Thyroid – From A to Z
an update
Louis Cady, MD

CONTINUING MEDICAL EDUCATION
COMMERCIAL DISCLOSURE REQUIREMENT
I, Louis B. Cady, MD, have the following commercial relationships to disclose:
• Speaker honoraria received from:
• Immunolaboratories, Great Plains Diagnostic Labs, LABRIX
• Speaker’s bureaus (active) for:
• NEOS, Neurocrine, Shire, Vaya Pharma
• Historical data – speaker’s bureau for Arbor, Allergan (Aventis),
Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Glaxo-Smith Kline,
Janssen, Lundbeck, McNeil, Pfizer-Roerig, Sanofi~aventis, Searle,
Sepracor, Shionogi, Sunovion, Takeda, Wyeth-Ayerst
• Distributor – Pharmanex supplements & Biophotonic scanner

Attention class!!
www.slideshare.net/lcadymd
Where (else!) to get “the slides”
Louis B. Cady, MD

The Lecture
I. The Basics
II. Practicum
III. Conclusions and “How to do it.”

THYROID TESTING – THE
CONVENTIONAL WAY.
What I was taught in medical school:
Louis B. Cady, MD

[ http://www.umm.edu/patiented/articles/how_serious_hypothyroidism_000038_6.htm -
accessed August 2015 and 08 20 2016]
• “Thyrotropin (Thyroid-Stimulating Hormone or
TSH). Measuring TSH is the most sensitive
indicator of hypothyroidism.” (hunh?!) –
accessed 9/5/2011
• “…blood tests for measuring levels of TSH and
free thyroxine (T4) are the only definitive way to
diagnose hypothyroidism” – 10/6/2012
Louis B. Cady, MD

Louis B. Cady, MD
http://umm.edu/health/medical/ency/articles/t
hyroid-function-tests accessed 7/31/2017

Factors for production of
thyroid hormones:
• Iron, iodine, tyrosine, Zn,
Se, E, B2, B3, B6, C, D
Factors affecting T4 to
REVERSE T3 (RT3):
• STRESS, trauma, low
calorie diet,
inflammation, toxins,
infections,
liver/kidney dysfxn,
certain Rx
Factors that INHIBIT proper T4
production:
• STRESS
• Infection, trauma, radiation, Rx
• Fluoride
• Toxins: pesticides, Hb, Cd, Pb
• Celiac disease
T4 T3 requires Se and Zinc!
T4
Factors that improve cellular
sensitivity to thyroid hormones:
• Vitamin A
• Exercise
• Zinc

• “Iron deficiency impairs thyroid hormone
synthesis by reducing activity of heme-
dependent thyroid peroxidase.”
• Zimmermann MB, Kohle J.
Thyroid. 2002 Oct;12 (10):867-78
–Subclinical
hypothyroidism assoc.
with Fe deficiency.
• Nekrasova TSA, 2013 Kloin Med
(Mosk).2013; 91 (9):29-33.
– Fe deficiency assoc with Thyroid
microsomal antibody levels.
• Wang YP et al. J Formos Med Assoc.
2014 Mar;113(3):155-60.
– Fe salts + T4 worked best.
• Ravanbod M et al. Am J Med. 2013
May;126(5):420-4.
Consider IRON deficiency
135 citations search on “iron deficiency
hypothyroidism” as of 6/19/2017

“the foot soldier” “the evil twin”
Selenium
required!
FEEDBACK
INHIBITION
CORTISOL
80% of T4 to T3
converted in the liver
Iodine
required
(65% of T4)

Conventional medical practice:
- Only TSH is typically considered.
- You get T4 if you’re lucky.
- Ill-considered: “T7”, Total T4, Total T3, %T3 uptake
- You DON’T get Free T3 or Rev T3
? ?
Louis B. Cady, MD
?

What are the TYPES of hypothyroidism
(from the top down)?
• Tertiary hypothyroidism – deficiency in
hypothalamus – not enough TRH
• Secondary hypothyroidism –pituitary
isn’t kicking out enough TSH “your
thyroid labs are ‘just fine’”
• PRIMARY hypothyroidism – where
thyroid gland can’t make thyroid
hormone
• This is the only one that high TSH is good
for diagnosing!!
• Low TSH
• Low TSH
Your doc is
happy!! 
• HIGH TSH
(finally!)
Louis B. Cady, MD

Functional Thyroid Deficiency:
FOUR MAIN CAUSES
• Over time the amount of thyroid hormone
decreases secondary to a decreased
production by the gland (primary)
• Decreased conversion of T4 to T3
(secondary)
• Less effectiveness at the receptor sites
causing low thyroid symptoms in spite of
“normal” blood levels (tertiary)
• ELEVATION OF REVERSE T3.

Review of all hypothyroid patients in a private
practice in Belgium between May 1984 and July1997
• 24 hour urine Free T3 correlates better with clinical
status of hypothyroid patients, and even better than
T4 by RIA.
• Conclusions: In this study symptoms of
hypothyroidism correlate best with 24 h
urine free T3 Baisier WV et al. 2000, Vol. 10, No. 2 , Pages 105-113

Key review article!
[Schroeder AC et al. Front Encorinol (Lausanne). 2014;5:40.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978256/ )
• Thyroid hormones effect on
brain relates to balance of T4
and T3.
• Thyroid receptor alpha1 =
70-80% of all TR expression
in adult vertebrate brain.
Louis B. Cady, MD

Who cares
about T3??
Effectively:
- These genes make THR alpha
- THR Alpha is a nuclear receptor for tri-
iodothyronine [T3].
- “[This receptor] has been
shown to mediate the
biological activities of
thyroid hormone.”
- This is where thyroid
(T3) works – AT THE
TISSUE LEVEL.
- (NOT TSH. NOT T4.) Source: Gene ID: 7067, updated 9-Jul-2017

“Euthyroid sick syndrome”
• Stages:
• EARLY:
• Normal TSH, Normal T4, but LOWER T3
• LATE:
• T4 also goes down
• Pro-inflammatory cytokines promote this
via direct activity on the thyroid gland, as
well as by inhibition of peripheral response
for conversion of T4 to T3, especially in
the liver.
Papanicolaou DA. Euthyroid sick syndrome and the role of
cytokines. Rev Endocr Metab Disord 1(1-2):43-48, 2000.

Clinical vignette – July 19, 2018 – “Euthyroid sick”
• 37 year old Family NP. Eyebrows began thinning at 33.
Fatigued. Not depressed. On supplements.
• Not on thyroid. Told her thyroid is “fine.”
• TFT’s
• TSH 1.17 {0.36 – 4.94}
• Free T4 1.04 {0.7 – 1.48}
• Free T3 3.3 {2.0 – 4.4}
• Reverse T3 20.1 {9.2 – 24.1}
• Thyroglobulin Ab <1.0 {0 – 0.9}
• Thyroid Peroxidase 12 {0 – 34}
• PHYSICAL EXAM:
• Delayed relaxation phase for biceps, triceps, brachioradialis, and
patellar muscle stretch reflex. (Achilles’ tendon not done).
Thinned out eyebrows.
• TREATMENT:
• Liothyronine working up to 5 MICROgrams three times daily.

Caloric Deprivation and Non-
Thyroidal Illness Causes Low T3
• “The effects of the low T3 syndrome at the tissue level
are in many instances comparable to those seen in
hypothyroidism.”
• “These effects are considered to constitute a beneficial
adaptive mechanism in situations in which the
organism is endangered.”
Hennemann G, Docter R, Krenning EP. Causes and effects of the low T3 syndrome during
caloric deprivation and non-thyroidal illness: an overview. Acta Med Austriaca. 1988;15(1):42-
45.

Why Reverse T3?
•Hibernating bears can:
–Lower temperature 9 – 11
degrees Farenheit
–Reduce their metabolism by 75%
–Drop heart rate from 55 to 9 bpm
•Rev T3 thought to “hibernate”
humans
Louis B. Cady, MD

What causes elevation in Rev T3?
• High Cortisol (emotional stress) or high copper
•Nutritional starvation
• Heavy metal toxicity – mercury, lead,
cadmium*
• Selenium or Zinc deficiency*
•And high dose of thyroxine
(T4) – a “pro-hormone”
–iatrogenic!)
*Integrative tip: hair analysis is an inexpensive and effective screen. Also
RBC-Selenium and RBC Zinc.
Louis B. Cady, MD

And you can’t tell by “looking”
• Patients with biochemically severe hypothyroidism
may present with only mild clinical manifestations
• Some patients with moderate changes in thyroid
hormones may present with severe signs of tissue
hypothyroidism.
Meier C, Trittibach P, Guglielmetti M, et al. Serum thyroid stimulating hormone in
assessment of severity of tissue hypothyroidism in patients with overt primary thyroid
failure: cross sectional survey. BMJ. 2003 Feb 8;326(7384):311-312.

Per HDRS – 17, remission in:
15.9% on Li
24.7% on T3
Per QIDS-SR16, remission in:
13.2% on Li
24.7% for T3 *
* Fava & Covino: Augmentation/Combination Therapy in STAR*D Trial, Medscape Psychiatry
LEVEL III RESULTS:
Louis B. Cady, MD

For resistant depression:
“The best-documented augmentation
strategies involve inexpensive medicines
(e.g., lithium or thyroid hormones) and
response, if it occurs, is often within 2
weeks.”
- Kaplan & Sadock’s Comprehensive Textbook of
Psychiatry, 2004 (Chapter 14, Mood Disorders)
Louis B. Cady, MD

WHERE ARE WE IN THE LITERATURE?
THYROID
Louis B. Cady, MD

Some recent citations…
• “Paucity of treatment options for bipolar disorder.” “Many
clues suggesting that T3 could augment and accelerate
treatment response [with lithium and antidepressants].”
• Parmentier T et al. J Affect Disord. 2018 Mar 15;229:410-414.
• “Backing into the future: pharmacological approaches to the
management of resistant depression” (failure of two
antidepressants)= Rx with atypical antipsychotics, lithium,
T3 (triiodothyronine). Ketamine. Anti-inflammatory agents.
Pramipexole (dopamine agonist).
• Psychol Med. 2017 Nov;47(15):2569-2577.

European Neuropsychopharmacology Jun;28(6):752-760.

European Neuropsychopharmacology Jun;28(6):752-760.
• Multicenter study of the European Group for the
Study of Resistant Depression
• 1410 patients – MDD patients with and without
thyroid disease
• Point prevalence – 13.2% of patients had
hypothyroidism.
• “In conclusion, our analyses suggest that abnormal
thyroid function, especially hypothyroidism, is linked
to depression severity and associated with distinct
psychopathologic features of depression.”
• However – treatment recommendation was NOT
thyroid replacement but other meds, including
antipsychotics, mood stabilizers, and pregabalin. (?!?!?!)

Dangers of HYPERthyroidism
• Depression
• Anxiety disorders (10-20%)
• Hyperthyroid dementia/cognitive impairmenet (5-
10%)
• Hypomania or mania (2-5%)
• Psychosis (2-5%)
From: Neuropsychiatry of Neurometabolic & Neuroendocrine Disorders – Kaplan & Sadock
Comprehensive Textbook of Psychiatry – Ch 2.14 612-13.

Does treatment with thyroid hormone cause
any of the following? Why or why not?
• Osteoporosis
• Tachycardia
• Atrial fibrillation
• Cardiac dysfunction
• Metabolic changes

The CAUSE of hyperthyroidism is critical
“Hyperthyroidism is associated with increased
morbidity and mortality from cardiovascular
disease.”
“whether the risk of cardiovascular disease is
related to the etiology of the hyperthyroidism
is unknown.”
“This article will focus on patients with Graves
disease, toxic adenoma and toxic multinodular
goiter, and will compare risks associated with
these diseases.”
Biondi B et al. Nat Rev
Endocrin6:431-443 (2010)

Kelly, T. An examination of myth: a favorable
cardiovascular risk-benefit analysis of high-dose thyroid
for affective disorders. J Affect Disord. 2015 May
15;177:49-58
CONCLUSION:
The cardiovascular risks of HDT appear
to be low. HDT is at least as safe as or
safer than many psychiatric medications.
It is effective and well tolerated.
CONCLUSION:
High circulating levels of thyroid
hormone is not the cause of the
sequelae of hyperthyroidism. The
reluctance to using high dose thyroid is
unwarranted.
Kelly, T et al. Elevated levels of circulating thyroid
hormone do not cause the medical sequelae of
hyperthyroidism.
Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jun
11;71:1-6.

Mild Thyroid Disease May Raise
Cardiac Risk
• Subclinical hypothyroidism is linked with a more-than-
twofold increase in heart attack risk among women
aged 55 and older, according to a recent study from
the Netherlands.
• Mild thyroid disease is in the same ballpark as well-
established cardiac risk factors like high cholesterol and
smoking.
• It does tip the balance toward recommending thyroid
replacement therapy, which is a relatively benign
treatment to your patients who have this common
condition.
Hak EA, Pols H, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and
myocardial infarction in elderly women: The Rotterdam Study. Ann Intern Med. 2000;132:270-278.

Subclinical Hypothyroidism Is an Independent Risk
Factor for Atherosclerosis and Myocardial Infarction
in Elderly Women: The Rotterdam Study
•Conclusion: Subclinical hypothyroidism
is a strong indicator of risk for
atherosclerosis and myocardial
infarction in elderly women.
Hak EA, Pols H, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for
atherosclerosis and myocardial infarction in elderly women: The Rotterdam Study. Ann Intern
Med. 2000;132:270-278.

More on HEART DISEASE risk
(2006)
• Medline search from 1966- April 2005
• 14 observational studies met criteria
• Subclinical hypothyroidism (elevated TSH,
normal T4) increased odds ratio of CHD
to 2.38 (CI 1.53-3.69) after adjusting for risk
factors
Subclinical hypothyroidism and the risk of coronary heart
disease: a meta-analysis. Rodondi N et al. Amer. Jour
of Med. July 2006, 119, 541-551. (meta-analysis)

“What is the association of hypothyroidism
with risks of cardiovascular events?” (2017)
• 55 cohort studies with 1,898,314 patients reviewed.
• Hypothyroid patients, compared to euthyroid patients
had
• Higher risk of ischemic heart disease - RR of 1.13
• MI (RR of 1.15)
• All cause mortality – RR 1.25
• Cardiac mortality - RR 1.96
• Cardiac disease patients with hypothyroidism
compared to euthyroid group had RR of 2.22
for all cause mortality
Ning Y et al. What is the association of hypothyroidism with risks of
cardiovascular events and mortality? A meta-analysis of 55 cohort studies
involving 1,898,314 participants. BMC Med 2017 Feb2;15(1):21

A favorable risk-benefit analysis of high dose thyroid
for treatment of bipolar disorders with regard to
osteoporosis.
• CONCLUSION:
•“High dose thyroid does not appear
to be a significant risk factor for
osteoporosis while other widely
employed psychiatric medications do
pose a risk.”
Kelly T. J Affect Disord. 2014 Sep;166:353 -8.

NOW – let’s look at the mental health
literature

63 patients with “subclinical hypothyroidism”
HAM-D and MADRS scales with serum TSH Free T4, free T3
TPO AB and Tg-AB levels
“This study suggests the importance of a psychiatric
evaluation in patients affected by subclinical
hypothyroidism.”
Prevalence of depressive symptoms in this
population was 63.5%
Hunh?
Louis B. Cady, MD

“Hypothyroidism depression” July 22, 2018
1004 citations
Louis B. Cady, MD

“SUBCLINICAL Hypothyroidism depression”
7/22/2018 – 149 citations
“subclinical hypothyroidism depression” –
July 22, 2018
149 citations

“Optimal intervention required
knowledge of thyroid pathology and
attention to the possibility of subtle
thyroid dysfunction in patients with
affective disorders. “

Best augmenting strategies available:
- Lithium
- Thyroid hormone
- Anti-anxiety medications
- Atypical antipsychotics.
Louis B. Cady, MD

Aim: Evaluate relationship of subclinical hypothyroidism and cognition in the
elderly.
- 337 outpatients; {177 = men; 160 = women}
“Patients with subclinical hypothyroidism had a probability about
2 times greater (RR = 2.028, p<0.05) of developing cognitive
impairment.”
MMSE scores were SIGNIFICANTLY lower in subclinical
hypothyroid patients compared to euthyroid (p<0.03)

Aim: Evaluate relationship of subclinical hypothyroidism and serum TSH and
cognition in the elderly. (TSH & Free T4 measured – NOT Free T3)
CONCLUSION:
Low TSH is associated with poorer performance on an
executive function test in middle-aged adults without overt thyroid
dysfunction.
Cross-sectional analysis of Brazilian Longitudinal Study of
Adult Health. N = 10,362. Mean age: 49.5 +/- 7.4 years.
- Exclusions: >/= 65 years of age, overt thyroid dysfunction,
neurologic disease, Asian or indigenous people
Szief C et al. Psychoneuroendocrinol. 2018 Jan;87:152-
158.

An opposing view:
•“Thus, any abnormal thyroid function tests
in psychiatric patients should be viewed
with skepticism. Given the fact that thyroid
function test abnormalities seen in non-
thyroidal illness usually resolve
spontaneously, treatment is generally
unnecessary, and may even be potentially
harmful.”
• Dicerman AL, Barnhill JW. Abnormal thyroid
function tests in psychiatric patients: a red
herring? Am J Psychiatry. 2012
Feb;169(2):127-33

• Early 20’s college student
• Weight gain, fatigue, brain fog
• Saw “numerous” MD’s asking for help
• Told “nothing is wrong with your thyroid; your
labs are fine.”
(permission granted to use photos & data)
Louis B. Cady, MD

A physician’s wife. “Fatigued”
“No sex drive.”
Louis B. Cady, MD

 Depressed mood 100%
 Reduced energy: 97%3
 Fatigue or loss of energy: 94%94%2
 Impaired concentration: 84%3
 Tiredness: 73%1
 Hypersomnia: 10%–16%4 (Insomnia)
Useful Target Symptoms in Major
Depression
1. Tylee et al. Int Clin Psychopharmacol 1999;14:139-151. 2. Maurice-Tison et al. Br J Gen Pract
1998;48:1245-1246. 3. Baker et al. Comp Psychiatry 1971;12:354-65. 4. Horwath et al. J Affect
Disord 1992;26:117-25. 5. Reynolds and Kupfer. Sleep 1987;10:199-215.
Louis B. Cady, MD

A FEW common symptoms of hypothyroidism
(adapted from multiple sources)
• Depression, fatigue
• Concentration problems
• Poor cognitive
performance
• Lack of motivation
• Reduced libido
• Psychosis – “myxedema
madness”
• Exacerbation of bipolar
symptoms 
• Cold intolerance
• Weight gain
• Slowed relaxation
phase of DTR’s
• Brittle hair/fingernails
• Decreasing eyebrows
• HIGH blood pressure
• Constipation
Louis B. Cady, MD

“Data supporting associations of subclinical
thyroid disease with symptoms or adverse
clinical outcomes or benefits of treatment are
few.” (JAMA 2004)
Louis B. Cady, MD

Subclinical hypothyroidism in
the US– what’s the latest?
As of August 6, 2015• Synthesis: treat only those with TSH >10
– Hennessey JV Espaillat R. Diagnosis and management of Subclinical
Hypothyroidism in Elderly Adults: A Review of the Literature. J
Am Geriatr Soc. 2015 Jul 22. epub ahead of print
• Synthesis: SCH [TSH >/= 4.5- 19.99] associated with hip and
other fractures.
– Blum MR et al. Subclinical thyroid dysfunction and fracture risk: a meta-
analysis. JAMA. 2015 May 26;3(20):2055-65.
• Synthesis: Treatment of SCH [TSH 4-11] improved risk of
coronary heart dz risks. “Direct evidence on the benefits
and harms of screening remains unavailable.”
– Rugge JB et al. Screening for and treatment of thyroid dysfunction: An
evidence review for the US. Rockville (MD) Agency for Healthcare Research
and Quality (IS);2014 Oct. Report No. 15-05217-EF-1.

Dr. Imre Zs-Nagy, MD – one more time!
Archives of Gerontology and Geriatrics, Volume 48, Issue 3, May-June 2009, 271-275
"[The] gerontological elite has instead sought to
obfuscate the facts ... the reason for this is
nothing less than an abject fear ... to avert their
loss of control, power, prestige, and position in
the multi-billion dollar industry of gerontological
medicine.”
Prof. Dr. Imre Zs.-Nagy, MD - part of the gerontology movement for four
decades; founder and Editor-in-Chief of the Archives of Gerontology and
Geriatrics

How much subclinical hypothyroidism?
• 4 – 8.5% of US population (for TSH> 5.1!!)
• Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4 and
thyroid autoantibodies in the United States population (1988–1994):
National Health and Nutrition Examination Survey (NHANES III) J Clin
Endocrinol Metab. 2002;87:489–99.
• Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado Thyroid
Disease Prevalence Study. Arch Int Med. 2000;160:526–3
• UK study (2011): 8% of women over 50 and men
over 65 have under-active thyroid and 100,000 could
benefit from treatment
• BBC News 2011 - January 24
Louis B. Cady, MD

Subclinical hypothyroidism in
the US– what’s the latest?
As of August 6, 2015
July 22, 2018

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN
COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THYROID
DYSFUNCTION CASE FINDING. [Hennessy JV. Endoc Pract. 2016 Feb;22(2):262-70
We recommend that thyroid dysfunction should be
frequently considered as a potential etiology for
many of the nonspecific complaints that physicians
face daily. The application and success of safe and
effective interventions are dependent on an
accurate diagnosis. We, therefore, advocate for an
aggressive case-finding approach, based on
identifying those persons most likely to have thyroid
disease that will benefit from its treatment.

This is it in a nutshell…
1. 70% of older patient with TSH > than 4.5 mIU/L were within their age-
specific reference range.
2. From the “Conclusion” statement: “TSH distribution progressively shifts
toward higher concentrations with age. The prevalence of SCH
may be significantly overestimated unless an age-specific range for
TSH is used.”

“But the doctor told me my thyroid was fine.”
• Can be “wnl” but suboptimal.
• TSH frequently only thing checked.
• Nothing known about Free T4 or Free T3.
• Free T4 can be converted to Reverse T3 under
stress (cortisol)
• Free T4 can be underconverted to T3 (Se def).
• Can have normal levels (or slightly elevated
levels) of everything and have auto-immune
thyroid disease.
Louis B. Cady, MD

Definition of “normal labs”:
“When your lab
values are as
crappy as
everyone else’s.”
- Neal Rouzier, MD
(World Link Medical Seminar II –
Spring 2011)
Louis B. Cady, MD

So what are people
doing out there?
What does the literature say?
Louis B. Cady, MD

“Subtle deficits in specific cognitive domains
(primarily working memory and executive function)
likely exist in subclinical hypothyroidism and
thyrotoxicosis, but these are unlike to cause major
problems in most patients.” (Endocrinol Metab Clin
North Am. 2014 Jun)
“Patients with mild thyroid disease and significant
distress related to mood or cognition most likely
(??) have independent diagnoses that should be
evaluated and treated separately.”

So what does the American Association of Clinical
Endocrinologists (ACEE) say?
• “The upper limit of TSH should remain
at 4.5 mIU/L, rather than 3.0-3.5 as
some other organizations have suggested.”
• “Routine T4 treatment for patients with TSH
between 4.5 and 10mIU/L is not
warranted.”
–https://www.aace.com/files/final-file-hypo-
guidelines.pdf
• Garber JR et al. CLINICAL PRACTICE GUIDELINES FOR HYPOTHYROIDISM
IN ADULTS. In: Endocrine Practice vol 18, No. 6 – November/December
2012. Accessed July 22, 2018.

Lab values – one more time…”4.5” is where the American
Assn. of Clin. Endocrinologists wants the highest level of TSH
TSH = 0.45 4.12 source: % =
(2.5th% 97.5th% NHANES III
4.5 is the
upper limit
they want –
this is at c.
the 99th%
Louis B. Cady, MD

70 patients- ages 18-65 years of age. w/ primary hypothyroidism on stable T4 for 6
months.
Randomized to either dessicated thyroid extract (DTE) or T4 for 16 months, then
crossed over for another 16 months.
RESULTS:
- “No differences in symptoms” and neurocognitive measures.
BUT:
- DTE patients lost 3 lbs!
- 48.6% of patients (n=34) PREFERRED DTE.
- Those patients preferring DTE lost 4 lbs during the DTE treatment and
subjective symptoms were all significantly better while
taking DTE as per general health questionnaire-12 and
thyroid symptom questionnaire.

“Conclusions”:
- DTE therapy did not result in a significant improvement in quality of life; however,
DTE caused modest weight loss and nearly half (46.8%) of the study patients
expressed preference for DTE over L-T4.
DTE therapy may be relevant for some
hypothyroid patients.” [Can you believe it????]

Dx:
•TSH
•Free T4
•Free T3
•Reverse T3
• If indicated:
• Anti-thyroid antibodies (anti-
TPO)
• Anti-thyroglobulin antibodies
• Thyrotropin receptor antibodies
(TRAb’s)
• We typically do not do:
• Total T4, Total T3, or thyroid
reuptake
Test! Test! Test!

Thyroid “by the numbers.”
1. Review this lecture.
2. Go get good training. (Neal Rouzier, MD)
3. PSYCHIATRISTS! Acknowledge that “T3 augmentation” is in your
literature and it is your RIGHT TO PRACTICE IT. (Consider “HDT”!)
4. Therapists/other practitioners: wake up! Don’t fall into trap of “blaming”
the functionally hypothyroid patient. REFER!
5. Start LOW.
6. Go SLOW.
7. Test test test test test.
• MUST GET BASELINE (which typically hasn’t been done).
• If you are unsure or nervous, TEST.
• MONITOR THE THERAPY.
8. Explain “Goldilocks and the Three Bears” to your patients and start
LOW, giving them some flexibility.

Useful aphorisms to remember
•It’s difficult to be euthymic without being
euthyroid.
•Depression can start in the NECK.
•John Earl Shoaff: “The difference between
success and failure is about a half dozen
things.”

Framework:
• Decide where in the literature you want to be.
• Do you want to practice the way things “used
to be” or do you want to practice evidence
based medicine?
–[or just blindly listen to the specialty societies
who parrot from the past?]
• Do you want your patient to be “normal” or
“optimal”?
• And can you live with yourself and your
decision?
Louis B. Cady, MD

RX: You MUST Know This
Transthyretin = carrier protein)
• Terasaki, T. and Pardridge, W.M.: Stereospecificity of
triiodothyronine transport into brain, liver, and salivary gland: role
of carrier- and plasma protein-mediated transport. Endocrinology,
121(3):1185-1191, 1987.
• http://www.kingpharm.com/uploads/pdf_inserts/Cytomel_PI.pdf.
• Mooradian, A.D.: Blood-brain transport of triiodothyronine is
reduced in aged rats. Mech. Ageing Dev., 52(2-3):141-147, 1990.
• Cheng, L.Y., Outterbridge, L.V., Covatta, N.D., et al.: Film
autoradiography identifies unique features of [125I]3,3'5'-
(reverse) triiodothyronine transport from blood to brain. J.
Neurophysiol., 72(1):380-391, 1994.
• Rudas, P. and Bartha, T.: Thyroxine and triiodothyronine uptake
by the brain of chickens. Acta Vet. Hung, 41(3-4):395-408, 1993.
Or: The idiocy of T4 only thyroid treatment…

• Generally practice
guidelines and policy
statements are effective,
BUT…MANY people do not
respond to treatment.
• Clinicians face the
conundrum either
following the guidelines
(which are ineffective), or
ethically prescribing
alternatie (and effective)
Tx.
Pritchard, EK. Reducing the scope of
guidelines and policy statements in
hypothyroidism. Journal of
Othomolecular Medicine. Volume
28, Number 2, 2013.

• Per paper:
• Current guidelines are based on (a) suppression of
evidence that other scientific disciplines would
routinely accept.
• Alternative treatments, which are supported by
decades of research and practice, should not be
ignored.
• Response to prescribed treatment is as high as 1.7
million people in the US (90% of whom are women)
• Practicing “per guidelines” keeps patients suffering
from ongoing symptoms of hypothyroidism.
• Patients showing clear benefits on treatment
demonstrate that suffering is not necessary.
Pritchard, EK. Reducing the scope of guidelines and policy statements in hypothyroidism.
Journal of Othomolecular Medicine. Volume 28, Number 2, 2013.

Rx:
• Synthroid ® (levothyroxine)
• Cytomel ® (Tri-iodothyronine – “T3”)
• Instant release (cheap!)
• Compounded in SR capsule (easier
dosing)
• Armour® thyroid (brand or generic) =
T4 + T3
• NP Thyroid (cheapest & is excellent)
Naturethroid & Westhroid = T4 + T3 –
better tolerated in some
• OR Compounded dessicated thyroid

Consider T3 ONLY use…
• T3 raises T3 levels.
• T3 does NOT raise Reverse T3 levels
• (but T4 does).
• T3 (liothyronine) is generic and CHEAP.
• It can be microdosed and then spread out to
twice daily to three times daily.
• It can be converted to an SR preparation by a
compounding pharmacy. Example – 5
MICROgrams T3 three times daily becomes
15 MICROgrams SR T3 daily, (compounded).

TREAT WITH T3 AND T4
• Raising T3 levels to optimal will improve
symptoms
• Raising T3 level by itself cannot be
accomplished with just T4 alone
• (you will also elevate Reverse T3)
• A combination of T4 & T3 is frequently
required in order to optimize T3
• Desiccated thyroid is typically drug of
choice for combined treatment.

• Compounded, “DESICCATED” thyroid – still
porcine, but better absorbed secondary to no
binders like tabs
• Avoid Compounded synthetic T4 & T3(non-
desiccated) unless for religious reasons = not
porcine = not as efficacious
• Compounded T4 & T3(non-desiccated) not
absorbed as well as the desiccated compounded
form of T4 & T3
• Desiccated is premixed at 9ug T3 & 38ug T4-
concentration cannot be changed as it is pre-
blended together before distribution
• Also contains T1 & T2

The “roll your own” model of
thyroid dosing perspective
• T4 (levothyroxine)
PLUS
T3 (Liothyronine)
• Can ADD “T3” to conventional dosing regimen if
indicated.
• In rare cases, compounded porcine thyroid (T4 &
T3 at fixed dosage) PLUS additional T3.

Non-desiccated (REGULAR)
compounded T4 & T3
• Not premixed as is desiccated
• Can combine in any concentration
• T4 is mixed with T3 by the pharmacist to any
combination that is requested
• It is not premixed to 9ug & 38ug as is desiccated
thyroid
• Not as well absorbed=not recommended
• Not porcine; useful for religious preferences

Natural Thyroid = Desiccated thyroid
HOW TO DOSE IT
•Comes in ¼, ½ grain, 1 grain, 2 grains, 3
grains
•Initiate with 1 grain dose typically (Rouzier)
• Start with ¼ or ½ grain increments (Cady)
• Tell ‘em “Goldilocks”
•Increase by 1/2 to 1 grain increments per
month
•Monitor lab tests and symptoms monthly
until stable

Desiccated thyroid =
NP Thyroid = Armour Thyroid = = Westhroid =
Naturethroid = compounded dessicated thyroid
• T4 and T3 (FIXED RATIO) and T1 and T2
• Porcine not bovine
Porcine ¼ grain ½ grain 1 grain 2 grains 3 grains
Porcine = 15 mg 30 mg 60 mg 120 mg 180 mg
T4 25 ug 50 ug 100 ug 200 ug 300 ug
T3 6 ug 12 ug 25 ug 48 ug 72 ug
Contents and balance of T4: T3

Optimize labs:
•Free T3:
•Normal 2.3 – 4.3
•Optimal 4.0 – 4.3
+/o
•Optimize symptom improvement

Watch out for Reverse T3!
•It has the same effect
on humans that it
does on bears.
Louis B. Cady, MD

“Sit down before fact as a little child,
- Thomas H. Huxley
Louis B. Cady, MD
be prepared to give up
every preconceived notion,
follow humbly wherever …
nature leads,
or you shall learn nothing.”

Louis B. Cady, MD
Cady Wellness Institute
4727 Rosebud Lane – Suite F
Newburgh, IN 47630 USA
Office (812) 429-0772
info@cadywellness.com
www.facebook.com/cadywellness
Twitter: @LouisCadyMD
www.slideshare.net/lcadymd
www.cadywellness.com

Proposed appendix with holistic and other
references
Louis B. Cady, MD

Must have iodine to make T4!
Source: Office of Dietary Supplements, NIH accessed 8/11/2013
http://ods.od.nih.gov/factsheets/Iodine-QuickFacts/

Sources/locations of deficiency:
• Chlorinated or fluorinated drinking water
• Not using iodized salt
• Consumption of NaCL in processed foods
• Consumption of soy & “goitrogens” - cabbage,
broccoli, cauliflower and Brussels sprouts
• Being pregnant
• People living with iodine deficient soils &
eating local foods
Louis B. Cady, MD

North America 85%
South America 76%
Asia 76%
Africa 74%
Europe 72%
Australia 55%
% Mineral depletion from the soil during the
past 100 years, by continent
Source: UN Earth Summit Report 1992

- Selenium is one of the factors that may affect the risk of
cognitive decline. In selenium deficiency the brain remains
selenium replete the longest suggesting that Se plays an
important role in brain functions.
- Results from this study: “Low Se status is a risk factor for
cognitive decline even after taking into account vascular
risk factors.”
Louis B. Cady, MD

SELENIUM DEFICIENCY in FASEB:
• “Adaptive dysfunction of
selenoproteins from the
perspective of the ‘triage’
theory: why modest
selenium deficiency may
increase risk of
diseases of aging.”
Foundation of American Societies for
Experimental Biology
McCann, J, Ames BM. FASEB J.
2011 Jun;25(6):1793-814.
Louis B. Cady, MD

• “Low selenium status is associated with increased risk of thyroid
disease. Increased selenium intake may reduce the risk in
areas of low selenium intake.”
• Wu Q et al. Low population selenium status is associated with increased prevalence of
thyroid disease. J Clin Endocrinol Metab. 2015 Nov;100 (11):4037-47.
• “We demonstrated …the beneficial effects obtained by
selenomethionine treatment on patients affected by subclinical
hypothyroidism.”
• Nordio M. Combined treatment with myo-inositol and selenium ensures euthryoidism in
subclinical hypothyroidism patients with autoimmune thyroiditis. J Thyroid Res.
2013;2013:424163
Louis B. Cady, MD

The history of exploration
of the thyroid axis

Prange’s postulates. A historical
retrospective…
• 1963 case where hyperthyroid patient became toxic
when imipramine was introduced.
• Preclinical theories:
• thyroid hormone enhances noradrenergic
receptor sensitivity
• Perhaps modest amounts of T3 might
accelerate imipramine’s antidepressant
activity without producing toxicity.
Prange AJ. Paroxysmal auricular tachycardia apparently resulting from
combined thyroid-imipramine treatment. Am J Psychiatry 119:994-995, 1963.
Louis B. Cady, MD

Prange proceeds…
•Placebo controlled study of 20
depressed (but non-refractory)
patients, a more rapid onset of
antidepressant action was observed in
the imipramine-T3 group vs. placebo.
Prange AJ, et al. Enhancement of imipramine antidepressant activity by thyroid
hormone. Am J Psychiatry 126:457-469, 1969.
Louis B. Cady, MD

Open studies commenced
• THE STUDIES:
– Earle BV. Thyroid hormone and tricyclic antidepressants in resistant depression. Am J Psychiatry
126:1667-1669, 1969
– Ogura C, et al. Combined thyroid (tri-iodothyronine) tricyclic antidepressant treatment in depressive
states. Folia Psychiatrica et Neurologica Japonica 28:179-186, 1974
– Banki CM. Triiodothyronine in the treatment of depression. Orv Hetil 116:2543-2546, 1975.
– Tsutsui S et al. Combined therapy of T3 and antidepressants in depression. J Int Med Res 7:138-146,
1979.
– Schwartz G et al. Normal thyroid function in desipramine nonresponders compared to responders by
the addition to L-tri-iodothyronine. Am J Psychiatry 141:1614-1616, 1984
• THE FINDINGS:
–“When T3 was added to TCA’s for
treatment-refractory depressed patients,
there was a favorable outcome in about
two-thirds of the cases.”
• Charney DS et al. Treatment of Depression, Chapter 28 in: Textbook of Psychopharmacology,
American Psychiatric Press, Inc. © 1995.
Louis B. Cady, MD

Thyroid augmentation known to be useful in
refractory depression
• 292 patients and eight studies aggregated.
• (Medline data base 1966 – May 1995.)
• Patient treated with T3 augmentation – twice as like
to respond as controls
• (RR 2.09; 95% confidence interval)
• Improvements in depression scores were moderately
large (effect size 0.62, P<0.001)
Louis B. Cady, MD
Aronson R et al. Triiodothyronine augmentation in the treatment of refractory
depression. A meta-analysis. Arch Gen Psychiatry. 1996 Sep;53(9):842-8.

5HT joins NE
• 2002 - New findings:
• Thyroid hormones increase 5HT neurotransmission in
the cortex by increasing 5HT2 sensitivity, and by
reducing 5HT1A autoreception sensitivity in the
raphe
• Changes in gene expression of brain and
neurotrophins thought to be responsible.
Bauer M et al. Thyroid hormones, serotonin and mood of synergy and
significance in the adult brain, Mol Psychiatry 7:140-156, 2002.

• Cognition
• Head injury recovery
• Alzheimer’s disease prevention
Other areas of interest advertised in
lecture synopsis
Louis B. Cady, MD

Cognition: maternal low thyroid and ADHD in
kids
• Known impact of thyroid hormone deficiency in
pregnancy can affect ADHD symptoms in children
• “Generation R” Study in Rotterdam
• 4,997 eligible mother-child pairs studies (with data on
maternal thyroid levels) identified
• Of these, 3,873 visited a Generation R research center for
assessments.
• “Maternal hypothyroxinemia (n-127) in early
pregnancy was associated with higher scores for
ADHD symptoms in children at 8 years of age”
independent of confounding factors.
• Modesto T et al. JAMA Pediatr. 2015
Sep;169(9):838-45.

Impact of mild maternal thyroid hormone deficiency in
pregnancy – the Generation R Study
• Congenital hypothyroidism known to cause
irreversible brain damage.
• Before 12-14 weeks of gestation, maternal thyroid
hormone serves as the only source of thyroid
hormone for the fetus.
• T3 is generated locally from maternal T4 in the fetal brain
before mid-gestation.
• Iodine deficiency and thyroid autoimmune disorders
known as two of the main causes of thyroid
deficiency.
• Ghassabian A et al. Best Practice and Research Clinical
Endocrinology & Metabolism 28 (2014) 221 – 232

Results of Generation R study (cont)
• 3,659 maternal child pairs evaluated in this analysis.
– Higher results of maternal free T4 in early pregnancy predicted a
lower risk of expressive language delay in their children at 2 ½
years.
–“Severe hypothyroxinaemia:
• predicted a higher likelihood of expressive language delay in
children at 1 ½ and 2 ½ years of age.
• Also predicted a higher risk of non-verbal delay at 2 ½ years.
• Ghassabian A et al. Best Practice and Research Clinical Endocrinology & Metbaolism 28 (2014)
221 – 232
Louis B. Cady, MD

Multiple studies
• “Thyroid hormone regulates neurogenesis in the developing
and adult brain across different vertebrate species.”
• Gothie JD et al. Mol Cell Endocrinol. 2017 May 22.
• The development of infant visual attention is related to thyroid
hormone during early prenatal period.
• Bell MA et al. Am J Clin Nutr. 2016 Sept
• Thyroid dysfunction known to occur in autism spectrum
disorder and may be related to a blocking folate receptor
autoantibody
• Frye RE et al. J Neuroendocrinol. 2017 Mar; 29 (3)
Louis B. Cady, MD

Experimental induction of hypothyroidism during
early postnatal stages in rats.
• Hypothyroidism induces at 21 days of age using
propyl—2-thiouracil .
• Results:
– “hypothyroidism triggers a significant dysfunction in
learning and memory processes.
– “The cognitive impairment was correlated with a reduction
in hippocampal plasticity and depression.
– Also, decreased glucose utilization and increased oxidative
stress observed.
– Hypothyroidism in young rat model alters numerous
functions at the level of the hippocampus.
• Salazr P et a. Biochim Biophys Acta. 2017 April;1863(4):870-883.
Louis B. Cady, MD

Other studies in children
• Endocrine-disrupting chemicals (EDC’s) and perturb
normal levels of hormones required for normal neural
circuit development.
– Three ubiquitous endocrine disruptors studied
[polychlorinated biphenyls, polybrominated diphenyl
esters, and bisphenol A.]
– Impact of these disrupts goes beyond relative
hypothyroidism and affect memory, cognition, and social
behavior.
– Pinson A et al. Andrology. 2016 Jul;4(4):706-22
Louis B. Cady, MD

Thyroid hormone and aging
• Known correlation between increase in TSH during
ageing.
• Unclear if this is a normal adaptive response associated
with senescence or an actual mild thyroid dysfunction.
• Several meta-analyses showed a direct link between
subclinical hypothyroidism and cardiovascular events
(younger than 65) and cognitive impairment (in those
under 75 years of age.)
• Pasqualetti G et al. Recent Pat Endocr Metab Immune Drug Discov. 2016
(10(1):4 – 10
Louis B. Cady, MD

“Thyroid function and neuropsychological status
in older adults.”
• “Cross sectional associations between serum
thyroid hormone concentrations and several
neuropsychological function domains among men
and women aged 55 – 74 years” were reported.
• Findings:
– Higher thyroid hormone levels associated with improved
visuospatial function, as well as tasks of memory and
learning.
• Shrestha S et al. Physiol Behav. 2016 Oct 1; 164(Pt A):34-9
Louis B. Cady, MD

Thyroid hormone and its function on health status, mood,
and cognition in T4 treated subjects
• Cross sectional study of 132 otherwise health
hypothyroid subjects who received levothyroxine
replacement therapy.
– Generally, not much difference in health status, mood or
cognitive status.
– However, on the Iowa Gambling Task (which mimics real
life decision-making), subjects with low-normal TSH “made
more advantageous decisions than those with high-normal
TSH levels.”
– “Decision making – which encompasses many executive
functions, may be affected.”
• Samuel MH et al. Thyroid. 2016 Sep;26(9):1173-84.
Louis B. Cady, MD

Thyroid hormone: influences on mood and
cognition in adults (the need for a “happy
medium”)
• “Treatment of over thyroid dysfunction largely resolves
associated disturbances in mood and cognitive
dysfunction.”
• “However, in the setting of overt hypothyroidism subtle
detrimental effects on cognition may not be full reversed.”
• “Subclinical HYPERthyroidism and higher Free
Thyroxine ( Free T4) within the normal range have also
been associated with poorer cognitive outcomes.”
• Ritchie M, Yeap BB. Maturitas. 2015 Jun;81(2):266-75.
Louis B. Cady, MD

Prevalence of thyroid dysfunction and its impact
on cognition in older Mexican adults (SADEM
study)
• 1750 participants evaluated via interviews, TSH, and Free T4 levels.
• TSH of 0.4 – 4 was considered euthyroid.
• Over hypothyroidism = TSH>4.8
• Overt hyperthyroidism – TSH <0.3 IU/L
• Results:
• Overall estimated prevalence of thyroid dysfunction in Mexican
population was 23.7%.
• 15.4% we were classified as subclinical hypothyroidism.
• Thyroid dysfunction and cognitive impairment was most evident
in overt hypothyroidism [OR=1.261]
• Juarez-Decillo T et al. J. Endocrinol Invest. 2017 Mar 25.
Louis B. Cady, MD

TSH and cognition in older people (negative
study)
• 335 home-dwelling older people (>/= 75 yoa)
• Cognitive performance evaluated using the
Consortium to Establish a Registry of Alzheimer’s
Disease battery (CERA-nb)
– APO E4 genotype also defined.
– Subjects divided into quartiles by TSH.
• “Our results do not support the notion that higher
TSH concentrations, not even in the range of
subclinical hypothyroidism, would adversely affect
cognition among older people.”
– Ojala AK et al. Age Ageing. 2016 Jan;45(1):155-7
Louis B. Cady, MD

Thyroid hormones are associated with longitudinal
cognitive change in urban adult population (positive study)
• 1466 of 1602 participants was analytic sample size.
• Adults ages 30 – 64 years at baseline visit.
• Follow-up between first and second visit ranged from <1
to 8 years
• “In sum, higher baseline thyroid stimulating hormone
was associated with faster cognitive decline over
time among urban US adults, specifically in domains of
working memory and visuospatial and/or
visuoconstruction abilities.” Beydoun MA et al. Neurobiol Aging.
2015 Nov; 36(11):3056-3066.
Louis B. Cady, MD

Effects of Thyroxine as Compared with
Thyroxine plus Triiodothyronine in Patients
with Hypothyroidism
Bunevious R et al. N. Engl Journal of Medicine 1999 Feb 11:340(6):424-9.
• 33 hypothyroid patients treated in two phases
• Phase 1 – treated with usual dose of T4.
• Phase 2 – 50 MICROgrams of T4 was removed from dosing
and 12.5ug T3 put in its place.
• Post treatment with T3:
• 17 treated patients improved their scores on cognitive
performance and mood states.
• 10/15 patients were significantly better on T4 + T3 for the
visual analogue scales on wellness.
• “…this finding suggests a specific effect of the
triiodothyronine normally secreted by the thyroid
gland.”

Effects of Thyroxine as Compared with
Thyroxine plus Triiodothyronine in Patients
with Hypothyroidism
Bunevious R et al. N. Engl Journal of Medicine 1999 Feb 11:340(6):424-9.
• 20/33 preferred T4 plus T3
• Felt they had more energy, improved
concentration and “just felt better overall.”
• 11 had no preference
• Only 2 preferred T4 only.
•Conclusions:
• “Treatment with thyroxine plus
triiodothyronine improved the quality of
life for most patients.”

HEAD INJURY CONSIDERATIONS
Louis B. Cady, MD

Head injury considerations in children
• Hypopituitarism: 5 – 7% prevalence in children
following TBI. (includes low TSH)
• “The effect of hormonal replacement in patient
recovery is important enough to consider baseline
screening and reassessment between 6 and 12
months after TBI.”
• Cassano-Sancho P. Arch Dis Child. 2017 Jun; 102(6):572-
577
Louis B. Cady, MD

Evaluation of pituitary function for extended
periods s/p TBI
• 24 children s/p TBI evaluated.
• Mean age 9.5 (+/- 3.1) years
• Follow-up times were 29.4 (+/-9.8) months.
• TSH, Free T4, Free T3, IGF-1, sodium, FSH, LH, E2 in girls, Total
testosterone in both girls and boys
• No children found with hormonal deficiencies.
• Conclusion was that some pituitary dysfunction may present in the
late period, “therefore, all cases should be followed up at
outpatient clinics for a longer period”
• Aylanc H, et al. J Neurosci Rural Pract. 2016 Oct-Dec;7(4):537-543
Louis B. Cady, MD

TBI in childhood research
• The more severe the trauma, the greater the
risk of progressive reduction in long-term
serum TSH.
• Heather N et al. Clin Endocrinol (Oxf). 2016
Mar;84(3):465-7.
Louis B. Cady, MD

Thyroid hormone treatment activates protective
pathways following neuronal injury
• TBI in rats showed to be associated with reduction in T4 and T3.
• A single dose of levothyroxine (T4) one hour post-injury, increased
serum T4 and NORMALIZED serum T3 levels.
• Expression of genes important for thyroid actin in the brain
(MCT8 and Type 2 deiodinase) diminished after injury but were
partially restored with T4 treatment.
• The findings from both in vitro and in vivo studies support a role of
thyroid hormone in activating pathways important for neuronal
protection and promotion of neuronal recovery after injury.
• Li J et al. Mol Cell Endocrinol. 2017 Sep 5;452:120-130.
Louis B. Cady, MD

Emerging pharmacotherapy for treatment of TBI
– targeting hypopituitarism and inflammation
• Large body of evidence suggests that TBI may
adversely affect pituitary function – both acutely
and chronically.
• The time interval between injury and effect “is one
of the major factors responsible for variations in
the prevalence of hypopituitarism reported.”
• “euthyroid sick” syndrome reviewed
– Paterniti I et al. Expert Opin Emerg Drugs.
2015;20(4):583-96.
Louis B. Cady, MD

“Thyroid hormone in the frontier of cell
protection, survival and functional recovery”
• Thyroid hormones exerts important actions on
cellular energy metabolism.
• Enhances homeostatic potential including
antioxidant, antiapoptotic, anti-inflammatory and
cell proliferation responses.
• Psych uses:
– Reduce cognitive side effects of lithium
– Improves response to ECT in bipolar patients.
• Videla LA et al. Expert Rev Mol Med. 2015 May 25;17:e10.
Louis B. Cady, MD

Somatotropic and thyroid hormones in the
acute phase of subarachnoid haemorrhage.
• Complicated hospital course was associated
with a deeper fall in TSH and T3
concentrations.
• “Low concentrations of TSH and T3 were
connected to worse SAH [subarachnoid
haemorrhage] grade and poor outcome.”
–Implications for treatment? No conclusions
given.
–Zetterling M et al. Acta Neurochir (Wien). 2013
Nov;155(11):2053-62.

Exogenous T3 administration provides
neuroprotection in a murine model of traumatic brain
injury.
• Thyroid hormones noted to be decreased in patients with
brain jury.
• Controlled cortical impact injury (CCI) [widely used
experimentally] was used in adult male mice.
• Tx with T3 (1/2 MICROgrams/100 grams body weight IP)
one hour after TBI resulted in a significant improvement in
motor and cognitive recovery after CCI.
• 24 hours after brain trauma, T3 treated mice showed
significantly lower number of apoptotic neurons.
• T3 significantly enhanced post-TBI expression of BDNF
and GDNF compared to control vehicle.
– Crupi R et al. Pharmacol Res. 2013 Apr;70(1):80-9.

Multiple hormonal derangements seen as determinant
of cognitive decline in older men
• Thyroid, cortisol, and anobolic hormones [DHEA-S,
testosterone, and IGF-1] noted to decline with age.
• Frailty related to consequences of cognitive
impairment and cognitive decline.
• Correlation with changes of thyroid hormone and
anabolic hormones in older men was found.
– Maggio M et al. J Nutr Health Aging. 2012 Jan;16(1):40-
54.
Louis B. Cady, MD

THE ROLE OF THYROID HORMONE
Prevention/attenuation of Alzheimer’s
disease?
Louis B. Cady, MD

Thyroid hormone levels an in-vivo
Alzheimer’s disease pathologies
• Study evaluated TSH with two AD specific biomarkers
(cerebral amyloid beta burden and glucose metabolism.
– 148 individuals
– PET scan, T3, Free T3, Free T4 and TSH levels measured.
– Al patients were clinically euthyroid. But…
• Independent negative associations were found
between serum fT4 levels and global cerebral Aβ
deposition after controlling for the effects of age,
gender, and the apolipoprotein E ε4 (APOEε4)
genotype. (no other thyroid hormones showed a
relationship)
– Choi HJ et al. Alzheimers Res Ther. 2017 Aug 17;9(1):64.
Louis B. Cady, MD

Effects of Thyroid Hormones and their Metabolites on Learning and
Memory in Normal and Pathological Conditions.
• “The available literature suggests that both classical and
non-classical thyroid hormones act as neuroprotective
agents in the brain areas related to learning and memory.
Their role in these areas supports the idea that they may be
involved in the development of Alzheimer's disease.”
• CONCLUSION: Thyroid hormones produce significant
neurological effects, act as neuroprotective agents and
might be considered as future diagnostic and therapeutic
tools for Alzheimer's disease.
• Accorroni A et al. Curr Drug Metab. 2017;18(3):225-236.
Louis B. Cady, MD

• “…levothyroxine replacement therapy with vitamin
E supplementation may ameliorate cognitive deficit
in PTU-induced hypothyroidism [experimental
model of hypothyroidism] through the decrease of
oxidative stress status.”
• Note: BOTH were used.
• Pan T, et al. Endocrine. 2013 Apr;43(2):434-9.

Thyroid hormone prevents cognitive deficit
in a mouse model of Alzheimer's disease.
• Study examined feasibility of using T4 as a
therapeutic agent of Alzheimer’s disease.
• Mice injected IP with amyloid beta-peptide to produce
AD animal model.
• IP injection of levothyroxine prevented their
cognitive impairment and improved their memory
function.
• Fu AL et al. Neuropharmacology. 2010 Mar-Apr;58(4-
5):722-9.
Louis B. Cady, MD

Selenium and selenoproteins in health and disease.
• Selenoproteins – involved in redox regulation of intracellular
signaling, redox homeostasis, and thyroid hormone
metabolism.
• Reduced expression of selenoproteins directly linked to thyroid
hormone metabolism defects (specifically – deficiency of deodinases)
• Selenoprotein deficiencies have been linked to some forms of
cancer, Alzheimer’s disease, cardiovascular disease, and life
span.
• Papp LV et al. Antioxid Redox Signal. 2010 Apr 1;12(7):793-5.
Louis B. Cady, MD

And now – more research and
reading is in your future!
• This review has merely scratched the surface of
all of these topics.
• My thanks to everyone who attended my lecture
at IMMH 2017 (Orange County) and my best
wishes for the future!
Louis B. Cady, MD

HOW DOES THYROID WORK IN THE
BRAIN?

T3 regulates mitochondrial
biogenesis

PGC-1 alpha is T3 receptor in brain
• PGC-1 is rapidly regulated and is a direct target
of T3 – both in vivo and in cell culture.
• PGC-1 alpha then coactivates liganded thyroid
hormone receptors
• Autoregulatory feed-forward loop of PGC-1 alpha
activation upon T3 treatment is noted.
• Wulf A et al. T3-mediated expression of PGC-1 alpha via a
far upstream located thyroid hormone response element.
Mol Cell Endocrinol. 2008 Jun 11;287(102):90 – 5.
•

Aim: evaluate biological factors assoc. with suicide attempts in
naturalistic sample
439 patients with major depression, bipolar and psychotic
disorders consecutively assessed in the ER of an Italian Hospital
(Jan 2008-Dec 2009)
Suicide attempters were 2.27 times less likely to
have higher Free T3 values than non-attempters (odds
ratio = 0.44; 95% CI; p=0.01) (prolactin level differences failed to
reach significance)

The Beneficial Effect of L-Thyroxine on Cardiovascular Risk
Factors, Endothelial Function, and Quality of Life in Subclinical
Hypothyroidism: Randomized, Crossover Trial
• SCH treated by L-thyroxine leads to a significant
improvement in CV risk factor and symptoms of
tiredness.
• The CV risk factor reduction is related to the
increased level of free T4 concentration.
• (only T4 level checked – not T3.)
Razvi S et al. J Clin Endocrinol Metab. 2007 May;92(5):1715-23.

Thyroid Hormone Treatment of Congestive Heart
Failure
• Recent work has characterized the beneficial effects of thyroid
hormone on cardiovascular hemodynamics
• … administration of thyroid hormone has been shown to increase
cardiac inotropy and to lower systemic vascular resistance.
• Patients with advanced heart failure after coronary artery bypass
surgery and post myocardial infarction have altered thyroid
hormone metabolism with low serum triiodothyronine (T3) levels.
The decrease in serum T3 levels occurs primarily as a result of a
decrease in conversion of tetraiodothyronine (T4) to T3 … causing
low T3 or nonthyroidal illness syndrome
• Coupling the potential benefits of thyroid hormone to enhance
cardiac performance with the inherently low serum levels of T3, a
heart failure treatment regimen that includes thyroid hormone
replacement in a carefully monitored setting seems rational.
Klein I, Ojamaa K. Thyroid hormone treatment of congestive heart failure. Am J Cardiol. 1998
Feb 15;81(4):490-491.

Louis B. Cady, MD
“subclinical hypothyroidism bipolar disorder” 1/28/2018
43 citations
• “Thyroid abnormalities occur frequently in patients with BD regardless of
treatment.” [Lambert CG et al. Bipolar Disord. 2016 May;18(3):247-60]
• Patients with SCH had poorer performance than patients without SCH in
measures of verbal memory, attention, language, and executive functions.
[Martino DJ, et al. Subclinical hypothyroidism and neurocognitive
functioning in bipolar disorder. J Psychiatr Res. 2015 Feb;61:166-7]
• “There is no significant association between hypothyroidism and bipolar
disorder.” Menon B. Hypothyroidism and bipolar affective disorder: is
there a connection. Indian J. Psychol Med. 2014 Apr;36(2):125-8
• Hypothyroidism, either overt or more commonly subclinical, appears to the
commonest abnormality found in bipolar disorder. Chakrabarti S. Thyroid
functions and bipolar affective disorder. J Thyroid Res. 2011;2011;
2011:306367.

Louis B. Cady, MD
“subclinical hypothyroidism bipolar disorder” 1/28/2018
43 citations
• Study of 84 lithium treated patients with bipolar disorder vs. 65
gender/age matched controls.
• TSH & Free T4 drawn +USG exam of thyroid
• Mean TSH and thyroid volume significantly higher in the
lithium group
• 16.7% of lithium group had hypothyroidism vs. 10.8%
in control group
• Prevelance rate for goiter – 47.6%
• USG pathology – 83.3%
• Conclusion: “You can’t tell by looking at the blood tests.”
Kumn TO et al. Thyroid function and ultrasonography abnormalities in Lithium-treated
bipolar patients: a cross sectional study with healthy controls. Noro Psiklyatr Ars. 2017
Jun;54(2):108-115

NEW LITERATURE – AUGUST 2016 – “Association between serum
thyrotopin levels and mortality among euthyroid adults in the
United States. [Inoue K et al. Thyroid. 2016 Aug 18 [Epub ahead of print]
• Population – NHANES III study . N = 12,584 adults>/= 20 years of
age.
• Associations between TSH tertiles (high, medium, and low)
and mortalities (all cause, cardiovascular and cancer)
• Mean followup = 19.1 years with 3,395 deaths.
• Increase risk of all-cause mortality found in high normal TSH
compared to medium normal TSH group. ( Low normal
compared to medium also had higher all cause mortality).
• “This study indicated that the normal range of TSH levels may
require reevaluation.”
Louis B. Cady, MD

More studies
• 24.2% of an adult female population in Puerto
Rico = hypothyroid
• Vonzales-Rodriguez LA, et al. Thyroid dysfunction in an adult female
population: A population-based study of Latin American Vertebral
Osteoporosis Study (LAVOS) - Puerto Rico site. P R Health Sci J.
2013 Jun; 32(2):57-62.
Louis B. Cady, MD

A Low-Normal Free Triiodothyronine Level Is Associated with
Adverse Prognosis in Euthyroid Patients with Heart Failure
Receiving Cardiac Resynchronization Therapy (2017)
• Evaluate: whether or not free triiodothyronine (fT3) is
related to response to cardiac resynchronization
therapy (CRT)
• Patients with fT3 < 3.00 pmol/L had a significantly
higher overall mortality than those with fT3 ≥ 3.00
pmol/L (P = 0.027).
• A lower-normal fT3 level is correlated with a worse
cardiac function and adverse prognosis in euthyroid
patients with HF after CRT implantation.
Chen YY et al. Int Heart J. 2017 Dec 12;56(6):908-914

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