Hair loss due to elevated testosterone
   1. Reduce the testosterone dose by 50%
   2. Increase doses of the female hormones’ estradiol and progesterone
   3. Finasteride 2.5 mg/d
   4. Platelet-rich plasma (Increases hair count 30%, on average
   5. Injection or dermabrasion pen increases hair count by up to 30%
   6. 1% melatonin compounded cream applied nightly to scalp for six months
   7. Laser cap

Estrogen

• Females
  1. Bi-est gel, (80/20) dosed at 0.5-5.0 mg/gm
  2. Estriol 5 mg/gm @ 1 gm intravaginal suppository @ bedtime for vaginal dryness.
  3. Pellet insertion
  4. Estrogen target blood level is 75-100 pg/ml
  5. Estradiol 6-15 mg pellet
• Notes

1. Estrogen excess
   1. Progesterone offset-nights 14-25 pre-menopause
   2. Elagolix: 150-200 mg
   3. Weight loss
   4. Liver detox
   5. Ultrasound of pelvis Re: fibroids, tumor
   6. If estrone excess: 7 Keto DHEA (25-50 mg.)
   7. Breast Cysts
      1. Progesterone cream 50 mg/gm apply @ bedtime x 6-week minimum
   8. For vaginal bleeding, breast tenderness
      1. Lower Dose
      2. Double progesterone until symptoms disappear

Progesterone

• Females

Notes

1. 1. Progesterone excess
      1. Chasteberry
      2. Swedish pollen extract
   2. Combinations

Estrogen/Progesterone/Testosterone Combinations⁽²¹⁾

Growth Hormone Injectables

1. HGH 0.8-1.2 IU/day SQ5-7 IU day/wk
2. Sermorelin w or w/o GnRH 2 or 6 (2 causes nausea, 6 causes hunger)
3. Peptide CJC 1295 with DAC 0.5-2.0 mg q. week (can cause hot flash for 5-15 minutes)
4. Oral spray:

1. HGH spray (homeopathic) (3 sprays under tongue @ bedtime-let absorb)
2. Secretropin, Dynotropin-(3 sprays under tongue @ bedtime-let absorb

Thyroid

1. Medications
   1. T4 only (synthetic): Synthroid, Levothroid, Levoxyl, Levothyroxine
   2. T3 only: Cytomel, Liothyronine
   3. T3/T4 combo (synthetic): Thyrolar, Euthroid, Liotrix
   4. T3/T4 combo (bioidentical): Armour, Nature-Throid, Westhroid, desiccated thyroid
2. Diet
   1. Gluten free
   2. Allergen 4 Rs elimination
3. Autoimmune protocol
   1. Gluten-free diet
   2. Plant sterolins: Moducare, Wobezyme N
   3. Low-dose Naltrexone

Cortisol

1. Stress reduction techniques-reading, running, walking, Tai chi, yoga, etc.
2. Adaptogenic herbs: Rhodiola, ginseng, ashwagandha, and cordyceps based supplements
3. Adrenal glandulars
4. Low-dose hydrocortisone-7.5 mg in am, 5 mg at noon, 2.5 mg between 4 pmand 6 pm

The Three Secondary Hormones

DHEA

1. Men: 25-50 mg daily at bedtime
2. Females: 10-25 mg at bedtime

Pregnenolone

1. Maintenance: 30-60 mg
2. Memory loss: 100-150 mg am and pm

 Prolactin

1. Hyperprolactinemia (Pituitary Adenoma)
   2. Bromocriptine: 2.5 mg 2-3 x/d.
   3. Dostinex: 5 mg twice weekly
   4. Vitamin B 6-100 mg/d
   5. Chasteberry-lowers prolactin
   6. Ashwagandha-lowers prolactin
2. Hypoprolactinemia (manifesting as treatment-resistant anxiety/depression)
   1. Acupuncture
   2. Metoclopramide-10 mg twice daily
   3. H2 Blockers
   4. Estrogen
   5. Pituitary evaluation
   6. Neurotransmitters-GABA, serotonin

MY MAGNIFICENT SEVEN

Omega-3’s (EPA/DHA)

Attribute: Cognition

Dose: 1000-4000 mg/d

 

Medium Chain Triglyceride (MCT) Oil

Attribute: Energy, neuroprotection

Dose:

Titrate:

Days 1-3: 5-7g (1 teaspoonful)

Days 3-7: Up to 10g (2 tsp.)

Day 8: 14 g dose of MCTs.  1 Tbsp of MCT Oil

Vitamin D3

Attribute: Neurotransmitter production, memory storage, synapse density

Dose:

Typical: 5000-10,000 IU @ bedtime or 50,000 IU Vitamin D2 once weekly

Calculated dose For every 1000 IU supplementation raises 25 hydroxy D increase serum value eight ng/dl in approximately three months. Exposure to the sun for 20 minutes without sunscreen is equivalent to 20,000 IU/d

Example: 25 OH Vit D = 30 ng/dl; goal 50-80 ng/dl

Supplement with Vitamin D3 4000 IU (4×8=32) +30=62 ng/dl expected

Probiotics/Prebiotics

Attribute: Cognition, learning, memory

Dose: Probiotics

25-100 billion units daily

Administer with prebiotics and fiber

Spore-based probiotics: ½ cap daily x 7 days, then one cap daily x 7 days, then 2 caps daily

Attribute: Insulin sensitivity, bone preservation, weight control

Dose: Prebiotics ⁽²²⁾

Dietary fiber: 25-38g

Prebiotic fiber: 5g-20g

Resistant starch: 20g

Glutathione

Attributes: Liver detoxification, tremors, weight control

Dose:

50-100 mg 1-2 times/day in a liposomal base or

IV push (diluted in 3 ml. NSS) over 5 minutes

Magnesium L-Threonine

Attribute: Sleep, focus

Dose:

Magnesium 144 mg

L-Threonine 2000 mg

Branch Chain Amino Acids (BCAAs)

Attribute: Enzyme and hormone production

Dose:

5-7 grams pre, during, or post-exertion

SUMMARY OF HORMONES AND BRAIN FUNCTION

SUMMARY OF MYMAGNIFICENT SEVEN

Seven Supplements Essential for Recovery from Traumatic Brain Injury

RESOURCES

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6. Hypothalamus Disorders: Causes, Symptoms, Treatment, Prognosis. com.https://www.epainassist.com/brain/hypothalamus-disorder
7. Pituitary Injuries from Trauma. pituitaryinjuryfoundation.org https://www.pituitaryinjuryfoundation.org/about
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