Dr. Cady returned to IMMH in Orange County to deliver this talk on September 28, 2017. This is his fifth presentation on this topic to the Integrated Medicine and Mental Health conference. In this presentation, Dr. Cady reviews common misconceptions about the evaluation of the thyroid axis, dosing concerns, actual studies on patients and real-world clinical data. A large appendix and reference is included at this end of this presentation for things which were not able to be covered in the time allotted. These include the role of thyroid hormone on cognition, the role of thyroid hormone in head injury, and an exploration of the role of thyroid hormone in possibly preventing, and possibly actually treating Alzheimer's disease (as one of MANY targeted pharmaceutical, nutraceutical and integrative modalities.)

1. Thyroid IN My Mind
Louis B. Cady, MD

2. 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:
• Allergan (Aventis), Lundbeck, NEOS, Shire,
Takeda, Vaya Pharma
•Historical data – speaker’s bureau for Arbor, Bristol-Myers Squibb, Celltech,
Cephalon, Eli Lilly, Glaxo-Smith Kline, Janssen, McNeil, Pfizer-Roerig,
Sanofi~aventis, Searle, Sepracor, Shionogi, Sunovion, Wyeth-Ayerst
•Distributor – Pharmanex supplements & Biophotonic scanner
Louis B. Cady, MD

3. Attention class!!
www.slideshare.net/lcadymd
Cady Wellness Institute app – Apple
“app” store or Google Android store
Where (else!) to get “the slides”
Louis B. Cady, MD

4. Review on: “How to get the MOST out of this presentation”:
Louis B. Cady, MD

5. 4

6. 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

7. Prange’s postulate:
• 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

8. Prange proceeds…
• Placebo controlled study of 20 depressed
(but non-refractory) patients, a more rapid
onset of antidepressant action was
observed in the imipraime-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

9. 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

10. 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.

11. 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.
Louis B. Cady, MD

12. 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

13. Where are we in the literature?
THYROID
Louis B. Cady, MD

14. 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.
Louis B. Cady, MD

15. “Hypothyroidism depression” 7/31/2017
965 citations
Louis B. Cady, MD

16. “SUBCLINICAL Hypothyroidism depression”
7/31/2017 – 139 citations
Louis B. Cady, MD

17. “subclinical hypothyroidism depression children” 7/31/2017
5 citations

18. CONCLUSIONS: This is the first study to
demonstrate associations between CBCL-DP
[Child Behavior Checklist Dysregulation Profile]
and subclinical hypothyroidism.
Louis B. Cady, MD

19. “schizophrenia subclinical hypothyroidism” – 7 results
5/26/2017• “These findings render possible the diagnosis of
subclinical hypothyroidism in neuroleptic-treated
schizophrenic patients.”
Martinos A et al. Effects of six weeks’ neuroleptic treatment on the pituitary-=thyroid axis in schizophrenic
patients. Neuropsychobiology. 1986; 16 (2-3):72-7.
• The depressives and schizophrenics showed
subclinical or chemical hypothyroidism while the
manic showed slightly higher values for T(3), and
T(4), when compared to normal control subjects.
• Boral GC . Thyroid function in different psychiatric disorders. Indian J Psychiatry. 1980 Apr, 22(2):200 – 2
Louis B. Cady, MD

20. Louis B. Cady, MD
“subclinical hypothyroidism bipolar disorder” 5/26/2017
42 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.

21. Pause for background…
Louis B. Cady, MD

22. Louis B. Cady, MD

23. Louis B. Cady, MD

24. [ 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

25. Louis B. Cady, MD
http://umm.edu/health/medical/ency/articles/thy
accessed 7/31/2017

26. Louis B. Cady, MD

27. 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 T3 requires Se and Zinc!
T4
Factors that improve cellular
sensitivity to thyroid hormones:
•Vitamin A
•Exercise
•Zinc
Louis B. Cady, MD

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

29. 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
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
?

30. 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

31. 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

32. “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.
Louis B. Cady, MD

33. 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.
Louis B. Cady, MD

34. 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.

35. Key review article!
[Schroeder AC et al. Front Encorinol (Lausanne).
2014;5:40.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC39782
/ )
• 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

36. What does
Thyroid
receptor alpha1
bind?
Louis B. Cady, MD
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.”
Source: Gene ID: 7067, updated 9-Jul-2017

37. What does the literature show?
Louis B. Cady, MD

38. 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)

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

40. 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

41. 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)

42. 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
Louis B. Cady, MD

43. 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

44. 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

45. • 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

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

47. ♦ 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 MajorUseful Target Symptoms in Major
DepressionDepression
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

48. 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

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

50. 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.

51. As of August 21, 2016NEW 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

52. 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.
Louis B. Cady, MD

53. 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.”

54. 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

55. 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

56. “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

57. 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

58. Modern Medicine’s Paradigm: 2 Standard Deviations –
“if you are not sick, then you must be well.”
“NORMAL”
OPTIMAL TSH:
{<2 0r <1 per some experts)
TSH = 0.45 4.12 source:
Percentile (2.5th%
97.5th
%
NHANES III
Louis B. Cady, MD

59. Average (normal) or optimal?
• Would you like an normal wife (husband) or an
optimal one?
• Would you like a “normal” marriage or an exciting
and optimal one?
• Would you like a “normal” medical practice or an
incredible, exciting, and (optimal!!) stimulating one?
• Would you like “normal” thyroid labs or
OPTIMAL ones?
Louis B. Cady, MD

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

61. 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

62. “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)
“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.”
“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.”
Louis B. Cady, MD

63. 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/position-
statements/subclinical.pdf retrieved August 25, 2014
Louis B. Cady, MD

64. 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

65. 70 patients- ages 18-65 years of age. w/ primary hypothyroidism on stable T4 for 6
months.
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.
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.
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.
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.

66. “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????]
“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????]

67. 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:
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.
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.

68. 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.
1. Explain “Goldilocks and the Three Bears” to your patients and start
LOW, giving them some flexibility.

69. 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.”
Louis B. Cady, MD

70. 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

71. 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!
Louis B. Cady, MD

72. Rx:
• Synthroid ® (levothyroxine)
• Cytomel ® (Tri-iodothyronine – “T3”)
– Instant release (cheap!)
– Compounded in SR capsule (easier
dosing)
• Armour® thyroid (brand or generic)
= T4 + T3
• Naturethroid & Westhroid = T4 + T3
– better tolerated in some
Louis B. Cady, MD

73. “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.”

74. Louis B. Cady, MD
Cady Wellness Institute
4727 Rosebud Lane – Suite F
Newburgh, IN 47630 USA
Office (812) 429-0772
info@cadywellness.com
Available on Apple “app store” and
Google Android store.
www.slideshare.net/lcadymd
Louis B. Cady, MD

75. Appendix with holistic references
Louis B. Cady, MD

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

77. 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

78. 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

79. - 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

80. 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

81. As of August 20, 2016
• “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

82. • “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
Louis B. Cady, MD
135 citations search on “iron deficiency
hypothyroidism” as of 6/19/2017

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

84. 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.
Louis B. Cady, MD

85. Impact of mild maternal thyroid hormone
deficiency in pregnancy – the Generation R
Study
• Congenital hypothryoidism 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
Louis B. Cady, MD

86. 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

87. 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

88. 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

89. 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

90. 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 dysfuncion.
– 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

91. “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

92. 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

93. 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

94. 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

95. 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

96. 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

97. Head injury considerations
Louis B. Cady, MD

98. Head injury considerations in
children
• Hypopituitarism: 5 – 7% prevalence in children
following TBI.
• “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

99. 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

100. 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

101. 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

102. 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

103. “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

104. 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.
Louis B. Cady, MD

105. 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.
Louis B. Cady, MD

106. 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

107. The role of thyroid hormone
Prevention/attenuation of Alzheimer’s
disease?
Louis B. Cady, MD

108. 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

109. 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

110. • “…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.

111. 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

112. 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

113. 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